CLINICAL NEUROPHYSIOLOGY OF THE VESTIBULAR SYSTEM

SERIES EDITOR

Sid Gilman, MD, FRCP

William J. Herdman Distinguished University Professor of Neurology University of Michigan

Contemporary Neurology Series

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CLINICAL NEUROPHYSIOLOGY OF THE VESTIBULAR SYSTEM

Fourth Edition

Robert W. Baloh, MD, FAAN

Department of Neurology and Surgery (Head and Neck)

Reed Neurological Research Center UCLA School of Medicine

Los Angeles, CA

Kevin A. Kerber, MD

Department of Neurology

University of Michigan Health Center Ann Arbor, MI

2011

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without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data

Baloh, Robert W. (Robert William), 1942-

Clinical neurophysiology of the vestibular system / Robert W. Baloh, Kevin A. Kerber. — 4th ed.

; cm. — (Contemporary neurology series ; 77) Includes bibliographical references and index. ISBN 978-0-19-538783-4
1. Vestibular apparatus. 2. Vestibular function tests. 3. Neurophysiology. I. Kerber, Kevin A. II. Title. III. Series: Contemporary neurology series, 77. 0069-9446 ;
  [DNLM: 1. Vestibular Diseases—physiopathology. 2. Vestibular Function Tests. 3. Vestibule, Labyrinth—physiology. W1 CO769N v.77 2011 / WV 255 B195c 2011]
  QP471.B34 2011 612.8’58—dc22
  2010002663
  
  The science of medicine is a rapidly changing ﬁeld. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy occur. The author and publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is accurate and complete, and in accordance with the standards accepted at the time of publication. However, in light of the possibility of human error or changes in the practice of medicine, neither the author, nor the publisher, nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete. Readers are encouraged to conﬁrm the information contained herein with other reliable sources, and are strongly advised to check the product information sheet provided by the pharmaceutical company for each drug they plan to administer.
  
  9 8 7 6 5 4 3 2 1
  Printed in the United States of America on acid-free paper
  
  This book is dedicated to our families.
  
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  Foreword
  
  Even the most experienced clinical neurologist may need to take a deep breath before attempting to obtain a clear, crisp history from a patient whose chief complaint is “dizziness”. It is no secret that people with neurological symptoms have widely varying conceptions of the meaning of this word. In some patients, even providing hints or clues cannot induce the patient to express precisely the feeling experienced. It may help to suggest key words such as “off-balance”, “spinning sensa- tion”, “light-headedness”, and “faintness”. I have actually had the experience of running through a long series of words to help guide the patient to express his symptoms precisely when, in response to a hint from me, the patient informed me that he meant that he lost his vision brieﬂy! Taking a clear, precise history in a patient such as this is absolutely essential in order to determine whether the problem might be peripheral or central. This will help greatly in focusing the neurological examination and determining which diagnostic studies to request and how to manage the problem. Even when the clinician determines that the problem is either peripheral or central, the list of neurological disorders that might be responsible can be daunting. With all this in mind, it is a plea- sure to welcome a new contribution to this interesting and challenging ﬁeld in the fourth edition of the classic book, Clinical Neurophysiology of the Vestibular System. Dr. Robert Baloh, a senior clinician and renowned investigator famous for his seminal work on the interface between clinical neurology and vestibular physiology, has been an author of all of the previous volumes. He is joined in this new version of the book by Dr. Kevin Kerber, a brilliant young clinical neurologist trained in both neurology and in clinical vestibular neurophysiology.
  This edition of the book is divided into four parts: 1. Anatomy and Physiology of the Nervous System, 2. Evaluation of the Dizzy Patient, 3. Diagnosis and Management of Common Neurotologic Disorders, and 4. Symptomatic Treatment of Vertigo. The current volume has been completely reorganized and expanded to cover advances over the past decade. This book includes newly described molecular mechanisms of peripheral and central processing within the vestibular system. There is a lucid, clinically practical review of the key features to assess in the clinical evaluation of the patient to determine the site of the lesion. The discussion of the differential diagnosis of dizzi- ness is clear and complete, and I found the description of bedside tests of vestibular function to be practical and helpful. The clinical sections have been completely updated and expanded with an emphasis on evidence-based medicine, but the book is informative even for the clinical scenarios that are lacking in high-level evidence. The chapter on benign paroxysmal positional vertigo con- tains guides to the latest treatment maneuvers. This book also contains a strategy for deciding on which drugs to use for symptomatic control of vertigo and for designing a vestibular exercise pro- gram. This extremely valuable contribution will be useful to clinical neurologists, otolaryngologists, physiatrists, and general and emergency medicine physicians in practice as well as residents and fellows in these specialties. This book is also a comprehensive basic science source for professionals and trainees in vestibular neuroscience.
  Sid Gilman, MD, FRCP William J. Herdman Distinguished University Professor of Neurology
  Director, Michigan Alzheimer’s Disease Research Center
  Department of Neurology University of Michigan
  Ann Arbor, MI
  
  vii
  
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  Preface
  
  The purpose of this book is to provide a framework for understanding the pathophysiology of dis- eases involving the vestibular system. The book is divided into four parts: 1. Anatomy and physiol- ogy of the nervous system, 2. Evaluation of the dizzy patient, 3. Diagnosis and management of common neurotologic disorders, and 4. Symptomatic treatment of vertigo. Part 1 reviews the anatomy and physiology of the vestibular system with emphasis on clinically relevant material. Part 2 outlines the important features in the patient’s history, examination, and laboratory evalua- tion that determine the probable site of lesion. Part 3 covers the differential diagnostic points that help the clinician decide on the cause and treatment of the patient’s problem. Part 4 describes the commonly used antivertiginous and antiemetic drugs and the rationale for vestibular exercises.
  This completely reorganized and expanded fourth edition covers the rapid advances that have occurred in the basic and clinical vestibular sciences in the past 10 years. Recent breakthroughs in our understanding of the molecular mechanisms of peripheral transduction and central processing within the vestibular system are reviewed. We discuss the differential diagnosis of dizziness of both vestibular and nonvestibular etiology and demonstrate bedside tests of vestibular function. Videos showing tests and important clinical ﬁndings are available online. The chapter on the laboratory diagnosis of vestibular dysfunction has been expanded to include videonystagmography (VNG) and vestibular evoked myogenic potentials (VEMPs). In Part 3, the chapter on benign paroxysmal posi- tional vertigo includes all the latest treatment maneuvers. We emphasize controlled treatment trials whenever available. In Part 4 we provide a strategy for deciding on which drugs to use for symptomatic control of vertigo and for designing a vestibular exercise program for patients with different types of vestibular lesions.
  We believe that this book will be useful to all physicians who treat patients complaining of dizzi- ness. It should be particularly helpful for those in the ﬁeld of family practice, internal medicine, neurology, head and neck surgery, and neurosurgery. We hope that it will encourage students (in both the clinical and basic sciences) to choose neurotology as their ﬁeld of study, or at least help clinicians to enjoy the evaluation and management of patients with dizziness. Finally, we hope that the information in this book can contribute to efforts to optimize the care of patients.
  K. A. K.
  R. W. B.
  
  ix
  
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  Acknowledgments
  
  Our students and colleagues in Neurology and Head and Neck Surgery provided inspiration. We are grateful to the chairmen of our departments, John C. Mazziotta and David J. Fink, and the major sponsors of our research (National Institutes of Health and Agency for Healthcare Research and Quality) for their continued support. We would also like to thank Krister Brantberg, who pro- vided helpful suggestions for the chapter on the clinical evaluation of hearing.
  
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  Contents ‌
  
  PART 1 ANATOMY AND PHYSIOLOGY OF THE
  NERVOUS SYSTEM
  1. OVERVIEW OF VESTIBULAR ANATOMY AND PHYSIOLOGY 3 PERIPHERAL VESTIBULAR RECEPTORS 4
    Hair Cells  The Macules  The Cristae  Basis of Stimulus Speciﬁcity of the Inner Ear Receptor Organs
    
    CENTRAL VESTIBULAR PATHWAYS 11
    Vestibular Nuclei
    
    VESTIBULAR REFLEXES 12
    Horizontal Canal-Ocular Reﬂex  Nystagmus  Translational Vestibulo-Ocular Reﬂexes 
    The Ocular Tilt Reﬂex  Vestibulospinal Reﬂexes  Vestibulo-Autonomic Reﬂexes
    
    MOTION PERCEPTION AND ORIENTATION 19 PATHOPHYSIOLOGY OF VESTIBULAR SYMPTOMS 20 CENTRAL COMPENSATION FOR VESTIBULAR LESIONS 21 SUMMARY 22
  2. THE PERIPHERAL VESTIBULAR SYSTEM 25 TEMPORAL BONE 25
    Tympanic Membrane  Middle Ear  Facial Nerve
    
    INNER EAR (LABYRINTH) 29
    Phylogeny  Structure  Fluid Dynamics  Fluid Chemistry  Blood Supply  Innervation 
    Embryonic Development
    
    THE HAIR CELL 39
    Morphologic Characteristics  Sequence of Hair Cell Activation  Relationship between the Direction of Force and Hair Cell Activation  Mechanism of Hair Cell Activation  Hair Cell Inﬂuence on Afferent Nerve Activity  Signal Processing at the Hair Cell/Afferent Nerve Junction
    
    THE INNER EAR VESTIBULAR RECEPTORS 43
    Anatomy of the Semicircular Canals  Physiology of the Semicircular Canals  Anatomy of Otolith Organs  Physiology of the Otolith Organs
    
    xiii
    PRIMARY VESTIBULAR NEURONS 49
    Anatomy of Primary Neurons  Physiology of Primary Neurons
    
    EFFERENT VESTIBULAR NEURONS 56
  3. THE CENTRAL VESTIBULAR SYSTEM 63 VESTIBULAR NUCLEI 63
    Phylogeny  Anatomy  Neurotransmitters  Physiology
    
    VESTIBULO-OCULAR REFLEXES 72
    Overview  Rotational Vestibulo-Ocular Reﬂexes  Translational Vestibulo-Ocular Reﬂexes 
    Ocular Counterrolling  Semicircular Canal-Otolith Interaction
    
    CERVICO-OCULAR REFLEXES 86
    Anatomic and Physiologic Basis  Characteristics of Neck-Induced Eye Movements
    
    VISUAL–VESTIBULAR INTERACTION 89
    Visual Tracking Eye Movements  Organization of Visually Guided Tracking Eye
    Movements  Comparison of Vestibular- and Visual-Induced Eye Movements  Visuo-Vestibulo- Ocular Connections  Model of Visual-Vestibular Interaction  Adaptive Modiﬁcation of the Vestibulo-Ocular Reﬂex with Vision  Cellular Basis for Visual Vestibular Interaction
    
    VESTIBULOSPINAL REFLEXES 97
    Comparison of Ocular and Spinal Vestibular Reﬂexes  Vestibulospinal Connections 
    Cerebellar–Vestibular Interaction  Vestibulo-Collic Reﬂexes  Cellular Mechanisms
    
    SUBJECTIVE VESTIBULAR SENSATION 102
    Vestibulothalamocortical Connections  Response Properties of Thalamic Relay Neurons  Response Properties of Vestibular Cortex Neurons  Functional Brain Imaging in Normal Human Subjects  Lesions of the Vestibulocortical Pathways in Patients  Psychophysical Studies
    
    PART 2 EVALUATION OF THE DIZZY PATIENT
  4. EPIDEMIOLOGY OF DIZZINESS 121 SPECIFIC DISORDERS 123
    BURDEN ON PATIENTS 124 HEALTH CARE UTILIZATION 125 SUMMARY 125
  5. THE HISTORY OF THE DIZZY PATIENT 127
    
    VERTIGO 128
    Central versus Peripheral Causes  Time Course  Precipitating Factors  Associated
    Symptoms  Compensation  Predisposing Factors  Family History  Diagnosis and Management
    NEAR-FAINT DIZZINESS 132
    Orthostatic Hypotension  Postural Tachycardia Syndrome (POTS)  Vasovagal Attacks  Hyperventilation
    
    PSYCHOPHYSIOLOGIC DIZZINESS (CHRONIC SUBJECTIVE DIZZINESS) 134
    Panic Disorder  Phobic Dizziness  Chronic Anxiety  Pathophysiology  Diagnosis and Management
    
    DRUG-INDUCED DIZZINESS 137
    HYPOGLYCEMIA 138
    DISEQUILIBRIUM 138
    Common Causes  Gait Disorders in Older People  Falls in Older People 
    Diagnosis and Management
    
    OCULAR DIZZINESS 140
    Common Causes  Oscillopsia  Management
    
    MULTISENSORY DIZZINESS 142
    Management
    
    PHYSIOLOGIC DIZZINESS 142
    Motion Sickness  Space Sickness  Height Vertigo  Mal de Debarquement Syndrome
    
    SUMMARY: DISTINGUISHING BETWEEN VESTIBULAR AND NONVESTIBULAR TYPES OF DIZZINESS 144
  6. BEDSIDE EXAMINATION OF THE VESTIBULAR SYSTEM 149 EXAMINATION OF THE EAR 149
    Fistula Test
    
    TESTS OF VESTIBULOSPINAL REFLEXES 151
    Pastpointing  Static Posture  Walking Tests
    
    TESTS OF VESTIBULO-OCULAR REFLEXES 153
    Doll’s Eye Test (Oculocephalic Response)  Head-Thrust Test  Dynamic Visual Acuity 
    Cold Caloric Test  Rotational Testing
    
    TESTS FOR PATHOLOGIC NYSTAGMUS 156
    Methods of Examination
    
    TYPES OF PATHOLOGIC NYSTAGMUS 158
    Spontaneous Nystagmus  Gaze-Evoked Nystagmus  Positional Nystagmus 
    Vibration-Induced Nystagmus  Head-Shaking Nystagmus  Hyperventilation-Induced Nystagmus
    OTHER OCULAR OSCILLATIONS 165
    Dissociated Spontaneous Nystagmus  Voluntary Ocular Oscillations (Voluntary Nystagmus)  Convergence Retraction Nystagmus  Saccadic Intrusions  Ocular Bobbing  Palato-Ocular Myoclonus
    
    OCULAR TILT REACTION 166
  7. LABORATORY EXAMINATION OF THE VESTIBULAR SYSTEM 171 NYSTAGMOGRAPHY 171
    Methods of Recording Eye Movements  Interpreting the Recording  Recording Pathologic Nystagmus  Bithermal Caloric Test  Tests of Visual-Ocular Control
    
    ROTATIONAL TESTING OF VESTIBULO-OCULAR REFLEXES 189
    Relationship between Stimulus and Response  Results in Normal Subjects  Results in Patients
    
    VISUAL-VESTIBULAR INTERACTION 204
    Methodology  Results in Normal Subjects  Results in Patients
    
    TESTS OF OTOLITH-OCULAR REFLEXES 207
    Ocular Counterrolling  Eccentric Rotation  Off-Vertical Rotation  Linear Acceleration
    
    VESTIBULOSPINAL TESTING 208
    Static-Force Platforms  Moving-Platform Posturography
    
    VESTIBULAR-EVOKED POTENTIALS 209
    Brain Stem and Cortical  Vestibular Evoked Myogenic Potentials (VEMPs)
  8. CLINICAL EVALUATION OF HEARING 219 TYPES OF HEARING DISORDERS 219
    Conductive  Sensorineural  Central Hearing Disorders
    BEDSIDE TESTS OF HEARING 220 BEHAVIORAL AUDIOMETRY 221
    The Audiogram  Speech Recognition Tests  Stenger Test
    
    IMPEDANCE AUDIOMETRY 223
    TYMPANOMETRY 224
    The Acoustic Reﬂex
    
    AUDITORY-EVOKED RESPONSES 225
    Electrocochleography  Brainstem Auditory-Evoked Response
    
    GENERATING POTENTIALS 226
    TEST METHODOLOGY 227
    RESULTS IN PATIENTS 227
    CENTRAL AUDITORY SPEECH TESTS 228 SUMMARY OF AUDITORY TEST RESULTS 229
    PART 3 DIAGNOSIS AND MANAGEMENT OF COMMON NEUROTOLOGIC DISORDERS
  9. INFECTIOUS DISEASES 233
    
    ACUTE OTITIS MEDIA AND OTOMASTOIDITIS 233
    Diagnosis and Management
    
    CHRONIC MASTOIDITIS AND CHOLESTEATOMA 235
    Diagnosis  Management
    
    BACTERIAL LABYRINTHITIS 236
    Diagnosis  Management
    
    PETROSITIS 237
    Diagnosis  Management
    
    INTRACRANIAL EXTENSION OF EAR INFECTIONS 238
    Routes of Spread  Meningitis  Epidural Abscess  Lateral Sinus Thrombophlebitis 
    Brain Abscess  Otitic Hydrocephalus  Diagnosis  Management
    
    MALIGNANT EXTERNAL OTITIS 241
    Diagnosis  Management
    
    VIRAL INFECTIONS OF THE INNER EAR 242
    Clinical Syndromes  Diagnosis  Viral versus Other Causes of Peripheral Cochleovestibular Loss  Management
    
    SYPHILITIC INFECTIONS OF THE EAR 248
    Diagnosis  Management
    
    TUBERCULOSIS AND MYCOTIC INFECTIONS OF THE INNER EAR 249
    Tuberculous Mastoiditis  Mycotic Mastoiditis  Basilar Meningitis
  10. BENIGN POSITIONAL VERTIGO 255 HISTORICAL BACKGROUND 255
    CAUSES OF BENIGN POSITIONAL VERTIGO 257
    POSTERIOR CANAL VARIANT OF BENIGN POSITIONAL VERTIGO 258
    Clinical Features  Pathophysiology  Diagnosis  Management
    OTHER VARIANTS OF BENIGN POSITIONAL VERTIGO 265
    Horizontal Canal Benign Positional Vertigo  Anterior Canal Benign Positional Vertigo 
    Mimics of Benign Positional Vertigo
  11. ENDOLYMPHATIC HYDROPS (MENIERE’S SYNDROME) 273 BACKGROUND 273
    OCCURRENCE 274
    CLINICAL FEATURES 275
    PATHOPHYSIOLOGY 275
    ANIMAL MODELS 277
    ETIOLOGY 277
    Genetics  Migraine and Meniere’s Syndrome  Infection/Autoimmune
    
    DIAGNOSIS 278
    Audiometric Testing  Vestibular Testing  Imaging
    
    MANAGEMENT 280
    Medical Managment  Surgical Managment
  12. MIGRAINE 287
    
    BACKGROUND 287
    CLINICAL FEATURES 288
    Migraine without Aura  Migraine with Aura  Migrainous Vertigo  Basilar Migraine 
    Migraine and Meniere’s Syndrome  Migraine Equivalents
    
    PATHOPHYSIOLOGY 292
    Genetics  Spreading Wave of Depression  Vasomotor Abnormalities
    
    DIAGNOSIS 295
    Migraine without Aura  Migraine with Aura  Migraine Aura without Headache  Basilar Migraine  Migrainous Vertigo
    
    MANAGEMENT 297
    Symptomatic and Abortive Treatment  Prophylactic Treatment
  13. IMMUNE-MEDIATED DISEASES 303 AUTOIMMUNE INNER EAR DISEASE 303
    Background  Pathophysiology  Clinical Features  Diagnosis  Management
    
    PARANEOPLASTIC IMMUNE DISORDERS 309
    Background  Pathophysiology  Clinical Features  Diagnosis  Management
    MULTIPLE SCLEROSIS 312
    Background  Pathophysiology  Clinical Features  Diagnosis  Management
  14. VASCULAR DISORDERS 319 VERTEBROBASILAR ISCHEMIA 319
    Pathophysiology  Transient Ischemic Attacks (TIAs)  Stroke Syndromes  Diagnosis  Treatment
    
    INTRALABYRINTHINE HEMORRHAGE 332
    Diagnosis and Management
    
    HEMORRHAGE INTO THE BRAIN STEM AND CEREBELLUM 332
    Diagnosis and Management
    
    VASCULAR COMPRESSION SYNDROMES 334
    Vertebrobasilar Doliochoectasia  Vascular Compression by Normal Vessels (Vestibular Paroxysmia)  Rotational Vertebral Artery Syndrome
  15. TUMORS 339
    
    TUMORS OF THE MIDDLE EAR AND TEMPORAL BONE 339
    Malignant Tumors  Glomus Body Tumors (Paragangliomas)  Diagnosis  Management
    
    TUMORS OF THE INTERNAL AUDITORY CANAL AND CEREBELLOPONTINE ANGLE 341
    Schwannomas  Meningiomas  Epidermoid Cysts (Primary Cholesteatomas)  Cholesterol Granulomas  Metastatic Tumors  Diagnosis  Management
    
    BRAIN TUMORS 347
    Brain Stem  Fourth Ventricle  Cerebellum  Diagnosis and Management
  16. TRAUMA 353
    
    TRAUMA TO THE TEMPORAL BONE 353
    Fracture  Labyrinthine Concussion  Posttraumatic Positional Vertigo  Diagnosis  Management
    
    PERILYMPH FISTULA 356
    Pathophysiology  Diagnosis  Management
    
    SEMICIRCULAR CANAL DEHISCENCE SYNDROME 358
    Pathophysiology  Diagnosis  Management
    
    BRAIN TRAUMA 360
    Intracranial Complications Associated with Temporal Bone Fractures  Dizziness Due to Brainstem Trauma  Postconcussion Syndrome  Whiplash Injuries  Diagnosis  Management
  17. TOXIC/METABOLIC DISORDERS 367
    
    DIZZINESS AND SYSTEMIC METABOLIC DISORDERS 367
    Diabetes Mellitus  Uremia  Hypothyroidism  Alcohol and Thiamine Deﬁciency  Management
    
    METABOLIC DISORDERS OF THE TEMPORAL BONE 371
    Otosclerosis  Paget’s Disease  Other Disorders  Diagnosis  Management
    
    OTOTOXINS 374
    Aminoglycosides  “Loop” Diuretics  Anti-inﬂammatory Drugs  Platinum Compounds  Diagnosis  Management
    
    NEUROTOXINS 377
    Heavy Metals  Organic Solvents  Diagnosis  Management
  18. DEVELOPMENTAL AND GENETIC DISORDERS 383 THE INNER EAR 383
    Acquired Disorders  Hereditary Disorders  Pathology  Diagnosis  Management
    
    DISORDERS OF THE CRANIAL VERTEBRAL JUNCTION 390
    Basilar Impression  Bony Fusions  Atlantoaxial Dislocation  Chiari Malformation  Syringobulbia  Diagnosis  Management
    
    INHERITED SPINOCEREBELLAR ATAXIA SYNDROMES 393
    Autosomal Dominant Spinocerebellar Ataxia Syndromes  Autosomal Recessive Spinocerebellar Ataxia Syndromes  Episodic Ataxia and Vertigo Syndromes  Diagnosis  Management
    
    PART 4 SYMPTOMATIC TREATMENT OF VERTIGO
  19. ANTIEMETIC AND ANTIVERTIGO DRUGS 405 VESTIBULAR SUPPRESSANTS 407
    How Do They Work?  How to Use Them  Indications  Precautions  What to Tell the Patient
    
    ANTIEMETIC DRUGS 410
    How Do They Work?  How to Use Them  Precautions  What to Tell the Patient
    
    SPECIFIC DRUGS 413
    Scopolamine (Transderm Sc−o p)  Buclizine Hydrochloride (Bucladin-S)  Diphenhydramine Hydrochloride (Benadryl)  Meclizine (Antivert, Bonine)  Dimenhydrinate
    (Dramamine)  Promethazine Hydrochloride (Phenergan)  Betahistine (Serc)  Metaclopramide (Reglan)  Benzquinamide Hydrochloride (Emete-con)  Trimethobenzamide Hydrochloride (Tigan)  Diazepam (Valium)  Droperidol (Inapsine)  Diphenidol (Vontrol)  Prochlorperazine (Compazine)  Dronabinol (Marinol)
  20. VESTIBULAR REHABILITATION 419
    ADAPTIVE CONTROL OF NORMAL VESTIBULAR REFLEXES 420 MECHANISMS FOR COMPENSATION AFTER VESTIBULAR LOSS 420 SPECIAL CIRCUMSTANCES 421
    Vestibular Loss in Children  Vestibular Loss in the Elderly  Failure of Compensation
    CONTROLLED TRIALS OF VESTIBULAR EXERCISES 422 STRATEGY FOR DESIGNING VESTIBULAR EXERCISES 423
    Unilateral Vestibular Lesions  Bilateral Vestibular Lesions  Central Vestibular Lesions
    
    VESTIBULAR EXERCISES 425
    FUTURE DIRECTIONS 426
    APPENDIX 20-1. SAMPLE HOME EXERCISE PROGRAM 428
    Head-Turning Practice  Walking Practice  Other Exercises  Dizziness Exercises
  21. FUTURE DIRECTIONS 431
  VIDEO LEGENDS 433
  
  INDEX 435
  
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  PART
  1
  ‌
  
  Anatomy and Physiology of the Nervous
  System
  
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  Chapter 1 ‌‌
  
  Overview of Vestibular Anatomy and
  Physiology
  
  PERIPHERAL VESTIBULAR RECEPTORS
  Hair Cells The Macules The Cristae
  Basis of Stimulus Speciﬁcity of the Inner Ear Receptor Organs
  CENTRAL VESTIBULAR PATHWAYS
  Vestibular Nuclei
  VESTIBULAR REFLEXES
  Horizontal Canal-Ocular Reﬂex Nystagmus
  Translational Vestibulo-Ocular Reﬂexes The Ocular Tilt Reﬂex
  Vestibulospinal Reﬂexes Vestibulo-Autonomic Reﬂexes MOTION PERCEPTION AND
  ORIENTATION PATHOPHYSIOLOGY OF VESTIBULAR
  SYMPTOMS
  CENTRAL COMPENSATION FOR VESTIBULAR LESIONS
  SUMMARY
  
  The vestibular system like other sensory systems (i.e, auditory, visual, olfactory, gusta- tory, and somatosensory) serves the basic func- tion of translating environmental information into biological signals. However, unlike other sensory systems there is usually no conscious awareness of it during routine activities when the system is functioning normally. In fact, the inner ear vestibular receptors were not even recognized until the seminal work of Prosper Meniere in the mid 1800s.1 Meniere worked in a deaf-mute institute and noticed that many of his patients with hearing loss also had vertigo. Prior to Meniere, vertigo—the most common symptom of vestibular dysfunction—was con- sidered a cerebral symptom, similar to epilep- tic seizures. The semicircular canals had been identiﬁed but were considered to be part of the hearing apparatus. Meniere’s notion that ver- tigo could result from damage to the inner ear was met with great scepticism. The vestibular system continues to be underappreciated in
  most comprehensive clinical and basic science medical textbooks.
  The vestibular system has a “behind the scenes” role of maintaining spatial orientation and driving reﬂexes that stabilize vision and balance. To do this, it transforms forces associ- ated with head acceleration and gravity into biological signals that travel directly to motor centers for postural and ocular stability and to the cortex to aid in orientation. When the sys- tem functions normally, you have no awareness of these ongoing activities. Unlike the ability to appreciate visual, olfactory, or auditory stimuli, you do not appreciate the function of the ves- tibular system until something goes awry.
  This is not to say that you cannot perceive motion. The vestibular system projects to many areas of the cerebral cortex but unlike other sensory systems there is no primary vestibular cortex that only receives vestibular signals. All cortical neurons that receive vestibular signals also receive other sensory signals, particularly
  3
  visual and somatosensory. It is not possible to determine which signal is responsible for the perceived motion.‌‌
  An acute malfunction of the vestibular system causes a profound inability to function, leaving one completely disabled because of severe spatial disorientation, imbalance, nau- sea, and vomiting during the most intense peri- ods. These are some of the most bizarre and incapacitating symptoms in all of medicine. The patient simply cannot navigate the envi- ronment because, to the patient, the world is moving as though he is on an unremitting car- nival ride. Interestingly, however, a chronic lesion—even a bilateral loss of function—leads to relatively little disability in most patients affected by it. In fact, many patients with a bilateral vestibular loss probably go undiag- nosed because of few or mild symptoms that either do not lead to a medical evaluation or are not recognized by physicians. As opposed to gradual hearing loss or visual loss, a gradual vestibular loss can go virtually unnoticed.
  Vestibular symptoms pose a great deal of difﬁculty in clinical medicine. First, patients suffering vestibular symptoms often have difﬁ- culty describing the symptoms. Many patients with a vestibular disturbance will simply report “dizziness”—a nonspeciﬁc term that can refer to symptoms stemming from cardiac distur- bances, a psychological disorder, medication side effects, or many other disturbances. Second, there is much overlap among the symptoms and signs of vestibular disorders, and discriminating among vestibular lesions depends on appreciat- ing rather subtle differences in how the eyes are moving. In fact, most of the examination of the vestibular system involves observing eye move- ments since the vestibular structures cannot be visualized at the bedside and the most recogniz- able functions of the vestibular system are manifest by the vestibulo-ocular reﬂex. Most physicians can recognize nystagmus—a hall- mark movement of the eyes reﬂecting vestibu- lar function – but most physicians do not appre- ciate that characterizing the pattern of nystagmus can discriminate a benign disorder from a life-threatening disorder. Physicians typ- ically have little training in the basic science and clinical evaluation of the vestibular system, and this in turn results in overuse of tests, misdiag- nosis, and underuse of effective treatments.
  The purpose of this book, then, is to provide the basic science and clinical training needed
  to diagnose and treat vestibular system disorders. In this overview chapter, we provide the most salient information regarding the vestibular system. An overview chapter is important because it rapidly and succinctly presents the essential elements that can be periodically revisited. Whenever appropriate the reader is referred to later sections where the material is described in more detail.
  
  PERIPHERAL VESTIBULAR RECEPTORS
  The role of the inner ear vestibular receptors in maintaining orientation has remained the same from the earliest organisms in the animal king- dom.2 A primitive gravity-detection organ, the statocyst, appeared more than 600 million years ago in some bygastrulated animals such as jel- lyﬁsh, allowing the animal to regulate its static position in space (see Fig. 2–5 in Chapter 2). With the advent of modern ﬁsh (about 100 mil- lion years ago), the vestibular labyrinth reached its peak of development, and relatively little change has taken place since that time. The basic structure of the three semicircular canals, the utricle, and the saccule is similar in all higher vertebrates. The membranous laby- rinths of modern ﬁsh lie in the bony chamber of the skull directly behind the orbits. In its subsequent evolution in amphibians, birds, and mammals, the membranous labyrinth is com- pletely surrounded by a bony labyrinth enclos- ing the periotic space. This space is ﬁlled with perilymphatic ﬂuid and suspensory connective tissue acting as a shock absorber. The relative positions of the planes of the three semicircu- lar canals vary from species to species, although in primates they are approximately orthogonal to each other. The shape of each semicircular canal also varies considerably from that of a tri- angle in reptiles to an ellipse in birds to an almost true circle in mammals.2
  
  Hair Cells
  The basic element of the labyrinthine receptor organs that transduces mechanical force to nerve action potentials is the hair cell. Already developed in the statocysts of invertebrates, this specialized sensory cell becomes more
  
  sophisticated in mammals.2 Transducer cells are surrounded by supporting cells in special- ized areas in the walls of the sensory epithe- lium. Two types of hair cells occur in birds and mammals (Fig. 1–1). Type II cells are cylindri- cal, with multiple nerve terminals at their base, whereas type I are globular or ﬂask shaped, with a single large, chalice-like nerve terminal surrounding the base. A bundle of nonmobile stereocilia protrudes from the cuticular plate on the apical end of each hair cell. The height
  
  of the stereocilia increases stepwise from one side to the other, and next to the tallest stereo- cilia a thicker, longer cilia, the kinocilia, protrudes from the cell’s cytoplasm through a segment of the cell membrane lacking a cuticu- lar plate. The tips of the cilia are connected by tip-links that open and close mechanosensory channels (Fig. 1–1; also see Fig. 2–12 in Chapter 2).3
  IINNHIBITION
  IINNHIBITION
  The adequate stimulus for hair cell activation is a force acting parallel to the top of the cell,
  
  Kinocilium
  
  Cuticular plate Mitochondria
  
  EXCIITTAATTIIOON
  EXCIITTAATTIIOON
  Tip links
  
  Shaft links
  
  Cilia
  
  Ankle Links
  
  Supporting cell
  
  I II
  Efferent bouton
  Ribbon Synapses
  Calyx
  Afferent bouton
  
  Figure 1–1. Schematic drawing of the two types of hair cells. Inset illustrates relationship between the direction of force and maximum hair cell activation.
  resulting in bending of the cilia (a shearing force).4 Force applied perpendicular to the cell surface (a compressional force) is ineffective in stimulating the hair cell. The stimulus is maxi- mum when the force is directed along an axis that bisects the bundle of stereocilia and goes through the kinocilium (Fig. 1–1, insert). Deﬂection of the cilia toward the kinocilium opens the mechanosensory channels at the tips causing an inﬂux of potassium and depolariza- tion of the resting membrane potential.5 This opens voltage-gated calcium channels at the base and releases neurotransmitter (mostly glu- tamate) activating the afferent nerve terminals. Bending of the cilia in the opposite direction produces the reverse effect (closing of the channels and hyperpolarization of the hair cells).
  Much of the basic information regarding the physiological properties of hair cells and their afferent nerves has been obtained through the study of hair cell systems in nonmammalian spe- cies. Analysis of the lateral line organs of amphib- ians and ﬁsh has been particularly informative.6 The organs consist of groups of hair cells, the neuromasts, aligned in longitudinal rows on the side of the animal’s body and head. A free- standing gelatinous cupula covering the cilia transmits the force associated with water dis- placement into hair cell deﬂection, which in turn results in change in ﬁring rate of the affer- ent nerve. A key observation that has been conﬁrmed in all other hair cell systems is a con- tinuous spontaneous activity of the afferent nerves.7 A small percentage of the mechano- sensory channels remains open at rest, leading to the spontaneous afferent nerve discharge. Depolarization and hyperpolarization of the hair cells’ membrane potential result in modulation of this spontaneous activity (Fig. 1–2). Bending of the cilia toward the kinocilium increases the spontaneous activity, and bending of the cilia away from the kinocilium results in a decrease. The spontaneous ﬁring rate varies among differ- ent animal species and among different sensory receptors. It is thought to be highest in the afferent neurons of the semicircular canals of mammals (up to 90 spikes per second).8
  
  The Macules
  The membranous labyrinth forms two globular cavities within the vestibule: the utricle and
  the saccule. Each cavity contains a separate macule.9 In the saccule, the macule is located on the medial wall in the sagittal plane; in the utricle, the macule is mostly in the horizontal plane next to the opening of the horizontal semicircular canal (Fig. 1–3C). The surfaces of the utricular and saccular macules are covered by the otolithic membrane, a structure consist- ing of a mesh of ﬁbers embedded in a gel with a superﬁcial layer of calcium carbonate crys- tals, the otoconia (Fig. 1–3A).10 The stereocilia of the macular hair cells protrude into the oto- lithic membrane. The striola, a distinctive curved zone running through the center, divides each macule into two parts. The hair cells on each side of the striola are oriented so that the kinocilia are in opposite directions (as indicated by the arrows in Fig. 1–3C). In the utricle, the kinocilia face the striola, and in the saccule, they face away from it. Because of the different orientation, displacement of the otolithic membrane has an opposite effect on the set of hair cells on each side of the striola.
  The density of the otolithic membrane over- lying the hair cells of the macules is much greater than that of the surrounding endo- lymph, owing to the presence of the calcium carbonate crystals. The weight of this mem- brane produces a shearing force on the under- lying hair cells that is proportional to the sine of the angle between the line of gravitational force and a line perpendicular to the plane of the macule (Fig. 1–3B). During linear head accel- eration tangential to the surface of the recep- tor, the force acting on the hair cells is the result of the two forces: one in the opposite direction of the head displacement and the other in the direction of gravitational pull. Recordings of afferent neuronal activity from the macules of primates conﬁrm that the utric- ular and saccular macules are responsive to static tilt and dynamic linear acceleration forces (see Fig. 3–6 in Chapter 3).11
  
  The Cristae
  The cristae are the receptor organs of the semi- circular canals. The semicircular canals are aligned to form a coordinate system.12 The hor- izontal canal makes a 30-degree angle with the horizontal plane, and the vertical canals make 45-degree angles with the frontal plane (Fig. 1–4C). At the anterior opening of the
  
  Kc Kc
  
  II
  I
  
  Efferent
  
  Afferent
  
  PRIMARY AFFERENT
  FIRING RATE
  nerve nerves
  
  100 msec
  
  Figure 1–2. Hair cell modulation of spontaneous afferent nerve ﬁring rate. Bending of the stereocilia toward the kinocilium depolarizes the hair cell and increases the ﬁring rate, and bending away from the kinocilium hyperpolarizes the hair cell and decreases the ﬁring rate. Kc – kinocilium.
  
  horizontal and anterior semicircular canals and the inferior opening of the posterior canal, each tube enlarges to form the ampulla. The crista, the sensory epithelium composed of hair cells and supporting cells, crosses each ampulla in a direction perpendicular to the longitudinal axis of the canal (Fig. 1–4A).9 Hair cells are located on the surface of the crista, with the cilia pro- truding into the cupula, a gelatinous mass that extends from the surface of the crista to the ceiling of the ampulla, forming a watertight seal.
  
  The hair cells in each crista are oriented with their kinocilia in the same direction. In the horizontal canal, however, the kinocilia are directed toward the utricular side of the ampulla, whereas in the vertical canals the kinocilia are directed toward the canal side of the ampulla. This difference in morphological polarization explains the difference in direc- tional sensitivity between horizontal and verti- cal canals.13 The afferent nerve ﬁbers of the horizontal canals increase their baseline ﬁring when endolymph moves toward the utricle and
  1. (b)
    Otoconia Gelatin layer
    Reticular membrane
    Supporting cells
    Striola
    Kc
    
    Hair cells
    Static tilt Otolith
    displacement
    
    Gravitational force
    
    Dorsal
    Dorsal
    (c)
    
    Saccular macule
    
    Anterior
    Anterior
    Striola
    
    Lateral
    Lateral
    Utricular macule
    
    Figure 1–3. The macule: (a) anatomy, (b) mechanism of hair cell activation with static tilt, and (c) orientation of saccular and utricular macules. Arrows indicate the direction that the kinocilia point toward. (Adapted from Barber HO, Stockwell CW. Manual of Electronystagmography. CV Mosby, St. Louis, 1976.)
    ampulla (ampullopetal ﬂow), but the afferent nerves of the vertical canals increase their base- line ﬁring rate with endolymph ﬂow away from the ampulla (ampullofugal ﬂow).
    Since the cupula has the same speciﬁc grav- ity as the surrounding endolymph, it is not subject to displacement by changes in the line of gravitational force. The forces associated with angular head acceleration displace the cupula and bend the hair cells of the crista, however. The motion of the cupula can be lik- ened to that of a pendulum in a viscous medium.14,15 Sudden displacement of the cup- ula by a step change in angular velocity is fol- lowed by a gradual exponential return of the cupula to its baseline position (Fig. 1–5). The
    rate of return (time constant, Tc) is determined by the ratio of the viscous drag coefﬁcient of
    the endolymph to the elasticity coefﬁcient of
    the cupula according to the pendulum model
    (see Chapter 2).
    Precise measurements of primary afferent nerve activity originating from the cristae of animals during physiological rotatory stimula- tion reveal that the change in frequency of action potentials is approximately proportional to the deviation of the cupula as predicted by the pendulum model.8 For example, during sinusoidal head rotation in the plane of a semi- circular canal, a sinusoidal change in ﬁring fre- quency is superimposed on the rather high rest- ing discharge (about 90 spikes per second in the squirrel monkey). The peak ﬁring rate occurs at the time of maximum cupular displacement, which occurs at the time of peak angular head velocity. With small-amplitude sinusoidal rota- tion, the modulation is almost symmetrical about the baseline ﬁring rate. For larger
    (a)
    
    Utricular sac of macule
    
    Cupula
    Ampulla
  2. Cupula
    displacement Relative
    endolymph flow
    
    Angular acceleration
    
    Supporting cells
    
    Hair cells
    Semicircular canal
  Left and
  right HC
  
  30
  
  Right AC
  
  Left PC
  
  Right PC
  
  Left AC
  Figure 1–4. The crista: (a) anatomy, (b) mechanism of hair cell activation with angular acceleration, and (c) orientation of the semicircular canals within the head. AC, anterior canal; HC, horizontal canal; PC, posterior canal.
  
  Slow phase velocity (deg/sec)
  Slow phase velocity (deg/sec)
  100
  
  50
  
  0
  0 10 20 30
  Time (seconds)
  
  40 50
  Figure 1–5. Rate of return of the cupula to its initial position after a step change in angular velocity (thin solid line) and rate of decay in nystagmus slow phase velocity after the same step change in angular velocity (each blue dot represents a single beat of nystagmus). Note that the nystagmus outlasts the cupular deviation (and afferent nerve activity) due to central velocity storage.
  stimulus amplitudes, the response becomes increasingly asymmetrical. The excitatory responses can increase to more than 400 spikes per second in proportion to stimulus magni- tude, whereas the growth of inhibitory response is limited to the disappearance of spontaneous activity. This asymmetry in afferent nerve response partially explains the presence of a positive head thrust sign in patients with only one functioning labyrinth (see Chapter 6).
  
  Basis of Stimulus Speciﬁcity of the Inner Ear Receptor Organs
  The inner ear receptors all work on the same basic principal: activation of hair cells by an applied external force. The density of the oto- lithic membrane overlying the hair cells of the macule is greater than that of the surrounding endolymph. The hair cell cilia are embedded in the otolithic membrane and, when displaced, produce a shearing force (Ft) on the underlying
  hair cells that is proportional to the sine of the
  angle between the line of resulting gravitational vector and a line perpendicular to the plane of the macule. Each macule is bisected by a distinctive curved zone, the striola. Hair cells are oriented in opposite directions on each side of the striola so that displacement of the oto- lithic membrane has an opposite effect on the set of hair cells on each side of the striola (see Fig. 1–3C).
  The hair cell cilia in the cristae of the semi- circular canals are embedded in the cupula, a jelly-like substance of the same speciﬁc gravity as that of the surrounding ﬂuids. The cupula, therefore, does not exert a force on the under- lying crista and is not subject to displacement by changes in the line of gravitational force. The forces associated with angular head accel- eration, however, do result in a displacement of the cupula that stimulates the hair cells of the crista in the same way that displacement of the otoliths stimulates the macular hair cells (Fig. 1–4B). However, in the cristae, all the hair cells are oriented in the same direction in the crista surface. All hair cells are either excited or inhibited by motion of the ﬂuid in the canal, but the orientation is different in dif- ferent semicircular canals.
  In the cochlea, the hair cells are mounted on the ﬂexible basilar membrane in the organ
  of Corti. Covering the organ of Corti and rest- ing over the hair cells is the tectorial mem- brane, a relatively rigid structure attached to the wall of the cochlea. A small, acoustically induced pressure difference across the basilar membrane causes the organ of Corti and hair cells to vibrate at the frequency of sound. The motion of the basilar membrane has a different effect on the outer hair cells than on the inner. Outer hair cells have their cilia embedded in the tectorial membrane and are directly stimu- lated as the cilia are displaced in relation to the relatively ﬁxed tectorial membrane, which acts as a hinge.16 In contrast, the inner hair cell cilia are not embedded in the tectorial mem- brane but are instead surrounded by endo- lymph. Their stimulation is produced by the dragging viscous force of the ﬂuid on the cilia. Intracellular recordings in mammalian cochlear hair cells show a difference of phase between the receptor potentials of the inner and outer hair cells as predicted by the difference in the coupling of the cilia to the tectorial membrane.17 The outer hair cells respond to position and the inner hair cells respond to the velocity of the basilar membrane motion.
  In all cases, the effective stimulus to the sen- sory cells is the relative displacement of the cilia produced by application of mechanical force to their surroundings. Since the mechan- ical properties of the “supporting and coupling” structures are different, the frequency ranges at which the cilia can be moved by the applied force are different. Because of the great ﬂexi- bility of the basilar membrane, the range of sound frequencies to which the hair cells in the cochlea are sensitive varies from 20 to 20,000 Hz. In the macules, the otoconia are maximally displaced during constant accelera- tions such as those associated with steady head displacement. Owing to the characteristics of the restraining viscoelastic forces holding the otoliths to the macule, their motion rapidly diminishes if the linear acceleration changes at a frequency >0.5 Hz.18 The semicircular canals also respond maximally to constant angular acceleration, but they can respond to changes in angular acceleration as high as 40 to 50 Hz.19 This frequency limitation is due to the inertial and viscous forces restraining the displacement of ﬂuid and cupula in the narrow semicircular canals.
  CENTRAL VESTIBULAR PATHWAYS ‌‌
  Parallel to the separation of receptor organs, afferent nerve ﬁbers differentiate into bundles that maintain independent identity in the inter- nal auditory canal and at the entrance to the brain stem.20 The afferent nerve from the utricle and horizontal and anterior semicircular canals and some of the nerve ﬁbers from the saccule form the superior division of the vestibular nerve; most nerve ﬁbers from the saccule and the nerve from the posterior semicircular canal contribute to the inferior branch (Fig. 1–6). The afferent ﬁbers from the auditory organ form a separate nerve anterior and inferior to the ves- tibular nerve to innervate the organ of Corti, the auditory receptor organ. Together these two nerves constitute the eighth cranial nerve and, within them, a system of efferent ﬁbers from the central nervous system (CNS) gates or mod- ulates the activity of the peripheral organs.21–23 Phylogenetically, this neural feedback system is already present in gastropods, in which action potentials directed from the brain to the recep- tors have been recorded.24
  In comparison with the vestibular sensory organs, central vestibular connections become progressively more complex in higher
  vertebrates.25,26 This complexity accompanies the development of other afferent systems for the maintenance of equilibrium (vision, prop- rioception) and pathways for interaction of these systems with the vestibular system.
  
  Vestibular Nuclei
  The central processes of the primary vestibular neurons divide into an ascending and descend- ing branch after entering the brain stem at the inner aspect of the restiform body (see Fig. 3–1 in Chapter 3). The ascending branch ends either in the rostral end of the vestibular nuclei or in the cerebellum, and the descending branch ends in the caudal vestibular nuclei. None of the primary afferents cross the mid- line. Four distinct anatomical groups of neu- rons have traditionally been identiﬁed: medial, lateral, superior, and inferior nuclei (Fig. 1–7).27 Canal and otolith signals converge on most sec- ondary neurons that receive primary afferent input (Fig. 1–7C). Major connections run to and from the cerebellum, particularly the so- called vestibulocerebellum (uvula, nodulus, and ﬂocculonodular lobes) (Fig. 1–7E). The two sides are connected by reciprocal commissural
  
  Nerve from horizontal canal
  
  Nerve from posterior canal
  Round window
  
  Nerve from anterior canal
  
  Utricular nerve
  
  Scarpa’s ganglion
  Vestibular nerve superior division inferior division
  
  Facial nerve
  
  Auditory nerve
  
  Internal auditory canal
  
  Cochlea
  
  Figure 1–6. Innervation of the labyrinth.
  Saccular
  nerves Spiral ganglion
  1. Afferent inputs to the vestibular nuclei
    (B)
    Efferent outputs from the vestibular nuclei
    Visual inputs
    Thalamus/Hypothalamus Cerebellum
    
    Hippocampus
    
    VN Vestibular nerve afferent inputs
    Commissural projections to contralateral
    side
    VN
    Extraocular motoneurons
    
    Proprioceptive spinal inputs
    
    (C)
    (C)
    Labyrinthine nerve afferent projections ‌
    
    (D)
    Neuronal integrator
    (Ncl. prepositus hypoglossi)
    
    Vestibular commissural projections
    
    (E)
    
    Spinal cord
    Afferent and efferent cerebellar projections
    
    SVN
    
    Semicircular
    
    SVN
    
    SVN
    Flocculus Uvula / Nodulus SVN
    afferent
    afferent
    canal/otolith
    MVN MVN
    MVN
    LVN
    
    DVN
    nerve fibers
    LVN MVN LVN LVN
    DVN DVN
    DVN
    
    Figure 1–7. Main afferent and efferent connections of the vestibular nuclei (A and B). The vestibular nuclei (VN) receive afferent signals related to head motion in space (A) and project to target areas involved in stabilization of gaze and posture as well as in vegetative and cognitive functions (B). The MVN is the major relay station for vestibular signals related to gaze and postural stabilization. A large area of the MVN receives afferent labyrinthine inputs from the semicircular canal and otolith organs (C). The MVN is the largest source and target area for reciprocal commissural pathways (D). The MVN is the major vestibular nucleus for signals from and to the ﬂocculus (E). DVN, LVN, MVN, SVN, for descending, lateral, medial and superior vestibular nucleus. (From Straka H, Vibert N, Vidal PP, Moore LE, Dutia MB. Intrinsic membrane properties of vertebrate vestibular neurons: function, development and plasticity. Prog Neurobiol. 2005;76:349, with permission.)
    
    pathways most of which originate in the medial nucleus (Fig. 1–7D). Secondary vestibular neu- rons project to target areas involved in stabiliza- tion of gaze and posture, vegetative regulation, and higher cognitive function (Fig. 1–7B).
    Vestibular nucleus neurons receive afferent visual and proprioceptive signals in addition to primary vestibular signals (Fig. 1–7A).28 For example, visual and proprioceptive signals are organized such that movement of the visual surround in one direction excites and inhibits the same neurons that are excited and inhibited by movement of the head and neck in the opposite direction. The vestibular nucleus is
    therefore not simply a relay station for vestibu- lar signals but rather an important sensorimo- tor interaction center.
    
    VESTIBULAR REFLEXES
    The basic elements of a simple vestibular reﬂex arc are a hair cell, an afferent bipolar neuron, an interneuron, and an effector neuron (Fig. 1–8).29 This simple three-neuron reﬂex arc is already developed in the phylum Mollusca, among which the class Cephalopoda
    
    Primary afferent
    
    Interneuron
    
    Motoneuron
    
    Figure 1–8. Three neuronal reﬂex arc. The primary affer- ent neuron carries signals generated by the hair cells to interneurons in the brainstem which in turn activate motoneurons that initiate the motor response.
    
    has contributed to many classic anatomic and physiologic studies of gravitational reﬂexes.30 Vestibular reﬂexes have developed further in vertebrates and mammals with the addition of multiple neuronal pathways.29
    The terminal ﬁbers of the afferent neuron make synaptic contact with the hair cell and transmit nerve signals to neuronal sensory pools on the same side of the CNS (the vestibular nuclei) that contain both excitatory and inhibi- tory neurons. Besides receiving signals from excitatory ﬁrst-order neurons from the ipsilat- eral ear, the excitatory neurons also receive signals from the inhibitory neurons of the con- tralateral side by way of crossed neural path- ways. The output of the excitatory vestibular nuclei interneurons is transmitted to the effec- tor motor pools, which consequently reﬂect the activity of both ears. The effector neuron, in turn, controls the activity in an appropriate muscle to coordinate orienting behavior.
    In 1947, Sherrington noted, “The simple reﬂex is probably a purely abstract conception
    because all parts of the nervous system are con- nected together and no part of it is probably ever capable of reaction without affecting and being affected by various other parts….”31 The maintenance of body equilibrium and posture in everyday life is a complex function involving multiple receptor organs and neural centers in addition to the labyrinths. Visual and proprio- ceptive reﬂexes in particular must be integrated with vestibular reﬂexes to ensure postural sta- bility. The prominent role of sensory interac- tion in orientation can already be appreciated in the behavior of gastropods. The invertebrate Hermissenda has only rudimentary vestibular and visual receptors, yet the two systems fully interact to control behavior.32 Afferent signals from photoreceptors in the eye and from hair cells in the statocyst converge on interneurons in the cerebroplural ganglia, which control a putative motor neuron in each pedal ganglion. Excitation of the motor neuron produces turn- ing of the animal’s foot in the ipsilateral direc- tion, consistent with the animal’s turning behavior toward light. In humans, during most natural head movements, gaze stabilization is achieved by a combination of vestibular, neck proprioceptive, and visual inputs; the interac- tion can be synergistic or antagonistic. For example, when the vestibular induced eye movements lie in a direction opposite to that required to maintain the desired gaze position, the visual reﬂexes override the vestibular reﬂex. The kind of head rotation that would produce compensatory eye movement in the dark does not do so in the light if the subject ﬁxates on a target moving in phase with the head (Fig. 1–9). In this simple example, failure to override the vestibular signal leads to disorientation.
    
    Horizontal Canal-Ocular Reﬂex
    The direct pathways from the horizontal canals to the horizontal extraocular muscles deserve particular attention, since the horizontal ves- tibulo-ocular reﬂex is the focus of most clinical vestibular testing (Fig. 1–10).33,34 The second- ary vestibular neurons lie in the medial and lat- eral vestibular nuclei. The more medial group of excitatory neurons projects to the contralat- eral abducens nucleus, while the more laterally located excitatory neurons (in the medial part of the lateral nucleus) project to ipsilateral
    
    Chair velocity
    60°/sec 0
    60°/sec
    Chair velocity
    60°/sec 0
    60°/sec
    
    Eye movements in the dark
    Eye movements in the dark
    
    5 sec
    15°
    Eye movements with fixation
    Right
    Left
    5 sec
    15°
    Eye movements with fixation
    Right
    Left
    
    Figure 1–9. Eye movement induced in a normal human subject by sinusoidal angular acceleration (0.05 Hz, maximum velocity 60°/sec) in the dark and in the light with a target moving in phase with the subject.
    
    LR MR MR LR
    
    Oculomotor IR nucleus (III) IO
    SR
    MR
    
    Trochlear ATD
    nucleus (IV)
    
    MLF
    
    Abducens nucleus (VI)
    
    S L
    SG
    
    M I
    Vestibular nucleus
    
    Figure 1–10. Direct pathways of the horizontal semicircular canal-ocular reﬂex. The darkened cell body indicates an inhibitory secondary vestibular neuron. SG – Scarpa ganglion, S – superior nucleus, L – lateral nucleus, M – medial nucleus, I – inferior (descending) nucleus, MLF – medial longitudinal fasciculus, ATD – ascending tract of Deiters, IR – inferior rectus, IO – inferior oblique, SR – superior rectus, MR – medial rectus, LR – lateral rectus.
    medial rectus motoneurons via the ascending tract of Deiters (ATD). The ipsilateral medial rectus neurons also receive a strong excitatory input via the medial longitudinal fasciculus (MLF) from interneurons in the contralateral abducens nucleus. These interneurons are
    CLOCKWISE
    
    Right
    ROTATION
    
    Left
    excited by the same secondary vestibular neu- rons that excite the abducens motoneurons.35 The relative contributions to the horizontal vestibulo-ocular reﬂex of the ATD and MLF
    horizontal canal
    horizontal canal
    excitatory pathways is not entirely clear, but the MLF pathway seems more important since the eyes cannot adduct past the midline if
    R+ L+
    
    R–
    the MLF is sectioned.36 Inhibitory secondary neurons in the rostral part of the medial ves- tibular nucleus run directly to the ipsilateral abducens nucleus. Contralateral medial rectus
    Vestibular nucleus
    Vestibular
    L– nucleus
    motoneurons apparently do not receive disyn- aptic inhibition from the horizontal semicircular canals.
    In addition to the direct and indirect con- nection between secondary vestibular neurons and oculomotor neurons, commissural connec- tions between the two vestibular nuclei play an important role in controlling the rotational ves- tibulo-ocular reﬂex.37 Through GABAnergic interneurons, secondary vestibular neurons
    R+ L– R– L+
    
    motoneurons
    motoneurons
    motoneurons
    motoneurons
    
    Agonist
    Agonist
    Antagonist
    Antagonist
    Increased Decreased
    on one side inhibit their counterparts of the Excitatory
    opposite side (see Fig. 3–4 in Chapter 3). As
    Inhibitory
    will be seen later, the commissural connections are particularly important after unilateral loss of vestibular function since they provide a mechanism for a single labyrinth to control the vestibular nuclei on both sides, thus maintain- ing a functional vestibulo-ocular reﬂex.38
    Because physiological stimuli activate both labyrinths, the horizontal vestibulo-ocular reﬂex is controlled by a four-way push-pull mechanism (Fig. 1–11). For example, physio- logical stimulation of the crista of the right horizontal semicircular canal excites the left lateral rectus and the right medial rectus and inhibits the right lateral rectus. Because of the symmetry between the labyrinths, the same receptor in the other ear simultaneously diminishes its afferent output, thereby disfacili- tating the left medial rectus and right lateral rectus and disinhibiting the left lateral rectus. The end result is contraction of the left lateral and right medial rectus muscles and relaxation of the left medial and right lateral rectus muscles.
    Figure 1–11. Organization of the horizontal semicircular canal–ocular reﬂex. R – right, L – left.
    
    Nystagmus
    When the head is rotated back and forth in the dark in the plane of the horizontal semicircular canals, compensatory eye movements are pro- duced, with eye velocity approximately equal and opposite to the head velocity. This is easily demonstrated in lower animals such as the rab- bit, who have few spontaneous eye movements (Fig. 1–12A,B). If the angle of rotation is large, such that it cannot be compensated for by the motion of the eye in the orbit, the slow com- pensatory vestibular-induced eye movement is interrupted by quick movements in the oppo- site direction. This combination of rhythmic slow and fast eye movements is called nystag- mus.39 Because of the fast components, the tra- jectory of the eye motion during the slow components effectively compensates for head rotation as if the eye had unlimited range
    
    ANGULAR HEAD POSITION
    
    q = 3
    EYE MOVEMENT RECORDINGS
    
    a.
    
    Rt. Lt.
    q = 6 4
    
    1sec
    
    rt.
    lt.
    1 sec
    b.
    
    q = 12
    
    q c.
    
    q = 24
    
    d.
    q
    
    Figure 1–12. Compensatory eye movements in the rabbit that are produced by sinusoidal angular acceleration of the head (0.2 Hz) at four different peak angular displacements ().
    of motion. If the fast components were removed from the tracings in Figure 1–12C,D and the slow components joined end to end, the result- ing sinusoidal eye movement would be approx- imately equal and opposite in direction to the sinusoidal head movement just as in Figure 1–12A,B. Thus, the quick component of nys- tagmus is a strategy developed in the brain to increase the functional capabilities of the reﬂex.
    Spontaneous nystagmus occurs after lesions of the labyrinth, the vestibular nerve or the central vestibulo-ocular neurons and intercon- necting pathways. The driving force of the spontaneous nystagmus is an imbalance of tonic signals within the vestibulo-ocular pathways. Damage to one labyrinth or its vestibular nerve results in spontaneous nystagmus, with the slow phase directed toward the damaged side; the tonic input from the intact side is no longer balanced by tonic input from the damaged side. This spontaneous nystagmus is similar to nys- tagmus produced by physiological stimulation of the horizontal semicircular canals (Fig. 1–13; also see Video 6–4). The direction of nystag- mus associated with lesions of the brain stem is less predictable, depending on the location and extent of the lesion.40 Central spontaneous nystagmus can be purely vertical or torsional, since tonic signals for vertical and torsional eye movements run in different tracts from the
    vestibular nuclei to the oculomotor neurons. By contrast, peripheral spontaneous nystagmus aligns with the planes of the semicircular canals, producing a combination of torsional and linear components. After a complete unilateral peripheral vestibular loss, the nystagmus is horizontal/torsional because the vertical com- ponents from the loss of vertical canal input cancel out.
    Groups of neurons in the paramedian pon- tine reticular formation (PPRF) adjacent to the abducens nuclei ﬁre in short bursts just before the onset of horizontal fast components.41 Pathways interconnect neurons in the vestibu- lar nuclei with neurons in this region of the PPRF, and these neurons project directly to oculomotoneurons and interneurons in the abducens nucleus. Neurons in the PPRF moni- tor vestibulo-ocular signals and intermittently trigger bursts of ﬁring in the opposite direction mainly based on the eye position in the orbit. During angular rotation, the fast components of the initial beats of nystagmus are larger in amplitude than the preceding slow components so that the eyes deviate in the direction of the fast components. The apparent advantage of this strategy is that the eyes are ready to follow new targets arriving in the ﬁeld of vision and ﬁxation can be maintained during the subse- quent slow component. Unilateral lesions of the PPRF impair ipsilateral rapid eye movements
    PHYSIOLOGIC NYSTAGMUS SPONTANEOUS NYSTAGMUS
    
    AC Damaged
    
    PC
    
    HC
    Ampulla
    
    Utricle
    
    PRIMARY AFFERENT FIRING RATE
    100 msec
    Figure 1–13. Primary afferent nerve activity associated with rotation-induced physiological nystagmus and spontaneous nystagmus resulting from a lesion of one labyrinth. The thin straight arrows indicate the direction of the slow components; the thick straight arrows indicate the direction of fast components; curved arrows show the direction of endolymph ﬂow in the horizontal semicircular canals. AC – anterior canal, PC – posterior canal, HC – horizontal canal.
    (both voluntary and involuntary), and the eyes deviate to the contralateral side of the orbit.42 Stimuli that normally would produce nystagmus with ipsilateral fast components simply cause a tonic contralateral deviation of the eyes.
    
    Translational Vestibulo-Ocular Reﬂexes
    Natural head movements consist of a combina- tion of rotation and translation. For images to remain stable on the retina, vestibular reﬂexes must compensate for both types of movement. Translational movements are sensed by the otolith organs of the inner ear, and compensa- tory eye movements are generated by the oto- lith ocular reﬂexes. Although the rotational vestibulo-ocular reﬂexes are highly conserved throughout evolution, translational reﬂexes develop later in frontal-eyed animals with foveal vision. Unlike the rotational vestibulo- ocular reﬂexes where an equal and opposite eye movement sufﬁces regardless of target dis- tance, the translational vestibulo-ocular reﬂexes must be scaled to viewing distance to compen- sate for the fact that the size of the required
    compensatory eye movement increases as the target moves closer, the so-called motion paral- lax (see Chapter 3).43,44
    Furthermore, unlike the rotational vestib- ulo-ocular reﬂexes that stabilize images on the entire retina, the translational vestibulo-ocular reﬂexes only stabilize images on one spatial location in the visual ﬁeld, usually the fovea. Not surprisingly, there is a close functional relationship between the translational vestib- ulo-ocular reﬂexes and the other foveal stabi- lizing systems, the smooth pursuit and the vergence systems.45
    
    The Ocular Tilt Reﬂex
    If a subject is tilted in the roll plane (about the nasal occipital axis), there is a reﬂex counter- rolling and skewing of the eyes to maintain gaze stabilization (see Fig. 6–7 in Chapter 6). This represents an utriculo-ocular reﬂex primarily mediated by excitation of the utricle of the dependent ear with synapses in the ipsilateral vestibular nucleus and in the contralateral ocul- omotor complex in the rostral brain stem.46,47 Unlike the translational vestibulo-ocular reﬂex,
    it develops early in evolution being particularly prominent in lateral-eyed animals. It is a rudi- mentary reﬂex in humans since the amount of ocular counterrolling is only about 10% of the angle of head tilt.48 Attempts to use this reﬂex as a clinical test of otolith function have been largely abandoned because of the large vari- ability in normal subjects and the lack of consis- tent asymmetry after unilateral lesions. However, understanding the connections of this otolith-ocular reﬂex is critical for localizing peripheral and central lesions that cause double vision due to skew deviation (see Chapter 6).47
    
    Vestibulospinal Reﬂexes
    At least three major functional roles for vestibu- lospinal reﬂexes can be identiﬁed.49,50 The ﬁrst is to maintain posture, namely, the upright posi- tion in relation to the earth vertical. Vestibular reﬂexes of this kind induce muscle contractions that produce negative geotropic movement or forces that compensate for steady changes in the direction of the force of gravity. If the pull of gravity on the body were unopposed by forces developed in the muscles, the body would col- lapse. Reﬂexes in this category in humans are dependent on the function of the otolith organs but not on that of the semicircular canals. The second role is to produce “kinetic,” or transi- tory, contractions of muscles for maintenance of equilibrium during movement. This category
    includes reﬂexes arising from both the semicir- cular canals during angular acceleration and the otolithic organs during linear acceleration.51 Most natural head movements contain both types of acceleration, and the vestibular reﬂexes act in combination to maintain equilibrium. A third role of vestibular reﬂex activity is to help maintain muscular tone, a role in which both the macules50 and cristae participate.52 The labyrinthine contribution to skeletal- muscle tone can be demonstrated by the change in posture that follows unilateral laby- rinthectomy in normal animals.53 Tone is increased in the extensor muscles of the con- tralateral extremities and decreased in the ipsi- lateral extensor muscles. An even more striking demonstration of the vestibular role in mainte- nance of muscle tone is the removal of decerebrate rigidity after sectioning of both vestibular nerves or destruction of the vestibu- lar nuclei (see later discussion).54,55 The exten- sor rigidity that results from transection of the nervous system at the caudal end of the mesencephalon is markedly decreased when the tonic labyrinthine input is removed.
    The anterior horn cells of the antigravity muscles (extensors of the neck, trunk, and extremities) are under the combined excitatory and inhibitory inﬂuence of multiple supraspi- nal neural centers (Fig. 1–14).54 At least in the cat, one ﬁnds two main facilitatory centers (the lateral vestibular nucleus and rostral retic- ular formation) and four inhibitory centers
    
    1
    
    –
    2 –
    –
    3
    –
    –
    –
    + 5 6 +
    +
    
    4 –
    
    Figure 1–14. Facilitatory (+) and inhibitory (−) pathways inﬂuencing the myotatic spinal reﬂex in the cat. Inhibitory path- ways are (1) corticobulboreticular, (2) caudatospinal, (3) cerebelloreticular, and (4) reticulospinal. Facilitatory pathways are
    1. reticulospinal and (6) vestibulospinal. (From Lindsley DB, Schreiner LH, Magoun HW. An electromyographic study of spasticity. J Neurophysiol. 1949;12: 197, with permission.)
      (the pericruciate cortex, basal ganglia, cerebel- lum, and caudal reticular formation). The bal- ance of input from these different centers determines the degree of tone in the antigrav- ity muscles. If one removes the inhibitory inﬂu- ence of the frontal cortex and basal ganglia by sectioning the animal’s midbrain, a characteris- tic state of contraction in the antigravity mus- cles results—so-called decerebrate rigidity. The extensor muscles increase their resistance to lengthening and the deep tendon reﬂexes become hyperactive. As noted earlier, the ves- tibular system contributes largely to this increased extensor tone since there is a marked decrease upon bilateral destruction of the laby- rinths.56 Unilateral destruction of the labyrinth or the lateral vestibular nucleus results in an ipsilateral decrease in tone, indicating that the main excitatory input to the anterior horn cells arrives from the ipsilateral lateral vestibulospi- nal tract.55‌‌
      In a decerebrate animal with normal laby- rinths, the intensity of the extensor tone can be modulated in a speciﬁc way by changing the position of the head in space.31,49,50 The tone is maximal when the animal is in the supine posi- tion with the angle of the mouth 45 degrees above horizontal and minimal when the animal is prone with the angle of the mouth 45 degrees below horizontal. Intermediate positions of rotation of the animal’s body about the trans- verse or longitudinal axis result in intermediate degrees of extensor tone. If the head of the upright animal is tilted upward (without neck extension), extensor tone in the forelegs increases; downward tilting of the head causes decreased extensor tone and ﬂexion of the fore- legs. Lateral tilt produces extension of the extremities on the opposite side. These tonic labyrinthine reﬂexes, mediated by way of the otoliths, seldom occur in intact animals or human subjects because of the inhibitory inﬂu- ence of the higher cortical and subcortical cen- ters; however, they can be demonstrated in premature infants.57
      
      Vestibulo-Autonomic Reﬂexes
      The strong connections between vestibular and vegetative centers are apparent based on the prominent vegetative symptoms that accom- pany vestibular lesions. Nausea and vomiting, diarrhea, perfuse sweating, and fainting can be
      the predominant presenting symptoms of a ves- tibular lesion. Animal and human studies have shown that electrical or physiological stimula- tion of the vestibular receptors alters the activ- ity of sympathetic efferents.58,59 Neurons in the caudal vestibular nuclei project to medullary regions known to participate in regulation of blood pressure, heart rate, and breathing; lesions in this region abolish cardiovascular and respiratory responses to stimulation of vestibu- lar afferents. Loss of vestibulocardiac and ves- tibulovascular reﬂexes may explain the fainting and near fainting often associated with vestibu- lar lesions. There are also connections from the vestibular nuclei to the locus coeruleus, area postrema, and more centrally to the hypothala- mus, amygdale, and limbic cortex that could explain the motion sickness and symptoms of fear and panic that commonly accompany vertigo.60
      
      MOTION PERCEPTION AND ORIENTATION
      Several important clinical observations support the existence of a speciﬁc vestibular sensation. Probably the most convincing is that patients without vestibular function (either on an acquired or congenital basis) do not experience a turning sensation when rotated in the dark if visual and tactile cues are eliminated.61 In contrast, in patients with the sensation of move- ment, it is not dependent on vision or associ- ated nystagmus, since blind subjects and patients with complete oculomotor paralysis experience a spinning sensation comparable to that of normal subjects when their vestibular end organs are stimulated. Focal cortical lesions can interfere with spatial orientation and the performance of three-dimensional construc- tion tasks, and epileptic discharges from many different areas of the cortex can be associated with a subjective illusion of movement (usually spinning). These observations imply a cerebro- cortical representation for vestibular sensation. The vestibulocortical pathway via the thala- mus is concerned with the control of body posi- tion and orientation in space (Fig. 1–15).63,64 Thalamic and cortical units that receive ves- tibular signals are also activated by propriocep- tion and visual stimuli. Most units respond in a similar way to rotation in the dark, or to moving
      
      Cerebral cortex
      
      IPL
      
      VPL
      
      PIVC
      
      STG
      Thalamus
      
      Muscle and cutaneous afferents ‌
      
      S
      
      L
      
      M
      M
      Vestibular
      I nucleus
      
      Figure 1–15. Vestibulothalamocortical projections. I, inferior nucleus; IPL, intra-parietal lobe; L, lateral nucleus; M, medial nucleus; PIVC, parieto-insular vestibular cortex; S, superior nucleus; STG, superior temporal gyrus; VPL, nucleus ventralisposterior lateralis.
      
      visual ﬁelds, indicating that they play a role in relaying information about self-motion. From a functional point of view, the vestibulothalamo- cortical projections appear to integrate vestibu- lar, proprioceptive, and visual signals to provide one with a “conscious awareness” of body ori- entation. Beginning at the vestibular nuclei, a stepwise integration of body-orienting signals occurs, reaching its maximum at the level of the cortex.
      
      PATHOPHYSIOLOGY OF VESTIBULAR SYMPTOMS
      Much of our knowledge of labyrinthine func- tion was accumulated at the turn of the twenti- eth century from clinical and experimental observations in humans and animals with uni- lateral and bilateral lesions of the peripheral labyrinth.65–67 At that time, a controversy existed
      concerning whether the symptoms associated with acute unilateral labyrinthine damage was due to irritation or paralysis of the affected labyrinth. The subsequent discovery of the continuous ﬂow of action potentials in the vestibular nerve at baseline led to the present concept that symptoms are usually caused by an imbalance of the normal resting state activity—that is, by a unilateral decrease in activity.
      Symptoms and signs after labyrinthine lesions can largely be traced to asymmetric tone or loss of function within the vestibular reﬂex pathways (Table 1–1). The magnitude of symptoms and signs depends on (1) whether the lesion is unilateral or bilateral, (2) the rapidity with which the functional loss occurs, and (3) the extent of the lesion. In most experimental animals, simultaneous removal of both labyrinths does not produce severe abnormalities, although vestibular reﬂex activ- ity is lost and ocular and postural stability is
      Table 1–1 Symptoms and signs after labyrinthine lesions result from asymmetric tone and/or loss of function within vestibular reﬂex pathways‌‌
      Pathway Asymmetric Tone Loss of Function
      Vestibulo-ocular Spontaneous nystagmus
      Ocular roll & skew
      Vestibulo-spinal Head tilt Lateropulsion
      Vestibulo-autonomic Nausea, vomiting, fainting,
      fear, anxiety Vestibulo-cortical Illusion of movement
      Tilt of subjective vertical
      Head movement dependent oscillopsia Imbalance worse with eyes closed Resistant to motion sickness
      Decreased motion perception, visual dependency
      
      impaired. Similarly, patients who lose vesti- bular function bilaterally (e.g., secondary to gentamicin treatment) usually do not com- plain of vertigo, but they do report visual blur- ring or oscillopsia with head movements and instability when walking at night (due to loss of vestibulo-ocular and vestibulospinal reﬂex activity).
      In contrast, animals and humans develop severe symptoms and signs following acute unilateral labyrinthectomy. Lower mammals are initially unable to walk and develop head tilt and decreased ipsilateral muscle tone. Nystagmus is prominent, with the slow compo- nent directed toward the damaged side and the fast component toward the intact side. These signs abate with time but may persist for months after surgery.
      A sudden unilateral loss of labyrinthine function in humans is a dramatic event.68 The patient complains of severe vertigo and nausea, is pale and perspiring, and usually vomits repeatedly. The patient prefers to lie motion- less but can walk if forced to (deviating toward the side of the lesion). Head and ocular tilt and changes in extremity tone occur but less fre- quently than in lower animals. A brisk, sponta- neous nystagmus interferes with vision. These symptoms and signs are temporary, and the process of compensation starts almost immedi- ately. Within 1 week of the occurrence of the labyrinthine lesion, a young patient can walk without difﬁculty and, with ﬁxation, can inhibit the spontaneous nystagmus. Within 1 month, most patients return to work with few, if any, residual symptoms. If a patient slowly loses vestibular function unilaterally over a period of months or years (e.g., with a vestibu- lar schwannoma), symptoms and signs may be absent.
      CENTRAL COMPENSATION FOR VESTIBULAR LESIONS
      In animals immediately after a labyrinthec- tomy, ipsilateral secondary vestibular neurons lose their afferent input, become silent, and do not respond to ipsilateral angular rotation.69–71 At the same time, contralateral healthy second- ary neurons lose their inhibitory contralateral input, and their spontaneous activity increases in comparison to normal levels. An imbalance in ocular and skeletal muscle tone takes place, resulting in the clinical signs of labyrinthec- tomy—nystagmus and disequilibrium. A few days after the labyrinthectomy, the previously silent secondary neurons on the damaged side recover their spontaneous activity and begin to respond to physiologic stimulation of the con- tralateral labyrinth, the result of their connec- tions through the commissural pathways. Although the responses of secondary neurons on the damaged side are not as intense as those on the normal side, they are qualitatively simi- lar. The recovery of sensitivity in the ipsilateral secondary neurons after a labyrinthectomy parallels the time course of recovery in clinical symptoms and signs.
      The genesis of the renewed tonic input to ipsilateral secondary neurons several days after a complete labyrinthectomy is not entirely known. It does not come from the healthy side, since afferent activity on that side does not change. It probably results from changes in ion channels expressed in the cell membrane, from the sprouting of axons from other sources (e.g., neck proprioceptive), and from up and down regulation of synaptic receptors (particularly GABA receptors) (see Chapter 3).72–75 In ani- mal studies, the course of compensation is affected by exercise,76 visual experience,77 and
      drugs (as a rule, stimulants accelerate and sed- atives slow compensation).78 If a second laby- rinthectomy is performed after compensation for the ﬁrst occurs, the animal again develops signs of acute unilateral vestibular loss with nystagmus directed toward the previously operated ear (Bechterew’s compensatory nys- tagmus),79 as if the ﬁrst labyrinthectomy had not taken place. Compensation after the sec- ond labyrinthectomy is slightly faster than after the ﬁrst, but it still requires several days.‌‌
      
      SUMMARY
      The vestibular system transduces the forces associated with head acceleration and gravity into a biologic signal. The control centers in the brain use this signal to develop a subjective awareness of head position in relation to the environment and to produce motor reﬂexes for
      avenues of research in the study of vestibular function in health and in disease.
      
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Chapter 2 ‌‌

The Peripheral Vestibular

System

TEMPORAL BONE

Tympanic Membrane Middle Ear ‌

Facial Nerve

INNER EAR (LABYRINTH)

Phylogeny Structure

Fluid Dynamics Fluid Chemistry Blood Supply Innervation

Embryonic Development

THE HAIR CELL

Morphologic Characteristics Sequence of Hair Cell Activation

Relationship between the Direction of Force and Hair Cell Activation

Mechanism of Hair Cell Activation

Hair Cell Inﬂuence on Afferent Nerve Activity Signal Processing at the Hair Cell/Afferent

Nerve Junction

THE INNER EAR VESTIBULAR RECEPTORS

Anatomy of the Semicircular Canals Physiology of the Semicircular Canals Anatomy of the Otolith Organs Physiology of the Otolith Organs PRIMARY VESTIBULAR NEURONS

Anatomy of Primary Neurons Physiology of Primary Neurons EFFERENT VESTIBULAR NEURONS

TEMPORAL BONE

The ear is divided into three anatomic parts: the external, middle, and inner ear. Except for the auricle and soft tissue portion of the external auditory canal, the ear is enclosed within the temporal bone of the skull.

The temporal bone contributes to the base and lateral wall of the skull and forms part of the middle and posterior fossae.1,2,3 It is divided into four parts: the squamous, tympanic, petrous, and mastoid areas. The petrous por- tion, or pyramid, contains the sense organs of the inner ear. The seventh and eighth cranial nerves enter the petrous portion through the internal auditory canal; the facial nerve exits via the stylomastoid foramen of the mastoid por- tion (Fig. 2–1). The internal carotid artery and internal jugular vein enter the skull through the temporal bone, their bony canals forming part of the anteroinferior wall of the middle ear.

The anatomical proximity of these major ves- sels to the inner ear can explain pulsatile tinni- tus in a patient without vascular abnormalities. A cross section of the temporal bone in Figure 2–2 illustrates the relationship between the three functional parts of the ear. Although the external and middle ear are auditory organs with no direct bearing on vestibular function, a knowledge of their structure, particularly those of the middle ear, is important for under- standing diseases involving the inner ear.4 For example, infection arising in the middle ear can spread directly through its medial wall (oval and round windows) into the inner ear, or it can enter the intracranial cavity by breaking through the roof of the epitympanic recess. The aditus ad antrum interconnects the epitympanic recess with the middle ear by means of air cells throughout the mastoid portion of the temporal bone so that infection beginning in the middle ear can spread to the

Squamous part

Pore of internal acoustic meatus

Vestibulo acoustic (VIII), facial (VII) nerves

part

Mastoid

Subarcuate fossa

Superior, inferior petrosal sinuses

Petrous part

Vestibular

aqueduct

Transverse sinus

Internal carotid artery

Internal jugular vein

Superior bulb of jugular vein

Stylomastoid foramen

Facial (VII) nerve

Figure 2–1. Medial view of the temporal bone. (From Anson BJ, Donaldson JA. Surgical Anatomy of the Temporal Bone and Ear. WB Saunders, Philadelphia, 1973, with permission.)

vessels and nerves passing through the temporal bone.

Tympanic Membrane

The ear drum, or tympanic membrane, forms a partition between the external and middle ear. The tympanic membrane has a thickness of

0.1 mm and a diameter of 8.5 to 10 mm. It con- sists of three layers, an inner mucosal layer, a middle ﬁbrous layer, and an external epidermal layer. It is attached to the tympanic ring in the external canal at a distance of 2 to 5 mm from the opposite (medial) wall of the middle ear. From the external canal, the tympanic mem- brane appears as a thin, semitransparent disk that normally has a glistening, pearly-gray color

Integument Facial musculature

Squama of temporal bone

Meninges Brain

Auricle

Cartilages of external ear

Epitympanic recess

Auditory ossicles

Semicircular ducts (in canals)

Endolymphatic duct

(in vestibular aqueduct)

Endolymphatic sac (in dura mater)

Perilymphatic duct

(in cochlear canaliculus) Scala tympani Cochlear duct

Scala vestibuli Mucous membrane

Eustacian tube Levator veli palatini

Secondary tympanic membrane

Vestibule

Mastoid air cells

Mastoid process

Tympanic membrane and cavity

Styloid process

Figure 2–2. Cross section of the ear. (From Anson BJ, Donaldson JA. Surgical Anatomy of the Temporal Bone and Ear. WB Saunders, Philadelphia, 1973, with permission.)

(see Fig. 6–1 in Chapter 6). It is concave on its external surface as if under traction from the manubrium—the long process (5.8 mm) of the malleus.

The mallear stria (the manubrium shining through the tympanic membrane) passes from slightly inferior and posterior of the center (umbo) toward the superior margin of the tym- panic membrane. Near the superior margin, the mallear prominence is formed by the lat- eral process of the malleus. From the mallear prominence, two folds stretch to the tympanic sulcus of the temporal bone, enclosing the tri- angular area of the pars ﬂaccida, or Shrapnell’s membrane.

Middle Ear

The middle ear, or tympanic cavity, is a ﬂat cleft with a volume of approximately 2.0 cc, containing three tiny bones whose main role is to provide an interface for transmitting to the inner ear the changes in atmospheric pressure produced by sound waves (Fig. 2–3).5 The manubrium is attached, like the radius of a circle, to the inner side of the tympanic mem- brane in a superoanterior direction. Superiorly, the head of the malleus is bound to the incus,

forming the incudomalleal articulation, a type of diarthric joint. The so-called long process of the incus (7 mm), directed down and anteri- orly, is connected to the stapes, the smallest of the three middle ear ossicles. The footplate of the stapes articulates with the walls of the ves- tibule at the oval window to which it is attached by a ring of ligaments. The dimensions of the window are 1.2 by 3 mm, with a total area that is one-seventeenth that of the tympanic mem- brane. Sound-induced displacements of the tympanic membrane and its attached manu- brium are transmitted through the medial arm of the assembly of middle ear bones, acting as a lever to the inner ear; in this fashion the middle ear functions as a mechanical transformer. Additional ampliﬁcation is produced as the force applied over the surface of the tympanic membrane is funneled into the smaller area of the oval window. The middle ear compensates for the loss of energy—approximately a 99.9% loss—that would occur if sound were transmit- ted directly from air to the ﬂuids of the inner ear.6

The ossicles are suspended by several liga- ments and are dynamically controlled by the action of two muscles. The tensor tympani, innervated by a branch of the trigeminal nerve, is connected by a tendon to the upper part of

Superior malleal ligament

Posterior ligament incus

Lateral malleal ligament

Tympanic membrane pars flaccida (Shrapnell’s membrane)

Tendon tensor tympani muscle

Tympanic mambrane pars tensa

Fabrous annulus

Epitympanic recess

Horizontal semicircular canal

Facial nerve

Tendon stapedius muscle Oval window

Cochlear promintory

Round window

Eustachian tube

Bony annulus

Figure 2–3. Cross section of the middle ear.

the manubrium. Coursing in a lateral direction from the anterior part of the medial wall of the tympanic cavity, this muscle draws the manu- brium medially, tensing the tympanic mem- brane. The stapedius muscle, innervated by the facial nerve, is attached to the posterior wall of the tympanic cavity and is directed anteriorly to anchor in the upper part of the stapes. Contraction of these muscles leads to stiffening of the middle ear system and thus less sound transmitted to the inner ear (i.e., increased impedance) (Fig. 2–3). This is the reason that a lesion of the facial nerve (e.g., Bell’s palsy) can result in hyperacusis on the affected side. Another condition involving these muscles, middle ear myoclonus, results in repetitive clicking sounds in the affected ear.

The medial, or labyrinthine, wall of the mid- dle ear is an irregular surface because of the structures bulging from the inner ear: the promontory of the basal turn of the cochlea and the prominences of the facial canal and horizontal semicircular canal (Fig. 2–3). Beneath the cochlear prominence is the mem- brane of the cochlea or round window, which seals the scala tympani of the cochlea and its ﬂuid from the middle ear. It provides an outlet for equilibrium of pressure in the inner ear whenever sound displaces the stapes. Without this compliance, sound energy could not dis- place the basilar membrane of the cochlea because the endolymph ﬂuid is incompress- ible. The vestibular, or oval, window is located just above the cochlear prominence, where it is closed by the base of the stapes and the annular ligament. These windows between the middle and inner ear can be a route for infection or toxins to spread from the middle to inner ear, or they can rupture, allowing perilymph to leak from the inner ear to the middle ear (perilymph ﬁstula).

Facial Nerve

The facial nerve arises at the inferior border of the pons and proceeds to the internal auditory canal on the superior surface of the cochlear nerve. Within the temporal bone, four portions of the facial nerve can be classiﬁed: (1) the canal (meatal) segment (7 to 8 mm), (2) the labyrin-

thine segment (3 to 4 mm), (3) the tympanic

(horizontal) segment (12 to 13 mm), and (4) the mastoid (vertical) segment (15 to 20 mm)

(Fig. 2–4). The canal segment runs in close company in an anterosuperior position with the vestibular and cochlear divisions of the eighth nerve, while in its remaining segments the facial nerve lies separately within a bony canal—the facial or fallopian canal. The laby- rinthine segment runs at nearly a right angle to the petrous pyramid superior to the cochlea and vestibule to reach the geniculate ganglion. At the geniculate ganglion, the nerve takes a sharp turn posteriorly, marking the beginning of the tympanic segment. The horizontal tym- panic segment courses in a posterior direction along the medial wall of the middle ear supe- rior to the oval window and inferior to the hor- izontal semicircular canal (see Fig.2–3). At the sinus tympani, the nerve bends inferiorly, marking the beginning of the vertical, or mas- toid, segment that continues toward the stylo- mastoid foramen. At this level, the facial nerve consists exclusively of motor ﬁbers that inner- vate the muscles of the facial expression after coursing through connective tissue septa in the parotid gland. Three major groups of ﬁbers have been recognized that are directed to (1) the auricular and occipital muscles, (2) the orbicu- laris and muscles of mimetic facial expression, and (3) the buccinator and buccolabial muscles. Three major branches of the facial nerve lie within the temporal bone: (1) the greater superﬁcial petrosal nerve, arising from the geniculate ganglion; (2) the nerve to the stape- dius muscle, arising from the initial part of the mastoid segment; and (3) the chorda tympani, leaving the facial nerve approximately 5 mm above the stylomastoid foramen. The greater superﬁcial petrosal nerve is composed of

(1) parasympathetic efferent ﬁbers originating in the superior salivatory nucleus for innerva- tion of the lacrimal glands and seromucinous glands of the nasal cavity and (2) afferent cuta- neous sensory ﬁbers from parts of the external canal, tympanic membrane, and middle ear, destined for the nucleus of the solitary tract. The nerve to the stapedius muscle and the main facial nerve trunk are motor nerves originating from the facial nucleus in the caudal pons. The chorda tympani, like the greater superﬁcial petrosal, is a mixed nerve containing (1) para- sympathetic efferent ﬁbers from the superior salivatory nucleus, destined for the sublingual glands, and (2) afferent taste ﬁbers from the anterior two-thirds of the tongue, ending in the nucleus of the solitary tract.

Superior salivatory nucleus

Internal auditory canal

Nucleus of the solitary tract

Facial nucleus

Cochlear nerve

Vestibular nerve

Horizontal (intratympanic segment)‌

Labyrinthine segment

Greater superficial petrosal nerve for lacrimation

Geniculate ganglion

Lesser superficial petrosal nerve to parotid gland

Lower (posterior) genu

Vertical (mastoid) segment

Stylomastoid foramen

Nerve to stapedius muscle

Chorda tympani Upper division

Tongue

Lower division

Submaxillary salivary gland (salivation)

Figure 2–4. Schematic diagram of the facial nerve within the temporal bone.

Knowledge of the structure and function of each division of the facial nerve allows the cli- nician to localize disease affecting the nerve within the temporal bone.7,8 Lesions in the internal auditory canal commonly involve both the seventh and eighth cranial nerves. Lesions of the labyrinthine segment of the facial nerve above the geniculate ganglion impair ipsilateral

lacrimation (resulting in dry eyes and increased tearing), (2) stapedius reﬂex activity (resulting in hyperacusis), (3) taste on the ante- rior two-thirds of the tongue, and (4) facial muscular strength. A lesion of the tympanic segment central to the nerve of the stapedius muscle affects only the latter three functions (2–4) listed above, and a lesion of the mastoid segment before the origin of the chorda tympani
affects only the latter two (3, 4). Finally, a lesion at the stylomastoid foramen causes only ipsilat- eral facial muscle weakness or paralysis. Pain is another common symptom particularly with inﬂammatory disorders (e.g., Bell’s palsy) and is typically postauricular pain with a lesion involving the geniculate ganglion.

INNER EAR (LABYRINTH)
Phylogeny
The most primitive gravity-detection organ, the statocyst, appeared more than 600 million years ago in the late Precambrian era.9–11 It is
present in some bygastrulated animals with the most developed Coelenterata, such as jellyﬁsh, allowing the animal to orient itself in relation to the horizon by sensing the direction of the gravitational force of the earth. The statocyst is a ﬂuid-ﬁlled invagination or sac containing a calcareous particle, the statolith, or multiple particles, the statoconia, of a density greater than that of the ﬂuid (Fig. 2–5a). Attracted by
gravity, the particles rest their weight differen- tially over cilia protruding from specialized sensory neurons in the wall of the cyst. A large central cilia, the kinocilia, is surrounded by rows of smaller cilia. Tethers between the cilia and the kinocilia open and close mechanosen- sory channels that control the ﬁring rate of the sensory neurons, allowing the animal to regu- late its static position in space.

a

S
CB

N N

K
b
tl Is

N N N

HC SN HC

Figure 2–5. a: Statocyst of the ctenophore comb jelly Pleurobrachia. Ciliary bundles (CB) of hair cells support the extracel- lular statoliths (S). N, neurons (transverse section). (Adapted from Budelmann BU. Morphological diversity of equilibrium receptor systems in aquatic invertebrates. In: Atema J, et al. (eds). Sensory Biology of Aquatic Animals. Springer-Verlag, New York, 1988, with permission.) b: Hair bundle complex of a sea anemone. Supporting cells located on opposite sides of the sensory neuron (SN) function in a manner comparable that of to hair cells (HC). Large-diameter stereocilia (Is) and the kinocilium (K) of the sensory neuron are also shown. During deﬂection with a vibratory stimulus, the sensory neuron integrates the input from the supporting cells and then signals other neurons in the nerve net. Note that when the cilia of the hair cell bend toward the kinocilium, the tip links (tl) open ion channels that lead to excitation of the sensory neuron. By contrast, the cilia of the hair cell to the right bend away from the kinocilium and the ion channels remain closed. (Adapted from Watson GM, Mire P. A comparison of hair bundle mechanoreceptors in sea anemones and vertebrate systems. Curr Top Dev Biol. 1999; 43: with permission.)
A primitive receptor organ for generating kinetic reﬂexes can be found on the tentacles of marine invertebrates, such as sea anemo- nes.12,13 A sensory neuron is coupled to two neighboring hair cells that act as mechanore- ceptors of water pressure waves in their vicinity (Fig. 2–5b). Supporting cells located on oppo- site sides of the sensory neuron function in a manner similar to that of hair cells. During deﬂection associated with a vibration stimulus, the sensory neuron integrates the input from the supporting cells and signals other neurons in the nerve net. Note that when the cilia of the supporting cell bend toward the kinocilium of the nerve cell, the tethers (tip links) open ion channels whereas when the cilia bend away from the kinocilium the ion channels are closed. Among important signals are vibrations pro- duced by minuscule prey animals. The neuron reaction leads to a “motor” response involving a sensory cell, a surrogate vestibular nucleus, and an effector neuron. The reﬂex response con- sists of the secretion of a paralyzing substance
by the enmatocyst, the “stinging organelle” of the anemones.
From these simple mechanotransduction receptors to the labyrinth of higher animals, a continuous increment in anatomic complexity occurs that accompanies the phylogenetic evo- lution of the taxa. Next developmentally are the mechanoreceptors of mollusks (e.g., octo- pus, sepia), in which both types of receptors, the static otolith and the kinetic cristae recep- tors are seen.14–17 These new receptors, incor- porated in an invaginated common cavity, accompany the appearance of motor responses to motion, including nystagmus.14 The statocyst cavity, previously open to the outside, is closed and ﬁlled by an endogenous secretion (endo- lymph). The otolith/macula system consists of a rounded plate of mechanosensory cells with a compact statolith (Fig. 2–6a). The force exerted by the statolith mass on the cilia of the mecha- nosensory cells depends on the magnitude and direction of any applied linear acceleration including gravity. The cristae/cupula system
the utricle and semicircular canals, and
the saccule and cochlear duct. The walls of the membranous labyrinth consist of an inner layer of ectodermal origin and an outer layer of mesodermal origin separated by a basement membrane. These regions of the inner layer subsequently develop into specialized sensory organs.

The timing of the development of the differ- ent inner ear structures is important to know since developmental defects can occur at each stage of development. The inner ear begins to develop approximately 3 weeks after concep- tion with development of the otic placode.

The placode invaginates into the otic pit, which becomes pinched off to form the otocyst (Fig. 2–10a-c). Concurrent with the placode-otocyst development, the statoacousticofacial ganglion forms from the neural crest at the end of the third week. The geniculate ganglion then migrates away leaving the vestibulocochlear ganglion next to the otocyst.

The otocyst differentiates into the endolym- phatic, vestibular, and cochlear ducts (Fig. 2–10d). By the ﬁfth week, the vestibular duct begins to differentiate into the three semicircular canals and the vestibule (Fig. 2–10e). Shortly after formation of the otocyst the medial part, the endolymphatic diverticulum, separates from the utriculosaccular chamber. This chamber then differentiates into an utric- ular chamber that gives rise to the utricle and semicircular canals and a saccular chamber that gives rise to the saccule and cochlea. The utricular chamber rapidly expands into three diverticula, the centers of which fuse, leaving the spaces around the perimeter to become the three semicircular ducts. The superior canal forms ﬁrst at about 6 weeks followed rapidly by the posterior and then the horizontal canals. One end of each canal dilates to form the ampulla and both ends remain connected to the utricle.

The cochlear duct becomes separated from the saccule by a narrowing at its dorsal end to form the ductus reunions. The cochlear turns begin to form by the sixth to seventh week, with completion of two and one-half turns by the eighth week. By the end of the ﬁfth month, the primitive organ of Corti has formed within the cochlear duct. The vestibulocochlear gan- glion divides into a superior portion that sends ﬁbers to the utricle and ampullae of the ante- rior and horizontal semicircular canals and into an inferior portion that sends ﬁbers to the sac- cule and the ampulla of the posterior semicir- cular canal. The remainder of the ganglion becomes the spiral ganglion of the cochlea.

The hair cells in the sensory epithelium do not develop until the afferent nerve endings arrive. By the end of the third week a large area of specialized neuroepithelium appears. The upper part of the neuroepithelium becomes the utricular macule and the cristae of the supe- rior and horizontal semicircular canals and the lower part becomes the saccular macule and the crista of the posterior semicircular canal. Vestibular hair cells showing typical synapses

(a)

Pharynx

Otic placode

Acoustico facial ganglion

Dorsal aorta

Entoderm Mesoderm Ectoderm

(b)

Hindbrain

Otic pit

Early phase
of otocyst Hindbrain

Differentiation of otocyst (otic vesicle)

Dorsal aorta

Mesenchymal condensation for future ossicles
Endolymphatic duct

Semicircular canals

Vestibular duct

Cochlear duct

Vestibule

Cochlea

Developing eustachian tube

Figure 2–10. Embryological development of the ear: (a) otic placode stage, (b) otic pit stage, (c) otocyst-otic vesicle development, (d) and (e) labyrinthine development. (Adapted from Pearson AA. The development of the ear: A manual. American Academy of Ophthalmology and Otolaryngology, Rochester, MN, 1967.)

with nerve endings are present by 9 weeks. The sensory epithelium is mature in the macules by about 15 weeks, in the cristae by about 23 weeks, and in the organ of Corti by about 25 weeks.

The molecular mechanisms underlying the development of individual sensory organs in the inner ear have largely been worked out in chicks, zebraﬁsh, and mice.65 Differences occur between species, but certain patterns are common. All of the sensory organs develop

from a prosensory region of the otocyst deﬁned by the asymmetric expression of transcription factors. The Notch signaling pathway is key for specifying the prosensory region and for determining whether a cell differentiates into a hair cell or a supporting cell (through the process of lateral inhibition). The level of Notch activation determines whether a cell becomes a hair cell (low), sup- porting cell (high) or a prosensory progenitor cell (intermediate).

THE HAIR CELL ‌‌

Morphologic Characteristics

In the vestibular organs of avians and mam- mals, there are two different types of hair cells—type I and type II (Fig. 2–11, also see Fig. 1–1 in Chapter 1). Type I hair cells are globular and are completely surrounded by a large calyx nerve terminal. The afferent ﬁbers that give rise to these nerve calices are among the largest in the body, measuring more than 20 µm in diameter in some lower animals and 10 µm in humans. Efferent nerves synapse on the outside surface of the calices. Type II hair cells are cylindrical and receive numerous small

synaptic terminals from afferent and efferent neurons. The hair cells are surrounded by sup- porting cells whose top surface is covered with microvilli. The supporting cells extend the whole length of the sensory neuroepithelium from the basal membrane to the surface. Their nuclei line up in a row immediately above the basal membrane (Fig. 2–11A,B). By contrast, the nuclei of the hair cells are midway between the basal membrane and the luminar surface. This pattern of nuclear organization is similar throughout all vertebrates. Supporting cells can differentiate into new hair cells following destruction of the sensory epithelium. This was initially seen in the cochlea of quail and chicken after acoustic trauma66,67 and then in the cochlea

Figure 2–11. Mammalian hair cells. (A, B) Photomicrographs of chinchilla crista (cross section). Long arrows, type I hair cells; open arrows, type II hair cells; arrow heads, supporting cells, curved arrows, afferent nerve ﬁbers. B is an enlargement of the box outlined in A. Bar, 10 µm. (C, D) Electron micrographs of type I and type II hair cells from the chinchilla. Type I hair cells are surrounded by the chalice ending of an afferent nerve ﬁber, whereas type II hair cells are contacted by afferent nerve boutons (arrows). SC, supporting cell. Bar = 1 µm.

and vestibular labyrinth of mammals after drug ototoxic exposure.68,69

TIP-LINKS

The tips of the cilia are connected by extracel- lular linkages called tip-links.70–72 These struc- tures are already seen in primitive aquatic animals. The basic elements of a tip link include an ion channel, an interconnecting tether, and a motor protein (Fig. 2–12). The motor protein moves along actin ﬁlaments and is critical for adaptation to prolonged stimuli.73 Mechano- sensory ion channels are already present in single-cell organisms where they function to prevent osmotic shock as the bacterium moved from salt to fresh water.74,75 These primitive mechanosensory channels have an iris-like opening that enlarges with tension acting in the plane of the cell membrane. The next major development is a tether that couples the chan- nel to intracellular or extracellular structures so that stretch on the tether opens the channel. The tethers are attached to stiff elements within the cell such as microtubules or actin ﬁlaments or outside the cell to protruding parts

Motor proteins Mechanosensory

channels

Tip link

Actin filaments

Motor proteins Mechanosensory

channels

Tip link

Actin filaments

Figure 2–12. Schematic model of hair cell transduction. Shearing with positive deﬂection increases tension in tip links, which pull open a transduction channel at each end. Myosin motors slip or climb on actin ﬁlaments to restore resting tension. An elastic gating spring likely exists between a channel and the actin cytoskeleton. (Adapted from Vollrath MA, Kwan KY, Corey DP. The microma- chinery of mechanotransduction in hair cells. Ann Rev Neurosci. 2007;30:339, with permission.)

of the same or other cells or the extracellular matrix.70,71 Many of the genes and proteins associated with mechanosensory transduction in the vestibular organs of invertebrates and vertebrates have been identiﬁed and some are highly conserved, particularly those coding for proteins in the tethers.70,75 Cadherins and pro- tocadherins form part of the tethers from the most primitive metazoan phyla to vertebrates, including primates. Mutations in the rare tip- link motor protein, myosin VIIa, cause vestibu- lar and auditory loss in humans and ﬂies. Channel genes are less conserved, and so far the gene for the putative mechanosensory channel in vertebrates has not been identiﬁed. The transient receptor potential (TRP) super- family of mechanosensory channels is critical for hearing in the fruit ﬂy and touch in the nematode but not for hearing or vestibular function in mammals.76

RIBBON SYNAPSE

The basal portion of the hair cells makes contact with afferent nerve terminals by way of ribbon synapses (see Fig. 1–1 in Chapter 1).77,78 These structures that are remarkably efﬁcient in con- verting Ca2+ inﬂux into neurotransmitter release are only seen in the inner ear and eye.79 There are approximately 10 to 20 synapses per hair cell, and each synapse contains 100 to 200 synaptic vesi- cles. Of these about 15 vesicles are docked beneath the ribbon ready to release their con- tents into the extracellular space. Within each receptor central hair cells of both types have more synaptic ribbons than do peripheral hair cells. 80

Sequence of Hair Cell Activation

Bending of the hair bundle toward the kinocil- ium opens the mechanically gated ion channels, causing an inﬂux of potassium. The resting potential of the hair cells is between –50 and

–70 millivolts and as the potential rises above

–50 millivolts, voltage-gated calcium channels at the base open, allowing an inﬂux of calcium ions. The calcium binds to a calcium sensor pro- tein in the ribbon synapse (otoferin in cochlear hair cells), activating the SNARE complex of proteins releasing packets of glutamate into the synaptic cleft.77,81 AMPA receptors in the affer- ent nerve terminals are activated, leading to an approximate linear relationship between Ca2+ inﬂux and afferent nerve ﬁring.82 A glutamate

transporter removes glutamate from the synap- tic cleft.83 About 13% of the transduction chan- nels are open at rest, resulting in a resting current ﬂow through the hair cells and a resting ﬁring rate of the afferent nerves (see Hair Cell Inﬂuence on Afferent Nerve Activity).84

Relationship between the Direction of Force and Hair Cell Activation

The adequate stimulus for hair cell activation is a force acting parallel to the top of the cell, resulting in bending of the hairs (a shearing force).85 A force applied perpendicular to the cell surface (a compressional force) is ineffec- tive in stimulating the hair cell.86,87 The stimulus is maximal when the force is directed along an axis that bisects the bundle of stereocilia and passes through the kinocilium (see Fig. 1–1 inset in Chapter 1). Deﬂection of the hairs toward the kinocilium decreases the resting membrane potential of the sensory cells (depolarization). Bending in the opposite direction produces the reverse effect (hyperpolarization).88 The effect is minimal when hair deﬂection is perpendicu- lar to the axis of maximal excitation.

Mechanism of Hair Cell Activation

The top surface of hair cells in mammals faces the endolymph, a ﬂuid rich in K+ (like the intra-

cellular space), while the basolateral membrane is surrounded by perilymph rich in Na+ (like the extracellular space). In the cochlea, the peri- lymph is at zero voltage in relation to the rest of the extracellular space of the body, but the endolymphatic space has a positive potential (+80 mV). In the vestibular labyrinth, the posi- tive potential is smaller (+5 to 10 mV). The hair-bearing surface of the cell membrane is morphologically different from the rest, being thicker and more electron dense. This part of the cell membrane is depolarized because of the equal K+ concentration outside of the cell in the endolymph and inside of the cell. It acts as a passive resistor between the inside and outside of the hair cell whose value is modulated by the mechanical deformation associated with the dis- placement of the hairs (Fig. 2–13). This concept represents the essence of the Davis mechano- electric theory of hair cell function.89–93 Because of the electrical gradient across the luminal (top) part of the membrane, a current ﬂow exists from the endolymph to the inside of the cell and out, through the basolateral membrane, which is known as the “current of silence,” a resting cur- rent. The basic concept of the Davis theory has been upheld by demonstration of transmembrane potential changes and associated impedance modulation during deﬂection of the stereocilia. Intracellular recordings from hair cells of amphibians and mammals have expanded our knowledge of the mechanoelectric transduction process.92,93 When hair cells are stimulated,

Hair cell displacement

Hair cell resistance

Endolymph voltage

–

Hair cell current

VIIIth nerve activity

Figure 2–13. Mechanism of hair cell activation. Sinusoidal displacement of the stereocilia produces a sinusoidal modula- tion or the vestibular nerve ﬁring rate. See text for details.

there is a change in the electric current begin- ning at the tips and the lumen of the stereocilia to the inside of the cell. This “transduction” cur- rent causes a series of additional changes in the permeability of different ion channels in the basolateral membrane, leading to depolariza- tion of the hair cell membrane and release of neurotransmitters (see earlier discussion). There is a diversity of ion channels expressed in the hair cells.94–96 For example, type I hair cells express a K+ channel that results in an unusually low input resistance compared to that expressed by type II hair cells.97

Measurement, with intracellular electrodes, of the hair cell responses to cilia deﬂection shows that the curve relating the receptors’ potential to the stimulus has greater sensitivity and linearity for small signals.98,99 Larger stimuli exhibit saturation or nonlinearity that is greater for hyperpolarizing than for depolarizing stim- uli, leading to smaller responses, hence lower gains for deﬂection away from the kinocilium (Fig. 2–14). The voltage drop produced in the vicinity of the hair cells by the changing current is known as the microphonic potential, the so- called generator potential of these receptor organs.89 It is maximal at the tips of the hairs.91,99

Flexion

In contrast to nerve action potentials, the gen- erator potentials have no refractory period (fol- lowing the frequency of the stimulation above several thousand hertz), are highly resistant to anoxia, and may remain partially active after the animal’s death. The electric current associ- ated with the generator potentials acts upon the synaptic contacts between hair cells and nerve terminals by activating chemical trans- mitters to modulate the ﬁring of action poten- tials by the afferent neurons (Fig. 2–13).

% Full responce

Hair cells are not passive elements; they actively participate in the mechanotransduction process.100 In particular, outer cochlear hair cells, which contain several contractile pro- teins,101 vary their length under direct electrical stimulation.102,103 This electromotility of the outer hair cells is dependent on a protein, prestin, isolated with comparative cDNA analysis of the inner and outer hair cells.104 Recombinant prestin introduced into cultured kidney cells provides them with contractile properties normally not present. Presumably, during acoustic stimulation, prestin experiences an electric charge realignment that results in morphological changes in the shape of the outer hair cells, elongating during hyperpolarization and contracting during depolarization. These conformational changes would inﬂuence the

10°

Responce (mV)

6

4

2 0

2

0 10°

100

displacement of the basilar membrane in a pos- itive feedback conﬁguration facilitating the physiological stimulation of inner hair cells, in essence acting as the ampliﬁer of the acoustic energy entering the ear.105 In vestibular hair cells, the stereocilia contain actin molecules and can carry out ﬂagella-type movement.97,106,107 The cilia length varies among hair cells and location, but it is logical to expect that anatomic differences in stereocilia will result in differ- ences in the process of transducing head-motion

1.0 0 1.0

Displacement (m)

Figure 2–14. Intracellular voltage changes (mV) associ- ated with displacement of cilia of a hair cell from the frog saccule. Cilia bending toward the tallest stereocilia produce a positive depolarizing change whereas motion in the oppo- site direction results in a negative hyperpolarizing change. Note that the curve relating the receptor potential to the degree of deﬂection (µm) has the greatest sensitivity and linearity for small deﬂections and exhibits a saturation non- linearity for large displacements that is greater for hyper- polarizing than depolarizing stimuli. (From Hudspeth AJ, Corey DP. Sensitivity, polarity, and conductive change in response of vertebrate hair cells to controlled mechanical stimuli. Proc Natl Acad Sci USA. 1977; 74:2407–2411 with permission.)

information into neural signals. Although not proven, it is possible that hair cells at the periph- ery of the vestibular organs actively pull the cupula or otolithic membrane to inﬂuence the response of the more centrally placed hair cells, analogous to the effect of cochlear outer hair cells on inner hair cell walls.

Hair Cell Inﬂuence on Afferent Nerve Activity

One of the most signiﬁcant ﬁndings concerning hair cell function was the discovery by Hoagland

in 1932 that the afferent nerves from lateral-line organs of ﬁsh generated continuous spontaneous activity.108 This observation has subsequently been conﬁrmed in all other hair cell systems and represents a fundamental discovery in sensory physiology. As noted earlier, baseline current ﬂow through the hair cells generates the sponta- neous activity and depolarization and hyperpo- larization of the hair cells’ membrane potential modulates the spontaneous activity. Bending of the hairs toward the kinocilium results in an increase of the spontaneous ﬁring rate, and bending of the hairs away from the kinocilium results in a decrease of the ﬁring rate.109 The spontaneous ﬁring rate varies in different animal species and in different sensory receptors. It is thought to be greatest in the afferent neurons of the semicircular canals of mammals (up to 90 spikes/sec) and lowest in some of the acoustic nerve ﬁbers innervating mammalian cochlear hair cells (1 to 2 spikes/sec).110,111 Given the non- linear behavior of the hair cell transduction mechanism, it is not surprising that the modula- tion of the spontaneous neuronal ﬁring rate is likewise nonlinear. Responses to excitatory stim- uli are more than those to inhibitory stimuli. This asymmetry in response is of great physiological and clinical signiﬁcance, as will be shown later.‌‌

Signal Processing at the Hair Cell/ Afferent Nerve Junction

The hair cell is a relatively simple force transducer mirroring the biomechanics of the forces acting on the surrounding tissues. Yet complex signals originate from the afferent nerves at the base. Signal processing must be interposed between the hair cell and the afferent nerve to account for the wide range of afferent nerve responses.112,113 This signal processing can be traced to at least four different processes: (1) neurotransmitters released by the hair cells, (2) neurotransmitters released by efferent terminals, (3) adaptation at the ribbon synapse, and (4) a diversity of receptors and ion channels in the afferent terminals. Glutamate is the main neurotransmitter at the hair cell–afferent nerve junction, but other trans- mitters, including gamma-aminobuteric acid (GABA), are also released. Hair cells in different receptors and in different locations within the receptors release different combinations of trans- mitters. Acetylcholine (Ach), released by the efferent system, modulates afferent nerve ﬁring

through both presynaptic and postsynaptic mech- anisms. The number of vesicles (both total and docked) at the ribbon synapse can be up and down regulated based on a number of factors, including synaptic activity.78 The afferent nerve terminals express AMPA, NMDA, and GABA type B recep- tors along with a wide range of ion channels, all of which can be up and down regulated. For exam- ple, the number of AMPA receptors (GLuR 2-4) expressed depends on the amount of glutamate released and on NMDA receptor activity.114

THE INNER EAR VESTIBULAR RECEPTORS

The vestibular system monitors the forces asso- ciated with angular and linear accelerations of the head by means of ﬁve organs located within the labyrinthine cavities of the temporal bones on each side of the skull.115 The saccular and utricular macules sense linear acceleration, and the cristae of the three semicircular canals sense angular acceleration of the head.

Anatomy of the Semicircular Canals

The semicircular canals are three membranous tubes with a cross-sectional diameter of 0.4 mm; each one forms about two-thirds of a circle with a diameter of about 6.5 mm.116 They are aligned to form a coordinate system (see Fig. 1–4c in Chapter 1).117,118 The plane of the horizontal semicircular canal with two openings on the lateral wall of the utriculus makes a 30-degree angle with the horizontal plane. The other two canals are in vertical positions almost orthogo- nal to each other. The anterior canal is directed medially and laterally over the roof of the utric- ulus, and the posterior canal is directed down- ward and laterally behind the utriculus. The two vertical canals share a common opening on the posterior side of the utriculus. Precise mea- surement of the planes of the canals, however, indicates that they are not aligned perfectly orthogonal. All angular movements stimulate at least two canals and often all three.

CRISTA

At the anterior opening of the horizontal and anterior canal and the inferior opening of the

posterior canal, each tube enlarges to form the ampulla. A crest-like septum, the crista, crosses each ampulla in a perpendicular direction to the longitudinal axis of the canal (see Fig. 1–4a,b in Chapter 1). It rests on the bone of the canal and consists of sensory epithelium lying on a mound of connective tissue, where blood vessels and nerve ﬁbers reach the sen- sory receptor area. In the human vestibular organ, there are approximately 23,000 hair cells (type I and type II) in the three cristae and about 52,000 in the two macules.119,120 The number of neurons innervating the three cris- tae is approximately 5700 and the two macules, approximately 8600, for a total of approximately 14,300 nerve ﬁbers.121 In the chinchilla, for which more accurate measurements are avail- able, the number of hair cells (type I and type

II) in the crista of the horizontal semicircular canal is about the same as the number of sup- porting cells (about 5000 of each). In the mon- key crista, type I hair cells outnumber type II hair cells by almost 3:1 with the ratio being

>4:1 in the central zone and <2:1 in the periph- eral zone.122 In the chinchilla crista the ratio of type I to type II hair cells is near 1:1 through- out.122

CUPULA

The cupula is composed of a mixture of glycoproteins and proteoglycans secreted into the endolymph by specialized endothelial cells.123 It is composed of densely packed ﬁlaments 40–60 nm in diameter cross bridged by thinner ﬁlaments. Between the crista and the cupula a subcupular meshwork is composed of long branching ﬁlaments (50–70 nm in diameter) oriented parallel to the main axis of the stereocilia. The subcupular ﬁlaments are connected to the cupular ﬁlaments on one side and to the sensory epithelium on the other side. The cupula extends all the way to the roof of the ampulla. The tips of the stereocilia are tightly connected to the subcupular meshwork and sometimes the longest stereocilia or the kinocilia protrudes into the cupula and is connected to the cupular ﬁlaments. The subcupular meshwork may help transmit the shearing force of the cupula to the ciliary bundle and dampen unwanted vibrations.

Physiology of the Semicircular Canals

HISTORICAL BACKGROUND

The functional role of the semicircular canals was ﬁrst linked to their gross anatomic features by Flourens in 1842.124 While studying the audi- tory labyrinth in pigeons, he noted that opening a semicircular canal resulted in characteristic head movements in the plane of that canal. Several subsequent investigators proposed that movement of endolymphatic ﬂuid within the canal was responsible for excitation of the cris- tae.125–127 It was not until the studies of Ewald in 1892, however, that a clear relationship was established between the planes of the semicir- cular canals, the direction of endolymph ﬂow, and the direction of induced eye and head movements.128 Exposing the membranous laby- rinth of the semicircular canals of pigeons, Ewald applied positive and negative pressure to each canal membrane to cause ampullopetal (toward the ampulla) and ampullofugal (away from the ampulla) endolymph ﬂow. Three important observations, which became known as Ewald’s laws, were (1) the eye and head movements always occurred in the plane of the canal being stimulated and in the direction of endolymph ﬂow, (2) ampullopetal endolymph ﬂow in the horizontal canal caused a greater response (i.e., induced movements) than did ampullofugal endolymph ﬂow, and (3) ampull- ofugal endolymph ﬂow in the vertical canals caused a greater response than did ampullopetal endolymph ﬂow.

Steinhausen129 and later Dohlman130 visual- ized the movement of the cupula during endo- lymph ﬂow. By injecting India ink into the semicircular canals of ﬁsh, these investigators demonstrated that the cupula formed a seal with the ampullary wall and moved with the endo- lymph. Steinhausen, noticing the similarity between the cupular movement and that of a pendulum in a viscous medium, proposed a model for the description of cupular kinematics that became known as the pendulum model. Although the large movements observed by Steinhausen were later realized to be artifactual, the basic principle has been upheld by most experimental131 and theoretical studies.132,133

Physiologic veriﬁcation of the model has been made by detailed study of the relationship

between angular head acceleration and the ﬂow of action potentials in isolated ampullary nerve ﬁbers. These studies were ﬁrst conducted in elasmobranchs by Lowenstein and Sand,134 later in frogs,135,136 pigeons,137 and mam- mals,138–141 and ﬁrst in primates by Goldberg and Fernández.111,142,143

cupula–endolymph system can be obtained if the values of these coefﬁcients are known.

For natural to-and-fro head movements, the magnitude of the elastic and inertial forces is negligible and the following simpliﬁed equation describes the kinematics of the cupula system:

PENDULUM MODEL

C (t)

[2]

The pendulum model is the most useful didac- tic model for describing the physiologic prop- erties of the semicircular canals and, as will be shown later, for describing the semicircular canal-induced reﬂexes, especially the vestib- ulo-oculomotor reﬂexes.132,144

The cupula acts as the coupler between the force due to angular acceleration of the head and the hair cells (the transducer of mechanical to biological energy), leading to the production of action potentials in the vestibular afferent ﬁbers. Because of the conﬁguration and dimen- sions of the canals, the endolymph can move in only one direction along the cylindrical canali- cular cavity. According to Newton’s third prin- ciple, when an angular acceleration [and hence

a force M¨ h(t)] is applied to the head, displace- ment of the cupula–endolymph system acting

as a solid mass is opposed by three restraining forces: (1) an elastic force [Kc (t)] due to the cupula’s spring-like properties (which is pro-

portional to the magnitude of its displacement),

the force due to the cupula–endolymph vis-
The force applied to the cupula–endolymph system during angular head acceleration is opposed mostly by the viscous drag of the cup- ula. Integrating Equation 2 we have
h
h
 M ( [3]
Thus, the displacement of the cupula system during natural head movements is proportional to the velocity of head motion rather than head acceleration. The magnitude of the proportion- ality constant (M/C) relating angular deviation of the cupula in degrees to the velocity of the head in degrees per second has been estimated to be approximately 0.003 sec, based on the physical characteristics of the canals and endo- lymph.145 Most likely, during fast head move- ments with velocities as great as 800 degrees / sec, the deviation of the cupula does not exceed 1degree of deﬂection.120
Figure 2–15 illustrates the relationship between the time course of head acceleration, head velocity, and cupular displacement as
c
c
cosity [C˙ (t)] (whose magnitude is propor-
predicted by the pendulum model for three
tional to the velocity of its displacement), and
an inertial force [M¨ c(t)] due to the ﬂuid’s mass (proportional to the acceleration of the

ﬂuid–cupula complex). Cupular displacement can be described by the following equation, which is referred to as the equation of the pen- dulum model of semicircular canal function:

different types of angular rotation commonly used in clinical testing. The description of cup- ular displacement during constant angular acceleration (Fig. 2–15a) can easily be derived from Equation 1. At the beginning of head acceleration, endolymph movement lags behind the displacement of the head and thereby that of the walls of the semicircular

M t K (t) M (t) [1]

canals. After a few seconds, however, a balance is established between the applied and restrain-

where c is the angular displacement of the cupula–endolymph system with respect to the

ing forces, and the endolymph moves simulta- neously with the walls of the labyrinth. At this

wall of the canals, ˙ and ¨ are the ﬁrst (veloc-

time the position of the ring of ﬂuid within the

ity) and second (acceleration) time derivatives of the cupular displacement, and ¨ h is the angular acceleration of the head. M is the

moment of inertia; C, the moment of viscous friction; and K, the moment of elasticity. A complete description of the kinematics of the

canal and therefore the position of the cupula

c(t) differ from the initial conditions, having been displaced by a certain amount in the

direction of the force. The magnitude of the displacement can easily be calculated. Once the endolymph is stationary, the cupula

Stimulus

100%

Constant acceleration stimulus

Acceleration

Velocity

Cupula displacement
Cupula displacement
100%
63
37
0

Stimulus
Stimulus
100%

T1 T1
Impulse stimulus

Acceleration
0
Velocity

Cupula displacement
Cupula displacement
100%

37
0
T1 Time

Stimulus
Stimulus
max

0

max
Sinusoidal stimulus Acceleration

Velocity

Cupula displacement

100%

Figure 2–15. Relationship between cupular displacement and three types of angular acceleration of the head (a–c) as predicted by the pendulum model.

velocity ˙ (t) and its acceleration ¨ (t) in

The relationships embodied in Equations 3

c c

relation to the walls are zero and, consequently, the terms for viscous and inertial restrain- ing forces vanish in Equation 1, which now reduces to

K (t)

and 4 are two of the fundamental concepts of cupular function. To restate them: the maxi- mum deviation of the cupula increases propor- tionally to the magnitude of head velocity during sinusoidal head rotations at the frequen- cies of natural head movements and to the magnitude of head acceleration during rotation with constant angular acceleration.

 M (t [4]

That is, the ﬁnal displacement of the cupula depends on a proportionality constant and on the magnitude of the constant angular acceleration.

Cupula displacement after a constant angu- lar acceleration stimulus follows an exponential time course (Fig. 2–15a) that can be deter- mined by a more detailed mathematical treat- ment of Equation 1. Sixty-three percent of the total cupular deviation, regardless of its ﬁnal value, always takes place after a ﬁxed delay

determined by what is known as the long time

constant (T1) of the system. The subsequent deviation of the cupula increases at the same

rate (63% of the remainder every T1 seconds), so that 95% of the ﬁnal deviation will take place

after approximately 3T1 sec. The magnitude of the time constant depends on the viscous and

elastic coefﬁcients: T1 = C/K. That is, the time the cupula takes to reach a maximum deviation

is directly proportional to the viscosity of the endolymph and inversely proportional to the elasticity of the cupula. T1 cannot be measured

directly, but it has been estimated to be

about 7 sec, based on the average response of primary afferent neurons in the squirrel monkey.111,142,143

According to the pendulum model, not only is the initial deviation of the cupula related to the constant acceleration stimulus, but after the stimulus is terminated the cupula returns to the resting position with the same exponential time course. It was precisely the observation by Steinhausen119 of the slow exponential-like return of the cupula to the resting position after it had been deviated that led to the formulation of the pendulum model.

The cupular displacement following a brief impulse of angular acceleration is given in Figure 2–15b. This type of angular accelera- tion, although the least natural, is of great value in clinical vestibular testing. An impulse of acceleration is generated by changing the

the cosine function at that instant in the cycle of motion. Since this value oscillates between

+ 1 and −1, the head velocity ranges between

+A and −A. These relationships are felt to apply for sinusoidal rotations between 0.1 and

4.0 Hz and therefore cover the range of most natural to-and-fro head movements.118

Anatomy of the Otolith Organs

MACULES

The two otolith organs consist of a sensory area (i.e., the macules) and a surface area (i.e., the otolithic membrane), which are located in the middle chamber of the inner ear (i.e., the vesti- bule). The vestibule is oval in shape, connecting to the membranous semicircular canals via ﬁve openings. The saccule lies on the medial wall of the vestibule in a spherical recess inferior to the utricle with which it is in contact but without direct connection.115 It communicates with the endolymphatic duct (and thus the utricular duct) by the saccular duct and with the cochlea by the ductus reuniens (see Fig. 2–8). The mac- ule of the saccule is a differentiated patch of membrane in the medial wall, is hood shaped, and lies predominantly in a vertical position (see Fig. 1-3c in Chapter 1). The macule of the utricle is located next to the anterior opening of the horizontal semicircular canal and lies mostly

velocity of the head (˙

acceleration possible.

h) with the maximum

maximum deviation

in a horizontal position in a recess on the anterior

part of the utricle. The utricle communicates by

The

of the cupula takes almost immediately

the utricular duct with the endolymphatic duct

place

and is proportional

magnitude of the

at the same level as, but by different openings

instantaneous

to the

head velocity

from, those of the saccular duct. Thus, the

 (t)  ˙ .

change in

Of particular note, the cupular

endolymph in the superior or utricular part of the labyrinth is separated from that of the sac-

deviation thereafter decays exponentially with

the same time constant to return to 63% of the maximum deviation.

The sinusoidal rotation in Figure 2–15c most closely resembles natural head movements because movement in one direction is followed by movement in the opposite direction. Most natural head movements can be broken down into a series of sine waves with different fre- quencies and amplitudes. According to Equation 3, the cupular displacement c(t) is

given by A cos t (the differential of head dis-

placement A sin t), where  is the radian fre- quency (2 f) of head rotation and A is the angular head displacement. The head velocity at a given time t is proportional to the value of

cule and cochlea by these tiny ducts.

PRODUCTION AND MAINTENANCE OF OTOCONIA

Otoconia are complex calcium carbonate (CaCO3) biominerals that serve an important

role in both normal and abnormal vestibular

function (also see Chapter 10). Otoliths is another word for otoconia. Thousands of tiny calcium carbonate crystallites (0.1 to 25 micrometers) surround a glycoprotein/proteo- glycan core that is bound to the underlying amorphous gelatinous layer by ﬁbrous proteins (Fig. 2–16, also see Fig. 1–3 in Chapter 1).147,148

Otoconia

Otogelin

-tectorin

-tectorin Otoancorin

Otopetrin 1

NOXA 1

NOX 3

tc hc sc

Gelatinous layer

Subcupular meshwork

Macula

Hair cells (hc) Support cells (sc) Transitional cells (tc)

Basement membrane

Figure 2–16. Schematic representation of the utricular macule. The macule is composed of sensory hair cells (hc) and sup- porting cells (sc); transitional cells (tc) border the edge of the macules. Directly above the macule, the otoconial membrane is composed of the subcupular meshwork, a ﬁbrillar structure which rings the stereociliary projections of each hair cells, and the gelatinous membrane which is amorphous. Otoconia, CaCO3 biominerals precipitated around a proteinaceous core, are embedded in the gelatinous membrane and maintained in place by strands of noncollagenous extracellular matrix proteins that resemble beads on a string. Proteins that have been identiﬁed to inﬂuence the activity or structure of each of these layers are listed on the left. (Adapted from: Hughes I, Thalmann I, Thalmann R, Ornitz DM. Mixing model systems: Using zebraﬁsh and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development. Brain Res. 2006;1091:58 with permission.)

Between the gelatinous layer and the sensory epithelium a dense reticular network of ﬁbril- lar proteins ring the stereocillary projections of the hair cells. In the mouse, otoconia form over the sensory epithelium of the macules when core proteins (mostly Otoconin 90) coalesce into distinct structures at approximately embry- onic day 14.149 Calciﬁcation of the protein structures rapidly occurs over the next few embryonic days. Normal production of the otoconial membrane requires an ordered sequence of events, including localized pro- duction and export of otoconial matrix proteins, assembly of the protein core from free-ﬂoating matrix proteins, and locally increasing Ca2+ and CO3– concentrations. Inhibitors of calciﬁcation

in other areas prevent more generalized calciﬁ-

cation.

The rapid deposition of calcium carbonate on the protein matrix requires adequate Ca2+ and CO – ions. The plasma membrane calcium ATPase 2 (PMCA2) is the primary calcium pump for maintaining endolymph Ca2+ levels and carbonic anhydrase generates CO –.150,151

otoconia and may have an increased risk of developing benign positional vertigo.153

Much of the information regarding the genes and proteins critical for otoconia production and maintenance have been determined through the study of mutant mice and zebraﬁsh.148 Many of these animals were ﬁrst identiﬁed as having a possible vestibular disor- der after observing behavioral features that might suggest inner ear dysfunction (e.g., dancer, backstroke, head tilt, twirler). Knockout models have also provided insight into impor- tant proteins for otoconia production. Interestingly, despite the numerous animal models with absent or abnormal otoconia, so far no human counterparts have been found. Abnormal or reduced otoconia have been pro- duced in humans and experimental animals by a range of pharmacological agents, includ- ing aminoglycosides, phenytoin, carbonic anhydrase inhibitors, prostaglandins, and ethacrynic acid.154–159 It appears that mainte- nance of normal otoconia requires the mainte- nance of normal hair cells. Animal models that

Once formed there is normally a low rate of

lose hair cells with aging also lose otoconia.148

turnover of otoconial calcium in adult mice.152 Like bone, otoconia mineralization and turn- over may be sensitive to hypo and hypercalce- mia. Patients with osteoporosis have abnormal

Aminoglycosides damage hair cells and lead to otoconial degeneration. Alteration in endolym- phatic ion concentration may be the cause of both hair cell and otoconial degeneration.

Physiology of the Otolith Organs

HISTORICAL BACKGROUND

Over a century ago, Mach,125 Crum-Brown,126 and Breuer127 each concluded that linear and angular acceleration must be mediated by dif- ferent end organs, and Breuer in particular pos- tulated the mechanism by which the otoliths sense linear acceleration. As in the case of the semicircular canals, a gross anatomic feature of the macules—the dense, calciﬁed otolithic membrane—suggested the mechanisms by which they sense the direction of gravitational force. The afferent neuronal activity from the macules associated with precise static and dynamic linear acceleration forces has only recently been investigated in primates.160–162 These studies conﬁrm that the utricular and saccular macules are responsive to static tilt and dynamic linear acceleration, resolving an earlier controversy as to whether the saccular macule functions as an auditory or vestibular organ. However, we also know that the sacculus can be stimulated by loud sounds, which is the basis for the vestibular evoked myogenic potentials (VEMP) test (see Chapter 7). The pattern of afferent nerve response is complex, with vari- ous neurons exhibiting different resting activity, frequency response, and adaptation properties.‌

MECHANISM OF STIMULATION

During head displacement, the calciﬁed otolithic membrane is affected by the combined forces of applied linear acceleration and gravity and tends to move over the macule, which is mounted in the wall of the membranous labyrinth (see Fig. 1–3b in Chapter 1). The otolithic mem- brane is restrained in its motion by elastic, vis- cous, and inertial forces analogous to the forces associated with cupular movement. De Vries146 measured the displacement of the large saccular otolithic membranes of several ﬁsh and obtained estimates of the forces restraining the mem- brane to the macules. He proposed a model, analogous to the pendulum model, that described the dynamics of otolithic membrane displace- ment as those of a low-pass ﬁlter. Displacements due to sinusoidal linear acceleration would be greatest at low frequencies, including static head tilts. At greater frequencies, the otolithic mem- brane displacement would decrease by one-half each time the frequency was doubled.

The nerve ﬁbers of the macule are activated by linear accelerations and by changes in head positions in space.160 Each neuron has a charac- teristic functional vector that deﬁnes the axis of sensitivity for head acceleration. Individual neurons appear to be stimulated only by con- tiguous hair cells whose kinocilium is oriented with the same vector of excitability, creating a sensorineural unit (see Fig. 1–3c in Chapter 1). The combined functional units from the mac- ules cover all possible positions of the head in three-dimensional space. However, most of the units are oriented in the horizontal plane in the utricular macule and in the vertical plane in the saccular macule.160–162

In the utricular macule, tilting of the head ipsilaterally results in an increase in ﬁring of units on the medial side of the striola and a decrease in ﬁring of units on the lateral side of the striola. With the subject in the upright posi- tion, most of the units are at baseline because the vector orientation of the utricular macule is orthogonal to the gravitational vector. Because of the curvature of the macule, some afferent units are sensitive to forward and backward tilting of the head.

Since the saccular macule is oriented in the sagittal plane, the vectors of most of the func- tional units are parallel to gravity when the head is in the upright position. Because of the push–pull relationship of hair cells on either side of the striola, some functional units are excited, whereas others are inhibited. The stri- ola of the saccular macule has less curvature than that of the utricle and therefore most of the units have an orientation in the rostro- caudal direction. Baseline ﬁring of neurons innervating the saccule and macule are about the same.160

PRIMARY VESTIBULAR NEURONS

Anatomy of Primary Neurons

The bipolar primary vestibular neurons of Scarpa’s ganglia are located within the internal auditory canal. The ganglia is shaped like an hourglass with a superior division, an inferior division, and an isthmus (see Fig. 1–6 in Chapter 1).163 The superior division innervates the horizontal and anterior canals, the utricular macule, and part of the saccular macule, while

the inferior division innervates the posterior canal and the rest of the saccular macule. During development the vestibular ganglia elongates with the growth of the nerves and temporal bone, leading to the fusiform appear- ance seen in adults. On average there are approx- imately 25,000 neurons in the human Scarpa’s ganglion.164,165 Neuronal diameters vary greatly in each division of the ganglia. The largest neu- rons innervate type I hair cells in the center of the cristae and macules, and the smallest neu- rons innervate type II hair cells in the periphery of the cristae and macules. Intermediate-sized neurons innervate combinations of type I and type II hair cells throughout the cristae and mac- ules (dimorphic units). Immunohistochemical studies show a differential expression of calcium- binding proteins in large and small neurons.166 Only large cells show immunoreactivity (IR) for calbindin and calretinen, while all cells show IR for parvalbumin. Large neurons also show greater IR for neuroﬁlament proteins than do small neurons.167

Detailed study of the vestibular nerve in ani- mals and humans reveals a highly organized arrangement of the nerve ﬁbers originating from the different inner ear receptors and from the two types of hair cells within each receptor.168–171 There is a similar unimodal distribution of pri- mary afferent neurons with regard to axon and

cell body diameter in several species studied (Fig. 2–17). As noted earlier, small ﬁbers (<2.5 µm) project preferentially to the periph- ery of the sensory epithelium, whereas larger ones (>4.5 µm) project to the center.

INNERVATION OF THE CRISTAE

The highly organized innervation of the crista in the chinchilla is shown in Figure 2–18.172 Underneath the sensory organ, the main nerve divides into two smaller ones. Each of the two nerve branches innervates half of the crista and thus half of the hair cells. Within half a milli- meter from the sensory epithelium, each nerve divides into 8 to 10 bundles of ﬁbers that align in two rows, one for each slope of the crista. Among these smaller bundles, those that inner- vate the center of the crista have a greater pro- portion of thick ﬁbers, whereas the bundles that innervate the periphery have a preponder- ance of thin ﬁbers (Fig. 2–18a, inset).

The bundles of ﬁbers that innervate a dis- crete area of the crista travel together toward the nervous system and, in all probability, innervate groups of neighboring neurons in the vestibular nuclei. There appears to be a topo- graphical representation of the vestibular end organ in the central nervous system that is comparable to the topographical projection of

Diameter:

µm

< 2.5

2.5 – 4.5

> 4.5

Human Monkey Chinchilla

500 600 300

Number of fibers

1.0 9.0

1.0

9.0

1.0 9.0

Binwidth = 0.5 µm

Figure 2–17. Distribution of primary afferent ﬁbers of different diameters (including myelin) within the cristae of humans, monkeys, and chinchillas. The smallest ﬁbers (< 2.5 µm) are concentrated in the periphery while the largest libers (> 4.5 µm) are more numerous at the center of the cristae. Intermediate-size ﬁbers tend to be equally distributed throughout the cristae.

Figure 2–18. Cross sections of the superior semicircular canal nerve as it enters the crista in the chinchilla. (a) At 20 µm below the base of the crista the nerve ﬁber bundles are arranged in rows and each bundle consists of 30–50 nerve ﬁbers. Fibers in the periphery have smaller diameters than those in the center. (b) At 400 µm below the surface of the crista. The nerve trunk is separated into two parts by a bony septum. (c) At 600 µm below the base of the crista. The nerve bundles of different sizes are surrounded by the ﬁbrous perineurium to form a single nerve trunk.

different parts in the basilar membrane of the cochlea to the auditory nuclei. Each of the afferent bundles containing ﬁbers of different diameters—thick, medium, and thin—is derived from the same restricted area of about

0.2 mm2 on the crista and carries information about localized cupula movement.

Classical morphologists identiﬁed three types of nerve endings in the receptors: large-diameter ﬁbers had caliceal endings, small-diameter ﬁbers had bouton endings, and intermediate-size ﬁbers had both types of ending.173

With techniques for labeling individual neu- rons and ﬁbers by intracellular injection of horseradish peroxidase, detailed information has been obtained in the chinchilla regarding the association of ﬁber diameter size with dif- ferent nerve endings in different parts of the receptors. In the crista, neurons with large axon diameters (2.8 ± 0.6 µm) innervate one or a few hair cells with caliceal endings (type I) in the center (Fig. 2–19).174,175 Neurons with interme- diate-size axon diameters (2.3 ± 0.6 µm) have both bouton and caliceal endings and are more

Figure 2–19. Different types of primary afferent nerve endings labeled by intracellular injection of horseradish peroxidase. Reconstructions of two calyx units with simple (a) and complex (b) endings, a dimorphic unit (c), and a bouton unit (d), all taken from a single horizontal canal crista, are shown. The points at which the parent axons of labeled afferents enter the sensory epithelium are indicated on a standard surface reconstruction (center). Bar = 10 µm. (From Fernandez C, et al. The vestibular nerve of the chinchilla. 1. Peripheral innervation patterns in the horizontal and superior semicircular canals. J Neurophysiol. 1988;60:167, with permission.)

or less evenly distributed throughout the crista. Neurons with small axon diameters (1.4 ± 0.4 µm) have only bouton endings and innervate multiple type II hair cells predomi- nantly in the periphery. Of a sample of 368 ﬁbers, 40 (11.1%) were calyx units, 79 (21.5%) were bouton units, and 248 (67.4%) were dimorphic units. Approximately the same dis- tribution of ﬁbers according to diameter size is seen in the crista of the squirrel monkey and in humans (Fig. 2–17).

INNERVATION OF THE MACULES

In the macules, as in the cristae, the diameter of the nerve ﬁbers has a unimodal distribu- tion.176 Fibers of large diameter with only cal- iceal endings predominate near the striola, whereas the thinner ﬁbers innervate the periph- ery. Fibers of intermediate diameter (dimor- phic) are distributed evenly throughout the macule. In the chinchilla macule, as in the crista, dimorphic units outnumber caliceal units by 3 to 1. Caliceal units typically innervate more hair cells (10–40) than dimorphic units (5–20).

NEUROTRANSMITTERS

Glutamate is the main excitatory neurotrans- mitter of primary afferent neurons.177 Immunohistochemical studies in a range of species, including primates, found glutamate immunoreactivity (IR) in all bipolar neurons in the vestibular ganglia. The majority of neu- rons also showed a graded IR to glycine and choline acetyltransferase (ChAT) in a highly overlapping neuronal population.178 Similar co-localization of glycine and ChAT was also seen in afferent terminals in the end organs. Glycine and acetylcholine presumably have a co-transmitter or modulatory function.

Physiology of Primary Neurons

SPONTANEOUS FIRING RATES

Just as there is a continuous spectrum in axon diameters, primary afferent neurons have a wide range of spontaneous ﬁring rates and dynamic properties. It has proved useful to divide them on the basis of the regularity of

Table 2–1 Classiﬁcation of primary afferent neurons based on their spontaneous ﬁring rate

Firing regularity	Response dynamics	Size	Conduction velocity	Galvanic Stimulation	Epithelial zone	Afferent type
Regular Irregular	Tonic Phasic	Small Large	Low High	Less sensitive More sensitive	Peripheral/ extrastriola Center/striolar	Bouton/ dimorphic Calyx/ dimorphic

their spontaneous discharge rate (Table 2–1).179–181 Neurons with the most irregular baseline ﬁring rate (given by the coefﬁcient of variation [CV] of the mean interspike interval) are the most sensitive to galvanic stimulation, while neurons with the most regular baseline ﬁring rate are least sensitive to galvanic stimulation. As a general rule, a primary afferent’s sensitivity to angular acceleration (in spikes/sec per degree/ sec2) is inversely related to the regularity of its baseline ﬁring rate—that is, irregular units with high CV values have a higher sensitivity than regular units with low CV values.

Early in vivo experiments showed that regu- lar afferents have a different after-hyperpolariz- ing potential (AHP) following each spike than do irregular afferents.182 More recent in vitro studies of isolated primary afferent neurons conﬁrmed these ﬁndings and suggest that dif- ferential expression of ion channels accounts

for these electrical properties (Fig. 2–20, Table 2–2).166 In isolated rat vestibular ganglia neu- rons, Kv1 potassium blockers converted phasic

ﬁring cells to tonic ﬁring cells, indicating

that Kv1 potassium channels control the ﬁring patterns of irregularly discharging primary neu-

rons.183 Blocking of calcium-activated potassium channels decreased the number of spikes origi- nating from tonic primary afferent neurons. Ca2+ binding proteins and Ca2+ channels regu- late the activation of Ca2+-dependent potassium channels and thus regulate ﬁring frequency.166

AFFERENTS FROM THE CRISTAE

As noted earlier, the primary vestibular afferent ﬁbers maintain a constant baseline ﬁring rate of action potentials. Recordings from the primary afferent ﬁbers of the cristae in mammalian and nonmammalian species reveal that physiologic

Table 2–2 Pattern of expression of ion channels in large and small vestibular ganglion somata in rodents

Large neurons Small neurons

Firing regularity Irregular Regular

Spike shape Prominent AHP Brief AHP

Ca++ dependent K+ channels

Lower total density; proportionally more BK

More dense, more blocker resistant current

Voltage-gated K+ channels A A

KCNQ channels KCNQ4 ?

Voltage-gated Ca++ channels HVA, LVA (T) HVA

Voltage–gated Na+ channels Nav 1.5? Nav 1.8, 1.9?

HCN channels Yes Yes

Acid-sensing ion channels More Less

AHP – afterhyperpolarizing potential; BK – class of Ca++dependent K+ channels with large single-channel conductances; A – rapidly inactivating voltage gated K+ channels of heterogenous molecular composition; HVA – high voltage activated Ca++ channels; LVA – low voltage activated Ca++ channels (T current); HCN – hyperpolarization-activated cyclic- nucleotide-modulated channels. (Adapted from Eatock RA, Xue J, Kalluri R. Ion channels in mammalian vestibular afferents may set regularity of ﬁring. Primary afferents J Exp Biol. 2008;211:1764, with permission.)

Striola Extrastriola

Tip links Mechanosensory ion channels

Nav 1.5

I I I

KCNQ4

Ribbon

Sunapses *Na

II II

LVA

C HCN

ASIC HCN

D B

Na HVA

HVA

A IK

Figure 2–20. Schematic showing classiﬁcation of vestibular afferent neurons by terminal morphology as pure-calyx (C), dimorphic (D) and pure-bouton (B). Trunkated ﬁbres are efferents, arising from neurons in the brainstem. Pure-calyx afferents exclusively innervate the centre and striola and often form complex calyces around multiple type I hair cells, as illustrated. Pure-bouton afferents exclusively innervate the peripheral zone and extrastriola and can innervate tens of type II hair cells. Dimorphic afferents innervate both zones, but have more compact dendritic trees in the centre and striola than in the periphery and extrastriola (not shown). Pure-calyx afferents express calretinin, calbindin and parvalbumin; dimorphic afferents are thought to express calbindin and parvalbumin; and pure-bouton afferents, which are the thinnest, express only parvalbumin. Some differences in ion channel expression have been noted between large and small isolated ganglion somata and are indicated here on the pure-calyx and pure-bouton somata and summarized in Table 2–2. Whether dimorphic somata, which are likely to be mid-sized, have intermediate expression is not known. Asterisks indicate possible sites of spike initiation on each afferent. Abbreviations deﬁned in Table 2–2. (Adapted from Eatock RA, Xue J, Kalluri R. Ion channels in mammalian vestibular afferents may set regularity of ﬁring. Primary afferents J Exp Biol. 2008;211:1764, with permission.)

stimulation producing endolymph ﬂow toward the ampulla (i.e., ampullopetal ﬂow) in the horizontal semicircular canal increases the baseline ﬁring rate. Conversely, endolymph ﬂow away from the ampulla (i.e., ampullofugal ﬂow) decreases the baseline ﬁring rate. In the vertical canals the reverse occurs: ampullopetal endolymph ﬂow decreases the baseline ﬁring rate, and ampullofugal ﬂow increases the ﬁring rate. Considering these observations and the previous anatomic descriptions, it is apparent that endolymph displacement that deviates the hairs of the sensory cells toward the kinocilium results in increased ﬁring of the afferent nerve, whereas displacement away from the kinocil- ium results in decreased ﬁring of the afferent

nerve. The differences in the physiological characteristics of responses from the horizontal and vertical canals are the physiological basis to the formulation of Ewald’s second and third laws.

Detailed measurements of afferent nerve activity from the cristae of squirrel monkeys show that the ﬁring rate associated with physio- logic rotatory stimulation follows qualitatively the prediction of the pendulum model;111 that is, the magnitude of change in frequency of action potentials is proportional to the theoretic devia- tion of the cupula. For example, during sinusoi- dal head rotation, the ﬁring rate follows the time course of cupular displacement shown in Figure 2–15c. A sinusoidal change in ﬁring frequency is

superimposed on a rather high resting discharge (70 to 90 spikes/sec). The peak ﬁring rate occurs at the time of the peak angular head velocity. For sinusoidal rotation of small magnitude, the mod- ulation is almost symmetrical about the baseline ﬁring rate. For higher stimulus magnitudes, the responses become increasingly asymmetrical. For the largest magnitudes, the excitatory responses can increase up to 350 to 400 spikes/ sec in proportion to the stimulus magnitude, while the growth of inhibitory response is limited to the disappearance of spontaneous activity. This asymmetry in afferent nerve response to stimuli of large magnitude explains Ewald’s sec- ond and third laws because the “pneumatic ham- mer” that he used to apply pressure to the canals produced a massive stimulus.128

When the cristae are subjected to prolonged constant acceleration, a substantial proportion of nerve ﬁbers undergo a slow decline in ﬁring rate (adaptation) rather than maintaining a steady state as predicted in Figure 2–15a. Because of adaptation, the ﬁring rate does not return to baseline after cessation of accelera- tion, but rather, drops to a lower level before slowly returning to the resting level.111,138 Similar overshooting of the baseline occurs after stimulation with an impulse of accelera- tion. Instead of the monotonic response pre- dicted by the pendulum model (Fig. 2–15b), the afferent nerve ﬁring pattern exhibits a biphasic reaction with a prolonged secondary phase that slowly returns to baseline. It is not known whether the behavior is due to anatomic or synaptic processes. The process is more pro- nounced in “irregular” neurons. As will be shown later, the vestibulo-ocular reﬂex also reﬂects this deviation from the predicted pat- tern (see Fig. 7–19d).

How are these physiological properties related to the anatomical features of primary afferent neurons described earlier? The anatomical and physiological properties of a single primary afferent neuron can be studied by ﬁrst record- ing the neurons’ dynamic response to angular acceleration with a micropipette and then injecting it with a tracer to study its anatomical connections. Initial studies in the bullfrog dem- onstrated that “irregular” neurons had thick, rapidly conducting ﬁbers that preferentially innervated the central ridge of the crista, while “regular” neurons had thin, slowly conducting ﬁbers that predominantly innervated the periphery.184 In mammals three patterns of

nerve terminals within the crista can be delin- eated: (1) caliceal endings, (2) bouton endings, and (3) combined caliceal and bouton endings (dimorphic units). All caliceal units are at the center of the crista and have “irregular” dynamic properties, whereas bouton units are in the periphery and have “regular” dynamic properties (Fig. 2–21). Dimorphic units can be either “irregular” or “regular,” with the former usually innervating the center of the crista and the latter, the periphery. Surprisingly, the cal- iceal units at the center of the crista have a lower rotational sensitivity than that of dimor- phic units with similar-size axons innervating the same region. Possibly the lower sensitivity of these caliceal units extends the dynamic range of vestibular reﬂexes—that is, they do not become saturated by the large velocity active head movements. Dimorphic units innervating different regions of the crista vary in their dynamic properties, even though they contacted similar numbers of type I and type II hair cells. Taken together, these ﬁndings indi- cate that the dynamic properties of a semicir- cular canal afferent neuron reﬂect the number and type of synaptic connections, and location within the crista. However, these factors alone cannot explain regularity of ﬁring. For this one must look to the intrinsic membrane properties of the primary afferent neurons as described earlier.

AFFERENTS TO THE MACULES

As in the crista, the neurons of the macule can be classiﬁed according to the regularity of the spontaneous ﬁring rate.162 Recordings from neurons whose nerve endings were visualized with intracellular labeling show that caliceal units (mostly near the striola) are irregular, whereas bouton units (in the periphery) are regular (Table 2–1). Dimorphic units that innervate the areas near the striola are more irregular than those innervating the periphery. In the chinchilla, regular units outnumber irregular units by a ratio of 3 to 1. As in the crista, irregular units are more sensitive and have a wider frequency range of response than that of regular units. They adapt promptly to stimuli of constant linear acceleration (e.g., head tilt). By contrast, regular units maintain a constant relation between the gravity vector and the ﬁring rate during static tilts. As in the crista, large primary afferent neurons with an irregular

(a)

d c PI

c d

I I

d d

P P

d b

(b)

Calyx Dimorphi Bouton ‌

Figure 2–21. (a) Dynamic properties of afferent ﬁbers originating in different parts of the chinchilla crista. This cross sec- tion of the crista is divided into peripheral (P), intermediate (I), and central (C) zones. Calyx (c) ﬁbers innervate the central zone; bouton (b) ﬁbers, the peripheral zone; and dimorphic (d) ﬁbers innervate all three zones. (From Fernandez C et al. The vestibular nerve of the chinchilla. I. Peripheral innervation pattern of the horizontal and superior semicircular canals. J Neurophysiol. 1988;60:167–181, with permission.) (b) Locations of intraaxonally labeled ﬁbers in the chinchilla cristae. (Left) Units are sorted by their normalized coefﬁcients of variation into three categories: regular (open symbols), interme- diate (half-ﬁlled symbols), and irregular (ﬁlled symbols). (Right) Units are sorted into three categories according to their phases with regard to head velocity for 2 Hz sinusoidal head rotation: tonic (open symbols), intermediate (half-ﬁlled sym- bols), and phasic (ﬁlled symbols). (From Baird R et al. The vestibular nerve in the chinchilla. 11. Relation between afferent response properties and peripheral innervation patterns in the semicircular canals. J Neurophysiol. 1988;60:182–203, with permission.)

spontaneous ﬁring rate have a different ion channel proﬁle than do small afferent neurons with a regular spontaneous ﬁring rate.156

EFFERENT VESTIBULAR NEURONS

In all vertebrates the inner ear efferent neu- rons are located in the hindbrain with cell bod- ies near brachial motor nuclei within the pons and medulla.185,186 Typically axons separate from the facial nerve and join the eighth nerve to innervate the different receptor organs. Even though they innervate sensory epithe- lium, efferent neurons are derived from the motor column and share a common embryo- logical origin with motor neurons. In ﬁsh and amphibians all efferent neurons are localized in a single nucleus, the octavolateralis nucleus, near the rostral end of the facial motor nucleus, whereas in mammals cochlear and vestibular efferent neurons are in separate nuclei. Cochlear efferent neurons are located near the

seventh nucleus, while vestibular efferent neurons are located near the sixth nucleus. Although there are only about 300 vestibular efferent neurons on each side of the brain stem, their axons branch extensively such that in the sensory epithelium efferent boutons out- number afferent boutons by a ratio of 3:1.187 Each labyrinth receives about an equal num- ber of efferent ﬁbers from each side of the brain stem. Consistent with its role as a sensory feedback system, the efferent neurons receive input from the ipsilateral vestibular nerve and both vestibular nuclei.

Consistent with its embryological origin from motor neurons acetylcholine is the princi- pal neurotransmitter of the vestibular efferent system.188 Choline acetyltransferase (ChAT) immunoreactivity (IR) was found in nerve ﬁbers and boutons adjacent to afferent nerve calyces and type II hair cells in the vestibular receptors of multiple animals including humans.189–193 GABA and the neuropeptide cal- citonin gene-related peptide (CGRP) IR was

found in a subpopulation of efferent neurons varying among species.194 Nitric oxide synthase (NOS) was also identiﬁed in a subpopulation of efferent neurons and peripheral efferent bou- tons, suggesting that nitric oxide might be another efferent transmitter.195

In mammals, including primates, electrical stimulation of brainstem efferent neurons results in a predominantly excitatory response, increased ﬁring of afferent neurons.186,196 Efferent responses are larger and more rapid in irregularly discharging afferents and smaller and slower in regularly discharging efferent neurons. Only a few studies have used physio- logical stimulation of the vestibular efferent system, but overall the ﬁndings are similar to those obtained with electrical stimulation.186 Evoked responses are excitatory for rotations in both directions, are larger in more irregu- larly discharging afferents, and consist of a rapid and slow response component. These rotational responses were efferent mediated, since they were abolished when the vestibular nerve was cut between the recording electrode and the brain stem.

The functional role of the vestibular efferent

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by stimulation of any of the sensory organs on the same or opposite sides and by rotations that excite or inhibit the afferent nerve response. Furthermore, the responses are small com- pared to those produced by conventional affer- ent stimulation. The efferent system may play a role in the normal development of the periph- eral vestibular end organs.185

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Bernard C, Cochran SL, Precht W. Presynaptic actions of cholinergic agents upon the hair cell-afferent ﬁber synapse in the vestibular labyrinth of the frog. Brain Res. 1985;338:225.
Gacek RR, Nomura Y, Balogh K. Acetylcholinesterase activity in the efferent ﬁbers of the stato-acoustic nerve. Acta Otolaryngol (Stockh). 1965;59:541.
Caston J, Rousell H. Curare and the efferent vestibu- lar system. Acta Otolaryngol (Stockh). 1984;97:19.
Schrott-Fischer A, Kammen-Jolly K, Scholtz A, Rask- Andersen H, Glueckert R, Eybalin M. Efferent neu- rotransmitters in the human cochlea and vestibule. Acta Otolaryngol (Stockh). 2007;127(1):13.
Matsubara A, Usami S, Fujita S, Shinkawa H. Expression of substance P, CGRP, and GABA in the vestibular periphery, with special reference to spe- cies differences. Acta Otolaryngol Suppl (Stockh). 1995;519:248.
Lysakowski A, Singer M. Nitric oxide synthase local- ized in a subpopulation of vestibular efferents with NADPH diaphorase histochemistry and nitric oxide synthase immunohistochemistry. J Comp Neurol. 2000;427(4):508.
Marlinski V, Plotnik M, Goldberg JM. Efferent actions in the chinchilla vestibular labyrinth. J Assoc Res Otolaryngol. 2004;5:126.
Chapter 3 ‌‌

The Central Vestibular
System

VESTIBULAR NUCLEI
Phylogeny Anatomy Neurotransmitters Physiology ‌
VESTIBULO-OCULAR REFLEXES
Overview
Rotational Vestibulo-Ocular Reﬂexes Translational Vestibulo-Ocular Reﬂex Ocular Counterrolling
Semicircular Canal–Otolith Interaction
CERVICO-OCULAR REFLEXES
Anatomic and Physiologic Basis Characteristics of Neck-Induced Eye
Movements
VISUAL–VESTIBULAR INTERACTION
Visual Tracking Eye Movements Organization of Visually Guided Tracking
Eye Movements Comparison of Vestibular- and
Visual-Induced Eye Movements Visuo-Vestibulo-Ocular Connections Model of Visual–Vestibular Interaction

Adaptive Modiﬁcation of the
Vestibulo-Ocular Reﬂext with Vision Cellular Basis for Visual Vestibular
Interaction
VESTIBULOSPINAL REFLEXES
Comparison of Ocular and Spinal Vestibular Reﬂexes
Vestibulospinal Connections Cerebellar–Vestibular Interaction Vestibulo-Collic Reﬂexes Cellular Mechanisms
SUBJECTIVE VESTIBULAR SENSATION
Vestibulothalamocortical Connections Response Properties of Thalamic Relay
Neurons
Response Properties of Vestibular Cortex Neurons
Functional Brain Imaging in Normal Human Subjects
Lesions of the Vestibulocortical Pathways in Patients
Psychophysical Studies

VESTIBULAR NUCLEI
The vestibular system must integrate multiple internal representations of head and body movement obtained from several different sen- sory systems into a single internal coding of space that provides a frame of reference for encoding motor commands. Secondary vestibu- lar neurons are at the center of this sensorimo- tor transformation. They receive a multiplicity of signals originating in the vestibular end organs. Thousands of axons of primary vestibu- lar neurons enter each side of the brain stem to
innervate second-order neurons in four ana- tomically distinctive groups, located on the ﬂoor of the fourth ventricle.1–5 Afferents from the semicircular canals stay separate from each other, but they converge with afferents from the macules in a speciﬁc spatial pattern.6,7 Secondary vestibular neurons form a column of different lengths depending on the species, being the longest in humans (13.5 mm) and smaller in animals with evolutionarily smaller brains—frogs (2.2 mm), chinchillas (4.0 mm), and squirrel monkeys (5.0 mm). However, not all of the neurons in these nuclei receive
63
primary afferent vestibular nerve ﬁbers and most receive input from other sensory systems and other nuclei (Figs. 3–1 and 3–2).
The main vestibular nuclei are the superior (angular or Bechterew’s), the lateral (Deiters), the medial (triangular nucleus of Schwalbe), and the descending (inferior or spinal) vestibu- lar nuclei. In addition, the vestibular nuclear complex includes several small groups of cells that are closely associated topographically with the main nuclei but have distinct morphologic characteristics and anatomic connections (e.g., the interstitial nucleus).8–10
There are a number of questions about the organization and function of the vestibular nuclei that are pertinent to clinical neurophysi- ology of the vestibular system. The amount of information arriving at the vestibular nuclei from different sources reaches staggering levels. In primates, since afferent vestibular neurons are characterized by their high level of sponta- neous activity, the nuclei receive about 100 action potentials/sec/nerve ﬁber (see Chapter 2). In humans, since each vestibular nerve has approximately 15,000 ﬁbers, more than 1.5 million action potentials are received every second from the vestibular organs alone. How are the signals that originate in different receptor organs dis- tributed within the vestibular nuclei? Studies
using intracellular labeling techniques can trace the trajectory of afferent neurons to answer this important question. Each ﬁber usually inner- vates a restricted number of secondary neurons in all four of the vestibular nuclei. There are clear separations of afferent ﬁbers such that speciﬁc areas in each nucleus preferentially receive afferents from speciﬁc receptors. At the same time, secondary vestibular neurons receive a converging input from different sensory organs from each ear—that is, where interactions between the organs of the two ears take place. The emerging picture is a complex one of both separation (channeling) and convergence of afferent signals at the level of the vestibular nuclei.
The biology of individual neurons in the ves- tibular nuclei is an important aspect of vestibu- lar physiology that is just beginning to be addressed. What transmitters are released and what ion channels and receptors are expressed in the different nuclei and within different neurons in the same nucleus? How do the characteristics of these secondary neurons inﬂuence signals arriving from the primary afferents and the organization of reﬂexes involved in the maintenance of gaze, equilib- rium, and orientation? Finally, how do neurons in this major sensorimotor integration center
1. (b)

Cerebellum Cerebellum

L M

HC UT

SA D

1 mm

Figure 3–1. Distribution of primary vestibular afferent ﬁbers (shaded blue areas) within the vestibular nucleus of the chin- chilla. (a) superior vestibular nerve, (b) inferior vestibular nerve. AC, anterior canal; D, descending nucleus; HC, horizontal canal; L, lateral nucleus; M, medial nucleus; PC, posterior canal; S, superior nucleus; SA, saccule; UT utricle.

SVN LVN

GAD+ GAD– Dorsal

GAD+ GAD–

DVN

Lateral Medial Ventral

MVN

GAD+ GAD– GAD+ GAD–

Figure 3–2. Immunohistochemical staining of the vestibular nuclei (VN) in the chinchilla showing distribution of neurons that are glutamic acid decarboxylase (GAD) positive and GAD negative. Shaded blue areas receive primary vestibular afferents.

adapt to conﬂicting sensory perceptions that occur in daily life or after damage to the inner ear or motor apparatus?

Phylogeny

The vestibular nuclei are one of the ﬁrst supraspinal cell groups that differentiate them- selves from the reticular formation.11,12 Lampreys have two discernible vestibular nuclear groups, the dorsal and ventral, com- posed of granular and spindle-shaped cells.

Modern ﬁsh (teleosts) have four discernible vestibular nuclei, although the nuclei contain relatively few cells. This basic organization of four vestibular nuclear groups is maintained throughout the higher vertebrates, although the relative size of each nuclear group varies from species to species (see earlier discussion). In invertebrates and early vertebrates, sec- ondary connections of the vestibular nuclei are primarily vestibulospinal, in keeping with their major role in maintaining body orientation.13 Vestibulocerebellar connections become pro- gressively more prominent in higher vertebrates.

The development of these “modern” vestibular pathways accompanies the development of increasingly complex somatic and ocular motor skills. In primates, vestibulocerebellar and vestibulo–ocular connections form a large part of the central vestibular pathways, and vestibu- lospinal connections are less prominent.13 The lateral vestibular nucleus (Deiters’ nucleus), a major source of vestibulospinal ﬁbers, is the most prominent nuclear group in lower mam- mals, whereas in human beings it is small and almost conﬁned to the vestibular root entry zone. By comparison, the superior vestibular nucleus is barely detectable in lower vertebrates but is prominent in humans, where it is the major source of vestibulo-ocular ﬁbers. It extends ros- trally from the root entry zone (at the medullo- pontine junction) to the midpontine region.11

Anatomy

PRIMARY AFFERENT ENDINGS

The thousands of primary afferent vestibular nerve ﬁbers arrive in the vestibular root in a speciﬁc orientation depending on their organ of origin (Fig. 3–1).1–5 After entering the brain stem, they divide into secondary ascending and descending branches that form a clearly deﬁned vestibular tract in all animals studied. Branches from ﬁbers in the ascending tract end in the rostral part of the vestibular nuclei or in the cerebellum, while branches from the descend- ing tract course in a ventrolateral direction in relation to the fourth ventricle, ending in the caudal vestibular nuclei.1–5

Individual primary afferent neurons provide multiple branches; in the bullfrog and cat, there is an average of 200 branches per affer- ent ﬁber.14–17 As illustrated in the chinchilla (Fig. 3–1), not all areas of the vestibular nuclei are innervated by the labyrinthine afferents. In addition, in the areas that receive primary afferents, signals from the vestibular organs interact with afferent ﬁbers from other systems (visual and proprioceptive) and centers (especially the cerebellum).8,10

SUPERIOR VESTIBULAR NUCLEUS

The superior vestibular nucleus in humans extends from the caudal pole of the trigeminal motor nucleus approximately to the level of the

abducens nucleus.18–20 It is the smaller of the main nuclei with a length of 2.7 mm, contain- ing approximately 20,000 neurons.20,21 Medium- size neurons of about 15–30 µm in diameter predominate, with some large multipolar cells at the center. Most of the primary afferent pro- jections to the superior vestibular nucleus come from the cristae of the semicircular canals, arriving at the nucleus in the form of fascicles with a variety of ﬁber diameters.4 Large ﬁbers terminate preferentially on the larger neurons in the center of the nucleus.2,10,22 Fibers from the superior semicircular canal are found medially, those from the horizontal and posterior canals more laterally (Fig. 3–1). Fibers from the utricle and saccule innervate only the periphery of the nucleus on the lateral side.

Another major group of afferent ﬁbers origi- nates in the cerebellum. Those from the ﬂoc- culus end in the central region and those from the fastigial nucleus, nodule, and uvula end in the peripheral region.10,23 A group of ﬁbers from the contralateral medial and descending nucleus connects the two sides.

Axons from the neurons in the superior ves- tibular nucleus run in the ipsilateral and con- tralateral medial longitudinal fasciculus (MLF) to innervate the motor nuclei of the extrinsic eye muscles; others project to the cerebellum and dorsal pontine reticular formation.24,25 Dendrites of neurons in the periphery of the nucleus extend into the adjacent reticular for- mation and into the principal trigeminal nucleus. Because of the pattern of afferent and efferent connections, the superior vestibular nucleus is a major relay center for ocular reﬂexes mediated by the semicircular canals.

LATERAL VESTIBULAR NUCLEUS (DEITERS’ NUCLEUS)

Beginning at the caudal end of the superior nucleus and ending below the level of the abducens nucleus, the lateral nucleus is trans- versed by the initial segments of the vestibular tract ﬁbers corresponding to the root entry zone. In humans, the length of the lateral nucleus is 5.6 mm. It contains approximately 25,000 neurons.20,21 It is distinguished by the presence of giant cells (30 to 60 µm) that are relatively more numerous in the dorsocaudal than in the central ventral part.8,10 No sharp anatomic distinction divides these two parts of

the nucleus; in cats and chinchillas, only the rostroventral part receives primary vestibular afferents (the majority originating from the utricular macule). The dorsocaudal part receives afferent ﬁbers from the vermis and fastigial nucleus of the cerebellum (see Fig. 3–26). Afferent components from other sources (spinal and commissural ﬁbers) are few in comparison with those from the cerebellum and vestibular nerve. The lateral nucleus sends most of its efferent ﬁbers to the spinal cord as the ipsilateral vestibulospinal tract (see Fig. 3–25). This projection is somatotopically organized in that ﬁbers to the cervicothoracic cord originate from the rostroventral part of the nucleus, while ﬁbers to the lumbosacral cord originate from the dorsocaudal part.26,27 The lateral nucleus also sends efferent ﬁbers bilaterally to the MLF, which connect with the various oculomotor nuclei. Based on its ﬁber connections, the lateral vestibular nucleus is an important station for control of vestibulospi- nal reﬂexes, particularly those involving the forelimbs.28

MEDIAL VESTIBULAR NUCLEUS

The medial vestibular nucleus is located beneath the ﬂoor of the fourth ventricle caudal to the superior nucleus and medial to the descending (inferior) nucleus (see Fig.1–7). In humans, it is the largest nucleus (about 10 mm in length and a total volume of about 30 mm3) with by far the greatest number of neurons (about 125,000).20,21 It consists of cells of many different sizes (12 to 33 µm in diameter) and shapes that lie rela- tively close together, embedded in a ﬁne mesh- work of very thin ﬁbers that course in almost all directions.8,10,18 It differs from the other nuclei in that it does not receive large-diameter ﬁbers.29 Anatomic separation from the superior nucleus is not well deﬁned. Neurons in the upper part of the nucleus receive afferent ﬁbers from the cristae of the semicircular canals as well as from the fastigial nucleus and ﬂocculus of the cerebellum. Saccular and utricular affer- ents project to the medial lateral section of the nucleus.2,5,7 The caudal part receives its main afferents from the cerebellum (the ipsilateral and contralateral fastigial nucleus and the ipsi- lateral nodule). Other afferent contributions include a large projection from the contralat- eral medial vestibular nucleus and a small projection from the reticular formation.

Efferent connections from the medial nuclei run in the descending MLF to the cervical and thoracic spinal levels by way of the medial ves- tibulospinal tract (see Fig. 3–25). From the rostral area (receiving afferent input from the cristae), efferent ﬁbers pass to the ascending MLF bilaterally to reach the nuclei of the ocul- omotor nerves.30 Other efferents are distrib- uted to the vestibular cerebellum, the reticular formation, and the contralateral vestibular nuclei.18 Because of its projections in the MLF to extraocular muscles and the cervical cord, the medial vestibular nucleus appears to be an important center for coordinating eye, head, and neck movements.31 The prominent com- missural connections are probably important for the compensatory processes following peripheral vestibular lesions.

DESCENDING (INFERIOR) VESTIBULAR NUCLEUS

The descending, or inferior, vestibular nucleus is difﬁcult to differentiate anatomically from the adjacent medial vestibular nucleus. In humans, it has a length of about 8 mm with approximately 55,000 neurons.20,21 It consists of small and medium-sized cells with occasional giant cells.4,10,18 Projections from the labyrinth are restricted to the lateral side, with those from cristae extending more to the center and those from the macules to the periphery (utric- ular being more ventral, saccular–dorsal). Cerebellar afferents from the ﬂocculus, nod- ule, and uvula are scattered throughout the nucleus, intermingling with the vestibular afferents. Projections from other sources, including spinal afferents, are minimal. Most of the efferent ﬁbers from the descending nucleus pass to the cerebellum and to the reticular formation.28 Numerous commissural ﬁbers supply the contralateral superior, descending, medial, and lateral nuclei.8,32 The descending nucleus apparently integrates ves- tibular signals from the two sides with signals from the cerebellum and reticular formation.

INTERSTITIAL NUCLEUS OF THE VESTIBULAR NERVE

Of the small groups of cells associated with the vestibular nuclei (such as groups x, f, p, m, and others), the interstitial nucleus is most clearly deﬁned.4,10 It consists of small strands of

elongated cells, some as large as the giant cells of the lateral nucleus, interspersed between the root ﬁbers of the vestibular nerve near the brainstem entry zone. In the chinchilla, the interstitial nucleus receives numerous short afferent collaterals from the macules of the utricle (rostral) or saccule (caudal), but only a few from the cristae of the semicircular canals. Efferent projections from the interstitial nucleus enter the ascending MLF and may be important in mediating VOR.33

Neurotransmitters

Signal processing in the secondary vestibular neurons depends not only on anatomical con- nectivity but also on the type of synaptic recep- tors expressed and neurotransmitters released. At least eight neurotransmitters and four neu- ropeptides are involved.34–38 Among the major neurotransmitters, -aminobutyric acid (GABA), glutamate (glu), and glycine (gly) are believed to be the most important in both the synaptic input and output.37

All primary vestibular ﬁbers release gluta- mate, an excitatory neurotransmitter, at their synapses in the vestibular nuclei.39 Glycine acts as a cotransmitter in large-diameter ﬁbers. Most other neural inputs to the nuclei utilize terminals that express GABA immunoreactiv- ity, which suggests that they have an inhibitory inﬂuence upon vestibular nuclei neurons.39–41 The afferent excitatory action of glutamate on secondary vestibular neurons is mediated by both -amino-3-hydroxy-5-methyl-4- isoxasoleproprionic acid (AMPA) and N-methyl-d-aspartate (NMDA) glutamate receptors.42–44 In situ hybridization techniques found that all secondary vestibular neurons express the AMPA-selective receptor subunit GluR2 with the highest levels of expression in the giant Deiters’ cells.44 GABA receptors were found ubiquitously in the vestibular nuclei neurons by Lopez et al.41

Among the second-order vestibular neurons, most use glutamate as their excitatory37 and GABA as the inhibitory neuro- transmitter.36,39,40,45,46 In the chinchilla, the vestibular nuclei contain approximately 40,000 neurons—about 15,000 each in the medial and descending nuclei and the rest in the remain- ing nuclei. A large percentage of these neurons (about 60%) express glutamic acid

decarboxylase (GAD)—the enzyme used for synthesizing GABA—and consequently may act as inhibitory neurons.47 The distribution of neurons capable of releasing GABA (GAD+ neurons) among the four major vestibular nuclei is shown in Figure 3–2. Ninety percent of neurons < 7 µm in diameter are GAD- positive neurons, whereas 80% of neurons with a diameter >15 µm are GAD negative. Overall, it appears that most large neurons are excitatory and most small neurons are inhibitory.

Physiology

Vestibular signals originating in the two laby- rinths ﬁrst interact with signals from other sen- sory systems at the neurons of the vestibular nuclei.32 Only a fraction of the neurons receive direct vestibular connections and, with the exception of the interstitial nucleus of the ves- tibular nerve, the neurons that receive primary vestibular afferent ﬁbers also may receive affer- ents from the cervical area, the cerebellum, the reticular formation, the spinal cord, and the contralateral vestibular nuclei.31,48 Consequently, efferent signals from the ves- tibular nuclei reﬂect the interaction of these various afferent systems.49 For example, visual signals relayed through the cerebellar ﬂocculus to neurons in the superior and medial vestibu- lar nucleus modulate the activity of the VOR.50–54 Inputs from neck proprioceptors modulate the vestibulocollic reﬂexes.55 The cerebellum inﬂu- ences the vestibulospinal reﬂexes by means of connections between the vermis and the lateral and descending vestibular nuclei.56 Through connections with the reticular substance, ves- tibular neuron outﬂow interacts with descend- ing corticobulboreticular and reticulospinal signals.57

TYPES OF SECONDARY VESTIBULAR NEURONS

Following stimulation of the vestibular nerve with a single brief electric pulse, two different groups of secondary vestibular neurons have been identiﬁed on the basis of ﬁeld potentials produced in areas of the brain stem receiving vestibular inputs (Fig. 3–3).58–60 This ﬁeld potential consists of three components: an ini- tial positive–negative deﬂection from action

a b c

1.2

0.36

1.35

Figure 3–3. a Field potential recorded in the medial vestibular nucleus after electric stimulation of the ipsilateral ves- tibular nerve. N1 is generated by monosynaptic activated secondary vestibular neurons and N2 by multisynaptic activated neurons. b Response of a monosynaptic activated neuron N1 ﬁeld potential is not seen because of superposition of spikes. c Response of a multisynaptic activated neuron demonstrating spikes timed with N2 ﬁeld potential. Each recording is com- posed of about 20 superimposed traces. (Adapted from Precht W, Shimazu H. Functional connections of tonic and kinetic vestibular neurons with primary vestibular afferents. J Neurophysiol.1965;28: 1014.)

currents in the primary vestibular ﬁbers, a neg- ative deﬂection wave (N1) with a short latency of

<1.0 msec (generated by monosynaptically

activated secondary vestibular neurons and ﬁbers), and a delayed negative deﬂection (N2)

with a latency of about 2.5 msec (generated by

multisynaptically activated neurons and ﬁbers) (Fig. 3–3a). By carefully placing microelec- trodes in the vicinity of or inside secondary ves- tibular neurons and tailoring the electric stim- uli, it has been demonstrated that some neurons produce action potentials at the time of the extracellular N1 wave with latencies between

0.5 and 1.0 msec (Fig. 3–3b), suggesting

that they receive monosynaptic input. Other neurons produce delayed action potentials (Fig. 3–3c), which suggests that they might be activated through multisynaptic connections. Only about 75% of neurons are activated by nerve stimulation and approximately half of these are monosynaptically activated.58,60 All monosynaptic connections are ipsilateral and excitatory. Among the monosynaptically acti- vated neurons, about 37% respond to small electrical stimuli with very short latencies that activate only the thickest, most sensitive irreg- ular primary afferents.61 The rest of the neu- rons respond to larger electrical currents. This suggests that they receive a predominant input from thinner, regular afferents. This differen- tial input is at least in part reﬂected in the output of the secondary neurons with vestibulospinal neurons receiving more input from irregular afferents and vestibulo-ocular neurons receiv- ing more input from regular ﬁring afferents. However, it would be wrong to view secondary vestibular neurons as narrowly tuned channels, with each receiving only a single kind of pri- mary afferent input.61 Most vestibular nuclei neurons, even those predominantly related to regular and irregular afferents, receive a broad range of afferent inputs.

The second-order vestibular neurons can be divided into two groups: type I neurons, which are excited, and type II neurons, which are inhibited by ipsilateral head rotations.48,54,62,63 Type I neurons are also excited by electrical stimulation of the ipsilateral vestibular nerve. The physiological response of type I neurons is similar to that of primary vestibular afferents. Type II neurons respond to electrical stimula- tion of the contralateral vestibular nerve with greater latency than do type I neurons to ipsilat- eral stimulation. The physiological response of type II neurons is opposite that of type I neu- rons—that is, type II neuronal response is qualitatively similar to the response of primary afferent neurons innervating the contralateral ear. Among the type I neurons there are two groups (Fig. 3–4). One group activates the agonist motor neurons—for example, motor neurons innervating the lateral rectus of the opposite side and the medial rectus of the ipsi- lateral side for the horizontal semicircular canal reﬂex. These neurons are excitatory, that is, GAD-negative neurons, as illustrated in Figure 3–2. The second group of type I neurons inhib- its the antagonist muscles—for example, the ipsilateral lateral rectus and the contralateral medial rectus. These neurons are GAD posi- tive. Type II neurons are activated by type I neurons from the contralateral side.62 After destruction of the labyrinth, excitation of type II neurons by stimulation of the contralateral nerve inhibits neighboring type I neurons. Type II neurons are GAD positive, which is con-

sistent with their inhibitory action (Fig. 3–4).

In summary, during physiological rotatory stimulation of the horizontal semicircular canals, the central vestibular neurons on one side receive ampullopetal signals (increased ﬁring), while the neurons on the opposite side receive ampullofugal signals (decreased ﬁring). However, since excitatory type I neurons are

Right

Middle Line

Type II GAD+

Left

Horizontal Semicircular Canal

Scarpa’s Ganglion

Type I GAD–

Type I GAD+

Vestibular Nucleus

Rt MR Lt LR

Lt MR Rt LR

Rt MR Lt LR

Lt MR Rt LR

Oculomotor Neurons

Figure 3–4. Interrelation of type I and type II secondary vestibular neurons. Blue neurons are inhibitory and white neurons are excitatory. LR, lateral rectus; MR, medial rectus.

connected to inhibitory type II neurons of the opposite side, the excitatory type I neurons receive a combination of stimulation from the two ears, corresponding to the sum of the ampullopetal (excitatory signals) from the ipsi- lateral side and the inverted ampullofugal (dis- inhibitory) signal mediated by the type II (inhibitory) neurons (Fig. 3–4). Most of the cells in the vestibular nuclei also respond to visual stimulation.64,65 The main visual input to the vestibular neurons comes from the cerebel- lum, particularly the ﬂocculonodular lobe.52,53,66,67

INTRINSIC MEMBRANE PROPERTIES OF SECONDARY NEURONS

In most physiological studies, secondary ves- tibular neurons are identiﬁed either by their location within the know boundaries of the ves- tibular nuclei or by their activation by stimula- tion of the eighth nerve or some of its branches. Secondary neurons are most clearly identiﬁed in whole-brain preparations where the eighth nerve or nerves from individual canals or macules can be selectively stimulated. These preparations have been particularly useful for studying vestibulo-motor signal processing in central networks. By contrast, slice prepara- tions that are disconnected from most inputs and outputs have been particularly useful for studying membrane properties in individual neurons with the disadvantage that neurons

can only be identiﬁed as secondary vestibular neurons based on their location within the boundaries of the known vestibular nuclei.

Just as with primary vestibular neurons sec- ondary neurons can be classiﬁed as regular (tonic) and irregular (kinetic) based on their spontaneous ﬁring pattern.58 Spontaneous activity is probably due to a combination of intrinsic membrane properties of the second- ary vestibular neurons and excitatory and inhibitory input from primary afferents.68–71 Based on an average spontaneous ﬁring rate for secondary vestibular neurons of about 30 spikes/sec one can estimate that about half of the spontaneous rate is generated by intrinsic pacemaker activity and half by spontaneous primary afferent input since the spontaneous rate is reduced to 16 spikes/sec in alert animals that undergo bilateral labyrinthectomy.32,72

In vitro slice preparations from the medial vestibular nucleus of rat and guinea pig have allowed a classiﬁcation of secondary vestibular neurons based on action potential shapes and membrane properties (Table 3–1).68,73–75 Type A secondary neurons show a single deep after- phyperpolarization (AHP) after each action potential and a rectifying IA-like K+ current when

released from hyperpolarization (Fig. 3–5a). By

contrast, type B secondary neurons have an ini- tial fast AHP followed by a delayed slow AHP

and no IA-like rectiﬁcation (Fig. 3–5b). Also, type A neurons have wider action potentials than

type B neurons. Type A secondary neurons

Table 3–1 Functional classes of different secondary vestibular neurons identiﬁed in the rodent medial vestibular nucleus

Type A Neurons Type B Neurons

After-hyperpolarization Monophasic, large amplitude Biphasic, small amplitude A-like rectiﬁcation Strong Weak

Action Potential Broad Thin

Discharge regularity Regular Irregular

Dynamic response Mostly tonic Phasic-tonic

Major afferent inputs Thin afferents; no input from

ﬂocculus

Thin and thick afferents; some receive ﬂoccular input

predominantly receive input from thin primary afferents, have a regular spontaneous ﬁring rate, and have a wide linear range, whereas type B neurons receive input from thick and thin affer- ents, have an irregular spontaneous ﬁring rate, and have a relatively smaller linear range.32 It appears that type A neurons correspond to the tonic secondary neurons and type B neurons correspond to kinetic neurons in the earlier classiﬁcation of Shimazu and Precht.58

Potassium channels are critical for determin- ing resting potential, shaping action potentials, and controlling discharge regularity; prelimi- nary studies suggest that K+ channels have differential expression in type A and type B secondary vestibular neurons.32,74,75 As with primary vestibular neurons Ca2+-dependent K+ channels play a key role in shaping the AHP.76 Initial studies attempting to correlate physio- logical properties with neurochemistry indicate

that the majority of type A secondary neurons are GABAergic neurons, while type B neurons can be either GABAergic or glutamatergic.77

COMPENSATION AFTER LABYRINTHECTOMY

Knowledge of the different types of secondary vestibular neurons and their interconnecting pathways is important for understanding the sequence of recovery following a unilateral loss of labyrinthine function.78–80 On the basis of connections depicted in Figure 3–4 it can be anticipated that immediately after a labyrinth- ectomy, the ipsilateral type I neurons lose their spontaneous activity and become unresponsive to ipsilateral angular rotation due to excessive inhibitory activity arriving via commissural pathways. At the same time, contralateral healthy type I neurons lose their inhibitory

a b c

Type A MVN neuron

20 mV

50 ms

Type B MVN neuron

Spike threshold

Contralesional side Control

Ipsilesional side

5 mV

2 ms

Figure 3–5. Changes in spike proﬁles of guinea pig medial vestibular nucleus (MVN) neurons after unilateral labyrinth-

ectomy. A: typical spikes of a type A MVN neuron a with a monophasic after-hyperpolarization (AHP; arrow) and a type B MVN neuron b with a biphasic AHP (double arrow) recorded on the contralesional side of slices taken one month post-lesion; superposition at spike threshold of averaged spikes of type B MVN neurons at the resting membrane potential c recorded in control slices and from the ipsi- and contralesional sides of slices taken one month after the lesion. All neurons were identiﬁed as type B MVN neurons by the presence of the biphasic AHP at hyperpolarized membrane potentials. Note the inverse changes in the amplitude of the AHP of spikes recorded on the two sides. (From Straka H, Vibert N, Vidal PP, Moore LE, Dutia MB. Intrinsic membrane properties of vertebrate vestibular neurons: function, development and plasticity. Prog Neurobiol. 2005;76:349, with permission.)

contralateral input, and their spontaneous activity increases in comparison to normal levels.81 Contralateral type II neurons lose their inputs from deafferented excitatory type I neu- rons and cannot be identiﬁed electrophysiolog- ically. Speciﬁcally, an imbalance in the muscle tone takes place, resulting in the signs of laby- rinthectomy—spontaneous nystagmus, yaw and roll tilt of the head, asymmetric tone in extensor muscles, and falling toward the side of the lesion.

A few days after a labyrinthectomy, the pre- viously silent type I neurons on the damaged side recover their spontaneous activity and begin to respond to physiologic stimulation of the contralateral labyrinth,82–84 as a result of their connections with ipsilateral type II neu- rons. These reactivated type I units are inhib- ited when the type I neurons on the healthy side are excited and are disinhibited when the contralateral type I neurons are inhibited. The recovery of sensitivity in the ipsilateral type I neurons after a labyrinthectomy parallels the time course of or improvement in clinical symptoms and signs. Experimental studies in rodents conﬁrm that immediately after a uni- lateral labyrinthectomy there is a marked increase in GABA release in the ipsilesional vestibular nucleus that is not prevented by bilateral ﬂocculectomy, indicating that it is due to hyperactivity of the inhibitory commissural pathway.85 With vestibular compensation and recovery of vestibular symptoms and signs, the elevated GABA levels on the ipsilesional side return toward normal levels.86 At the same time there is a downregulation of GABA receptor efﬁcacy, decreasing the response to commis- sural inhibitory drive.‌

The return toward normal spontaneous ﬁr- ing in secondary neurons after labyrinthectomy is associated with changes in both active and passive membrane properties.87–90 Overall the resting membrane properties of secondary neurons on the ipsilesional side shift toward type A-like properties and those on the contral- esional side shift toward type B-like properties (Fig. 3–5c). The AHP and discharge regularity of type B neurons on the ipsilesional side are selectively augmented, while the reverse occurs on the contralateral side.91,92 These changes result from changes in expression of a variety of genes and proteins that determine each cell type.32 On average, secondary neurons on the ipsilesional side develop a more regular

spontaneous ﬁring rate with tonic dynamics, whereas those on the contralesional side have a more irregular spontaneous rate with phasic dynamics. The result is a switch from the balanced “push-pull” mode in the normal con- dition to a state where the ipsilesional side provides more tonic activity in vestibular cir- cuits while the contralesional side provides more of the dynamic responses.32

After labyrinthectomy, in parallel with the changes in membrane properties, there is a reorganization of synaptic inputs onto the deaf- ferented secondary neurons, changes in synap- tic sensitivity to neurotransmitters, and changes in vestibular neuronal networks.80,89,91,92 Similar lesion-induced plasticity is seen in other sen- sory systems and appears to be a general reac- tion pattern to injury, the so-called distributed process described by Llinas and Walton.32,93 Triggers for the plastic changes after unilateral labyrinthectomy are not entirely clear. Intracellular messenger systems are activated to initiate the gene/protein changes required for the compensation process.94 The transcrip- tion factor c-Fos is activated in secondary neu- rons on both sides and could be a trigger for changes in expression of channel proteins and transmitter receptor subtypes.95–97 There is an increased expression of the transmembrane phosphoprotein GAP-43, known to be involved in growth, regeneration, and remodeling of neuronal pathways.98 The neurotrophic factor BDNF is transiently expressed in some sec- ondary vestibular neurons after labyrinthec- tomy and mutant mice deﬁcient in BDNF have impaired vestibular compensation.99 Increases in intracellular Ca2+ concentration seen in sec- ondary vestibular neurons after labyrinthec- tomy might be a link between changes in genetic regulation and changes in membrane and discharge properties.32

VESTIBULO-OCULAR REFLEXES

Overview

All sensorimotor reﬂexes have a reference frame for coding spatial information.100 The vestibular receptors are ﬁxed in the head so they have a head-centered reference frame. They provide no information about how the head moves relative to the body or how the

outside world moves relative to the head. For this the brain must rely on information from the somatosensory and visual systems each with their own reference frame. Coordinating head, eye, and body movements requires transforma- tions so that signals from the different systems can interact appropriately. For example, by combining head-centered vestibular signals with neck proprioceptive information that sig- nals the static position of the head relative to the body, head-centered motion signals are transformed into a body-centered reference frame. Whether it is necessary for the brain to bring all sensory information into a common reference frame or whether separate reference frames can be maintained even at the highest level of integration is still debated.101

The inner ear does provide information in a world-reference frame generated by the gravi- ty-sensing otolith organs. As will be seen later, the velocity storage system uses this informa- tion to align the low-frequency rotational VOR with gravity. Angular velocity from the semicir- cular canals is combined with gravitational information from the otoliths into two compo- nents, one parallel to gravity and the other perpendicular to gravity.102,103

As noted earlier, the otolith organs detect net linear acceleration but do not distinguish between translational movements and gravity, the so-called tilt-translation ambiguity. One solution to the tilt-translation ambiguity is to frequency ﬁlter the otolith signals such that low-frequency otolith components are inter- preted as gravitational acceleration and high- frequency components are interpreted as inertial accelerations.104 Another solution is convergence of canal and otolith signals begin- ning at the vestibular nuclei.105,106 Unlike pri- mary afferent neurons that ﬁre the same regardless of the type of linear acceleration, many secondary neurons ﬁre selectively for translational motion and are relatively silent during changes in head position relative to gravity (Fig. 3–6). These translational sensitive neurons are not only found in the vestibular nuclei but also in the cerebellum, particularly in areas that receive primary vestibular affer- ents. The translation-only secondary neurons disappear after canal plugging, proving that they result from convergence of canal and otolith signals. The tilt-translation ambiguity is not always resolved at the perceptual level, however, because the canals do not provide a

reliable estimate of angular velocity at very low frequencies (<0.1 Hz).107,108 It was the illusion of tilt experienced when riding a curve in the railroad line that lead Mach to postulate a “sixth sense” for the perception of acceleration in the head. Somatogravic and oculogravic illusions commonly occur during airplane landings and takeoffs due to the tilt-translation ambiguity. Extravestibular signals are required to avoid these illusions.

The brain must also differentiate between self-generated and externally applied move- ments. Primary afferents ﬁre the same regard- less of whether the movement is active or pas- sive. A common strategy for solving this problem is the principle of reafference—a copy of the expected sensory result of a motor com- mand is subtracted from the sensory signal.109 This principle has been well studied in mechanosensory systems of primitive animals where self-generated behaviors are selectively suppressed in central neurons.

Rotational Vestibulo-Ocular Reﬂexes

The basic organization of the rotational VOR in the horizontal plane is shown in Figure 3–4. Type I secondary neurons make direct contact with oculomotor neurons and provide axon col- laterals to other secondary neurons and to the cerebellum (not shown).110 Commissural con- nections connect the two sides. These and other feedback pathways form the velocity stor- age system, which allows signals from different vestibular receptors and other sensory systems to interact with vestibular signals while sustain- ing the activity in the vestibular nuclei beyond the time of arrival of the primary afferent signal.111

The effect of velocity storage is graphically illustrated in Figure 3–7 (see also Fig. 1–5). After an impulse of head acceleration, the time constant (TCOR) of the oculomotor response is

prolonged beyond that of the primary afferent

response (T1) because of feedback onto the secondary vestibular neurons. Quantitatively, the

positive feedback loops perform the equivalent of a partial mathematical integration on the primary afferent signal.112 The interneurons in these feedback pathways can be viewed as valves con- trolling the spontaneous activity and dynamic properties of the secondary vestibular neurons.

Translation only net accel: 0.2 g

Roll tilt only net accel: 0.2 g

Roll tilt-translation net accel: 0 g

Roll tilt + translation net accel: 0.4 g

Otolith afferent

IFR

Htrans

100 sp s–1

20 cm

Hroll

12º

Vestibular nucleus neuron

IFR

Htrans

100 sp s–1

20 cm

Hroll

12º

Figure 3–6. Instantaneous ﬁring rate (IFR) from a primary otolith afferent (top) that encodes net linear acceleration, and a central vestibular nucleus neuron (bottom) that encodes translational motion during four movement protocols: Translation only, Tilt only, Tilt – Translation and Tilt + Translation (0.5 Hz). The stimulus (bottom) traces show sled position (Htran) and roll tilt position (Hroll). (From Angelaki DE, Cullen KE. Vestibular system: the many facets of a multimodal sense. Annu Rev Neurosci. 2008;31:125, with permission.)

Velocity storage

Canal

signal 

TCOR

to EOM’s

Figure 3–7. Prolongation of the dominant time constant of the canal ocular reﬂex (TCOR) by velocity storage within the feedback pathways shown in Figure 3–4. A step change in head angular velocity occurred at time 0 (vertical arrows). T1 represents the long time constant of the cupula measured from the average response of primary afferent neurons. EOM, extra ocular muscle.

From the above-described experimental data and model simulations, the rotational VOR is thought to be mediated by two components: a rapid, or “direct,” and a slow “indirect,” or “velocity storage,” pathway.111 The three- neuron chain that conveys neural signals from the labyrinth to the motor neurons of the extraocular muscles constitutes the direct path- way. It has been modeled as a direct pathway because it does not substantially alter the dynamics of the semicircular canal responses transferred to the eye muscles. The indirect VOR pathway also receives semicircular canal input, but it has slow charge and discharge time constants. It holds, or “stores,” activity from the vestibular periphery and discharges it over a more prolonged time span, thus the term “velocity storage” and the designation “indi- rect” in models of the VOR. Commissural path- ways between the two vestibular nuclei are involved in both direct and indirect pathways, but the ﬁbers appear to cross at different lev- els.113 In monkeys, an experimental midline section of rostral medullary commissural ﬁbers abolishes oculomotor and vestibular functions attributable to velocity storage, whereas the direct VOR pathway remains intact.113 Utrastructural studies after such lesions indi- cate that the commissural neurons related to velocity storage are located in the lateral cres- cents of the rostral medial vestibular nucleus. Immunohistochemical staining of the neurons in this portion of the medial vestibular nucleus in monkeys identiﬁed at least two types of GABAergic neurons: neurons related to the velocity storage pathway and vestibular interneurons.114 A variety of GABAergic bouton endings was also identiﬁed in this region of the medial vestibular nucleus: type A boutons cor- responding to Purkinje cell afferents, type B

terminals from axons of GABAergic medial ves- tibular neurons, and type C boutons originating from the vestibular commissural pathway of velocity storage.115

SEMICIRCULAR CANAL–OCULAR CONNECTIONS

Detailed information about the connections that link vestibular receptors and different eye muscles was initially obtained by recording the eye muscle response following either physiologic or electric stimulation of each receptor.116–118 By measuring the muscle tonus, the excitatory or inhibitory nature of each connection was established. Table 3–2 summarizes the primary excitatory and inhibitory connections of each semicircular canal with the muscles of both eyes.117 Note that each semicircular canal is connected to the eye muscles in such a way that stimulation of the canal nerve results in eye movement approximately in the plane of that canal. For example, stimulation of the left posterior canal nerve causes excitation of the ipsilateral superior oblique and the contralat- eral inferior rectus muscles while inhibiting the ipsilateral inferior oblique and the contralateral superior rectus. An oblique downward move- ment in the plane of the left posterior canal is the end result. As suggested in Chapters 1 and 2, the spontaneous activity of neurons in each canal leads to a resting level of contraction at each eye muscle from all the labyrinthine organs and provides an important background upon which these more speciﬁc reﬂexes act.116 By systematically recording responses in different vestibular and oculomotor nuclei after selective stimulation of each semicircular canal, it has been possible to trace the main disynaptic excitatory and inhibitory pathways

Table 3–2 Connections of the Semicircular Canals with Muscles of the Eyes

Semicircular Canal	Excitation	Inhibition
Horizontal	I–MR C–LR	C–MR I–LR
Posterior	I–SO C–IR	I–IO C–SR
Anterior	I–SR C–IO	I–IR C–SO

C, contralateral; I, ipsilateral; IO, inferior oblique; IR, inferior rectus; LR, lateral rectus; MR, medial rectus; SO, superior oblique; SR, superior rectus.

connecting the semicircular canals with the extraocular muscles, as shown in Figure 3–8 and Table 3–2.117,119,120 As a general rule, excitatory connections run in the contralateral MLF and inhibitory connections run in the ipsilateral MLF.121

Each muscle receives an excitatory input originating from the ampullopetally activated canal and a disinhibiting input from the ampull- ofugally activated canal pair on the opposite side operating in reciprocity. For example, the right medial rectus receives an excitatory input from the right horizontal semicircular canal via the ipsilateral type I excitatory (GAD-negative) neurons and a disinhibition input mediated through the contralateral type I (GAD-positive) neurons (see Fig. 3–4). Consequently, during clockwise rotation, the muscle will experience an increase in the excitatory input from the ampullopetally activated canal (right horizontal semicircular canal [Rt HSC]) and a decrease in the inhibitory signal from the ampullofugally

activated canal (Lt HSC). This push–pull organization provides more stability to the reﬂexes and improves the dynamic linear range of the system. The muscles are in a constant state of tension and respond to minimal modulation of activity of the peripheral organs.

The connections illustrated in Table 3–2 are only part of the picture, however. Since the planes of the semicircular canals are not exactly aligned with the planes of the three pairs of eye muscles, a spatial transformation from canal to muscle coordinates must occur if eye move- ments are to compensate for head movements. In other words, it is not adequate to simply connect afferents from a single canal to a set of eye muscles as shown in Figure 3–8; other con- nections must also exist. Studies of labeled sec- ondary vestibular neurons, identiﬁed as part of the canal ocular reﬂex, indicate that the spatial transformations occur through both a conver- gence of signals at the level of the vestibular

a b c

SR MR LR SO

III IO

ATD

MLF

IR III

LR MR

VN PC

Figure 3–8. Excitatory (a, b, c) and inhibitory (d, e, f) pathways between the individual semicircular canals and eye muscles in the cat.96,97 AC, anterior canal; ATD, ascending tract of Dieters; HC, horizontal canal; III, oculomotor complex; IO, inferior oblique; IR, inferior rectus; IV, cochlear nucleus; L, lateral nucleus; M, medial nucleus; D, descending nucleus; LR, lateral rectus; MLF, medial longitudinal fasciculus; MR, medial rectus; PC, posterior canal; S, superior nucleus; SO, superior oblique; SR, superior rectus; VI, abducens nucleus; VN, vestibular nuclei.

nuclei and a divergence of signals at the level of the oculomotor nuclei.122,123

COMPENSATORY EYE MOVEMENTS

The semicircular canal–ocular reﬂexes produce eye movements that compensate for head rota- tions. Angular and sinusoidal head rotation of small amplitude within the frequency range of natural head movements (0.1 to 4.0 Hz) results in compensatory sinusoidal eye movement ampli- tudes that are 180 degrees out of phase with the head (i.e., eye movements in the opposite direc- tion as the head movement) (as illustrated in Fig. 1–12a, b). The various transformations involved in this process are illustrated in Figure 3–9. The natural stimulus for the semicir- cular canals is head angular acceleration, as shown in Figure 3–9b. During sinusoidal rota- tion, at the frequencies of natural head move- ments, the viscoelastic properties of the canal– cupula complex (as deﬁned by the pendulum model in Chapter 2) produce the equivalent of one step of mathematical integration (a 90-degree phase shift) so that the vestibular nerve ﬁring rate (Fig. 3–9e) is in phase with head

velocity (Fig. 3–9c) rather than head acceleration (Fig. 3–9b). But the normal reﬂex response pro- duces a compensatory eye movement amplitude that is equal and opposite to the amplitude of the head movement (compare a and g in Fig. 3–9). This eye movement results from activation of, among others, the abducens nerve to the left lat- eral rectus muscle (Fig. 3–9f) during ampullo- petal stimulation of the right cupula–vestibular nerve (Fig. 3–9d, e). However, the timing of the recorded activity in the abducens nerve lags behind the activity in the vestibular nerve by an additional 90-degree delay. This raises a key question ﬁrst asked by Skavinski and Robinson: what produces the phase shift (i.e., increase from 90 degrees to 180 degrees) between the ﬁring rates of the vestibular nerve and abducens nerve (between Fig. 3–9e and Fig. 3–9f)?124 To answer this question, they introduced the concept of an oculomotor integrator, a hypothetical neural net- work that integrates, in a mathematical sense, velocity-coded signals, such as those originating in the vestibular end-organ, to position-coded signals required by the oculomotor neurons. Although the concept of neural integration is now generally accepted, the speciﬁcs are

R a

+ b

–

center d

spikes/sec

baseline

R g

Head position

Head acceleration

Head velocity

Right cupula displacement

Right vestibular nerve firing

Left abducens nerve firing rate

Left eye position

Figure 3–9. Mechanism by which sinusoidal change in head position (a) is converted to an equal and opposite-eye position (g). R, right; L, left; Af, ampullofugal (i.e., away from the ampulla); Ap, ampullopetal (i.e., toward the ampulla). See text for details.

still debated. Some investigators feel it is “local- ized” in a region of the brain stem125,126 or cere- bellum,127 whereas others consider it a “distrib- uted property” of the feedback pathways shown in Figure 3–4. Mathematical models show how these feedback pathways, particularly those via the commissural connections, can produce the necessary integration.128,129

Although the VOR operates as an effective integrating angular accelerometer for frequen- cies >0.1 Hz, at lower frequencies the VOR is progressively less effective, which is manifest by a phase lead of eye velocity relative to head velocity, reaching a maximum of 90 degrees at about 0.001 Hz. Velocity storage within the central VOR feedback pathways improves the low-frequency gain and phase deﬁcit of incom- ing primary afferent signals but does not cor- rect it completely. As will be shown later, this low-frequency gain and phase deﬁcit of the VOR is of little functional signiﬁcance, since natural head movements combine visual and vestibular stimulation and the combination of visuovestibulo-ocular responses results in essentially perfect compensation, even at the lowest frequencies. However, the low- frequency phase shift does have important implications for clinical testing since an increase in the low-frequency phase two-standard devi- ations above the mean normal value is a non- speciﬁc sign of damage to the canal-ocular reﬂexes (see Chapter 7).

In summary, the rotational VOR involves the activity of many nuclei and a countless number of neurons whose group behavior may differ from that of the isolated units. One must keep this complexity in mind when attempting to evaluate the effects of lesions on VOR activity. It is often impossible to interpret the results of vestibular tests in terms of deﬁcits in a single neural pathway.

NEURONAL MECHANISMS

Based on recordings from the vestibular nuclei in animals three groups of secondary vestibular neurons likely provide the main premotor drive for the rotational VOR: (1) position-ves- tibular pause (PVP) neurons, (2) eye-head (EH) neurons, and (3) burst tonic (BT) neurons.130–132 PVP neurons modulate their ﬁring rate during visual suppression of the VOR and during smooth pursuit and stop ﬁring during saccades. Their response to angular

head velocity and eye velocity is in the opposite direction so that the signals are complimentary during visualization of an earth-ﬁxed target. EH neurons also modulate their ﬁring rate during both smooth pursuit and vestibular sup- pression but in the opposite direction of PVP neurons such that the two signals oppose each other during visualization of an earth-ﬁxed tar- get. BT neurons do not modulate their activity during vestibular suppression, but their ﬁring rate is strongly correlated with all types of eye movements. Based on these features it appears that BT neurons carry a fully transformed motor signal, whereas PVP and EH neurons carry signals with intermediate features in the transformation of sensory input from the semi- circular canals to motor signals required by the oculomotor neurons.

The relationship between the ﬁring rate of oculomotor neurons and the movements of the eyes during each phase of nystagmus has been studied extensively. During the production of an agonist slow component, the membrane potential is slowly depolarized by excitatory postsynaptic potentials arriving via the vestibulo- ocular pathways discussed in the previous sections.133,134 Toward the end of the slow com- ponent, the membrane potential rapidly becomes hyperpolarized and the motoneuron abruptly terminates its discharge. This hyper- polarization is produced by inhibitory activity of a group of neurons different from those producing the slow component.

Figure 3–10 illustrates the ﬁring rate of a single right abducens nerve ﬁber during sinu- soidal angular rotation at three different mag- nitudes.135 The concurrent nystagmus of the left eye is shown above each ﬁring record. With slow components to the right, the right abducens nerve innervates an agonist muscle, and a steady increase in nerve ﬁring occurs that is roughly proportional to the eye displace- ment. Just before initiation of the fast compo- nent in the opposite direction (to the left), the ﬁring of the right abducens nerve suddenly decreases and, in many instances, stops com- pletely. During the subsequent slow compo- nent, the nerve ﬁber remains silent until the eye reaches a position in the orbit that is above threshold for this particular abducens neuron. With slow components to the left, an abrupt increase in ﬁring rate occurs just before the onset of the fast component, followed by a slow decrease during the slow components.

Whereas the change in nerve ﬁring rate during the slow component bears a close relationship to the change in eye position, during the fast component a much larger increase in action potentials occurs per unit of time.

Measurement of the relationship between motoneuron ﬁring rates and eye movement induced by vestibular or visual stimuli has shown that the motoneurons behave the same regardless of the nature of the stimulus.136 Almost all oculomotor neurons exhibit a thresh- old above which they increase their ﬁring rate roughly in proportion to the change in eye posi- tion in the orbit. A small percentage of the change in ﬁring rate (approximately 20%) is proportional to the velocity of the eye move- ment. It is as though the ﬁring rate of the ocul- omotor neurons were designed to overcome the elastic and viscous forces (roughly in a ratio of 5 to 1) restraining the eye in the orbit. This relationship can best be appreciated by exam- ining the rate of ﬁring of an oculomotor neuron associated with a visually induced reﬁxation saccade (Fig. 3–10d), where the goal is to move the eyes as rapidly as possible from one posi- tion in the orbit to another and to maintain the new position once it is reached. During the high-velocity saccade, the oculomotor neu- ron increases its ﬁring rate to a high level to compensate for the viscous drag of the eye

ligaments.137 Once the new position is reached, a much lower rate of discharge produces com- pensation for the elastic restraining force and maintains the new position. Although the reﬂex pathways for vestibular and visually induced eye movements involve different neuronal cir- cuits, the motoneurons governing the extrinsic eye muscles ﬁre in the same manner regardless of the original sensory input.

FAST COMPONENT GENERATION

As noted in Chapter 1, neurons in the parame- dian pontine reticular formation (PPRF) ﬁre in short bursts just before the onset of horizontal fast components and voluntary saccades.138–140 Fast eye movements, whether voluntary or involuntary, apparently are generated by a common neuronal mechanism.138,141 The PPRF is not a discrete anatomic structure but rather a region that has been designated as such because ofitsapparentfunctionalspeciﬁcity. Stimulation in the PPRF produces ipsilateral slow and rapid eye movements, depending on the stimulus variables.139,140 The latency of induced eye movements suggests that one or two synapses lie between the pontine neurons and the oculomotor neurons. Anatomic pathways between this area of the reticular formation and the eye muscle motor nuclei were

100

0 10 20 30

Seconds

Figure 3–10. Right abducens motoneuron activity during induced nystagmus in the cat. In each pair of traces, the top trace represents the electrooculographic recording of eye movement and the bottom trace, the motoneuron ﬁring fre- quency, (a–c) The animal was rotated at the frequency of 0.1 Hz at peak velocities of 30°, 60°, and 120°/sec, respectively,

Spontaneous eye movements (saccades).
ﬁrst reported by Lorente de Nó110 and subse- quently conﬁrmed by other investigators.140 Numerous documented anatomic pathways also interconnect the vestibular nuclei with the PPRF.140,142

PATTERN OF EYE MOTION
Intuitively one might assume that the slow phases of nystagmus deviate the eyes toward the periphery of the orbit and the fast compo- nents reset them back to the center. Indeed, this pattern occurs in the rabbit (see Fig. 1–12 in Chapter 1). In animals with more developed visual oculomotor function, however, the fast components act as anticipatory movements taking the eyes toward the periphery.143 The fast components of the initial beats of nystag- mus are larger than the preceding slow compo- nents, and the eyes deviate in the direction of the fast component (see Fig. 7–19a, b, and c in Chapter 7). In humans, the exact threshold position for the generation of a saccade varies with the velocity of the slow component of nystagmus, but it is usually near the mid- position.144 The apparent advantage of this strategy is that the eyes are ready to focus on newly arriving targets in the ﬁeld of rotation, and ﬁxation can be maintained during the subsequent slow component.

EFFECT OF EXPERIMENTAL LESIONS
Spontaneous vestibular nystagmus is produced by lesions of the labyrinth, the vestibular nerve, and the vestibular nuclei.118,145 A key ingredient for the production of spontaneous nystagmus is an imbalance of tonic activity within the vestibulo-ocular pathways. If a pro- cess simultaneously removes both labyrinths, spontaneous nystagmus does not result, dem- onstrating that, for production of nystagmus, the relative balance of input is more important than the absolute magnitude of input. Spontaneous nystagmus produced by section- ing of the vestibular nerve duplicates that resulting from labyrinthectomy. The slow com- ponent is directed toward the side of the lesion. The direction of spontaneous nystagmus asso- ciated with lesions of the vestibular nuclei, however, is less predictable and depends on the location and extent of the lesion. Typically, the slow phase of nystagmus is contralateral to lesions in the superior and rostral medial
nuclei and ipsilateral to lesions in the lateral and caudal medial nuclei. The imbalance between inhibitory and excitatory secondary vestibular neurons undoubtedly determines the direction of spontaneous nystagmus.
Lesions involving the vestibulo-ocular path- ways in animals may affect either the slow or the fast component and occasionally both phases of induced nystagmus. Interruption of the connec- tions linking the semicircular canals to the oculo- motor neurons decreases the velocity of the slow components of induced nystagmus. Lesions involving the peripheral vestibular structures (end organ and nerve) affect the nystagmus in both eyes equally, since the central pathways are symmetrically connected. A single remaining labyrinth senses angular rotation in both direc- tions and produces conjugate nystagmus in both directions. The maximum slow component veloc- ity of induced nystagmus may be asymmetric, however, because of the asymmetry in afferent nerve ﬁring rate produced by ampullopetal and ampullofugal endolymph ﬂow. Central lesions lying anywhere from the vestibular nuclei to the oculomotor neurons often produce disconjugate nystagmus, since the pathways to the eye muscles diverge beginning at the vestibular nuclei.146 A lesion of the MLF, for example, impairs slow and fast components made by the ipsilateral medial rectus muscle but leaves normal slow and fast components at the contralateral lateral rectus (see Fig. 7–29d in Chapter 7).
The proposed role of the PPRF in the pro- duction of rapid horizontal eye movements is supported by the results of experimental lesions in several species of animals. Animals with uni- lateral lesions of the PPRF lose all types of rapid ipsilateral eye movement, and the eyes move into the contralateral hemiﬁeld.147,148 Ipsilateral voluntary saccades and quick phases of vestibular and optokinetic nystagmus are affected equally. Stimuli that normally would produce nystagmus with ipsilateral fast compo- nents simply cause a strong tonic contralateral deviation of the eyes (see Fig. 7–29c in Chapter 7). By contrast, vestibular stimuli that produce contralateral fast components result in normal nystagmus, that is, ipsilateral slow phases that are normal. Lesions in the pretectal region have a similar effect on vertical rapid eye movements without affecting horizontal eye movements,149,150 an effect consistent with the separate neural organization of horizontal and vertical saccades.
LEVEL OF AROUSAL AND HABITUATION
Since the turn of the twentieth century, numer- ous investigators have noted a relationship between the magnitude of induced nystagmus and the state of arousal of the animals or human subjects receiving vestibular stimulation.151 In animal studies, amphetamines are routinely used to maintain alertness. During rotational and caloric testing in human subjects the veloc- ity of the slow components of induced nystag- mus depends on the type of mental activity.152 If subjects are instructed to relax and daydream, the velocity is less than when they are instructed to perform continuous mental arithmetic (suc- cessive division). Although other techniques of mental alerting, such as having the subject report on the turning sensation or estimate the time of auditory stimuli, are also effective, men- tal arithmetic tasks are most effective in main- taining mental alertness. The mental task has to achieve a certain degree of complexity since simple forward-counting may not be effective in maintaining the nystagmus response.151
If a normal subject is continuously rotated at low sinusoidal frequencies in the dark, there is a gradual decrease in gain and an increase in the phase lead of eye velocity relative to head velocity (so-called habituation).153,154 The effect peaks in about an hour and can persist for days. Presumably, with habituation, there is a gradual decrease in velocity storage within the multi- neural pathways, illustrated in Figure 3–7, shifting the low-frequency response of the canal-ocular reﬂex toward that of the primary afferent signal (i.e., the VOR time constant decreases toward that of the cupula). Since a caloric stimulus is equivalent to a very low- frequency rotational stimulus (approx- imately 0.002–0.004 Hz), habituation with repeated caloric testing is explained on a similar basis. Alerting techniques (including stimulant drugs) may work by activating the multineural feedback pathways and thereby improving the low-frequency response of the canal–ocular reﬂex.

SUMMARY
Several basic principles underlie the connec- tions between the semicircular canals and eye muscles. First, a receptor organ is connected to a group of motoneurons whose activity
produces an eye muscle contraction that com- pensates for a speciﬁc head movement with the objective of maintaining gaze stability. Second, null spots do not exist in the receptive ﬁeld of the semicircular canals because the organs in each ear form a complementary set of accel- eration sensors capable of reacting to the indi- vidual components of angular acceleration associated with head movement in any direc- tion in three-dimensional space. Third, each receptor organ simultaneously activates an excitatory and an inhibitory pathway to agonist and antagonist muscles, resulting in a push– pull system of control. Fourth, most natural head movements activate several receptors simultaneously and inputs from multiple recep- tors converge on secondary neurons. Fifth, alternate pathways complement the elemen- tary disynaptic connections. These pathways consist of chains of interneurons that form reverberating circuits by means of which dif- ferent reﬂexes interact and “ﬁne-tune” the more speciﬁc end-organ reﬂexes. Finally, it is becoming evident that, because of multisen- sory interactions and neurochemical weights, the strength and even the speciﬁcity of the reactions from these pathways can be physiologically modulated.

Translational Vestibulo-Ocular Reﬂex
OVERVIEW
Sensory cells of each macule are oriented along either side of an equatorial boundary created by the striola, as shown earlier. The orientation of the cells in multiple directions in each mac- ule is different from that in the cristae. All the sensory cells of a semicircular canal are aligned in the same direction and are either excited or inhibited by a stimulus acting in the plane of the canal. The study of the otolith-ocular reﬂexes is, therefore, more complex than that of canal–ocular reﬂexes and also technically more difﬁcult.155
To simplify the discussion of otolith-ocular reﬂexes, it has been traditional to consider the otolith organs (utriculus and sacculus combined) as a unitary sensor capable of resolv- ing all of the linear forces acting on the head into a single resultant vector force. This “uni- tary” three-dimensional otolith receptor is
positioned at the center of the head with the x- and y-axes orthogonal to and the z-axis paral- lel to the earth’s vertical axis. The receptor computes the angle () between the resultant vector force and the earth’s vertical axis and sends this information to the central nervous system (CNS), where a compensatory eye devi- ation is generated with the goal of maintaining the eyes at normal orientation to the earth’s vertical axis. The perfect macular reﬂex would be one that rotates the eyes at an angle equal and opposite to . In the case of head tilt in the sagittal plane, as illustrated in Figure 3–11, the efﬁciency or gain of the reﬂex can be represented by the relation of the angle of eye deviation to the angle of head tilt  (gain equals /).
Following this simple model of otolith func- tion, one would predict that linear acceleration along the occipitonasal axis (y-axis) would result in vertical eye movements and linear acceleration along the interaural axis (x-axis), in torsional eye movements (just as lateral tilt produces ocular counterrolling). However, lin- ear acceleration in the occipitonasal axis pro- duces minimal vertical eye movements, and acceleration along the interaural axis induces predominantly horizontal eye movements.155,156 This is reasonable from a functional point of view, since the logical function of the reﬂex is to augment visual pursuit during linear dis- placement of the head (analogous to the role of the canal-ocular reﬂex during angular displace- ment of the head).157 Lateral head movements require horizontal, not torsional, eye move- ments to maintain ﬁxation on an earth-ﬁxed
target. Similarly, with fore–aft movements, vertical eye movements would impair rather than improve ﬁxation on an earth-ﬁxed target in the axis of movement.
Furthermore, the translational VOR can only stabilize images on one area of the retina. Consider the circumstances one experiences when walking straight ahead. Objects in the periphery of the visual ﬁeld appear to move faster than those on the fovea and objects move in different directions based on their location within the visual ﬁeld. The amplitude and direction of the translational VOR is designed to minimize image slip on the fovea.
As noted earlier, most natural head move- ments are composed of a combination of linear and angular displacements so that the canal- and otolith-ocular reﬂexes must work together to ensure steady ﬁxation. There is an important difference, however, between the geometry of target displacement during angular and linear accelerations. With the latter, the angle of the required compensatory eye movement increases as the target moves closer to the subject. A simple model of canal-otolith-ocular reﬂex interaction during horizontal head movements assumes the gain of the canal- ocular reﬂex is ﬁxed while the otolith-ocular reﬂex gain increases with decreasing target distance.158 This simple model ignores interoc- ular spacing and the separation of the vestibu- lar organs from the eyes (i.e., it assumes a central cyclopean eye), but this is not a major problem as long as the target distance is greater than a meter. With this model, if the head rotates with angular velocity A and translates
1. (b) (c)
  
  a
  
  q
  a Fg
  Fg
  Ft
  q
  F´g
  
  Figure 3–11. Compensatory eye movement induced by static head tilt (b) and by linear acceleration tangential (Ft) to the “unitary” otolith receptor (c);  = the angle of eye rotation and  = the angle between the resultant force of gravity (Fg) and a line orthogonal to the receptor.
  with linear velocity T, then the eye angular velocity  = −A − KT, where K inversely depends on target distance. Studies in primates includ- ing humans found that the magnitude of induced eye movements measured during combined linear and angular accelerations (by varying the radius of head rotation) was depen- dent on target location.159,160 Furthermore, the adjustments for target distance occurred too fast (within 10 msec) to be visually guided.
  
  OTOLITH–OCULAR CONNECTIONS
  The pathways from the macules to the extraoc- ular muscles are less clearly deﬁned than those from the semicircular canals. The latency of eye muscle activation after stimulation of the utricular and saccular nerves is similar to that recorded after semicircular canal nerve stimu- lation; disynaptic pathways also exist from the macules to the extraocular muscles.161–163
  However, electricallyinducedmuscleresponses are not as useful for determining the speciﬁc connectivity as responses to semicircular canal nerve stimulation. Because of the varied orien- tation of hair cells within the macules, simulta- neous electrical stimulation of all the nerve ﬁbers coming from a macule produces the equivalent of a heterogeneous activation of dif- ferently oriented hair cells.164 The induced eye movements fail to represent those seen with naturally occurring hair cell stimulation. Likewise, direct mechanical displacement of the otolithic membrane has similar limitations.165–167 As one would expect, stimula- tion on each side of the striola produces oppo- site-directed eye movements. In the utricle, on the basis of the type of eye movements observed experimentally, the macule can be divided into three sections: anterior, posterior, and central (Fig. 3–12).166 Each section is divided by the striola into two unequal parts—peripheral and
  
  Anterior
  (a)
  
  Lateral
  
  Central
  Medial
  
  Posterior
2. Superior
  
  Posterior
  Anterior
  
  Inferior
  Figure 3–12. Separation of the utricular (a) and saccular (b) macules into different sections based on the eye muscles activated by electrical stimulation of each section (as shown in Table 3–2). Arrows indicate polarity of hair cells on each side of the striola (dark blue area).
  medial. The eye muscles activated by stimula- tion of each section are those required to produce compensatory eye movements in the plane of the hair cells activated—that is, those required to compensate for linear head move- ments or head tilts in that plane (Table 3–3). The saccular macule is much simpler in its organization. It can be divided into a superior and an inferior area (Fig. 3–12).167 As with the utricular macule, the eye movements produced by discrete electrical stimulation of the saccu- lar macule occur in the direction expected to compensate for the physiological stimulus (Table 3–3).
  Unlike the horizontal semicircular canal that makes strong disynaptic excitatory connections with the contralateral abducens motoneurons and disynaptic inhibitory connections with the ipsilateral abducens neurons, abducens motoneurons and internuclear neurons receive only weak disynaptic excitation after stimula- tion of the ipsilateral utricular nerve and only trisynaptic inhibition after stimulation of the contralateral utricular nerve.168–173 Only trisyn- aptic connections have been found between the utricle and the medial rectus motoneurons. Also unlike the canal activated secondary ves- tibular neurons, only about half of utricular activated secondary neurons receive commis- sural inhibition and almost none of the saccular activated secondary neurons receive commis- sural inhibition. However, due to the opposite
  
  Table 3–3 Connections of the Utricle and Saccule with Muscles of the Eyes
  UTRICLE
  Lateral Medial
  Anterior I–SR I–IR
  C–IO C–SO
  Central C–MR I–MR
  I–LR C–IR
  Posterior I–IO I–SO
  C–SR C–IR
  SACCULE
  Superior Inferior
  I–SR I–SO
  C–IO C–IR
  C, contralateral; I, ipsilateral; IO, inferior oblique, IR, inferior rectus, LR, lateral rectus; MR, medial rectus; SO, superior oblique; SR, superior rectus.
  polarity of hair cells on each side of the striola, convergence of input from both sides of the striola on secondary neurons could take the place of commissural inhibition.172,173 Cross- striolar inhibition was observed in two-thirds of saccular activated and one-third of utricular activated secondary vestibular neurons.174,175 This cross-striolar convergence on secondary neurons might make it possible for one laby- rinth alone to generate the translational VOR.
  There is an important difference between the signals coded by the canal and otolith affer- ents. Within the range of natural head movements, otolith afferents code linear accel- eration while canal afferents code angular velocity. An additional integration or low-pass ﬁlter of the otolith signals as compared to canal signals is needed in the VOR pathways. Several models have been developed to account for the needed extra low-pass ﬁlter.155,176,177 Otolith sig- nals could undergo a separate neural integra- tion prior to convergence on the common neural integrator shared with canal ocular sig- nals or the otolith signals could enter the shared but distributed velocity-to-position integrator network at different sites such that signals from the canals are only integrated once while those from the otolth organs are integrated twice. One way to achieve the latter is to assume that both the angular and translational VOR share the same neural integrator pathway but have completely different direct pathways (a reason- able assumption based on the above). The direct pathway of the rotational VOR is strong while that of the translational VOR is weak. The strong rotational VOR pathway generates a lead that can compensate for the low-pass dynamics of the eye plant while the weak trans- lational VOR pathway does not generate a lead. The low-pass ﬁlter dynamics of the eye plant, which remains uncompensated, can provide the second integration for the translational VOR but only at high frequencies above the dominant time constant of the eye plant (a prediction consistent with experimental ﬁndings).
  
  CHARACTERISTICS OF EYE MOVEMENTS INDUCED BY TRANSLATION
  Brief high-acceleration steps of the whole body along the interaural axis have been used to assess the function of the otolith-ocular reﬂex
  in primates and in normal human subjects and patients. Paige and Tomko178,179 studied the translational VOR in squirrel monkeys and found a short latency response that was depen- dent on viewing distance. Lempert et al.180 studied humans with step accelerations of
  Percentage (%)
  Percentage (%)
  100
  80
  60
  40
  20
  0
  i-LVSTMVST c-L
  
  C1/2 C3
  T1 L3
  80
  Percentage (%)
  Percentage (%)
  60
  40
  20
  0
  i-LVST MVST
  
  C1/2 C3
  T1 L3
  80
  Percentage (%)
  Percentage (%)
  60
  40
  20
  0
  i-LVST MVST
  
  C1/C2 C3
  T1
  L3
  VST
  c-LVST
  c-LVST
  
  Figure 3–24. Projection level and pathway of vestibulospinal neurons originating from ﬁve different vestibular end-organs. a Utricular nerve-activated vestibulospinal neurons. b Saccular nerve-activated vestibulospinal neurons. c Horizontal semicircular canal nerve-activated vestibulospinal neurons. d Anterior semicircular canal nerve-activated vestibulospinal neurons. e Posterior semicircular canal nerve-activated vestibulospinal neurons. The vertical axis in each plot indicates the relative percentage of the sum of the neurons activated from the C1/C2 junction to the total number of vestibulospinal neurons (100%). Note that, in (e), many of the ipsilateral-lateral vestibulospinal tract (i-LVST) neurons descended to or caudal to the L3 segment level. (From Kushiro K, Bai R, Kitajima N, Sugita-Kitajima A, Uchino Y. Properties and axonal trajectories of posterior semicircular canal nerve-activated vestibulospinal neurons. Exp Brain Res. 2008 Nov;191:257, with permission.)
  
  vestibular nucleus. There may also be some crossed pathways. Activation of vestibulospinal ﬁbers by electric stimulation in the lateral nucleus produces monosynaptic excitation of extensor motoneurons and disynaptic inhibi- tion of ﬂexor motoneurons.317,318 The main pri- mary afferent input to the lateral vestibulospi- nal tract is from the utricule and posterior semicircular canal particularly for ﬁbers termi- nating in the lumbar cord (Fig. 3–24).307
  
  MEDIAL VESTIBULOSPINAL TRACT
  The ﬁbers of the medial vestibulospinal tract originate mostly from neurons in the medial vestibular nucleus and enter the spinal cord in the descending MLF (Fig. 3–25).8 The ﬁbers travel bilaterally in the ventral funicle as far as the midthoracic level with the vast majority ending on neurons in the cervical cord. In monkey, medial vestibulospinal neurons labeled with biocytin terminate in lamina VII,
  VIII, and XI of the cervical cord with the unique feature that crossed axons show a high degree of collateralization throughout the cer- vical cord, while uncrossed axons often termi- nate in a single cervical segment.301 The medial vestibulospinal tract receives afferent input from both otolith organs and all three semicir- cular canals, but the saccular input is more prominent than the utricular input and the horizontal and anterior canal input is more prominent than the posterior canal input (Fig. 3–24).
  
  RETICULOSPINAL TRACT
  The reticulospinal tract originates from neurons in the bulbar reticular formation but is heavily inﬂuenced by vestibular inputs .319 The nuclei reticularis gigantocellularis and pontis caudalis provide most of the long ﬁbers passing into the spinal cord, although most of the neurons in the caudal reticular formation also contribute ﬁbers.
  S
  M L
  CR Dorsal
  
  Medial Lateral
  
  Ventral Rostral
  
  Medial vestibulo-
  
  Lateral
  
  Ventral Dorsal
  spinal tract
  
  C8
  
  VII
  IX
  VIII
  vestibulo- spinal tract
  Caudal
  Fibers to:
  Cervical cord Thoracic cord Lumbosacral cord
  
  I-III
  
  L7 VII
  IX
  VII
  IX
  VIII
  Medial vestibulo- spinal fibers
  Lateral vestibulo- spinal fibers
  Figure 3–25. Lateral and medial vestibulospinal tracts. Topographical organization within the lateral vestibular nucleus (upper right) and endings within the spinal cord (lower right). CR, Corpus Restiform; S, superior nucleus; M, medial nucleus; L, lateral nucleus. (From Brodal A. Anatomical organization of cerebello-vestibulo-spinal pathways. In: De Renck AVS, Knight J (eds). CIBA Foundation Symposium: Myotatic, Kinesthetic and Vestibular Mechanisms. Churchill, London, 1967, with permission.)
  Both crossed and uncrossed ﬁbers transverse the length of the spinal cord, terminating in the seventh and eighth laminae of the gray matter.320 Stimulation of the pontomedullary reticular formation in the regions where the long descending spinal projections originate results in inhibition of both extensor and ﬂexor motoneurons throughout the spinal cord.321,322
  The vestibular nuclei are one of many struc- tures that send ﬁbers to the reticular formation. Axonal branches and collaterals of cells in all four main vestibular nuclei are distributed to the pontomedullary reticular formation. Only a small number of primary vestibular
  
  ﬁbers end in the reticular formation; the main vestibular inﬂuence on reticulospinal outﬂow is mediated by way of the secondary vestibular neurons. A pattern exists within the vestibu- loreticular projects such that each nucleus projects to different areas of the reticular for- mation, but no detailed somatotropic organiza- tion has been identiﬁed.8
  
  Cerebellar–Vestibular Interaction
  The “spinal” cerebellum provides a major source of input to neurons whose axons form the
  VI
  V
  VII
  
  IV VIII
  
  III
  IX
  II
  I X
  
  Rostral
  Hook bundle fibers
  
  Fastigial nucleus
  
  Caudal
  
  Ventral
  
  + Dorsal
  ++
  ++
  ++
  +
  
  Ventral
  Rostral
  
  Dorsal
  Rostral
  
  Ventral
  
  Dorsal
  
  Lateral vestibular nucleus
  
  Forelimb Hindlimb
  Figure 3–26. Topographical organization of cerebellar vermian, fastigial nucleus, and lateral vestibular nucleus connec- tions. Filled circles, forelimb; +, hindlimb. (From Brodal A. Anatomy of the vestibular nuclei and their connections. In: Kornhuber HH (ed). Handbook of Sensory Physiology, Vol VI, Part I. Springer-Verlag, New York, 1974, with permission.)
  
  lateral vestibulospinal and reticulospinal tract. A somatotopic organization of projections to the lateral nucleus occurs in both the vermian cortex and fastigial nuclei (Fig. 3–26).56,302,323 The caudal part of the fastigial nucleus gives rise to a bundle of ﬁbers that cross the midline (Russell’s hook bundle), curving around the brachium conjunctivum before running to the contralateral lateral vestibular nucleus and dor- solateral reticular formation. In addition, direct ipsilateral outﬂow passes from the fastigial nucleus to areas of the reticular formation that send long ﬁbers to the spinal cord in the reticulospinal tract. The cerebellar–reticular pathways do not appear to exhibit somatotopic organization.56 The cerebellar vermis and fasti- gial nuclei receive input from secondary vestibular neurons, the spinal cord, and the pontomedullary reticular formation. The result is a close-knit vestibular–reticular–cerebellar
  functional unit for the maintenance of equilib- rium and locomotion.
  
  Vestibulo-Collic Reﬂexes
  The VCR stabilizes the head in space and pro- duces smooth coordinated movements to track a moving target. The head and neck represent a complex biomechanical system with a large eccentric mass located on top of a column of cervical vertebrae.324 Although theoretically there are multiple degrees of freedom about each of the eight vertebral joints, most move- ments are made about a restricted set of joint axes; for example, yaw movements are mostly
  made about C1-C2 and pitch movements about C1-skull or C6-7-T1.
  Both lateral and medial vestibulospinal tracts
  send ﬁbers to the cervical cord, but the medial
  vestibulospinal tract is most important for coordinating neck-vestibular-ocular reﬂexes. As noted previously, two types of MVST ﬁbers have been identiﬁed based on labeling studies in monkey: crossed axons with a high degree of collateralization throughout the cer- vical cord and uncrossed axons with few collat- erals that target selective cervical segments.301 The former could provide tonic input to widely distributed motor neurons to stabilize the head, while the latter could provide canal speciﬁc input to motor neurons that initiate head move- ments about selective vertebrae. Convergence of canal and otolith input onto vestibulospinal neurons is also important for generating the “spatiotemporal” convergence within the VCR.308‌‌
  
  Cellular Mechanisms
  Recordings made from identiﬁed secondary vestibulospinal neurons in squirrel monkey indicate that the neurons encode the velocity of externally applied head movement but not head velocity in space during self-generated head movements.325 So-called vestibular-only (VO) neurons, deﬁned based on the lack of eye movement–related ﬁring, show marked sup- pression of ﬁring during active head move- ments compared to passive movements.326–329 Furthermore, these neurons continue to ﬁre selectively with passive movements even dur- ing a combination of active and passive move- ments. Many of these VO neurons control the vestibulocollic reﬂexes through their projec- tions to the cervical spinal cord. When the goal is to make an active head movement, vestibular drive to the reﬂex would cause an inappropri- ate head movement in the direction opposite to the intended goal. Logically secondary neurons in these reﬂexes should be less responsive dur- ing active head movements. Since these neurons selectively monitor passive head move- ments even during active movements they can selectively respond to an unexpected head movement such as one that might occur while tripping over a curb while walking.Convergence of somatosensory, neck, and vestibular signals on Purkinje cells in the cerebellar vermis could provide the substrate for adaptive plasticity within the vestibulo-spinal reﬂexes analogous to the role of the ﬂocculus in the vestibulo- ocular reﬂexes.330
  SUBJECTIVE VESTIBULAR SENSATION
  Unlike those sensory organs that respond to energy sources external to the body, the laby- rinths respond to self-generated forces within the head. During natural head movements, these forces are not under voluntary control and therefore the vestibular responses are more automatic than those of the other sensory modalities. For example, one can remove vision simply by closing one’s eyes, whereas one can- not suppress vestibular stimuli during head movement. The recognition of the existence of a “sixth sense” for the perception of accelera- tions (motion) is a relatively late concept that resulted from the imaginative experiments of Mach in the 1870s.331 Mach observed that the perception of motion in his different experi- ments could be altered by changing the posi- tion of the head in relation to the body, which suggested to him that the sensory organs were located in the head. His ﬁndings, along with the physiologic and histologic work of contem- poraries such as Flourens,332 Breuer,333 and Crum-Brown,334 led him to the conclusion that the semicircular canals and the otoliths were responsible for the perception of angular and linear acceleration, respectively.
  
  Vestibulothalamocortical Connections
  Microelectrode recordings from multiple dif- ferent cortical regions in multiple species have documented trisynaptic connections between the cortex and the labyrinthine end organs. The pathways from the labyrinths to the cortex have been dissected using electrophysiolocal recordings along with anterograde and retro- grade tracer techniques. Secondary neurons are located in all four vestibular nuclei and in the fastigial and anterior interposed cerebellar nuclei, and tertiary neurons are mainly located in the ventroposterior thalamus (see Fig. 1–15 in Chapter 1).335–340 Cortical regions that receive trisynaptic vestibular inputs include the parie- to-insular vestibular cortex (PIVC), the soma- tosensory cortical area 3aV, the anterior tip of the intraparietal sulcus, the medial superior temporal area, the ventral intraparietal area and the frontal eye ﬁelds and premotor/motor cortex (Fig. 3–27).341–347
  
  2v
  2v
  3a V
  c
  Monkey 7 a,b
  Galvanic (fMRI)
  VTS
  
  PIVC
  
  Calorics right (PET)
  
  –10 +10 +20
  
  R L
  
  Figure 3–27. Illustration of the normal activation–deactivation pattern during unilateral vestibular stimulation in healthy volunteers (activations in black, deactivations in blue). For comparison a schematic drawing of a monkey brain with the neu- rophysiologically determined multisensory vestibular areas 6, 3aV, 2v, 7a, b, PIVC and VTS is given (top left). Note that the locations of the activated areas during galvanic stimulation of the vestibular nerve (fMRI; top right) are similar in humans. During caloric irrigation of the right ear in healthy right-handers, activations (H215O-PET) occur in temporo-parieto-insular areas of both hemispheres, but there is a dominance of the non-dominant right hemisphere (middle: surface view of the right and left hemispheres; bottom: transverse sections Z = –10, +10, +20 mm). Deactivations are located in areas of the visual cortex bilaterally. (From Dieterich M, Brandt T. Functional brain imaging of peripheral and central vestibular disorders. Brain. 2008;131:2538, with permission)
  
  Electrophysiological and tracer studies in rats and cats have found bilateral projections to large parts of the thalamus originating from all four vestibular subnuclei.348,349 Based on selec- tive nerve stimulation in cats it appears that
  utricular-thalamic projections are mostly ipsilateral, while posterior semicircular canal and saccular-thalamic projections are mostly contralateral.350,351 Two anatomically separate graviceptive vestibulothalamic pathways have
  been identiﬁed based on tracer studies in mon- key and lesion studies in patients; a crossed pathway running within the MLF and an uncrossed pathway running near to or within the medial lemniscus.352 Lesions in the former pathway result in a combination of eye and perceptual tilt, while lesions of the latter path- way cause only a perceptual tilt. In monkey the vestibulothalamic projections end mostly in the somatosensory VPL region but some also end in VPI and VPM and even in the somatomotor VL region.340,353 The largest number is at the border between VPL and VL. Different thal- amic regions project to different cortical regions. In the squirrel monkey the PIVC receives its main thalamic input from the caudal VPL and the pulvinar, while the soma- tosensory cortex (area 3aV) receives its main input from the rostral and dorsal VPL.340,343
  
  Response Properties of Thalamic Relay Neurons
  Thalamic neurons receiving vestibular input show a range of dynamic properties similar to neurons in the vestibular nuclei but with the major exception that few have eye movement sensitivity.340,353 With angular rotation most thal- amic relay neurons show a modest phase lead but unlike primary afferents, these neurons show little additional phase lead and little drop in gain at low frequencies of rotation reﬂecting the addi- tion of velocity storage to the primary afferent signal.337,340 For translational movements response phase and gain differed somewhat from vestibular nucleus neurons, suggesting additional processing.340,353 As in vestibular nucleus neu- rons, most thalamic neurons reﬂected a combi- nation of net linear acceleration originating from otolith afferents and an estimate of gravitational acceleration derived from spatially and tempo- rally transformed canal afferents. Although some cells encoded just translation or net linear accel- eration, most had intermediate properties. Most of these were more sensitive to translation than to net acceleration.
  
  Response Properties of Vestibular Cortex Neurons
  Although vestibular activity can be found in multiple cortical regions from the frontal
  cortex to the parieto-occiptal cortex, a portion of the retroinsular cortex, the parieto-insular vestibular cortex (PIVC), is felt to be at the center of the vestibular cortical network.341,342 About two-thirds of neurons in PIVC respond to vestibular stimulation and almost all vestibu- lar activated neurons also respond to soma- tosensory and visual stimuli. Vestibular signals to this region mostly originate from the semi- circular canals with only rare responses to steady tilt in darkness. The optimal activation of these canal-related neurons is not in the planes of the semicircular canals but rather is distributed through all possible spatial planes through the head. Neurons with the same spa- tial plane tend to cluster in subdivisions of PIVC. Furthermore, the response to optoki- netic stimuli is best when the plane of the visual movement is in the optimal vestibular plane indicating a change to a head co-ordinate frame of reference. The gain of the vestibular and optokinetic responses is similar for low fre- quencies, but at 1 Hz the optokinetic gain is low while the vestibular gain remains strong. Overall the gain of PIVC neurons to angular acceleration is lower by a factor of four com- pared to vestibular neurons in the vestibular nuclei and in the thalamus.
  
  Functional Brain Imaging in Normal Human Subjects
  Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies in normal humans after galvanic stimulation of the vestibular nerve or after caloric activation of the horizontal semicircular canal have largely conﬁrmed the multiple ves- tibulocortical projection areas identiﬁed in ani- mals (Fig. 3–27).347,354,355,356 As in monkey, the temporo-insular and temporo-parietal regions seem to be at the center of the vestibulocortical network in humans. The degree of activation in these cortical areas after vestibular stimulation is greater in the nondominant hemisphere, in the hemisphere ipsilateral to the stimulated ear, and in the hemisphere ipsilateral to the slow phase of caloric nystagmus. Interestingly, there is a deactivation of visual and somatosen- sory areas of both hemispheres after unilateral vestibular stimulation, suggesting reciprocal inhibitory interactions between the sensory systems.357 Activation of the hippocampus after
  caloric stimulation is consistent with animal studies showing connections between the ves- tibular nuclei and hippocampal CA1 neurons.358,359 So-called place cells in the hippocampus encode location within the envi- ronment and are critical for normal spatial ori- entation and navigation.
  
  Lesions of the Vestibulocortical Pathways in Patients
  As discussed earlier, lesions of the vestibular nuclei or more peripheral vestibular structures lead to a combination of motor and perceptual abnormalities. For example patients with infarction of the dorsolateral medulla (Wallenberg syn- drome) typically have an ocular tilt response, spontaneous nystagmus, lateropulsion, and tilt of the perceived vertical. By contrast patients with lesions of the posterolateral thalamus or vestibular cortex have deviations of the per- ceived vertical and imbalance but without ocul- omotor signs. The imbalance associated with thalamic infarcts has been called “thalamic astasia,” a severe imbalance but without weak- ness or incoordination.360 Only lesions that involve the posterolateral thalamus cause the perception of tilt and imbalance. 362
  
  Psychophysical Studies
  SEMICIRCULAR CANALS
  As Mach described,331 a subject rotated about an earth-vertical axis on a rotatory platform will perceive turning that is dependent on the per- ceived “speed of turning.” The sensation that subjects qualitatively describe as “moving” to the left or to the right progressively increases with prolonged constant acceleration, although the turning sensation increases at a lesser rate than the platform velocity. Mach noted that below a minimum or threshold angular accel- eration the subject does not perceive turning. The modern era of vestibular psychophysics began with attempts to correlate the threshold and magnitude of subjective sensation with the magnitude of angular acceleration. Although considerable difference exists in reported values, the threshold to constant angular acceleration is in the range of 0.1 to 0.5 degrees/sec2.363,364 This is approximately an
  order of magnitude lower than the constant angular acceleration necessary to produce nystagmus.365 For stimulation with angular sinusoidal rotations, the perception of motion corresponds to the prediction of the pendulum model, just as the pendulum model predicts the velocity of the slow phases of nystagmus. In accordance with this model, the threshold for the perception of motion is approximately
  1 degree/sec for all frequencies within the range of natural head movements.
  Cupulometry developed by van Egmond and associates366 was the ﬁrst quantitative test used for assessing vestibular function on the basis of subjective sensation. With this test, the subject is maintained at a constant velocity of angular rotation and then suddenly stopped. The durations of “after-turning” sensation are measured for impulses of different ampli- tude (usually 15 to 60 degrees/sec) and plotted versus the log of impulse magnitude (to obtain the so-called cupulogram). The intercept of the line with the abscissa corresponds to a sub- jective sensation threshold and the slope, a time constant of after-turning sensation. Normative data for the subjective threshold vary from 1 to 4 degrees/sec and the time con- stant of after-turning sensation, from 2 to 14 sec.365 Studies using low-frequency sinusoi- dal rotations have found identical phase shifts in the subjective sensation of turning and the VOR in normal subjects and in patients after unilateral labyrinthectomy.367 Furthermore, in patients with unilateral vestibular loss, the duration of the subjective sensation of turning during ampullofugal stimulation of the remaining intact labyrinth is shorter than the duration of the sensation of turning during ampullopetal stimulation—similar to the asym- metry in VOR amplitude seen in these patients.
  Sinha et al.368 studied the perception of self- rotation with constant velocity angular rotations and found a delay of 2–5 sec before subjects perceived constant velocity and a plateau of 9–14 sec at maximum perceived velocity before they perceived a decay in velocity. Since there is a rapid rise and an immediate decay in nys- tagmus slow-phase velocity, they concluded that sensory signals from the semicircular canals must undergo additional neural process- ing beyond the contribution of the velocity storage mechanism.
  OTOLITH ORGANS
  Data on threshold and accuracy of estimation of earth visual vertical have been obtained with static (postural) tilt experiments.369–373 The sub- ject is strapped to a tilt platform in darkness and asked either to estimate the deviation of his head from the earth-vertical or to adjust a luminous line on a dark ﬁeld to a vertical posi- tion. Normal subjects respond with an accuracy of 2 to 4 degrees for tilt angles up to 40 degrees (accuracy falls off progressively for larger angles of tilt). The subjective estimate of tilt obviously depends on the gravitational force (Fg).374 If the
  subject is asked to estimate the angle of tilt
  under different gravitational forces, the esti- mate will vary with Fg. For g values <1, the
  angle of tilt is underestimated, whereas for g
  values >1, the angle of tilt is overestimated. In experiments carried out at “zero g” in parabolic aircraft ﬂights and in orbiting spacecraft, the subjects are unable to perceive tilt. Patients with unilateral vestibular lesions report a static tilt of the visual vertical toward the side of the lesion and have impaired estimation of the visual vertical when tilted toward the damaged ear compared to toward the intact ear.375–376 These illusionary effects are transient, disap- pearing within several weeks of the lesion.
  A subject undergoing linear oscillation (e.g., on a parallel swing) reports experiencing two separate types of motion: one is a sensation of linear movement in the horizontal plane and the other is a sensation of tilt. Both sensations
  
  vary with the changing velocity (acceleration) of the platform.365 Beginning with low ampli- tudes of oscillation, the subject initially per- ceives motion without a speciﬁc direction. This is followed by perception of the direction of linear movement and ﬁnally at higher intensi- ties of stimulation by a perception of tilting. Using dynamic stimuli, estimates of the minimal horizontal linear acceleration that normal subjects can perceive range from 5 to
  15 cm/sec2.363 Interestingly, these threshold values are similar to the values obtained by Mach for the perception of vertical linear acceleration (10 to 12 cm/sec2).
  During centrifugal stimulation, normal sub- jects have the illusion that a horizontal small luminous bar is roll-tilted in the direction of the resultant force by the same amount that they feel roll-tilted—the so-called oculogravic illusion (Fig. 3–28).377–379 Patients who undergo therapeutic unilateral vestibular nerve section show a marked asymmetry of this illusion: they perceive the illusion when the resultant force is directed toward their intact ear, but they per- ceive a much reduced illusion (roll-tilt) when the force is directed toward the operated ear. As with the tilt of the static visual vertical, this asymmetry in the oculogravic illusion gradually disappears over several weeks (presumably because of central compensation).377 Curthoys et al. likened this asymmetry in otolith function to the asymmetry of the semicircular canal function seen after similar operations.378
  
  a b c
  
  R R
  g  
  
  Sees bar at rest
  Sees bar during rotation
  Sets bar during rotation
  Figure 3–28. Oculogravic illusion experienced by normal subject seated on the arm of a centrifuge. At rest (a), the subject perceives the bar in the gravitational (g) horizontal. (b) When the centrifuge is revolving at a constant velocity (), he per- ceives himself as being roll-tilted and consequently judges that the bar has been roll-tilted in the same direction. (c) When instructed to set the rotatable bar to the gravitational horizontal, he rotates the bar through the perceived angle of roll-tilt ( in Fig. 1–1). R = resultant of the centrifugal and gravitational forces. (From Curthoys IS, et al. Human otolithic function before and after unilateral vestibular neurectomy. J Vestib Res. 1990;1: 199–209, with permission.)
  Although the utricular macule on the remain- ing intact side has bidirectional polarity because the hair cells are aligned in opposite directions on each side of the striola, there is a predomi- nance of receptors polarized toward the ipsilateral side (i.e., those central to the striola) (see Fig. 3–12a). Both peripheral and central vestibular neurons reﬂect this asymmetry in
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  1. Fasold O, von Brevern M, Kuhberg M, Ploner CJ, Villringer A, Lempert T, Wenzel R. Human ves- tibulat cortex as identiﬁed with caloric stimulation in functional magnetic resonance imaging. Neuroimage. 2002;17:1384.
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  8. Guedry FT. Psychophysics of vestibular sensation. In: Kornhuber HH, ed. Handbook of Sensory Physiology, The Vestibular System. Vol 6. Part 2. New York: Springer-Verlag; 1974.
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  PART
  2
  ‌
  
  Evaluation of the Dizzy
  Patient
  
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  Chapter 4 ‌‌
  
  Epidemiology of Dizziness
  
  SPECIFIC DISORDERS BURDEN ON PATIENTS HEALTH CARE UTILIZATION SUMMARY
  
  Dizziness consistently ranks among the most common symptoms experienced by patients, and it is also among the most common reasons that patients seek medical care.1,2 Accurate epi- demiological information is important for understanding the impact of a symptom or disorder on patients and on the health-care system. The prevalence of disorders can be deﬁned and the information can also be used to identify associations with the disorder, predic- tors of the disorder, and also links to outcomes. This information informs health-care policy and also care of individual patients. Knowledge about prevalence is needed when a physician formulates a differential diagnosis and also helps guide the interpretation of tests and use of treatments by enabling accurate assessments of the pretest probability of a disorder. But obtaining accurate epidemiologic data about dizziness is difﬁcult because of ambiguity regarding the term dizziness3 and also selection and information bias inherent to this type of research.4 For accurate estimates, required elements include a valid sampling method of a large population, valid tools for classifying participants, and a robust response rate.
  The most detailed information about dizzi- ness in the general population comes from a cross-sectional telephone survey of subjects age 18 years in Germany.5 A two-stage ran- dom sampling method was used. The ﬁrst stage was part of a general health survey in Germany.
  Nearly 16,000 households were called using random digit dialing and 52% (8318 subjects) of those contacted agreed to participate. All subjects were asked the following question, “Did you ever experience moderate or severe dizziness or vertigo?” Nearly 30% (29.3%, 95% CI 27.8%–30.9%) of participants responded “yes” to this question (Fig. 4–1).6 Other epide- miological studies have found similar preva- lence rates.7–9 The prevalence of dizziness was higher in women compared to men (35.9%, 95% CI 33.7%–38.3% versus 22.6%, 95% CI
  20.6%–24.7%, respectively).6
  Next, a random subsample of participants reporting “yes” to the dizziness question were invited to complete a detailed neurotologic phone interview (response rate 87%, 1003/1212). The neurotologic phone interview was validated by the authors. Of the partici- pants that experienced dizziness at some point, 24% (n = 243) reported “vestibular vertigo” as the type of dizziness. Vestibular vertigo was deﬁned as either rotational vertigo, positional vertigo, or recurrent dizziness with nausea and either oscillopsia or episodic imbalance. Rotational vertigo was deﬁned as an illusion of self-motion or object motion, and positional vertigo was deﬁned as vertigo or dizziness pre- cipitated by changes of head position, such as lying down or turning in bed. Applying this information to the broader general population sample, the lifetime prevalence of vestibular
  121
  
  Population Prevalence
  Population Prevalence
  30%
  
  20%
  
  10%
  
  “Moderate or severe dizziness
  “Moderate or severe dizziness
  or vertigo.” German Telephone
  or vertigo.” German Telephone
  “Dizziness in which respondent seems
  “Dizziness in which respondent seems
  “Dizziness in which things
  “Dizziness in which things
  around”, Scotland mail survey^
  around”, Scotland mail survey^
  “Unsteadiness, lightheadeness or
  “Unsteadiness, lightheadeness or
  feeling faint”, Scotland mail survey^
  feeling faint”, Scotland mail survey^
  “Vertigo associated with a moving
  “Vertigo associated with a moving
  sensation”, Finland mail survey
  sensation”, Finland mail survey
  †
  †
  spin
  spin
  0%
  
  Survey*
  Survey*
  to move”, Scotland mail survey^
  to move”, Scotland mail survey^
  *German National Telephone Health Survey 2003, response rate 8,318/15,996 (52%), Neuhauser HK, et. al., Neurology 2005;65:898–904.
  ^Scotland mail survey, response rate 7,244/12,100 households (60%). Hannaford PC, et. al., Family Practice 2005;22:227–233.
  †Finland mail survey, response rate 3,138/5,000 (63%).
  Havia M, et. al., Otolaryngology–Head and Neck Surgery 2005;133:762–768.
  Figure 4–1. Population prevalence of dizziness symptoms.
  
  vertigo in the general population was estimated to be 7.4% (95% CI, 6.5%–8.3%) (Fig. 4–2).
  The remainder of the subjects reporting both- ersome dizziness were classiﬁed as either a nonvestibular type of dizziness (n = 742) or a dizziness that could not be classiﬁed as either vestibular or nonvestibular (n = 18).6
  The proportion of vestibular vertigo among participants with moderate to severe dizziness increased with age, so that vestibular vertigo was the type of dizziness reported by 37% of those age 60 years.5 Vestibular vertigo was recurrent (at least two attacks) in 89% of sub- jects. Two-thirds of subjects who reported ves- tibular vertigo experienced it within the past 12 months—a rate suggesting recall bias. Of sub- jects with rotational vertigo (as opposed to diz- ziness with nausea and either oscillopsia or imbalance), approximately half reported spon- taneous attacks and half reported positionally triggered attacks. The duration of attacks was
  less than 1 minute in approximately half of the participants (mostly positionally triggered group), between 1 and 60 minutes in a quarter of participants, and an hour to several days in the remaining quarter of participants. Among subjects with vestibular vertigo, 80% reported a history of headaches and 62% met criteria for migraine headaches or probable migraine headaches. In a multivariable regression model examining the association of vestibular vertigo with sociodemographic factors and comorbid conditions among patients with vestibular ver- tigo in the last 12 months (163 subjects) com- pared with a dizzy-free comparison group (2816 subjects), the following factors demon- strated a signiﬁcant association: Female gender (OR 3.2, 95% CI, 2.2–4.7), self-reported depression in past year (OR 2.5, 95% CI, 1.5–4.0), bothersome tinnitus in the past 7 days (OR 3.7, 95% CI 2.4–5.6), hypertension (OR
  2.1, 95% CI 1.5–3.1), and increased blood
  Population Prevalence of Moderate or Severe Dizziness or Vertigo
  
  None (69.5%)
  Non-vestibular dizziness or undifferentiated (22.1%)
  
  Vestibular vertigo (7.4%)
  
  Position triggered rotational vertigo (43%)‌
  
  Spontaneous rotational vertigo (40%)
  
  Vestibular dizziness* (17%)
  
  *Vestibular dizziness = recurrent dizziness with nausea and either oscillopsia or episodic imbalance.
  
  From German National Telephone Health Interview Survey 2003. Neuhauser HK. Neurology. 2005; 65:898–904.
  Figure 4–2. Lifetime prevalence of moderate or severe dizziness or vertigo.
  
  lipids (OR 1.7, 95% CI, 1.2–2.4). Increasing age and many other covariates had a signiﬁcant bivariate association with vestibular vertigo but did not retain a signiﬁcant association in the multivariable model. The association of migraine with dizziness could not be tested in the model because a migraine history was not taken in the general survey portion, so that the migraine status of the comparison group was not known.
  
  SPECIFIC DISORDERS
  The German epidemiological study also sought to classify subjects with dizziness into speciﬁc causes of dizziness.5 A structured interview that had been validated in a specialty clinic set- ting against the expert diagnosis of clinicians
  was used. Based on responses to the phone interview, subjects were classiﬁed into benign paroxysmal positional vertigo (BPPV), migrain- ous vertigo, and Meniere’s disease.
  The most common speciﬁc cause of dizzi- ness was BPPV. The lifetime prevalence of BPPV was estimated to be 2.4% of the general population. BPPV accounted for 8% (80/1003) of all subjects with a history of moderate or severe dizziness and 33% (80/243) of all sub- jects with vestibular vertigo. In this survey study, the criteria for BPPV classiﬁcation included (a) recurrent vestibular vertigo, (b) attack duration always <1 min, (c) symptoms invariably provoked by changes of head posi- tion (speciﬁcally, lying down, turning over in the supine position, reclining the head, rising up from supine position, or bending forward), and (d) symptoms not attributable to another disorder. The prevalence of BPPV increased
  with age. In subjects age 80 years or greater, nearly 10% reported BPPV. Of those with BPPV, almost two-thirds reported attacks dur- ing the past year and 25% reported BPPV dur- ing the past 4 weeks. The mean age of onset was 49.4 ± 13.8 years. The median duration of the last bout of BPPV was 2 weeks (range 0.5 days to 104 weeks). One-third of subjects reported that the episodes lasted longer than ‌‌
  1 month. More than half (56%) reported recurrent bouts of dizziness. The type of dizzi- ness was rotational vertigo in most patients (86%) with the remainder reporting the symptom as dizziness with nausea and oscillop- sia rather than rotational vertigo. About half of the group also reported imbalance during attacks. All participants reported BPPV attacks triggered by either turning over in bed (85%) or getting in or out of bed. In a multi- variable logistic regression model (54 BPPV patients, 6136 general population controls), age, hypertension, increased blood lipids, stroke, and migraine were associated with BPPV diagnosis, though overﬁtting of the model is a concern.
  The lifetime prevalence of migrainous ver- tigo was estimated to be 0.98% (95% CI, 0.70%–1.37%).10 The criteria for migrainous vertigo were vestibular vertigo plus the follow- ing: (1) a history of migraine according to the criteria of the International Headache Society,
  (2) at least one migrainous symptom during at least two vertiginous attacks (i.e., migrainous headache, photophobia, phonophobia, or visual aura), and (3) symptoms not attributable to another disorder. Of those patients reporting vestibular vertigo (243), 33 (14%) were classi- ﬁed as migrainous vertigo. Two-thirds of the migrainous vertigo subjects reported spontane- ous rotational vertigo and 24% reported posi- tional vertigo (overlap with BPPV was not reported). The remainder (9%) reported ves- tibular dizziness rather than rotational vertigo. Headache always accompanied vertigo attacks in only 24%. Duration of attacks was <1 minute in 25%, 1–59 minutes in 44%, 1–24 hours in 28%, and >24 hours in 3%. Cochlear symptoms (i.e., tinnitus, aural fullness, or hearing loss) during vertigo attacks were reported by 12 sub- jects (36%) with migrainous vertigo but none had progressive hearing loss. Typical migraine triggers were reported in 61% of those with migrainous vertigo. In a multivariable model,
  only a history of coronary artery disease was signiﬁcantly associated with migrainous ver- tigo, but overﬁtting the model is a concern (tested 11 independent variables, but only 30 outcome positive subjects).
  In this study, very few subjects were classi- ﬁed with Meniere’s disease as the cause of diz- ziness.11 Of the 243 subjects with vestibular dizziness, only 4 (1.6%) met the criteria for Meniere’s disease. This translates to a popula- tion prevalence of 0.12% for Meniere’s disease. The criteria for Meniere’s disease included at least two vertigo attacks lasting at least 20 min- utes, interictal unilateral hearing loss, and at least one cochlear symptom (i.e., tinnitus, hear- ing loss, or aural fullness) during at least two vertigo attacks.
  
  BURDEN ON PATIENTS
  Many studies show that dizziness symptoms and particularly vertigo and vestibular disor- ders have an adverse effect on quality of life.12–22 In the German epidemiological study, one-ﬁfth (18.8%) of subjects with dizziness reported an interruption in daily activities and 12.2% reported avoiding leaving the house because of the dizziness symptoms.6 Of working subjects with dizziness, one-ﬁfth (20.7%) reported taking sick leave as a result of the dizziness. The burden was greater in the subgroup with vestibular vertigo compared to those with nonvestibular dizziness. More than 40% of those with vestibular vertigo reported an interruption in daily activities. And 80% of subjects with vestibular vertigo reported at least one of the following (as the result of the vertigo): interruption of daily activities, medical consultation, or taking sick leave. The rate was 57% in subjects with nonvestibular dizziness and 63% in the overall dizziness group. Quality of life, measured by the SF-8, was reduced in both vestibular vertigo subjects and nonvestibular dizziness subjects when compared to control subjects in the general population without dizziness, adjusting for age and sex.6 For BPPV subjects, 69% reported restricting head movements in order to avoid attacks.23 And during episodes, 24% reported giving up driving a car with 18% avoiding leaving their home.
  HEALTH CARE UTILIZATION ‌‌‌‌
  From the German epidemiological study, 58% of the subjects who reported bothersome dizzi- ness sought out a medical evaluation.6 This rate was lower in the Scotland postal survey (23%).9 A previous hospitalization because of dizziness was reported by 7% of those with dizziness.6 Both medical consultations and hospital visits were more common for subjects with vestibu- lar vertigo than for subjects with nonvestibular dizziness. Most of the subjects with a medical consultation reported seeing a general practi- tioner (52%), followed by a neurologist (16%) or an otolaryngologist (14%).6 About a quarter (24%) of subjects seeking a medical consulta- tion saw more than one type of physician. Subjects with BPPV had the highest rate of medical consultation (78%), followed by sub- jects with migrainous vertigo (67%), other ves- tibular vertigo (67%), other nonvestibular diz- ziness (61%), and orthostatic dizziness (46%).6 Diagnostic tests were commonly performed in dizziness patients but were not reported at the aggregate level of dizziness patients from the German study. For patients with migrain- ous vertigo who saw a physician, most under- went one or more diagnostic test, including an audiogram (27%), electroencephalogram (27%), brainstem auditory evoked potentials (21%), cranial computed tomography (CT) or magnetic resonance imaging (MRI) (21%), caloric test (18%), or ultrasound of carotid or vertebral arteries (12%).10 In subjects with BPPV, most also underwent diagnostic testing (77%), but only 27% reported diagnostic positional testing (i.e., Dix-Hallpike testing).23 Furthermore, most BPPV subjects who presented to a physician received either no treatment (45%) or medica- tion treatment (27%) for vertigo.23 Only 10% of BPPV subjects who presented to a physician underwent a particle repositioning maneuver.23 Most of the repositioning maneuvers were Brandt-Daroff exercises, rather than the most
  effective Epley or Semont maneuvers.
  Diagnostic testing among patients with dizzi- ness in the emergency room in the United States has been reported using the National Hospital Ambulatory Medical Care Survey (NHAMCS).2 NHMACS is an annual four-stage probability sampling study where patients are selected and medical records are reviewed. This ongoing study can be used to study trends over time.
  For patients reporting vertigo or dizziness as a reason for visiting the emergency room, about 10% underwent a CT scan in 1995 and this rate increased by 169% to nearly 30% in 2004.
  
  SUMMARY
  Dizziness is common among the general popu- lation and leads to substantial burden on patients and the health-care system. Dizziness that is vestibular in origin accounts for about a quarter of patients with dizziness symptoms, and the most common cause of vestibular ori- gin dizziness is BPPV. Migrainous vertigo also appears to be common. Meniere’s disease, on the other hand, was relatively uncommon in the general population and also as a proportion of vestibular origin dizziness. Most patients with vestibular origin dizziness present for a medical evaluation. Diagnostic tests are com- monly ordered and in the United States rates of use of imaging studies have dramatically increased. Positional testing and particle repo- sitioning seem to be underutilized.
  Though the German study is a large and detailed epidemiological study on dizziness and vertigo, more epidemiological studies are needed in other populations. Remaining needs from epidemiologic studies include more data from other populations and prospective longitudinal cohorts with relevant outcome measures so we can see how processes of care impact important patient outcomes in real-world settings.
  
  REFERENCES
  1. Kroenke K, Jackson JL. Outcome in general medical patients presenting with common symptoms: a prospec- tive study with a 2-week and a 3-month follow-up. Fam Pract. 1998;15:398.
  2. Kerber KA, Meurer WJ, West BT, Fendrick AM. Dizziness presentations in U.S. emergency depart- ments, 1995-2004. Acad Emerg Med. 2008;15:744.
  3. Newman-Toker DE, Cannon LM, Stofferahn ME, Rothman RE, Hsieh YH, Zee DS. Imprecision in patient reports of dizziness symptom quality: a cross- sectional study conducted in an acute care setting. Mayo Clin Proc. 2007;82:1329.
  4. Nallamothu BK, Hayward RA, Bates ER. Beyond the randomized clinical trial: the role of effectiveness stud- ies in evaluating cardiovascular therapies. Circulation. 2008;118:1294.
  5. Neuhauser HK, von Brevern M, Radtke A, et al. Epidemiology of vestibular vertigo: a neurotologic survey of the general population. Neurology. 2005;65: 898.
  6. Neuhauser HK, Radtke A, von Brevern M, Lezius F, Feldmann M, Lempert T. Burden of dizziness and vertigo in the community. Arch Intern Med. 2008;168:2118.
  7. Colledge NR, Wilson JA, Macintyre CC, MacLennan WJ. The prevalence and characteristics of dizziness in an elderly community. Age Ageing. 1994;23:117.
  8. Havia M, Kentala E, Pyykko I. Prevalence of Meniere’s disease in general population of Southern Finland. Otolaryngol Head Neck Surg. 2005;133:762.
  9. Hannaford PC, Simpson JA, Bisset AF, Davis A, McKerrow W, Mills R. The prevalence of ear, nose and throat problems in the community: results from a national cross-sectional postal survey in Scotland. Fam Pract. 2005;22:227.
  10. Neuhauser HK, Radtke A, von Brevern M, et al. Migrainous vertigo: prevalence and impact on quality of life. Neurology. 2006;67:1028.
  11. Radtke A, von Brevern M, Feldmann M, et al. Screening for Meniere’s disease in the general popu- lation - the needle in the haystack. Acta Otolaryngol. 2008;128:272.
  12. Tinetti ME, Williams CS, Gill TM. Health, functional, and psychological outcomes among older persons with chronic dizziness. J Am Geriatr Soc. 2000;48: 417.
  13. Aggarwal NT, Bennett DA, Bienias JL, Mendes de Leon CF, Morris MC, Evans DA. The prevalence of dizziness and its association with functional disability in a biracial community population. J Gerontol A Biol Sci Med Sci. 2000;55:M288.
  14. Grimby A, Rosenhall U. Health-related quality of life and dizziness in old age. Gerontology. 1995;41: 286.
  15. Hsu LC, Hu HH, Wong WJ, Wang SJ, Luk YO, Chern CM. Quality of life in elderly patients with dizziness: analysis of the Short-Form Health Survey in 197 patients. Acta Otolaryngol. 2005;125:55.
  16. Nazareth I, Landau S, Yardley L, Luxon L. Patterns of presentations of dizziness in primary care–a cross- sectional cluster analysis study. J Psychosom Res. 2006;60:395.
  17. Lopez-Escamez JA, Gamiz MJ, Fernandez-Perez A, Gomez-Finana M. Long-term outcome and health- related quality of life in benign paroxysmal posi- tional vertigo. Eur Arch Otorhinolaryngol. 2005;262: 507.
  18. Fife D, FitzGerald JE. Do patients with benign par- oxysmal positional vertigo receive prompt treatment? Analysis of waiting times and human and ﬁnancial costs associated with current practice. Int J Audiol. 2005;44:50.
  19. Kinney SE, Sandridge SA, Newman CW. Long-term effects of Meniere’s disease on hearing and quality of life. Am J Otol. 1997;18:67.
  20. Soderman AC, Bagger-Sjoback D, Bergenius J, Langius
    1. Factors inﬂuencing quality of life in patients with Meniere’s disease, identiﬁed by a multidimensional approach. Otol Neurotol. 2002;23:941.
  21. Yardley L, Owen N, Nazareth I, Luxon L. Prevalence and presentation of dizziness in a general practice community sample of working age people. Br J Gen Pract. 1998;48:1131.
  22. Nazareth I, Yardley L, Owen N, Luxon L. Outcome of symptoms of dizziness in a general practice com- munity sample. Fam Pract. 1999;16:616.
  23. von Brevern M, Radtke A, Lezius F, et al. Epidemiology of benign paroxysmal positional vertigo: a popula- tion based study. J Neurol Neurosurg Psychiatry. 2007;78:710.
  Chapter 5 ‌‌
  
  The History of the Dizzy
  Patient
  
  VERTIGO
  Central versus Peripheral Causes Time Course
  Precipitating Factors Associated Symptoms Compensation Predisposing Factors Family History
  Diagnosis and Management
  NEAR-FAINT DIZZINESS
  Orthostatic Hypotension
  Postural Tachycardia Syndrome (POTS) Vasovagal Attacks
  Hyperventilation
  PSYCHOPHYSIOLOGIC DIZZINESS (CHRONIC SUBJECTIVE DIZZINESS)
  Panic Disorder Phobic Dizziness Chronic Anxiety Pathophysiology
  Diagnosis and Management
  DRUG-INDUCED DIZZINESS HYPOGLYCEMIA DISEQUILIBRIUM
  Common Causes
  Gait Disorders in Older People Falls in Older People Diagnosis and Management OCULAR DIZZINESS
  Common Causes Oscillopsia Management
  MULTISENSORY DIZZINESS
  Management
  PHYSIOLOGIC DIZZINESS
  Motion Sickness Space Sickness Height Vertigo
  Mal de Debarquement Syndrome
  SUMMARY: DISTINGUISHING BETWEEN VESTIBULAR AND NONVESTIBULAR TYPES OF DIZZINESS
  
  Dizziness is a nonspeciﬁc term that patients use to refer to some sort of an ill feeling. The variety of symptoms that patients label as “diz- ziness” is large and includes visualized spinning of the environment, other types of movement of the environment (e.g., bouncing, rocking), “internal” movement sensations (i.e., move- ment sensation but no visualized movement of the environment), light-headedness, near-faint, unsteadiness standing or walking, disorienta- tion or confusion, or even anxiety. The initial task of the clinician is to obtain a description of
  what the patient means by dizziness. Patients should be encouraged to use their own words to describe the sensation and how the sensa- tion interferes with their daily activities. Some of these descriptions can be highly suggestive of a lesion location or even a speciﬁc etiology, but a patient’s description of the type of dizziness can also be unclear or even inconsis- tent.1 Because the dizziness description can be problematic, other important characteristics, including the circumstances, duration, associ- ated symptoms, and triggers, become equally
  127
  Table 5–1 Mechanisms of Common Types of Dizziness
  Type Mechanism
  Vertigo Imbalance in tonic vestibular signals Near-faint dizziness Diffusely decreased cerebral blood ﬂow
  Psychophysiologic dizziness
  Impaired central integration of sensory signals
  Hypoglycemic dizziness Inadequate brain glucose; increased circulatory catecholamines Disequilibrium Loss of vestibulospinal, proprioceptive, cerebellar, or motor function Ocular dizziness Visual–vestibular mismatch due to impaired vision
  Multisensory dizziness Partial loss of multiple sensory system function
  Physiologic dizziness Sensory conﬂict due to unusual combination of sensory signals
  Drug-induced dizziness CNS depression, cerebellar toxicity; change in cupula’s speciﬁc gravity (alcohol)
  
  important to detail—particularly when the symptom is vague or mild. Because the diagnostic evaluation and management differ markedly depending on the features of the diz- ziness, it is critical that the examining physician determine the type and characteristics of the dizziness (Table 5–1) before proceeding with exhaustive diagnostic studies.‌
  
  VERTIGO
  Vertigo is an illusion of movement, usually that of rotation, although patients occasionally describe a sensation of linear displacement or tilt. The afferent nerves from the otoliths and semicircular canals of each labyrinth maintain a balanced tonic rate of ﬁring into the vestibular nuclei. Asymmetric involvement of this baseline activity anywhere in the periph- eral and central vestibular pathways leads to an illusion of movement. For example, damage to a semicircular canal or its afferent nerve produces a sensation of angular rotation in the plane of that canal similar to the sensation experienced during physiologic stimulation. More typically, lesions affect the afferent input from all the canals and otoliths of one labyrinth, producing a sensation of rotation in a plane determined by the balance of afferent signals from the contralateral labyrinth (usually near the horizontal plane, inasmuch as the ver- tical canal and otolith signals partially cancel out). If a patient with a unilateral vestibular lesion attempts to ﬁxate on an object, it will appear blurred and seem to be moving in the direction opposite that of the slow phase of the
  patient’s spontaneous nystagmus (i.e., away from the side of the lesion). This illusion of movement occurs because the brain interprets the target displacement on the retina as object movement rather than as eye movement. An illusion of linear movement or tilting suggests isolated involvement of an otolith or its central connections.
  Vertigo is strongly suggestive of an imbal- ance within the vestibular system. The main caveat is that a symptom is subjective and subjective symptoms—including vertigo—can be inconsistent and unreliable.1 A description of vertigo is probably a less valid indicator of vestibular imbalance when it is mild or an “internal” (i.e., no visualized movement of the environment) sensation. It may also be less valid when the patient acknowledges vertigo only after being speciﬁcally asked about it rather than providing a spontaneous descrip- tion of it.
  
  Central versus Peripheral Causes
  The symptom of vertigo does not indicate where in the system a vestibular imbalance originates. The same sensation can result from lesions in such diverse locations as the inner ear, the deep paravertebral stretch receptors of the neck, the visual–vestibular interaction cen- ters in the brain stem and cerebellum, or in the subjective sensation pathways of the thalamus or cortex. Distinction between peripheral and central causes of vertigo can usually be made, however, on the basis of other features in the history (Table 5–2).
  Table 5–2 Differentiation between Peripheral (End-organ and Nerve) and Central Causes of Vertigo
  Nausea and Vomiting
  Imbalance Hearing
  Loss
  Oscillopsia Neurologic
  Symptoms
  Compensation
  
  Peripheral Severe Mild Common Mild Rare Rapid
  Central Moderate Severe Rare Severe Common Slow
  
  Well-documented lesions within the vestib- ular pathways sometimes produce only a non- speciﬁc sensation of disorientation without a clearly deﬁned illusion of movement. Normal subjects undergoing caloric stimulation (i.e., a physiologic imbalance in the vestibular system) occasionally describe the experience with terms such as ﬂoating or even giddiness. For these reasons one must not be too restrictive in clas- sifying dizziness on the basis of subjective description alone.
  
  Time Course
  Vertigo invariably occurs in episodes, usually abrupt in onset, followed by decreasing inten- sity as the inciting factor dissipates or as com- pensation occurs. Continuous dizziness without ﬂuctuation for long periods of time (e.g., weeks or longer) is not typical of vestibular disorders. Durations associated with several of the more common causes of vertigo are outlined in Table 5–3. Episodes lasting seconds suggest the diag- nosis of benign positional vertigo.2 During the acute phase, such patients may report a non- speciﬁc feeling of disorientation and imbalance along with nausea and vomiting that lasts for hours to days, but on careful questioning one can identify recurrent brief attacks of positional
  
  Table 5–3 Duration of Common Causes of Vertigo
  Seconds Benign positional vertigo Minutes Vertebrobasilar insufﬁciency,
  migraine*
  Hours Meniere’s syndrome
  Days Vestibular neuritis, infarction of
  labyrinth
  *Though migraine vertigo is commonly minutes in dura- tion, it can also last seconds, hours, or days.
  vertigo interspersed with a more persistent nonspeciﬁc dizziness. An episode of vertigo lasting minutes suggests a transient vascular ischemic attack.3 This is the typical duration of vertigo with transient ischemia within the basi- lar vertebral circulation. With a typical bout of Meniere’s syndrome, the vertigo reaches a peak within minutes, remains severe for an hour or two, and then gradually resolves over the next few hours.4 Vertigo gradually resolving over several days occurs with viral vestibular neuri- tis, labyrinthine trauma, infarction of the laby- rinth, or any lesion that produces permanent damage to the inner ear or vestibular nerve.5 Even with a complete unilateral loss of vestibu- lar function, the vertigo will gradually resolve as central compensation occurs. The onset is abrupt with trauma and vascular occlusion, whereas it is typically more gradual in onset (over hours) with viral vestibular neuritis.
  
  Precipitating Factors
  The events just prior to an episode of vertigo are important in determining the cause. Rapid head movements commonly induce vertigo because they accentuate any imbalance within the vestibular pathways. Even after compensa- tion has occurred, head movements or change in position can lead to a brief sensation of ver- tigo and disorientation. Positional vertigo is commonly induced by turning over in bed, sit- ting up from a lying position, extending the neck to look upward (so-called top shelf ver- tigo), or bending over and straightening up. Patients with a ﬁstula in the bony labyrinth develop brief episodes of vertigo precipitated by changes in middle ear pressure (coughing, sneezing).6 The pressure change in the middle ear is transferred directly to the inner ear (usu- ally the horizontal semicircular canal) through the ﬁstula. Occasionally, loud noises induce transient vertigo in patients with inner ear
  lesions (Tulio phenomenon). This phenome- non can occur with a range of clinical syndromes, including perilymph ﬁstula, dehiscence of the superior semicircular canal, Meniere’s syndrome, congenital deafness, and hypermobile stapes.7
  
  Associated Symptoms
  Autonomic symptoms such as sweating, pallor, nausea, and vomiting commonly accompany dizziness caused by vestibular lesions, but such symptoms are uncommon with other types of dizziness. Typically, the autonomic symptoms are more pronounced when the vertigo has a peripheral origin, although there are frequent exceptions to the rule. Occasionally, vegetative symptoms are the only manifestation of a vestibular lesion. Numerous interconnecting pathways between brainstem vestibular and autonomic centers account for this close asso- ciation of vestibular and autonomic symptoms. The site of the lesion determines the symp- toms that accompany vertigo (Table 5–4). In addition to vertigo, lesions of the labyrinth or eighth nerve commonly produce auditory symptoms such as hearing loss, tinnitus, a sen- sation of pressure or fullness in the ear, or pain in the ear. Lesions of the internal auditory canal also produce hearing loss and tinnitus and may be associated with ipsilateral facial weakness, whereas those in the cerebellar- pontine angle may be associated with ipsilateral
  facial numbness and weakness and ipsilateral extremity ataxia. As with vertigo, the time course of an associated hearing loss can help determine the cause. Fluctuating hearing loss and tinnitus are characteristic of Meniere’s syndrome. Patients with this disorder usually notice a buildup of pressure in the ear just prior to the onset of hearing loss, tinnitus, and ver- tigo. Complete unilateral deafness and vertigo occur with viral involvement of the labyrinth and or eighth nerve and with vascular occlusion to the inner ear. A slow, progressive unilateral hearing loss over months suggests the existence of an acoustic neuroma or other cerebellopon- tine angle tumor.
  Because of the proximity of other neuronal centers and ﬁber tracts in the brain stem and cerebellum, it is unusual to ﬁnd lesions in these areas that produce isolated vestibular symptoms. Lesions of the brain stem invariably are associated with other cranial nerve and long-tract symptoms. For example, vertigo caused by transient vertebrobasilar insufﬁ- ciency is associated with other brainstem and occipital lobe symptoms such as diplopia, hemi- anoptic ﬁeld defects, drop attacks, weakness, numbness, dysarthria, and ataxia. Lesions of the cerebellum (e.g., infarction or hemorrhage) may be relatively silent but are typically associ- ated with extremity or truncal ataxia in addition to vertigo. Hearing loss for pure tones is unusual with central lesions, even in the late stages.
  Vertigo can occur as part of an aura of an epileptic seizure.8 The cortical projections of
  
  Table 5–4 Symptoms Associated with Vertigo Due to Lesions at Different Anatomical Locations
  Inner Ear Hearing loss Tinnitus Pressure Pain
  Internal Auditory Canal
  Hearing loss Tinnitus
  Facial weakness
  Cerebellopontine angle
  Hearing loss Tinnitus
  Facial weakness and numbness Extremity incoordination
  Brain stem Diplopia Dysarthria
  Perioral numbness
  Extremity weakness and numbness Drop attacks
  Cerebellum Imbalance Incoordination
  Temporal lobe
  Absence spells
  Visual (formed), olfactory or gustatory hallucinations
  Occipital lobe
  Visual ﬁeld loss
  Visual hallucinations (unformed)
  
  the vestibular system are activated by a focal discharge within the frontal or temporal lobes. Such vertigo is nearly always associated with other typical aura symptoms such as an abnormal taste or smell and distortion of the visual world (hallucinations and illusions). Rarely, however, vertigo can be the only mani- festation of an aura. In such cases, the associa- tion with typical absence spells should lead one to the correct diagnosis.
  
  Compensation
  The severity of symptoms following a vestibu- lar lesion depends on (1) the extent of the lesion, (2) whether the lesion is unilateral or bilateral, and (3) the rapidity with which the functional loss occurs. Patients who slowly lose vestibular function bilaterally (e.g., secondary to ototoxic drugs) often do not complain of ver- tigo but will report oscillopsia with head move- ments and instability when walking (due to loss of vestibulo-ocular and vestibulospinal reﬂexes, respectively). If a patient slowly loses vestibu- lar function on one side over a period of months to years (e.g., with an acoustic neuroma), symp- toms and signs may be absent. A sudden unilat- eral loss of vestibular function, by contrast, is a dramatic and debilitating event. Patients com- plain of severe vertigo and nausea, are pale and perspiring, and usually vomit repeatedly. They prefer to lie quietly in a dark room but can walk if forced to (falling toward the side of the lesion). A brisk spontaneous nystagmus inter- feres with vision. These symptoms and signs are transient, however, and the process of compensation begins almost immediately. Within 1 week of the lesion, a young patient can walk without difﬁculty and with ﬁxation can inhibit the spontaneous nystagmus. Within 1 month most patients return to work with little if any residual symptoms. Occasionally patients will have difﬁculty compensating for unilateral loss of vestibular function. The presence of migraine, anxiety, or depression seems to cor- relate with persistence of symptoms.9
  
  Predisposing Factors
  The patient’s general state of health just prior to the onset of dizziness should be carefully investigated. Most severe systemic disorders
  are associated with dizziness due to either par- tial involvement of all the body-orienting sys- tems or a decreased capacity of the central ner- vous system (CNS) to deal with information from these systems (a type of multisensory dizziness). Some systemic disorders such as vasculitis, bacterial endocarditis, and septice- mia can selectively damage the vestibular sys- tem by interfering with its blood supply. Such patients may develop severe vertigo and vomit- ing typical of an acute peripheral vestibular loss. Patients with viral vestibular neuritis fre- quently report an upper respiratory tract illness either within 2 or 3 weeks before or at the time of onset of vertigo. Chronic middle ear infec- tions may lead to bacterial labyrinthitis or serous labyrinthopathy, and patients with bacterial meningitis may develop bacterial lab- yrinthitis through the direct cerebrospinal ﬂuid–perilymph connections. Patients with Meniere’s syndrome may have an attack of ver- tigo precipitated by foods high in salt content.
  Head injury can damage the delicate laby- rinthine membranes with or without associated bone fracture. Labyrinthine trauma may result in a single prolonged episode of vertigo or, more commonly, recurrent episodes of posi- tional vertigo. The more common nonspeciﬁc light-headed dizziness following head trauma is probably not related to vestibular damage, inasmuch as common associated symptoms and signs are absent. Surgery in or about the ear is a major cause of trauma to the labyrinthine membranes. Vertigo not infrequently follows surgery conﬁned to the middle ear. Past medi- cal history should focus on past or chronic medical illnesses, such as diabetes mellitus, atherosclerotic vascular disease, syphilis (con- genital or acquired), and major allergies, that might predispose the patient to vestibular sys- tem damage. Viral illnesses that damage the inner ear in utero or in infancy (e.g., rubella, mumps, rubeola) may be followed years later by recurrent episodes of vertigo.10 This so- called delayed endolymphatic hydrops may not be associated with auditory symptoms such as hearing loss, tinnitus, or ear pressure because the patient may be deaf in the damaged ear.
  
  Family History
  Common vestibular disorders with a genetic predisposition include migraine, Meniere’s
  syndrome, otosclerosis, neuroﬁbromatosis, and spinocerebellar degeneration. Migraine can present as isolated episodes of vertigo (a migraine equivalent) in some members of a family, whereas other members have classic migraine headaches.11 Some varieties of “famil- ial Meniere’s syndrome” are likely due to migraine. Patients with otosclerosis usually present with a conductive hearing loss, although sensorineural hearing loss and vertigo may result if the otic capsule becomes involved. Neuroﬁbromatosis type 1 (NF1) is manifested by the combination of pigmented skin lesions, multiple tumors of the spinal and cranial nerves, tumors of the skin, and intracranial gliomas. Neuroﬁbromatosis type 2 (NF2) is commonly manifested by bilateral acoustic neuromas and meningiomas without periph- eral manifestations. Any young patient (<30 years old) with an acoustic neuroma should be followed carefully for development of a tumor on the opposite side (due to NF2). Central varieties of positional vertigo are commonly seen in patients with the inherited ataxia syn- dromes (particularly common with spinocere- bellar atrophy type 6[SCA-6]).12 Positional vertigo and ataxia are also commonly seen with Hippel-Lindau disease. This autosomal domi- nant disorder is characterized by hemangio- blastomas of the cerebellar hemispheres, angiomas of the retina, and cystic changes in the kidney and pancreas. The diagnosis should be considered in any patient with a cerebellar tumor or hemorrhage who manifests an ele- vated hematocrit.‌‌
  Congenital deformities of the inner ear may result from abnormal genes or from abnormal development in utero. Most of the inherited malformations of the inner ear are associated with multiple malformations in other organs producing a characteristic clinical proﬁle (e.g., Alport’s and Waardenburg’s syndromes). Progressive atrophy of the cochlear and ves- tibular nerves may be seen as part of a more diffuse degenerative disorder (e.g., with
  Friedreich’s ataxia or olivopontocerebellar atrophy) or may occur as an isolated phenom- enon (both autosomal dominant and recessive inheritance). Although uncommon, the syn- drome of familial periodic ataxia and vertigo (episodic ataxia type 2[EA-2]) is important to recognize because it often responds dramati- cally to acetazolamide. With this dominantly inherited disorder, episodes of vertigo and ataxia recur throughout the patient’s life sometimes without objective ﬁndings between episodes.
  
  Diagnosis and Management
  The reader is referred to Chapters 9–18 for discussion in detail of the diagnosis and man- agement of common causes of vertigo.
  
  NEAR-FAINT DIZZINESS
  Near-faint dizziness or presyncope can best be described as the lightheaded sensation of an impending faint. It is often associated with a feeling of unsteadiness or even of falling. Near- faint dizziness results from pancerebral isch- emia.13 Common causes are summarized in Table 5–5. We emphasize that near-faint dizzi- ness is not a symptom of focal occlusive cere- brovascular disease (i.e., not a symptom of impending stroke).
  
  Orthostatic Hypotension
  All of us have experienced light-headedness after rapidly assuming the standing position from the supine or sitting position. This symp- tom is transient and of little consequence. Also, not uncommonly, susceptible subjects may develop presyncopal lightheadedness and may even faint after standing for a prolonged period
  
  Table 5–5 Common Causes of Near-Faint Dizziness
  Cause Precipitating Factors
  Orthostatic hypotension Reduced blood volume, hypotensive drugs, autonomic dysfunction Vasovagal attack Prolonged standing in hot sun, fear, severe pain, acute vertigo
  Hyperventilation Anxiety, stress, panic attacks
  Decreased cardiac output Arrhythmia, valvular disease, heart failure
  in the hot sun. Recurrent symptoms of postural hypotension, however, can usually be traced to either reduced blood volume, the chronic use of hypotensive drugs, or autonomic dysfunc- tion.14,15 Nearly all of the antihypertensive drugs, a large number of antidepressants and major tranquilizers, and long-term bed rest will pre- dispose a patient to orthostatic hypotension.
  
  DIAGNOSIS AND MANAGEMENT
  Near-faint dizziness with orthostatic hypoten- sion can develop immediately on standing or insidiously after several minutes of standing. The diagnosis is made by documenting an acute or progressive decline in mean blood pressure of more than 10 to 15 mmHg with a corre- sponding increase in pulse rate while the patient is in the erect position. In patients with autonomic insufﬁciency the pulse rate will remain unchanged despite the hypotension. Autonomic impairment can be documented at the bedside by taking the pulse while the supine patient performs a vigorous Valsalva maneuver. Normally, the pulse slows and the mean blood pressure increases by 10 to 30 mmHg in the immediate post-Valsalva period. Orthostatic hypotension can often be eliminated by remov- ing offending drugs or by correcting the causes of blood-volume depletion. In patients with autonomic insufﬁciency, increased salt intake can increase blood volume, and elastic stock- ings can prevent pooling of blood in the lower extremities.16,17 In severe cases the salt- retaining steroid ﬂuorocortisone can aid in expanding blood volume. Orthostatic lighthead- edness is particularly common in the elderly and in many cases may be an effect of arterio- sclerosis (manifest by white matter hyperinten- sities on magnetic resonance imaging [MRI]) leading to reduced cerebral blood ﬂow as opposed to the typical causes of orthostatic hypotension. Patients with arteriosclerosis have reduced cerebral blood ﬂow even though blood pressure measured at the arm is normal. 18
  
  Postural Tachycardia Syndrome (POTS)
  POTS is associated with orthostatic dizziness but without orthostatic hypotension.19 The pulse typically increases above 120 beats per minute on standing and there are associated
  autonomic symptoms. It most commonly occurs in young women (ages 20–40 years). Multiple pathophysiological mechanisms have been associated with POTS, including periph- eral denernation, hypovolemia, beta receptor hypersensitivity, deconditioning, and psycho- logical factors.
  
  DIAGNOSIS AND MANAGEMENT
  The diagnosis of POTS is made by documenting a heart rate increase of >30 beats per minute in a patient who develops orthostatic symptoms on standing. Treatment begins with a high-salt diet, copious ﬂuids, and postural training. Some patients beneﬁt from low doses of beta-receptor antagonists or vasoconstrictors.
  
  Vasovagal Attacks
  Prior to a common faint, one experiences sen- sations of light-headedness, giddiness, nausea, and an abdominal sinking sensation. Typically the subject is pale and there are associated signs of parasympathetic hyperactivity, includ- ing piloerection and sweating. These symptoms are induced when emotions such as fear and anxiety, initiated in the forebrain limbic sys- tem, activate the medullary vasodepressor cen- ters.13,20 The consequences are a fall in heart rate and blood pressure and a decline in car- diac output, leading to a decrease in cerebral blood ﬂow. Parasympathetic hyperactivity accounts for the slowing of heart rate, and diminished sympathetic tone leads to vasodila- tion. Normal cardiovascular reﬂexes are rein- stated if the subject lies supine or if there is loss of consciousness with a common faint.
  Vasodepressor light-headedness commonly occurs when a subject has fasted for a long period of time, is exposed to hot, moist weather, and/or has stood for a prolonged period of time. Some individuals are clearly more susceptible to presyncopal light-headedness and the common faint than others, and occasionally one can ﬁnd a family history with members in several gener- ations who are susceptible. Family pedigrees are most consistent with an autosomal dominant transmission with incomplete penetrance but so far no deﬁnite genetic mutation has been identi- ﬁed.21 Vasodepressor episodes can also be pre- cipitated by acute visceral pain or by a sudden severe attack of vertigo. This explains the
  occasional patient with an acute peripheral ves- tibular lesion who will present with a history of syncope. In this case, it is important to obtain a history of severe vertigo and autonomic symp- toms preceding the loss of consciousness.‌‌
  
  DIAGNOSIS AND MANAGEMENT
  The ﬁrst and most important step in the evalu- ation of a vasovagal event is to assess the risk for a serious cause (i.e., myocardial infarction, arrhythmia, stroke) or a future serious event. A clinical decision rule—the San Francisco Syncope Rule—was developed and validated for this purpose.22 The probability of a serious cause or future event (outcome at 30 days) is very low (<0.5%) when the patient has none of the following: history of congestive heart fail- ure, hematocrit less than 30%, abnormal electrocardiogram (EKG) (new changes or non-sinus rhythm), complaint of shortness of breath, or a systolic blood pressure less than 90 mmHg at triage.
  Patients found to be a low risk for severe causes or events can be treated symptomatically rather than requiring an extensive evaluation.
  
  Hyperventilation
  Chronic anxiety with associated hyperventila- tion is a common cause of persistent near-faint dizziness.23 Patients typically describe sensa- tions of light-headedness, faintness, and giddi- ness along with other sensations described later in the section “Psychophysiologic Dizziness.” Associated symptoms typically include fre- quent sighing, air hunger, perioral numbness, paresthesias of the extremities, lump in the throat, and tightness in the chest. Patients often report being unable to obtain the satis- faction of a full deep breath and they will sigh frequently as though they were trying to catch their breath. Studies in patients who hyperven- tilate with medical procedures such as blood drawing or injections showed excessively deep and irregular breathing which was associated with symptoms of dizziness and fainting.24 Hyperventilation causes presyncopal light- headedness by lowering the carbon dioxide content of the blood, thus producing constriction of the cerebrovasculature. In most subjects only a moderate increase in respiratory rate can drop the PaCO2 levels to
  25 mm of mercury or less in a few minutes. Once this level is achieved, the subject does not have to breathe excessively to maintain
  the low PaCO2, so it is possible to be chronically hypocapnic without appearing to
  hyperventilate.25
  
  DIAGNOSIS AND MANAGEMENT
  The diagnosis rests on identifying the charac- teristic associated symptoms in the setting of anxiety and dyspnea. It is usually helpful to have the patient voluntarily overbreathe to reproduce his or her symptoms and to provide insight into the mechanism.23 In addition to educating the patient, treatment must be directed at the underlying anxiety. Behavioral interventions directed at dysfunctional breath- ing can beneﬁt susceptible patients.24 Long- term use of tranquilizers should be avoided because increased tolerance and dependency commonly occur.
  
  PSYCHOPHYSIOLOGIC DIZZINESS (CHRONIC SUBJECTIVE DIZZINESS)
  A wide range of dizzy sensations are associated with psychiatric illnesses.26,27 Feelings of disso- ciation, as though one has left one’s own body, are common. Patients use terms such as “ﬂoat- ing,” “swimming,” and “giddiness” to describe the dizzy sensation. They may report a feeling of imbalance (commonly a rocking or falling sensation) or even of spinning inside the head— sensations that can usually be differentiated from vertigo because they are not associated with an illusion of movement of the environ- ment or with nystagmus.28 Psychophysiologic dizziness may be constant or occur in attacks and is typically associated with symptoms of anxiety. Common associated somatic com- plaints include tension headache, heart palpi- tations, gastric distress, urinary frequency, backache, and a generalized feeling of weak- ness and fatigue. Attacks may be provoked by sensory stimuli (driving on a freeway, walking on a brightly polished ﬂoor, watching a train go by) or by social situations (eating in a restau- rant, shopping in a department store, attending a reception). Symptoms often begin after a period of stress, especially after the death of a
  loved one or after a patient has been through an illness, and may continue for months or years.
  
  Panic Disorder
  Common causes of anxiety in daily life are cir- cumstances in which one must make a decision that could have major implications for future social and economic status. The symptoms associated with this type of anxiety are usually transitory and completely reversible.29 Anxiety can also be associated with a number of neuro- logic and psychiatric disorders. For example, the ﬁrst sign of dementia or manic depressive illness can be an attack of severe anxiety with- out obvious cause.
  Panic attacks are a distinct form of anxiety that typically occur in a background of persis- tent apprehension but at times when there appears to be no obviously threatening circum- stance.30,31 Such attacks often occur when it would be difﬁcult for one to make a rapid exit (e.g., traveling in an airplane or train, driving in the fast lane of the freeway, shopping in a crowded store, or waiting in a supermarket line). The condition typically builds up over 10 to 15 min with progressively increasing anxiety associated with dizziness, shortness of breath, sweating, ﬂushing, trembling or shaking, heart palpitations, paresthesias, and a generalized feeling of weakness (Table 5–6). The dizziness can take several forms, from a giddy, unsteady sensation to a progressing, presyncopal light- headedness. Patients may experience a tight- ness in the chest as though the lungs cannot be adequately ﬁlled. Hyperventilation and enhanced CO2 sensitivity are also common.32
  The person may try to ﬂee and in the future
  avoid the situation in which the panic attack occurred. There is a clear genetic predisposi- tion to panic disorders, distinguishing them from the more common anxieties that are a response to speciﬁc life situations.33
  
  Phobic Dizziness
  Agoraphobia, deﬁned as a morbid fear and avoidance of being in public places, is closely linked with anxiety disorders and panic attacks.29,34 Often agoraphobia is secondary to panic attacks; the patient restricts outside
  Table 5–6 Common Symptoms during Panic Attacks
  Shortness of breath, smothering, choking Palpitations, accelerated heart rate Chest pain or discomfort
  Sweating
  Dizziness, unsteady feeling, sensory illusions Nausea or abdominal distress Depersonalization or derealization
  Numbness or tingling sensations (paresthesias) Flushes (hot ﬂashes) or chills
  Trembling or shaking Fear of dying
  Fear of going crazy or doing something uncontrolled
  activities to the point of becoming housebound for fear of having a panic attack. The multiple symptoms of panic attacks (see Table 5–6), including dizziness, are commonly reported by patients with agoraphobia. By contrast, simple phobias, such as fear of ﬂying, heights, and snakes, are usually associated with generalized anxiety rather than panic episodes.
  Phobic postural vertigo is characterized by a frightening feeling of dizziness with subjective postural and gait instability.35 Although patients have multiple symptoms of panic attacks, often with a steadily mounting fear of impending death, they feel physically ill and the associated symptoms of anxiety are brought out only after appropriate questions have been asked. They describe their dizziness as a perception of illu- sory body motion that can occur in brief bouts lasting seconds or be prolonged over hours and days. Typically patients have a fear of falling when sitting or standing, and active body move- ments provoke unpleasant illusions of body acceleration along with simultaneous illusory movement of a stationary environment. With the attack, patients experience anxiety, psycho- motor restlessness with escape reactions, a sudden desire to ﬂee from the place where the attack is provoked, aimless walking, and, if seated, a rigid grasp of the arms of the chair. Anticipatory anxiety leads to further attacks of dizziness despite the discrepancy between the subjective fear of falling and the absence of objective unsteadiness. Although some patients develop typical symptoms of agoraphobia, oth- ers are able to continue their social and work habits despite symptoms they feel are dominat- ing their lives.34 The outlook for these patients
  is good with most having improvement or even complete resolution of symptoms.36
  Some patients develop a profound fear of falling in open spaces where a visuospatial reference is absent.37 Unlike the fear of public places found with agoraphobia, patients with space phobia fear open spaces where there is no “visual” support nearby. They will crawl on the ﬂoor to cross a room or walk close to walls or hedges in streets. The average age of onset of space phobia is later than that of agorapho- bia (55 years compared with 24 years), and the former is rarely associated with depression or free-ﬂoating anxiety, as typically seen with ago- raphobia. Marks suggested that many of these patients have an underlying organic disorder of balance, because they are resistant to the expo- sure treatments that are often successful with agoraphobics.37 A variant of space phobia (the so-called motorist’s disorientation syndrome) is an illusion of falling to the side or that the car is turning to the side when driving in open spaces, on featureless roads, or on the brows of hills.38 These abnormal sensations are typically accom- panied by a panic reaction. Typical of phobias, these patients develop avoidance behavior, either driving at very low speeds in restricted areas or completely stopping driving.
  
  Chronic Anxiety
  Unlike acute anxiety, chronic anxiety is often difﬁcult to ascribe to a speciﬁc inciting factor.29 Symptoms are less intense although qualita- tively similar to those of acute anxiety. The patient may complain of dizziness and giddi- ness that persist for years, present from morn- ing to night. The patient appears tense and on edge, and there are often symptoms of associ- ated chronic depression. As with acute anxiety, there are typically associated somatic com- plaints, and on examination there may be several physical signs of chronic tension mani- fested by a ﬁne tremor of the extended hands, very brisk deep tendon reﬂexes, chronic tachy- cardia, and pupillary dilatation.
  
  Pathophysiology
  The pathophysiologic mechanism of psy- chophysiologic dizziness is poorly understood. Although hyperventilation with its concomitant
  cerebrovascular vasospasm can explain the presyncopal light-headed sensation, it cannot explain the many complex sensory distortions such as feelings of dissociation, illusions of body movement, imbalance, and fear of fall- ing.39 Abnormalities within the autonomic ner- vous system may account for some of these symptoms.40 In susceptible patients, panic attacks can be precipitated, by a large number of substances, including carbon dioxide, lac- tate, caffeine, isoproterenol, yohimbine, and benzodiazepine receptor antagonists.33 All these agents interact with the central nora- drenergic neuronal system. A popular hypoth- esis is that panic attacks result from central dyscontrol of the locus ceruleus, leading to the episodic release of catecholamines. Studies using positron-emission tomography (PET) scanning in patients with panic disorder dem- onstrated an asymmetry of blood ﬂow and oxy- gen utilization in the parahippocampal gyrus (increased on the right side), 41,42 one of the major projection areas of the locus ceruleus. The parahippocampal region is closely interre- lated with the hippocampus, a key multimodal sensory integrative center that receives projec- tions from the association areas of all sensory modalities and projects to other limbic struc- tures and to autonomic centers in the hypo- thalamus and brain stem. Abnormalities in the hypothalamic orexin/hypocretin neuronal sys- tem may also explain the breathing and sleep dysfunction seen with panic disorder.43
  
  Diagnosis and Management
  The diagnosis of psychophysiologic dizziness rests on ﬁnding the characteristic associated symptoms of acute and chronic anxiety discussed previously. One must keep in mind that vestibular disorders can also cause anxiety and fear of further attacks of vertigo.44,45 A classic vicious cycle may develop whereby the vestibular disturbance causes anxiety, which in turn causes chronic dizziness that may persist after the vestibular imbalance has been compensated. A negative examination in the face of obvious signs of acute and chronic anxi- ety will help support the presumed diagnosis based on the history. It can sometimes be difﬁcult to recognize panic attacks because patients will focus on the somatic symptoms, especially the dizziness and autonomic
  symptoms, rather than the intense anxiety asso- ciated with the attack.‌‌
  The ﬁrst step in management of patients with psychophysiologic dizziness is to acknowl- edge their symptoms as “real,” due to physio- logic changes occurring in their bodies and that the pattern of symptoms is commonly reported by other patients. Patients are often convinced that they have a severe neurologic disorder and that the anxiety, which they have recognized, is secondary to the physical disorder. It is impor- tant to them that the physician understands that they are suffering from “physical symp- toms.” An explanation for how the release of catecholamines can produce symptoms such as tachycardia, chest pain, paresthesias, and dizzi- ness may improve their acceptance and provide the groundwork for therapeutic considerations. Three general classes of medications are com- monly used in the treatment of panic attacks:
  (1) the tricyclic amines (e.g., imipramine and desipramine), (2) benzodiazepines (e.g., alpra- zolam or clonzapam), and (3) the selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine and ﬂuoxetine).31 The SSRIs typi- cally have an acceptable side effect proﬁle and do not have the tolerance and dependency that occurs with benzodiazepines. These medica- tions should be used in conjunction with sup- portive psychotherapy. Patients with phobic dizziness may respond to cognitive behavioral therapy, although long-term beneﬁt has not been demonstrated.46 We strongly encourage patients to enter a progressive exercise program with the goal of gradually improving their diminished physical ﬁtness. It is very important that patients feel responsible for their therapy program.
  DRUG-INDUCED DIZZINESS
  A careful history of medications is critical in evaluating any patient complaining of dizziness (Table 5–7). Antihypertensive and antidepres- sant medications are common causes of near faint dizziness and falls in the elderly.47,48 Ototoxic drugs such as the aminoglycosides and cisplatin can cause vertigo if hair cell loss is asymmetrical, but more often they cause dis- equilibrium and oscillopsia from bilateral sym- metricalend-organdamage.49,50Carbamazepine, phenytoin, primidone, and alcohol can cause acute reversible disequilibrium and chronic irreversible disequilibrium from cerebellar dysfunction. Sedating drugs cause a nonspe- ciﬁc dizziness typically described as a fogginess, cloudiness, or giddiness that is presumably due to diffuse depression of the central nervous system. A number of commonly used drugs produce a characteristic drug intoxication syn- drome that might be confused with other types of dizziness. The associated confusion, disori- entation, memory and cognitive deﬁcits, gaze- evoked nystagmus, and gait and extremity ataxia indicate combined cortical and cerebel- lar dysfunction.51 These drugs affect multiple neurotransmitters within the central nervous system (CNS), but the cause of the drug intoxi- cation syndrome is unknown.
  The most commonly recognized syndrome is that associated with alcohol ingestion. A light- headed, swimming sensation is typically associ- ated with slowing of cognitive functions and motor responses. Gaze-evoked nystagmus with horizontal gaze deviation and gait ataxia are early reliable signs of the syndrome. With increased intoxication, gaze-evoked nystagmus occurs with
  
  Table 5–7 Type and Mechanism of Dizziness Associated with Commonly Used Drugs
  Drug Type of Dizziness Mechanism
  Aminoglycosides, cisplatin Vertigo, disequilibrium Damage to vestibular hair cells
  Antiepileptic: carbamazepine, phenytoin, primidone
  Tranquilizers: barbiturates, benzodiazepines, tricyclic amines, marijuana
  Disequilibrium, intoxication Cerebellar toxicity, CNS depression Intoxication CNS depression
  Antihypertensives, diuretics Near-faint Postural hypotension, reduced cere- bral blood ﬂow
  Alcohol Intoxication, disequilibrium, positional vertigo
  CNS depression, cerebellar toxicity, change in cupula-speciﬁc gravity
  
  vertical gaze deviation, and the upper extremi- ties are ataxic. The alcohol concentration in the blood can be reasonably well predicted by the degree of gaze-evoked nystagmus.‌‌
  The diagnosis rests on ﬁnding the character- istic combination of symptoms and signs in a patient taking one of the offending drugs. Blood levels can now be routinely obtained on most of these drugs, so a speciﬁc diagnosis is possible.
  
  HYPOGLYCEMIA
  Hypoglycemia may lead to behavioral changes, light-headedness, lethargy, confusion, amnesia, seizures, weakness, shakiness, fatigue, and diaphoresis.52 It usually is a complication of insulin or sulfonylurea treatment in diabetic patients, but it may occur with insulinomas or as a fasting or postprandial phenomenon. Postprandial symptoms of shakiness, palpita- tions, fatigue, and dizziness have been termed functional hypoglycemia because most such cases are not associated with signiﬁcantly low plasma glucose levels. The history in patients suspected of having hypoglycemia should focus on whether insulin or sulfonylu- reas have been taken. Diagnosis rests on mea- suring plasma glucose, insulin, and c-peptide. c-Peptide is the connecting peptide that is cleaved from proinsulin to form insulin.52 Elevation of c-peptide and insulin suggests excessive endogenous insulin (such as from an insulinoma). An elevated insulin level with nor- mal or suppressed c-peptide level indicates excessive exogenous insulin, since c-peptide is not present in pharmaceutical insulin and is in fact suppressed by it.‌
  
  DISEQUILIBRIUM
  Common Causes
  Patients often use the term “dizziness” to describe a sensation of imbalance or disequi- librium that occurs only when they are stand- ing or walking and is unrelated to an abnormal head sensation. Imbalance is common with acute unilateral peripheral vestibular lesions, but it is transient and invariably associated with
  subjective vertigo. Both the vertigo and imbal- ance are compensated for within a few days. Patients who slowly lose vestibular function on one side, such as with an acoustic neuroma, may not experience vertigo but often describe a vague feeling of imbalance and unsteadiness on their feet. Bilateral symmetrical vestibular loss results in a more pronounced and persis- tent unsteadiness, which may be incapacitating in elderly patients.53,54 The imbalance due to loss of vestibulospinal and proprioceptive func- tion is typically worse in the dark, when the patient is unable to use vision to compensate for the loss (Fig. 5–1). Patients with a severe bilateral vestibular loss will report movement induced oscillopsia, often described as a feel- ing of looking through the lens of a video cam- era. Patients with cerebellar lesions, on the other hand, show little change in their balance with and without vision (the basis for the Romberg test). Disequilibrium may be the presenting symptom of lesions involving the motor centers of the basal ganglia and fron- tal lobes such as with Parkinson’s disease, hydrocephalus, and the multiple lacunar infarct syndrome.
  
  Gait Disorders in Older People
  The gradual loss of cells in the sensory and motor centers of the brain with aging is usually a very subtle process that parallels similar slight changes in memory and other cognitive functions, generally considered the normal aging process.55 The gait of normal elderly men is characterized by slight anteroﬂexion of the upper torso with ﬂexion of the arms and knees, diminished arm swing, and shorter step length;56 the gait of older women tends to be more narrow based, with a waddling quality.57 When minor, these changes are not likely to lead to a speciﬁc medical complaint. However, a small number of older patients develop a progressive deterioration of gait, beginning in the eighth and ninth decades. Their steps shorten and the base widens until their gait is reduced to a shufﬂe. They turn en bloc rather than with a normal pivot, and upon arising they have great difﬁculty in initiating the ﬁrst step. Once they begin, their arms are held rigidly at their sides, and they exhibit a characteristic stooped posture. Walking in tandem is impossible.
  Unilateral peripheral vestibular lesion
  Unilateral peripheral vestibular lesion
  Imbalance
  
  Associated with acute vertigo
  Yes
  
  No
  
  Much worse in dark
  
  Yes
  
  Oscillopsia
  +/– hearing loss
  
  Yes
  
  Cerebellar lesion
  Cerebellar lesion
  Yes
  No
  
  Incoordination of extremities
  
  No
  No
  
  Bilateral vestibular lesion
  Bilateral vestibular lesion
  Associated numbness, weakness, bowel and bladder dysfunction
  
  Yes
  
  Proprioceptive loss
  Proprioceptive loss
  Slow, loss of associated movement
  
  Yes
  Frontal lobe, basal ganglia
  Frontal lobe, basal ganglia
  Figure 5–1. Logic for distinguishing between different causes of imbalance.
  
  On examination, patients are unable to relax their limbs voluntarily. This phenomenon has been described as Gegenhalten or paratonic rigidity. Cortical release signs commonly accompany the diffuse rigidity. The patients attribute their difﬁculty in walking to a lack of conﬁdence or a fear of falling, and, not surpris- ingly, major falls frequently occur. In the late stages, patients cannot walk unassisted and may have great difﬁculty sitting down from a stand- ing position. They land on the edge or side of the chair and fall off. Ultimately they are con- ﬁned to bed. The neuropathologic basis of this gait disorder is poorly understood. Postmortem examinations typically show diffuse cortical atrophy and subcortical small-vessel ischemic changes.58–60
  60, and it is greater in women than in men. Most falls in the elderly result from an acciden- tal slip or trip (Table 5–8). The cause can often be traced to decreased sensory input, slowing of responses, and weakness of support.53 Medications are a common contributing fac- tor.47 Falls can be directly traced to an acute attack of dizziness in less than 10% of patients.64 This low incidence probably can be attributed to the fact that most types of dizziness, includ- ing attacks of vertigo, begin slowly enough to
  
  Table 5–8 Common Causes of Falls in Older People64
  Cause %
  Accidental (falling on stairs, slips, trips) 40–50
  Falls in Older People
  Falls in the elderly are a common source of morbidity and mortality.61–63 The risk of falls
  Neurologic (drop attacks, weakness, ataxia)
  Dizziness (orthostatic hypotension, arrhythmia, vertigo)
  20–30
  
  5–10
  increases linearly with age beyond the age of
  Uncertain 5–10
  allow the patient to sit down or to grab onto a support to avoid falling.‌‌
  
  Diagnosis and Management
  Considering the many possible loci of dysfunc- tion, the examination of a patient complaining of disequilibrium must include a careful assess- ment of gait, strength, coordination, reﬂexes, and sensory function (particularly of the lower extremities).53,55 The broad-based ataxic gait of cerebellar disorders is readily distinguished from the milder gait disorders seen with ves- tibular or sensory loss. Furthermore, other cer- ebellar signs (e.g., dysmetria, dysarthria, inten- tion tremor, pathologically impaired smooth pursuit, and gaze-evoked nystagmus) usually accompany the gait ataxia. Bilateral vestibular loss may or may not be associated with hearing loss. The diagnosis rests on ﬁnding reduced vestibular function based on a positive head thrust test (bilateral) or decreased or absent response to caloric and rotational stimulation (see Chapter 7).
  The deterioration of gait that occurs with aging must be distinguished from that associ- ated with lesions of the cortical and subcortical motor centers.55 The shufﬂing, ﬂexed, steppage gait of Parkinson’s disease resembles the nor- mal gait of older males. The diagnosis of Parkinson’s disease rests on ﬁnding associated signs, including bradykinesia, cogwheel rigid- ity, and the characteristic “pill-rolling” tremor. Apraxia of gait, characterized by slow, halting, sliding steps as if the patient’s feet were adher- ing to the ﬂoor, is caused by bilateral frontal lobe dysfunction. Common causes include multiple subcortical infarcts, inﬁltrating tumors, and hydrocephalus. These abnormali- ties are easily identiﬁed with computerized tomography (CT) and MRI.
  With the exception of normal pressure hydrocephalus, which can be dramatically reversed with placement of a shunt, most gait disorders in the elderly are not reversible. Some can be helped by improving support with canes or a walker. Optimizing footwear is very important.65 Tranquilizing medications and polypharmacy should be scrupulously avoided, inasmuch as they can further impair the central integration of sensory information.66 Physical therapy programs consisting of gait and balance training and strengthening
  exercises help slow the progression. Exercise intervention has clearly been shown to reduce risk and rate of falls.67 The greatest beneﬁt of exercise on fall rates was seen with programs that included challenging balance exercises and long duration (>50 hours).68
  
  OCULAR DIZZINESS
  Common Causes
  Many patients complain of a vague dizziness when they ﬁrst wear glasses. They describe a feeling of disorientation, often accompanied by headache. The dizziness most frequently accompanies correction of astigmatism but also occurs after a change in magniﬁcation. It is nearly always mild and short-lived. A more per- sistent and distressing dizziness may occur in patients who are required to use high magniﬁ- cation or who have had a lens implant after cataract removal to correct severe visual loss. In these cases, the vestibulo-ocular reﬂex must adapt if visual objects are to be stabilized dur- ing head movements. This compensation pro- cess may be slow or inadequate in elderly patients or in subjects who require magniﬁca- tion so high that it is beyond the adaptive range of the vestibulo-ocular reﬂex.69 Multifocal glasses may predispose to dizziness and falls in older people.70
  Dizziness also can result from an imbalance in the extraocular muscles. After an acute ocu- lar muscle paralysis, looking in the direction of the paralyzed muscle causes dizziness (in addi- tion to diplopia). This dizziness results from a mismatch between where the brain “thinks” the eye is, based on its efferent innervation, and where it actually is, based on the visual sig- nal.71 As with other types of ocular dizziness, the nervous system usually adapts to this altered spatial information and the dizziness is rarely severe or prolonged.
  
  Oscillopsia
  The optic illusion that stationary objects are moving back and forth or up and down is called oscillopsia. It is usually a sign of vestibular, brainstem, or cerebellar involvement, although rarely it can result from paralysis of the eye
  Oscillopsia
  
  Spontaneous nystagmus
  
  Unilateral peripheral vestibular lesion
  
  Unilateral peripheral vestibular lesion
  No Yes
  
  Bilateral peripheral vestibular or cerebellar lesion
  Bilateral peripheral vestibular or cerebellar lesion
  Yes
  
  Head movement induced
  
  No
  
  Transient with vertigo
  
  No
  
  Yes
  
  Visual association cortex
  Central vestibular or cerebellar lesion
  Visual association cortex
  Central vestibular or cerebellar lesion
  
  Figure 5–2. Logic for distinguishing between different causes of oscillopsia.
  
  muscles or from a lesion in the visual associa- tion areas in the cortex (Fig. 5–2). Oscillopsia can be either a constant symptom or a move- ment-induced symptom. Not surprisingly, con- stant oscillopsia is associated with acquired spontaneous nystagmus. If a patient attempts to ﬁxate on an object after an acute unilateral peripheral vestibular lesion, it will appear blurred and seem to be moving in the opposite direction of the slow phase of the spontaneous nystagmus. Some patients will report a ﬂicking back and forth associated with the fast compo- nent of nystagmus. The oscillopsia associated with unilateral peripheral vestibular lesions is usually transient, disappearing as the acute ver- tigo and spontaneous nystagmus disappear. Patients with spontaneous nystagmus due to lesions of the central vestibular pathways report severe persistent oscillopsia, invariably associ- ated with other symptoms and signs of brain- stem dysfunction.
  Oscillopsia that occurs only with head move- ment suggests some abnormality of the vestib- ulo-ocular reﬂexes. Patients with symmetrical loss of vestibulo-ocular reﬂex function (e.g., due to ototoxic drugs) are unable to ﬁxate on objects when walking because the surround- ings appear to be bouncing up and down.72 The head oscillates in the vertical plane in the fre- quency range of 2 to 3 Hz. The visual pursuit system cannot compensate for the loss of ves- tibular function in this frequency range. In order to see the faces of passersby, patients learn to stop and hold their heads still. When reading, they learn to stabilize the head by
  placing their hand on their chin to prevent even the slightest movements associated with pulsatile cerebral blood ﬂow. Patients with cer- ebellar lesions cannot suppress their vestibulo- ocular reﬂex with ﬁxation. They experience a brief sensation of oscillopsia after each rapid head movement, owing to a transient, unwanted vestibular nystagmus. These patients typically have gaze-evoked nystagmus on lateral or verti- cal gaze, so they may experience oscillopsia with both head and eye movements.
  
  Management
  Ocular dizziness due to changes in refraction is rarely severe and usually disappears spontane- ously as the patient adjusts to the altered visual environment. Patients should be encouraged to return to normal activities even though the diz- ziness is initially worse. In the long term this will accelerate the central compensation process. By contrast, oscillopsia is often a severe, persistent symptom that can be disabling. The most both- ersome type is that associated with an acquired central spontaneous nystagmus (see “Spontaneous Nystagmus” in Chapter 6). With one exception (Baclofen for periodic alternating nystagmus), drugs are not effective in suppress- ing oscillopsia due to central spontaneous nys- tagmus.73 If the nystagmus has a clearly deﬁned null region, prisms ﬁtted in glasses or eye mus- cle surgery can sometimes be helpful. In patients with head movement–induced oscillopsia due to bilateral peripheral vestibular loss, the visual
  and neck ocular reﬂexes can compensate for the loss during low-frequency head movements but not during high-frequency movements.74,75 When walking, patients learn to stop and hold their head still to see clearly. Unlike the widely available devices used to augment an impaired auditory system, there are no current devices that augment the vestibular system. A number of devices that aim to improve the overall bal- ance function in patients with bilateral vestibul- opathy are in the development phase or early clinical testing phase.76–83 These devices gener- ally encode head or body movements into tactile cues that are delivered to the trunk and tongue.‌‌
  
  MULTISENSORY DIZZINESS ‌
  Occasionally, one can trace dizziness to disease involving multiple sensory systems, particularly in elderly patients and in patients with systemic disorders, such as diabetes mellitus.84 A typical combination might include peripheral neurop- athy resulting in diminished touch and proprio- ceptive input, decreased visual acuity (cataracts, glaucoma), and impaired hearing (as in presby- cusis). In such patients an added vestibular impairment (from ototoxic drugs, for example) can be devastating, making it impossible for them to walk without assistance. Patients with multisensory dizziness may be unable to adapt to unfamiliar surroundings, such as in the hospital. Not infrequently, their complaint of dizziness will improve when they return to familiar surroundings at home.
  
  Management
  Treatment is directed at increasing sensory input wherever possible. This might include improved diabetic control, surgery for cataracts or glaucoma, ampliﬁcation for presbycusis, and the use of a cane or walker to improve support and increase somatosensory signals. As with other balance disorders, sedating medications should be avoided.
  
  PHYSIOLOGIC DIZZINESS
  Physiologic dizziness refers to a group of phe- nomena that occur in normal subjects with
  physiologic stimulation of the vestibular, visual, or somatosensory systems. It typically results from a mismatch in sensory signals, resulting in a feeling of disorientation, imbalance, and veg- etative symptoms.
  
  Motion Sickness
  Motion sickness refers to the syndrome of diz- ziness, perspiration, nausea, vomiting, increased salivation, yawning, and generalized malaise induced by motion.85 It is usually produced by vestibular stimulation but also can occur with visual stimulation (e.g., with prolonged optokinetic stimulation). Both linear and angular head acceleration induce motion sick- ness if applied for long periods in susceptible subjects. Combinations of linear and angular acceleration or multiplanar angular accelera- tions are particularly effective. Rotation about the vertical axis, along with either voluntary or involuntary nodding movements in the sagittal plane, rapidly produce motion sickness in nearly everybody. This movement combines linear and angular acceleration (Coriolis effect).
  Autonomic symptoms are usually the initial manifestation of motion sickness.86 Sensitive sweat detectors can identify increased sweating as soon as 5 sec after onset of motion, and grossly detectable sweating is usually apparent before any noticeable nausea. Increased saliva- tion and frequent swallowing movements occur early. Gastric motility is reduced and digestion is impaired. Hyperventilation is almost always present, and the resulting hypocapnia leads to changes in blood volume with pooling in the lower parts of the body, predisposing the sub- ject to postural hypotension. Motion sickness affects the appetite so that even the sight or smell of food is distressing.
  Other symptoms of increased sensitivity may suggest a general hypersensitivity syndrome in these patients. Other hypersensitivity symp- toms include sensitivity to light, sound, and other pain syndromes, dry eyes, and irritable bowel syndrome.
  Some people are sensitive to development of motion sickness, but others are highly resistant. Most will adapt to prolonged vestibular stimula- tion, whereas some never adapt (the chronically seasick ocean voyager). For unknown reasons, babies are highly resistant to motion sickness.
  Unfortunately, there is no reliable way to predict who will develop motion sickness. Thresholds for vestibular stimulation (rotational or caloric) and the rate of habi- tuation to vestibular stimulation are no differ- ent in susceptible and resistant subjects.87 Patients whose labyrinths have been inacti- vated by congenital or acquired disease are resistant to motion sickness, whether induced by visual or vestibular stimuli. Such patients can withstand prolonged exposure to wave motion during a heavy storm at sea that would lead to motion sickness in even the most hard- ened seaman.
  Genetic factors clearly are important in sus- ceptibility to motion sickness. Twin studies indicate heritability for motion sickness in the range of 55% to 70%.88 Families with migraine have increased sensitivity to developing motion sickness.89 A functional polymorphism in the alpha2-adrenergic receptor gene was signiﬁ- cantly more common in subjects susceptible to motion sickness compared to those who were not sensitive to motion sickness.90 Since this receptor mediates central and peripheral auto- nomic responses, alleles that affect the level of expression could explain the varied autonomic responses to provocative motion. However, the ﬁndings need to be replicated in other populations.
  Motion sickness seems to result from a visual–vestibular conﬂict.91 This theory is sup- ported by the fact that visual inﬂuences during body motion have a clear effect on the develop- ment of motion sickness. The symptoms are aggravated if one sits in an enclosed cabin on a ship or in the back seat of a moving vehicle. Because the environment is moving with the subject, visual–vestibular conﬂict occurs. The vestibular system signals movement while the visual system signals a stationary environ- ment. Motion sickness can be alleviated by improving the match between visual and ves- tibular signals. This can be accomplished on a ship by standing on deck and focusing on the distant horizon or on land, if possible. When riding in a car, the susceptible subject should sit in the front seat to allow ample peripheral vision of the stationary surround. Motion sick- ness suppressants such as scopolamine and dimenhydrinate are effective, presumably by diminishing activity at the vestibular nucleus and thereby diminishing the potential for visual–vestibular conﬂict.85,92
  Space Sickness
  Space sickness is a kind of motion sickness that is induced by active head movements in space.93,94 It has occurred in approximately 50% of the astronauts and cosmonauts who have entered space. Most adapt within 2 to 3 days. Because active head movements do not elicit motion sickness within the gravitational condi- tions on earth, the absence of gravity appears to be a key factor. The leading theory at pres- ent is that the symptoms are generated by a mismatch between otolith and semicircular canal signals as well as between otolith and visual signals.94 On earth, the semicircular canals and otoliths work together, sensing the angular and linear acceleration components of active head movements, but in space the oto- liths fail to signal orientation of the head in the absence of gravity. Thus, the afferent signals generated by head movements in space are dif- ferent from the signals expected from prior calibration on earth. The vestibular system must recalibrate to account for the absence of gravity; presumably this recalibration takes about 3 days. Supporting this notion, some astronauts develop transient motion sickness when they return to earth, although it is usually of shorter duration than in space.
  
  Height Vertigo
  Height vertigo refers to the subjective sensa- tion of instability and imbalance along with a fear of falling and vegetative symptoms that normal subjects experience in high places. More appropriate terms might be “height diz- ziness” or “height sickness,” inasmuch as there is usually no illusion of movement. Height ver- tigo occurs when the distance between the observer and visible stationary contrasting objects in the environment becomes critically large.95 Presumably, the normal lateral and fore–aft body sway sensed by the vestibular system conﬂicts with the visual information of no sway (the greater the distance between the eyes and the nearest stationary object, the smaller the angular displacement on the ret- ina). The symptoms can be reduced by having the subject sit or lie down to increase soma- tosensory input or by having a nearby station- ary object in the visual periphery, such as a railing or window frame. Some subjects develop
  associated panic attacks and avoidance behav- ior typical of agoraphobia. Cognitive factors such as anticipatory anxiety and overestimation of somatic symptoms play an important role in the development of agrophobia.96
  
  Mal de Debarquement Syndrome
  Most of us have experienced the persistent rocking sensation after disembarking from a boat, particularly after a long voyage. This usu- ally subsides gradually over a few hours and seldom is of major signiﬁcance. Rarely, patients report the persistent rocking sensation of a boat long after returning to land (months to years).97,98 These patients often report that their symptoms are less bothersome when they are in motion such as driving, swimming, or going back on a boat. The syndrome typically devel- ops in middle age and is more common in women than in men.98 Both motion-triggered and spontaneous episodes occur with the latter more common in patients with migraine. The cause is unknown but presumably it represents maladaptation within the central vestibular pathways.‌
  
  SUMMARY: DISTINGUISHING BETWEEN VESTIBULAR AND NONVESTIBULAR TYPES OF DIZZINESS
  Although the description alone does not distin- guish between vestibular and nonvestibular causes of dizziness, certain words are commonly
  used to describe each type of dizziness (Table 5–9). A sensation of “spinning” nearly always indicates a vestibular disorder, particularly if it is moderate to severe in intensity and when the environment is seen moving (as opposed to an “internal” sensation). Patients with nonvestibu- lar dizziness occasionally will report a sensation of spinning inside the head, but the environ- ment remains still and they do not have nystag- mus. Patients with vestibular lesions often liken the sensation to that of being “drunk” or “motion sick.” They describe feelings of “imbalance,” as though they are “falling” or “tilting” to one side. Illusions of motion of the environment are rare but illusions of self-motion are common in patients with nonvestibular dizziness. These patients typically use terms such as “light- headed,” “ﬂoating,” “rocking,” “giddy,” or “swimming.” The sensation that one has left one’s body is characteristic of psychophysiologic dizziness.
  Vertigo is an episodic phenomenon, whereas nonvestibular dizziness is often continuous. An exception would be presyncopal light-headed- ness caused by postural hypotension or cardiac arrhythmia. Patients with psychophysiologic dizziness often report being dizzy from morn- ing to night without changes for months to years at a time. Vertigo is typically aggravated by head movements, whereas nonvestibular dizziness is often aggravated by movement of visual targets. Episodes of dizziness induced by position change suggest a vestibular lesion if postural hypotension has been ruled out. Although stress can aggravate both vestibular and nonvestibular dizziness, dizziness that is reliably precipitated by stress suggests a non- vestibular cause. Finally, episodes of dizziness
  
  Table 5–9 Distinguishing between Vestibular and Nonvestibular Types of Dizziness
  Factor Vestibular Nonvestibular
  Common descriptive terms
  Spinning (environment moves), merry-go-round, drunkenness, tilting, motion sickness,
  off-balance
  Light-headed, ﬂoating, dissociated from body, swimming, giddy, “internal” spinning (environment stationary)
  Course Episodic Constant
  Common precipitating or aggravating factors
  Commonly associated symptoms
  Head movements, position change
  Nausea, vomiting, unsteadiness, tinnitus, hearing loss, impaired vision, oscillopsia
  Stress, hyperventilation, cardiac arrhythmias, situations
  Paresthesias, syncope, difﬁculty concentrating, tension headache
  
  occurring only in speciﬁc situations (e.g., driv- ing on the freeway, entering a crowded room, or shopping in a busy supermarket) suggest a
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  Chapter 6 ‌‌
  
  Bedside Examination of the Vestibular
  System
  
  EXAMINATION OF THE EAR ‌
  Fistula Test
  TESTS OF VESTIBULOSPINAL REFLEXES
  Pastpointing Static Posture Walking Tests
  TESTS OF VESTIBULO-OCULAR REFLEXES
  Doll’s Eye Test (Oculocephalic Response) Head-Thrust Test
  Dynamic Visual Acuity Cold Caloric Test Rotational Testing
  TESTS FOR PATHOLOGIC NYSTAGMUS
  Methods of Examination
  TYPES OF PATHOLOGIC NYSTAGMUS
  Spontaneous Nystagmus Gaze-Evoked Nystagmus Positional Nystagmus Vibration-Induced Nystagmus Head-Shaking Nystagmus
  Hyperventilation-Induced Nystagmus
  OTHER OCULAR OSCILLATIONS
  Dissociated Spontaneous Nystagmus Voluntary Ocular Oscillations (Voluntary
  Nystagmus)
  Convergence Retraction Nystagmus Saccadic Intrusions
  Ocular Bobbing
  Palato-Ocular Myoclonus
  OCULAR TILT REACTION
  
  As noted earlier, the vestibular system works in conjunction with the visual and somatosensory systems to achieve ocular and postural stability. To examine the vestibular system adequately, one must isolate it from these other sensory systems. Historically this has been a difﬁcult task at the bedside, which is why most general textbooks only describe ways to assess the “audio” component of the audio-vestibular sys- tem or eighth cranial nerve. The contribution of the visual system can be removed with eye closure, but then the eye movements gener- ated by the vestibular system cannot be observed. There is no simple way to eliminate somatosensation.
  Unlike the visual system, in which the optic nerve can be directly visualized and acuity accurately measured, the inner ear is located
  deep within the temporal bone, and the subjec- tive sensation to vestibular stimulation is ill deﬁned. One can visualize the tympanic mem- brane and some structures within the middle ear, but this generally provides no information about the status of the inner ear.
  
  EXAMINATION OF THE EAR
  The neurotologist should be familiar with the normal anatomy of the external canal and tym- panic membrane (see Chapter 2), be capable of removing cerumen that interferes with visu- alization of the tympanic membrane, and be able to recognize certain common disorders on inspection (Fig. 6–1). Otoscopy is performed
  149
  Figure 6–1. Appearance of the tympanic membrane in a normal subject (A) and in patients with a superior marginal perforation and cholesteatoma (B), a tympanic glomus body tumor (C), and a step deformity caused by a longitudinal temporal bone fracture (D).
  
  with the largest speculum that ﬁts comfortably into the external canal: the pinna is gently pulled posterior and superior to straighten the canal. The tympanic membrane is normally translucent; changes in color indicate middle ear disease (e.g., an amber color with middle ear effusions). Tympanosclerosis, the conse- quence of a resolved otitis media or trauma, appears as a semicircular crescent or horse- shoe-shaped white plaque within the tympanic membrane. It is rarely associated with hearing loss but is an important clue to past otitic infections. The pars ﬂaccida region, the area superior to the lateral process of the malleus, should be carefully inspected for evidence of a retraction pocket or attic cholesteatoma. The ossicles and the color of the underlying mucous membrane of the middle ear can often be assessed through a normal translucent tym- panic membrane. Pneumatoscopy allows one to determine the mobility of the tympanic membrane. Lack of mobility may indicate an unsuspected perforation (usually under an anterior overhang), ﬂuid in the middle ear, or severe scarring of the tympanic membrane or middle ear.
  Fistula Test
  A ﬁstula test is performed by transiently increasing and decreasing the pressure in the external canal with a pneumatoscope.1 A posi- tive ﬁstula sign (a transient burst of nystagmus and vertigo) occurs in patients with a perfo- rated tympanic membrane and erosion of the bony labyrinth from conditions such as chronic infection, surgery, or trauma. The change in pressure is transmitted directly to the peri- lymph, compressing the membranous labyrinth and stimulating the semicircular canal cristae. The resulting nystagmus usually lasts from 10 to 20 sec. The direction of the nystagmus may be toward or away from the involved ear and is often the same for both positive and negative pressure changes.
  Lesser ocular and subjective responses may occur in patients with an intact tympanic mem- brane. Hennebert 2 ﬁrst described this sign in patients with congenital syphilis, but it can occur in patients with a wide range of labyrin- thine disorders. The response is a slow ocular deviation followed by a few beats of nystagmus even with sustained pressure. The abnormal
  eye movements are in the plane of the affected semicircular canal. With semicircular canal dehiscence syndrome the pressure changes are transmitted to the abnormal canal due to the presence of a “third window” in the bony laby- rinth (see Fig. 16–3 in Chapter 16). In the case of endolymphatic hydrops (idiopathic or sec- ondary to infection), ﬁbrous adhesions between the medial surface of the stapedial footplate and the membranous labyrinth could result in displacement of endolymph when the footplate moves.3 This sign can occasionally be elicited during routine pneumatoscopy in normal sub- jects. In these cases it is usually present bilater- ally. The mechanism by which pressure changes in the external auditory canal result in a pres- sure gradient across a normal vestibular recep- tor organs is unclear.‌‌
  Fistulas of the labyrinth can also be tested for by inducing pressure changes by pressing and releasing the tragus (induces less pressure changes in the external canal than pneumatos- copy), Valsalva maneuver against closed glottis (increases intracranial pressure which can be transmitted to the inner ear by an intracranial ﬁstula such as superior canal dehiscence), and Valsalva maneuver against pinched nostrils (increases pressure transmitted to the middle ear via the Eustachian tube).4
  TESTS OF VESTIBULOSPINAL REFLEXES
  As discussed in Chapter 3, the labyrinths inﬂu- ence spinal cord motoneurons through the lat- eral vestibulospinal tract, the reticulospinal tract, and the descending medial longitudinal fasciculus (MLF). Labyrinthine stimulation of the spinal cord increases extensor tone and decreases ﬂexor tone, resulting in a facilitation of the antigravity muscles. Both otolith and semicircular canal signals inﬂuence spinal cord anterior horn cells, but the former are more important in maintaining posture.
  
  Pastpointing
  Pastpointing refers to a reactive deviation of the extremities caused by an imbalance in the vestibular system (Fig. 6–2). The test is per- formed by having patients place their extended index ﬁnger on that of the examiner’s, close their eyes, raise the extended arm and index ﬁnger to a vertical position, and attempt to return the index ﬁnger to the examiner’s. Consistent deviation to one side is pastpointing (See Video 6–1).
  
  Past Pointing
  2 Test
  
  3 1
  
  Romberg Test
  
  Tandem Walking
  
  Figure 6–2. Bedside tests of vestibulospinal function.
  Pastpointing tests represent one of the earli- est attempts to clinically assess vestibular func- tion. In 1910, Bárány5 published a review of pointing deviation and emphasized the impor- tance of having patients sit with their eyes closed to avoid confusion with other orienting information. Bárány showed that caloric stimu- lation consistently induced pastpointing in the direction of the slow component of induced nystagmus. Cold caloric irrigation (inhibiting the horizontal ampullary nerves’ spontaneous ﬁring rate) resulted in pastpointing toward the irrigated ear, and warm caloric irrigation induced the opposite effect. As expected, patients with acute unilateral loss of vestibular function past-pointed toward the damaged side. Bárány and numerous others emphasized that repeated testing shows a large variability, occasionally with drift in the wrong direction. Subsequent investigators tried to improve test accuracy by eliminating tactile feedback and using small ﬁnger lamps that could be photo- graphed, but the large variability among nor- mal subjects and patients remained.
  It is apparent that results from a single point- ing test can be misleading and should not be considered clinically relevant when in isolation. Extralabyrinthine inﬂuences should be elimi- nated as much as possible by having the patient seated with eyes covered and arms and index ﬁngers extended throughout the test. The standard ﬁnger-to-nose test will not identify pastpointing, inasmuch as joint and muscle proprioceptive signals permit accurate localiza- tion even when vestibular tone is asymmetric. Although patients with acute peripheral ves- tibular damage usually past-point toward the side of loss, compensation rapidly corrects the pastpointing and can even produce a drift to the other side. The cortical and subcortical pathways to the spinal anterior horn cells, illus- trated in Figure 1–14 in Chapter 1, apparently account for the compensation.
  
  Static Posture
  Patients with damage to the vestibular system often suffer instability of the trunk and lower limbs so that they sway back and forth or even fall to one side. In 1846, Romberg6 noted that patients with proprioceptive loss from tabes dorsalis were unable to stand with feet together and eyes closed. Bárány7 ﬁrst emphasized the
  importance of vestibular inﬂuences in main- taining the Romberg position (Fig. 6–2). As with pastpointing, he noted that patients with acute unilateral labyrinthine lesions swayed and fell toward the diseased side, that is, in the direction of the slow component of nystagmus. However, like the pastpointing test, the Romberg test was found to be rather insensi- tive for detecting chronic unilateral vestibular impairment, and sometimes the patient would fall toward the intact ear. The so-called sharp- ened Romberg test is a more sensitive indica- tor of vestibular impairment. For this test the patient stands with feet aligned in the tandem heel-to-toe position with eyes closed and arms folded against the chest. Most normal subjects under the age of 70 can stand in this position for 30 sec: older normal subjects and patients with unilateral or bilateral vestibular impair- ment usually cannot sustain the position. Abnormalities on this test, however, are not speciﬁc to the vestibular system.
  Although lower mammals consistently develop ipsilateral hypotonia of extensor mus- cles after labyrinthectomy, one rarely ﬁnds this in human patients. Occasionally, slight asym- metry in posture is found with the ipsilateral upper extremity slightly ﬂexed and abducted compared to the contralateral upper extremity. The clinically elicited deep tendon reﬂexes are also unaffected by vestibular lesions. Apparently, other supraspinal inﬂuences on the anterior horn cells rapidly compensate for the loss of tonic vestibular signals.
  
  Walking Tests
  Unterberger8 was the ﬁrst to systematically study the tendency of vestibular stimulation or unilateral vestibular lesions to induce blind- folded subjects to turn in the earth’s vertical axis when walking. The direction of turning coincided with the direction of pastpointing and falling (in the direction of the slow compo- nent of nystagmus). Fukuda9 obtained similar results by having subjects take 50 to 100 steps on the same spot and recording the angle of rotation as well as forward and backward move- ments. Both of these tests were performed with arms extended parallel and horizontal in front of the subject, so upper extremity deviation (pastpointing) may have added to the tendency to rotate in a given direction. Tandem gait tests
  (Fig. 6–2) are widely used as part of the routine neurologic examination, and most clinicians recognize normal and abnormal performances. When performed with eyes open, tandem walk- ing is primarily a test of cerebellar function, because vision compensates for chronic vestibular and proprioceptive deﬁcits. Acute vestibular lesions, however, typically impair tandem walking, even with the eyes open.‌‌
  Recently, there has been an emphasis on timed walking tests to provide a semiquantita- tive measure of balance and risk of falling in older patients. These tests are not speciﬁc for vestibular function but rather provide an over- all measure of gait and balance. Gait speed (over a set path), timed tandem stance and walking, and maximum step length (ability to maximally step out and return to the initial position) have all been shown to predict the likelihood of falls in older people.10,11
  
  TESTS OF VESTIBULO-OCULAR REFLEXES
  Doll’s Eye Test (Oculocephalic Response)
  The doll’s eye test involves slowly moving the head back and forth in the horizontal plan to induce reﬂex eye movements. In an alert human these eye movements result from com- bined visual and vestibular stimulation. Therefore, a patient with complete loss of ves- tibular function will have compensatory eye movements on the test if the visuomotor sys- tem is intact. On the other hand, an alert human can also use the visuomotor system (i.e., the smooth pursuit system) to overcome or sup- press the vestibular eye movement in this test that uses slow passive movements of the head. In a comatose patient, however, the doll’s eye test is a useful bedside test of the vestibulo- ocular reﬂex since the pursuit system is not functioning.12 Conjugate compensatory eye movements indicate normally functioning vestibulo-ocular pathways (those shown in Fig. 3–8 in Chapter 3). This test is a standard component of the coma exam and also brain death exam because the reﬂex eye movements indicate intact function not only of the inner ear but also the brain stem. Absence of reﬂex
  eye movements in a comatose patient is usually an ominous sign, indicating massive brain stem damage if acute drug intoxication or metabolic disorders can be ruled out.13,14
  The doll’s eye test can also provide highly localizing information. For example, if the test results in disconjugate eye movements, then one could localize the lesion to MLF, the ocul- omotor neurons, or the ocular muscles (depend- ing on the abnormal pattern).
  
  Head-Thrust Test
  The head-thrust test is a simple way to identify a complete unilateral or bilateral loss of ves- tibular function at the bedside.15 The discovery of this test was a major breakthrough in the ability to examine the vestibular system at the bedside. Prior to the head-thrust test, the bed- side assessment was mostly limited to search- ing for surrogate signs of an acute vestibular imbalance (i.e., nystagmus). Tests such as past- pointing, the Unterberger test, and the doll’s eye test could be used, but these had major limitations as noted previously.
  The head-thrust test is used to directly assess for vestibular de-afferentation and thus is anal- ogous to the test for an afferent pupillary defect (i.e., the swinging light test). Though the affer- ent pupillary defect was ﬁrst reported around 1900,16 the head-thrust test was not reported until 1988.15 Despite the consensus opinion among neurotologists regarding the substantial value of the head-thrust test, it remains a test that is underappreciated and underutilized in the general medical community.
  The head-thrust test is performed by grasp- ing the patient’s head and applying brief, small- amplitude, high-acceleration head thrusts, ﬁrst to one side and then to the other (Fig. 6–3, See Video 6–2 and Video 6–3). Before the move- ment, the patient is instructed to ﬁxate on the examiner’s nose. During and after the quick movements, the examiner closely watches the patient’s eye position looking speciﬁcally for “catch-up” saccades, which are the sign of an inappropriate compensatory vestibular system response. If the vestibular system is intact on both sides, then movement to either side trig- gers the eye movements (the eye movements are triggered by a reﬂex, the vestibulo-ocular reﬂex) that keep the patient’s eyes ﬁxated on the examiner’s nose. On the other hand, if a
  (a) 20°
  
  Fixed target
  
  (b) 20°
  
  Figure 6–3. The head thrust test. The head thrust test is a test of vestibular function that can be easily done during the bedside examination. This maneuver tests the vestibulo-ocular reﬂex (VOR). The patient sits in front of the examiner and the examiner holds the patient’s head steady in the midline. The patient is instructed to maintain gaze on the nose of the examiner. The examiner then quickly turns the patients head about 10-15 degrees to one side and observes the ability of the patient to keep the eyes locked on the examiner’s nose. If the patient’s eyes stay locked on the examiner’s nose (i.e., no corrective saccade) (picture a), then the peripheral vestibular system is assumed to be intact. If, however, the patient’s eyes move with the head (picture b) and then the patient makes a voluntary eye movement back to the examiner’s nose (i.e., corrective saccade), then this indicates a lesion of the peripheral vestibular system and not the central nervous system. Thus, when a patient presents with the acute vestibular syndrome, the test result shown in picture A would suggest a CNS lesion (because the VOR is intact), whereas the test result in picture B would suggest a peripheral vestibular lesion (because the VOR is not intact).
  With permission from: Edlow JA, Newman-Toker DE, Savitz SI. Lancet Neurology. 2008; 7:951–964.
  vestibular lesion is present, then the movement in the direction of the lesion results in the eyes moving with the patient’s head (because the reﬂex is not working to move the eyes in the opposite direction). Thus, if a patient has a right vestibular lesion, then after a head thrust to the right, the patient’s eyes will move with the head (stay in midline position), and then the patient will have to make a voluntary saccade (“catch- up” or “corrective” saccade) back to the exam- iner’s nose.
  The passive head movement is fast enough (high enough acceleration) that the smooth pursuit system cannot be used to keep the patient’s eyes ﬁxated on the examiner’s nose (recall how the smooth pursuit system can cover up for vestibular impairment with the low- velocity and low-frequency movements of the doll’s eye test). In addition, the patient also can- not initiate a voluntary saccade fast enough to keep the eye’s on the nose and for this reason a “catch-up” saccade is required to move the eye back to the nose. Of course, if a patient can cor- rectly predict the direction of the head move- ment and then time the initiation of a saccade accurately, then a voluntary saccade can come very close to covering up for a vestibular lesion. In the same way that the afferent pupillary defect is mostly a test of the optic nerve func- tion, the head-thrust test is mostly a test of the vestibular nerve function. Intact end-organ (e.g., labyrinthine) function is of course required to generate the vestibulo-ocular reﬂex but a disorder of the end-organ may not result in a positive test unless it is severe or complete. Similarly, retinal lesions, unless severe, do not typically result in an afferent pupillary defect. For this reason, the head-thrust test is typically not positive in patients with Meniere’s disease unless a procedural lesion has been per- formed.17 In addition, the accuracy of the head- thrust test is also inﬂuenced by the severity of the nerve lesion. For example, the head-thrust test may not be positive if the vestibular nerve lesion is only mild to moderate in severity (i.e., resulting in approximately less than a 50% paresis) but is nearly always positive with lesions that are moderate to severe.18,19 It is not completely fair to gauge the value of the quali- tative positive versus negative results of the head-thrust test to the quantitative results of the caloric test. The reason is because the head thrust is a test of the vestibular system at high acceleration, whereas the caloric test is a test of
  the vestibular system at a very low acceleration. Furthermore, the caloric test, though generally regarded as the gold standard test for a unilat- eral vestibular lesion, is known to have con- cerning levels of false-positive results based on the limitations of the test and thus is not an optimal gold standard test.20
  The head-thrust test is nearly always positive in patients with acute vestibular neuritis because the lesion is of the vestibular nerve and is typically at least a moderate to severe lesion.21,22 For this reason, the head thrust is particularly valuable in the presentation of the acute vestibular syndrome because a positive head-thrust test is a very strong indicator of a lesion of the vestibular nerve (and thus the most common cause, vestibular neuritis). A negative head-thrust test in the acute vestibu- lar syndrome suggests the vestibular nerve is intact and thus the likelihood of a a brainstem or cerebellar lesion increases.21,22
  The head-thrust test is also particularly help- ful for identifying a bilateral vestibulopathy. A bilateral vestibulopathy can be difﬁcult to rec- ognize based on the symptom report and gen- eral examination. As a result, many patients likely go undiagnosed. However, a positive bilateral head-thrust test can clinch the diagno- sis at the bedside.
  
  Dynamic Visual Acuity
  The dynamic visual acuity test is performed by having the patient shake the head rapidly back and forth in the horizontal plane at approxi- mately 2 Hz while reading a Snellen visual acu- ity chart at the standard distance.23,24 Inasmuch as the smooth pursuit system functions best below 1 Hz and almost not at all at 2 Hz, this is primarily a test of the horizontal vestibulo- ocular reﬂex. A drop in acuity of more than one line on the Snellen chart suggests an abnormal vestibulo-ocular reﬂex. The test is most useful for identifying bilateral vestibular loss but can also be abnormal with unilateral vestibular loss and with cerebellar lesions.25,26
  
  Cold Caloric Test
  Because of its ready availability, ice water (approximately 0°C) is commonly used for bedside caloric testing.27 Tap water can be
  brought to 4°C in about 10 minutes after add- ing ice cubes. To bring the horizontal canal into the vertical plane, the patient lies in the supine position with the head tilted 30 degrees forward or in the sitting position with the head tilted 60 degrees backward (see Fig. 1–4C in Chapter 1). Infusion of ice water induces a burst of nystagmus with slow phase toward the side of infusion and the fast phase in the oppo- site direction, usually lasting from 1 to 3 min. The volume of ice water recommended for this test varies from 0.5 to 2 ml. Regardless of the volume used, however, it is critical that the stimulus reach the eardrum (i.e., not be injected into the canal wall or in a canal blocked by cerumen). Direct visualization of the eardrum is mandatory. We suggest using 1 or 2 ml of ice water infused directly against the tympanic membrane through a small rubber hose. The ear being infused is turned upward for approx- imately 30 sec after the infusion to be certain that the water stays against the drum. In an alert subject, a burst of nystagmus will develop within 30 sec to 1 min after infusion and last from 1 to 3 min. In a comatose patient, only a slow tonic deviation toward the side of stimula- tion is observed because the brain does not generate the fast phases. In normal subjects, duration and speed of induced nystagmus var- ies greatly, but >20% asymmetry in nystagmus duration suggests the possibility of a lesion on the side of the decreased response, though this test is less valid than standard bithermal caloric testing with nystagmography (see Bithermal Caloric Test in Chapter 7).‌‌
  In terms of the bedside vestibular evaluation in an alert subject, the use of the cold caloric test has largely been replaced by the head- thrust test.
  
  Rotational Testing
  Qualitative rotational testing of the horizontal vestibulo-ocular reﬂex can be performed at the bedside by using a swivel chair. Bárány7 intro- duced a rotatory test in which the chair on which the patient was seated was manually rotated 10 times in 20 sec and then suddenly stopped with the patient facing the observer. The duration of postrotatory nystagmus in each direction was then measured. In normal subjects an average of 22 sec was required for cessation of postrota-
  was large. Much of this variability could be traced to the difﬁculty in manually maintaining constant velocity and then a uniform sudden deceleration. Furthermore, the vestibular response to the initial acceleration was often not completed before deceleration began, resulting in interaction between the two responses. As with the ice water caloric testing, this type of qualitative testing can provide only gross information about the presence and sym- metry of vestibular function, and thus it is not felt to be as valuable as the head-thrust test. One aspect of rotational testing that is useful at the bedside is the ﬁxation-suppression test. With this test the subject extends the arm rig- idly and attempts to ﬁxate on the extended thumb while the entire body is rotated back and forth en bloc. Normal subjects can completely suppress their vestibulo-ocular reﬂex, keeping their eyes ﬁxed in the center of the orbits (as shown in Fig. 1–9 in Chapter 1). Abnormal ﬁxation-suppression (nystagmus) indicates impairment of the smooth pursuit systems and thus is an indicator of a central lesion, often involving the cerebellum (see “Visual-Vestibular Interaction” in Chapter 7).
  
  TESTS FOR PATHOLOGIC NYSTAGMUS
  Nystagmus can be deﬁned as a nonvoluntary rhythmic oscillation of the eyes. It usually has clearly deﬁned fast and slow components alter- nating in opposite directions. By convention, the direction of the fast component deﬁnes the direction of nystagmus (e.g., left-beating nys- tagmus indicates the fast phase is to the left). Physiologic nystagmus refers to nystagmus that occurs in normal subjects, whereas pathologic nystagmus implies an underlying abnormality (Table 6–1). Spontaneous nystagmus refers to nystagmus that occurs with the eyes in the pri- mary position, without external stimulation
  
  Table 6–1 Types of Nystagmus
  Physiologic Pathologic
  Rotational-induced Spontaneous
  Caloric induced Gaze-evoked
  Optokinetic Positional
  End-point
  tory nystagmus, but intersubject variability
  such as movement of the head or surroundings. Gaze-evoked nystagmus is induced by changes in gaze position. Nystagmus that is not present in the sitting position but is present in some other head and body position is called posi- tional nystagmus. This deﬁnition excludes nys- tagmus present in the sitting position that is modiﬁed by a change in position.
  
  Methods of Examination
  The clinical examination for pathologic nystag- mus should include a systematic study of changes in (1) ﬁxation, (2) eye position, and (3) head position. Omission of any of these three maneuvers may lead to overlooking the pres- ence of nystagmus or misinterpreting its type. Sometimes pathologic nystagmus can be trig- gered by vibration, head shaking, or hyperven- tilation.
  Spontaneous nystagmus may be present with ﬁxation, or it may occur only when ﬁxation is inhibited (See Video 6–4). There are several simple methods for achieving the latter at the bedside. Frenzel glasses consist of +30 lenses mounted in a frame that contains a light source on the inside so that the patient’s eyes are eas- ily visualized (Fig. 6–4). The light can be pow- ered by a battery, making the entire system portable. Frenzel glasses should be used only in a darkened room, because the patient can ﬁxate (at least partially) through the lenses in a lighted room. An ophthalmoscope can also be used to block ﬁxation and bring out a
  spontaneous nystagmus. While the fundus of one eye is being visualized the patient is asked to lightly cover the other eye with one hand. Nystagmus appears as a slow drift of the retina in one direction interrupted by ﬂicking move- ments in the opposite direction (the direction of the nystagmus is reversed, inasmuch as one is visualizing the back pole of the eye). Alternatively, one can simply shine a penlight in one eye while intermittently occluding the other eye.28 In some cases, simply holding a blank sheet of paper in front of the patient’s vision and asking the patient to stare through it is enough to bring out the spontaneous nystag- mus. When this is done, the examiner has to look at the patient’s eyes from the side. Occasionally, nystagmus can be seen even through closed lids. This can be misleading, however, because lid-twitch movements often mimic nystagmus.
  The effect of change in eye position is evalu- ated by having the patient ﬁxate on a target 30 degrees to the right, left, up, and down. Because horizontal eye deviation beyond 40 degrees may result in a low-amplitude, high-frequency torsional nystagmus in normal subjects (so- called end-point or end-gaze nystagmus), extreme eye positions should be avoided. Each eye position is held for at least 20 sec. First- degree nystagmus refers to nystagmus that is present only on gaze in the direction of the fast component. Second-degree nystagmus is pres- ent in the midposition (primary position) and on gaze in the direction of the fast component, and third-degree nystagmus is present even on
  
  Figure 6–4. Frenzel glasses.
  
  –
  
  –
  
  –
  
  –
  
  Peripheral Spontaneous Symmetric Gaze-evoked
  
  –
  
  –
  
  Congenital Spontaneous Downbeat Spontaneous ‌
  Figure 6–5. Method for describing the effect of eye position on nystagmus amplitude and direction. Arrows indicate direc- tion of nystagmus (direction of fast component) in each eye position.
  
  gaze away from the fast component. These terms are not applicable to all varieties of nys- tagmus and, therefore, can lead to confusion. A simple description can be rapidly summarized with a box diagram as illustrated in Figure 6–5. The size, shape, and direction of the arrows provide information about the amplitude and direction of the fast component of nystagmus in each eye position.
  Routinely, two types of positional testing are used: slow and rapid. With the ﬁrst, the patient slowly moves into the supine, right lateral, and left lateral positions. Positional nystagmus induced by slow positioning is persistent, low in frequency, and often present only when ﬁxa- tion is inhibited. Paroxysmal positional nystag- mus, however, is induced by a rapid change from the erect sitting to the supine head- hanging left (left Dix-Hallpike test), center, or right position (right Dix-Hallpike test) or from the supine to head-right or head-left position (supine positional testing). It is initially high frequency but rapidly dissipates within 30 sec to 1 min (see Chapter 10).
  For vibration-induced nystagmus, a hand- held vibrator (approximately 100 Hz) is placed on the mastoid and suboccipital bones on each side for 10 to 15 seconds. The test for head- shaking nystagmus is performed by having the
  patient shake the head back and forth in the horizontal and vertical planes for approximately 10 cycles. For hyperventilation-induced nys- tagmus, the patient breathes rapidly in and out for about a minute and a half.
  
  TYPES OF PATHOLOGIC NYSTAGMUS
  Spontaneous Nystagmus
  MECHANISM
  Spontaneous nystagmus results from an imbal- ance of tonic signals arriving at the oculomotor neurons. Because the vestibular system is the main source of oculomotor tonus, it is the driv- ing force of most types of spontaneous nystag- mus (tonic signals arising in the pursuit and optokinetic systems may also play a role, par- ticularly with congenital nystagmus).29 A ves- tibular imbalance results in a constant drift of the eyes in one direction (slow phase) inter- rupted by fast components in the opposite direction. If the imbalance results from a peripheral vestibular lesion, patients can use their pursuit system to cancel it. If it results from a central vestibular lesion, their pursuit
  Table 6–2 Differentiation between Spontaneous Nystagmus of Peripheral and Central Origin
  Appearance Fixation Gaze Mechanism Localization
  Peripheral Combined
  horizontal, torsional
  Inhibited Unidirectional
  (Alexander’s law)
  Asymmetric loss of peripheral vestibular tone
  Labyrinthine
  or vestibular nerve
  Central Often pure vertical, horizontal, or torsional
  Usually little effect
  May change direction
  Imbalance in central oculomotor tone; usually central vestibular, may be pursuit or OKN
  CNS, usually brain stem or cerebellum
  
  CNS, central nervous system; OKN, optokinetic nystagmus
  
  system usually cannot suppress it (because cen- tral vestibular and pursuit pathways are highly integrated; see “Visual–Vestibular Interaction” in Chapter 3). The features that separate peripheral from central varieties of spontane- ous nystagmus are summarized in Table 6–2.
  
  PERIPHERAL SPONTANEOUS NYSTAGMUS
  Lesions of the peripheral vestibular system (labyrinth or eighth nerve) typically interrupt tonic afferent signals originating from all of the receptors of one labyrinth so that the resulting nystagmus has combined torsional, horizontal, and vertical components. The hori- zontal component dominates, because the tonic activity from the intact vertical canals and otoliths partially cancels out. Gaze in the direction of the fast component increases the frequency and amplitude, whereas gaze in the opposite direction decreases the frequency and amplitude (Alexander’s law) (See Video 6–4, Video 6–5, and Video 6–6).30 Peripheral spon- taneous nystagmus is “unidirectional” meaning that the primary direction does not change. Thus, if the primary position nystagmus is right-beating, then it will not change to left- beating nystagmus even on left gaze. The slow phase is linear, resulting in a saw-toothed wave- form. As noted previously, peripheral sponta- neous nystagmus is strongly inhibited by ﬁxation. Unless the patient is seen within a few days of the acute episode, spontaneous nystag- mus will not be present when ﬁxation is permitted.
  CENTRAL SPONTANEOUS NYSTAGMUS
  Central spontaneous nystagmus is usually prominent with and without ﬁxation. It may be purely vertical, horizontal, or torsional, or have some combination of torsional and linear components (See Video Video 6–7 and Video 6–8). As with peripheral spontaneous nystag- mus, gaze in the direction of the fast compo- nent usually increases nystagmus frequency and amplitude, but unlike peripheral sponta- neous nystagmus, gaze away from the direction of the fast component will often change the direction of the nystagmus (i.e., direction changing nystagmus). There is typically a null region several degrees off center in the direc- tion opposite that of the fast component where nystagmus is minimal or absent. Gaze beyond this null region results in reversal of nystagmus direction. The slow phase of central spontane- ous nystagmus may be linear, exponentially increasing, or exponentially decreasing.31
  With spontaneous downbeat nystagmus the vertical amplitude increases with horizontal gaze deviation.32 Downward gaze also increases the amplitude in about two-thirds of cases, but in the other one-third it decreases it. Upward gaze may reverse the direction to upbeat. Downbeat nystagmus has been produced in monkeys after lesions of the uvula and ﬂoccu- lonodular lobes of the cerebellum.33 In the human it is localizing to the cervicomedullary junction (which includes the midline cerebel- lar regions). Common causes of downbeat nystagmus include cerebellar atrophy, verte- brobasilar ischemia, multiple sclerosis, and Arnold-Chiari malformation.34,35 The latter
  produces downbeat nystagmus, presumably by pressure on the ﬂocculonodular region of the cerebellum; in some cases it may be reversed by decompression of the foramen magnum region.36 Spontaneous upbeat nystagmus usu- ally results from lesions of the dorsal central medulla in the region of the medial vestibular and prepositus hypoglossi nuclei.35,37 Common causes include infarction, inﬁltrating tumors, and multiple sclerosis. Pure torsional sponta- neous nystagmus is frequently associated with syringomyelia and syringobulbia. A high- frequency, small-amplitude pendular sponta- neous nystagmus is commonly seen in the late stages of multiple sclerosis.38 This pendular nystagmus converts to a sawtooth pattern on lateral gaze to either side. Lesions involving the vestibular nuclear region can produce a horizontal torsional nystagmus similar to that seen with peripheral lesions, but, unlike the latter, the direction of nystagmus does not reliably indicate the side of lesion and the nystagmus persists with ﬁxation because of damage of visual–vestibular interaction pathways.39
  Central spontaneous nystagmus has gener- ally been attributed to an imbalance in either central vestibulo-ocular or smooth pursuit pathways.32 Horizontal and vertical pathways are usually separate so that lesions can com- monly lead to pure horizontal or pure vertical nystagmus. Often central spontaneous nystag- mus is altered by position change, suggesting that peripheral otolith input can alter the cen- tral imbalance. Marti and colleagues suggested that downbeat nystagmus results from damage to the inhibitory vertical gaze-velocity sensitive Purkinje cells in the cerebellar ﬂocculus.40 These neurons have spontaneous activity and most exhibit downward on-directions. Loss of these vertical ﬂocculus Purkinje cells would lead to disinhibition of their brainstem target neurons and spontaneous upward drift (i.e., downbeat nystagmus).
  
  CONGENITAL NYSTAGMUS
  Congenital spontaneous nystagmus is almost always highly dependent on ﬁxation, disappear- ing or decreasing with loss of ﬁxation.41 In some instances a slow nystagmus in the reverse direc- tion occurs when ﬁxation is inhibited. One common variety, so-called latent congenital
  nystagmus, occurs only when either eye is covered, permitting monocular ﬁxation. The resulting nystagmus beats toward the ﬁxating eye. Latent congenital nystagmus is usually associated with other congenital ocular defects such as concomitant squint and alternating hyperphoria.42
  Several characteristic clinical features help distinguish congenital from acquired spontane- ous nystagmus. It is usually purely horizontal and may diminish or disappear with conver- gence. The waveform may be pendular to saw- tooth shaped, with many variations in between.43 Different waveforms occur in the same patient in different eye positions. Gaze in the direction of the fast component converts a pendular nys- tagmus to a jerk nystagmus; often there is a null region where the nystagmus is minimal. Several different waveforms may be seen in members of the same family with congenital nystagmus. The frequency of congenital nystagmus is usually >2 beats/sec and at times reaches 5 to 6 beats/sec. Nystagmus of this high frequency is unusual other than on a congenital basis. Of course, most patients are aware that the nystag- mus has been present since infancy.
  The pathophysiologic mechanism of congen- ital nystagmus is only partially understood.31 Convincing evidence exists that the slow com- ponent causes the target to slip from the fovea, and the fast component brings the target back to the fovea. The slow component is not the result of, but the cause of, decreased vision. Maneuvers designed to decrease the target slippage (ﬁtting glasses with prisms and extraoc- ular muscle surgery) improve visual acuity. Patients with congenital nystagmus can make normal-velocity saccades, indicating that the extraocular muscles and orbital mechanics are normal. The vestibular system also appears to be normal in most of these patients. Abnormalities in smooth pursuit and optoki- netic slow phases are uniformly present, but it is difﬁcult to know whether these abnormalities are due to a superimposition of the spontane- ous nystagmus on attempted tracking eye movements or to an underlying abnormality.44 Recently mutations have been identiﬁed in two genes associated with X-linked congenital nys- tagmus: FRMD7 causing X-linked idiopathic congenital nystagmus and GPR143 causing X-linked ocular albinism and congenital nystag- mus.45,46 Characterizing these genes and other
  congenital nystagmus genes should provide insight into the pathophysiological mechanism of these poorly understood disorders.47
  
  PERIODIC ALTERNATING NYSTAGMUS
  Periodic alternating nystagmus (PAN) is a spontaneous nystagmus that periodically changes direction without a change in eye or head position.48 Cycle length varies between 1 and 6 min, with null periods between each half cycle varying from 2 to 20 sec. The nystagmus slowly builds in intensity and reaches a peak slow component velocity near the center of each half cycle before slowly decreasing. This type of nystagmus has been reported in associ- ation with such varied conditions as encephali- tis, brainstem ischemia, demyelinating disease, syringobulbia, syphilis, and trauma and as a congenital disorder. Unlike patients with other forms of congenital nystagmus, patients with congenital PAN frequently complain of oscil- lopsia because they are unable to adapt to the constantly changing direction of nystagmus. It is usually present with ﬁxation, although cases have been reported in which PAN occurs only with loss of ﬁxation.
  Necropsy studies from three patients with acquired PAN showed diffuse brainstem involvement, with a predilection for the caudal brain stem.49 Reported cases have been associ- ated with downbeat nystagmus, further sug- gesting caudal brainstem dysfunction. The pathophysiologic mechanism for production of PAN is unknown. The PAN cycles can be altered in both phase and magnitude by a ves- tibular stimulus (rotatory or caloric), suggest- ing that the PAN rhythm is not the result of an independent central nervous system (CNS) pacemaker but, rather, a response pattern of the central vestibulo-ocular reﬂex arc.50 It is
  from the primary position (See Video 6–9, Video 6–10, and Video 6–11). The eyes drift back toward the center with an exponentially decreasing wave form; corrective saccades (fast components) constantly reset the desired gaze position. Gaze-evoked nystagmus is therefore always in the direction of gaze. The site of abnormality can be anywhere from the neuro- muscular junction to the multiple brain centers controlling conjugate gaze (Table 6–3). Dysfunction of the oculomotor integrator (see Chapter 3) may be a common mechanism for several types of gaze-evoked nystagmus.
  
  SYMMETRIC
  Symmetric gaze-evoked nystagmus (equal amplitude to the left and right) is most com- monly produced by ingestion of drugs such as phenobarbital, phenytoin, alcohol, and diaze- pam. With these agents, high-frequency, small- amplitude nystagmus (<2 degrees) is found in all directions of gaze. A rough correlation exists between nystagmus amplitude and blood drug level.52,53 The nystagmus initially appears at extreme horizontal gaze positions and moves toward the midposition with higher drug levels. In addition to its association with drug ingestion, symmetric gaze-evoked nystagmus commonly occurs in patients with myasthenia gravis, multiple sclerosis, and cere- bellar atrophy.
  
  Table 6–3 Causes of Gaze-Evoked Nystagmus
  Localization Common Causes
  important to recognize this unusual form of spontaneous nystagmus because the acquired variety is markedly diminished by baclofen, a
  Symmetric Nonlocalizing or
  cerebellum
  
  Asymmetric Unilateral brain stem
  Drugs,
  metabolic disorders
  gamma-amino butyric acid (GABA) agonist.51
  Tumor,
  and/or cerebellum
  Unfortunately, congenital PAN does not respond to baclofen.
  
  Gaze-Evoked Nystagmus
  MECHANISM
  Patients with gaze-evoked nystagmus are unable to maintain stable conjugate eye deviation away
  
  Rebound Cerebellum
  
  Dissociated MLF, extraocular
  nerve, or muscle
  
  MLF, medial longitudinal fasciculus.
  infarction Tumor,
  infarction, atrophy
  Multiple sclerosis, myasthenia gravis
  ASYMMETRIC
  Asymmetric horizontal gaze-evoked nystagmus always indicates a structural brain lesion. When it is caused by a focal lesion of the brain stem or cerebellum, the larger amplitude nystagmus is usually directed toward the side of the lesion. Large cerebellopontine angle tumors com- monly produce asymmetric gaze-evoked nys- tagmus from compression of the brain stem and cerebellum (Bruns’ nystagmus). Some patients with large acoustic neuromas develop a combination of asymmetric gaze-evoked nys- tagmus from brainstem compression and peripheral spontaneous nystagmus from eighth nerve damage.54,55 Asymmetric gaze-evoked nystagmus may be present during the recovery from gaze paralysis (either cortical or subcorti- cal in origin), in which case it is large in ampli- tude and low in frequency and present only in one direction of gaze (the direction of the previous gaze paralysis).
  
  REBOUND
  Rebound nystagmus is a type of gaze-evoked nystagmus that either disappears or reverses direction as the lateral gaze position is held. When the eyes return to the primary position, another burst of nystagmus occurs in the direc- tion of the return saccade. Thus, the patient may have a transient primary position nystag- mus in either direction. Rebound nystagmus occurs in patients with cerebellar atrophy and focal structural lesions of the cerebellum; it is the only variety of nystagmus thought to be speciﬁc for cerebellar involvement.56
  
  DISSOCIATED
  Dissociated, or disconjugate, gaze-evoked nys- tagmus commonly results from lesions of the medial longitudinal fasciculus (MLF), so-called internuclear ophthalmoplegia. With early MLF lesions the eyes appear to move conjugately, but the abducting eye on the side opposite the MLF lesion develops a regular small-amplitude, high-frequency nystagmus in the direction of gaze. With more extensive MLF lesions, the adducting eye lags behind and develops a low- amplitude nystagmus while the abducting eye overshoots the target and develops large- amplitude nystagmus that has a characteristic peaked waveform.57 A MLF nystagmus can be
  bilateral or unilateral, depending on the extent of MLF involvement. Bilateral MLF nystag- mus is most commonly seen with demyelinat- ing disease, whereas unilateral MLF nystagmus most often accompanies vascular disease of the brain stem.58 Patients with myasthenia gravis develop dissociated gaze-evoked nystagmus similar to MLF nystagmus (pseudo-MLF nys- tagmus) because of unequal impairment of neuromuscular transmission in adducting and abducting muscles. Unlike MLF nystagmus, the dissociated nystagmus with myasthenia progressively increases in amplitude as the gaze position is maintained.59
  
  Positional Nystagmus
  MECHANISM
  Beginning with Bárány, positional nystagmus was attributed to lesions of the otoliths and their connections in the vestibular nuclei and cerebellum, as these are the receptors that are sensitive to changes in the direction of grav- ity.5,60 Subsequently, other mechanisms for the production of positional nystagmus have been identiﬁed, forcing reexamination of these tra- ditional concepts. If a semicircular canal cupula is altered so that its speciﬁc gravity no longer equals that of the surrounding endolymph or if debris inappropriately enters a semicircular canal, the canal becomes sensitive to changes in the direction of gravity and can produce positional nystagmus (see Causes of Benign Positional Vertigo in Chapters 10 and Alcohol and Thiamine Defeciency in Chapter 17).
  Traditional classiﬁcations of positional nys- tagmus are often confusing and can be difﬁcult to apply in clinical practice. Some classiﬁca- tions have been based on clinical observations obtained while the patient is ﬁxating, whereas others have been based on electronystagmog- raphy (ENG) recordings with eyes closed or with eyes open in darkness. Some investigators use slow positioning maneuvers, but others employ only rapid positioning. These different methods make it difﬁcult to compare classiﬁca- tions. Nylen60 initially described three types of positional nystagmus based on visual inspec- tion of nystagmus direction and regularity. Type I, direction changing, and type II, direc- tion ﬁxed, remained constant as long as the position was maintained. Type III was less clearly deﬁned, comprising all paroxysmal
  varieties of positional nystagmus and some per- sistent varieties that did not ﬁt into types I and
  II. Numerous modiﬁcations of Nylen’s original classiﬁcation have subsequently been pro- posed, and the deﬁnition of each type has changed. Most investigators do agree that two broad categories of positional nystagmus can be identiﬁed: paroxysmal and persistent.
  
  PAROXYSMAL POSITIONAL NYSTAGMUS (POSITIONING NYSTAGMUS)
  The most common type of paroxysmal posi- tional nystagmus is induced by a rapid change from erect sitting to the supine head-hanging left or right position (Dix-Hallpike test) (Fig. 6–6). It is initially high in frequency but dissipates rapidly. There is a 3- to 10-sec latency before onset and the nystagmus rarely lasts longer than 30 sec.61,62 The nystagmus has
  
  (a)
  
  (b)
  combined torsional (fast component toward the undermost ear) and vertical (fast compo- nent toward the forehead) components (See Video 6–12 and Video 6–13). Although infre- quent bilateral cases do occur, the nystagmus is usually prominent only in one head-hanging position, and a burst of nystagmus occurs in the reverse direction when the patient moves back to the sitting position. Another key feature is that the patient experiences severe vertigo with the initial positioning, but with repeated posi- tioning, vertigo and nystagmus rapidly disap- pear (fatigability). This type of paroxysmal positional nystagmus is speciﬁc for the posterior canal variant of canalithiasis (see Chapter 10). Horizontal canal variants also exist but are less common. They are induced by turning the patient’s head to the side while the patient lies supine.
  Paroxysmal positional nystagmus can also result from brainstem and cerebellar lesions. The central type does not decrease in ampli- tude or duration with repeated positioning, does not have a clear latency, and usually lasts longer than 30 sec. The direction is unpre- dictable and may be different in each position. It is often purely vertical with fast phase directed downward (i.e., toward the cheeks). The presence or absence of associated vertigo is not a reliable differential feature. Central paroxysmal positional nystagmus can be the initial presenting sign of a posterior fossa tumor such as a medulloblastoma or cerebellar glioma.63,64 It is therefore critical to distinguish it from the benign peripheral variety (Table 6–4).
  
  PERSISTENT POSITIONAL NYSTAGMUS
  This type of positional nystagmus remains as long as the position is held, although it may ﬂuctuate in frequency and amplitude. It may be in the same direction in all positions or change directions in different positions. Direction-changing and direction-ﬁxed static positional nystagmus are most commonly asso- ciated with peripheral vestibular disorders,
  although both occur with central lesions.65
  
  Figure 6–6. Method for inducing paroxysmal positional nystagmus (Dix-Hallpike maneuver). Patient is taken rap- idly from sitting to head-hanging right (a) or head-hanging left (b) position.
  One variety of persistent direction-changing positional nystagmus (apogeotropic) is thought to result from otolithic debris attached to the cupula or lodged in the ampulla of the horizontal semicircular canal (see Chapter 10).66 As with spontaneous nystagmus, lack of
  Table 6–4 Differentiation between Peripheral and Central Paroxysmal Positional Nystagmus
  Appearance Latency Duration Fatigability Mechanism Localization
  Peripheral Torsional, upbeat, or
  horizontal geotropic
  
  Central Pure vertical, often
  downbeat
  Usual < 60 sec Usual Change in
  cupula-speciﬁc gravity
  Unusual > 60 sec Unusual Damage to
  central otolith-ocular pathways
  Labyrinth
  
  Brain stem or cerebellum
  
  suppression with ﬁxation and signs of associ- ated brainstem dysfunction suggest a central lesion.
  
  CENTRAL POSITIONAL NYSTAGMUS
  Positional nystagmus can also stem from a cen- tral lesion. The most common pattern is a per- sistent downbeating nystagmus. In fact, a persistent downbeating positional nystagmus may be the most prominent examination ﬁnd- ing in a patient with a central lesion causing dizziness symptoms. Typical causes include a genetic cerebellar ataxia syndrome or a struc- tural lesion (e.g., Chiari malformation or tumor). Central positional nystagmus does not mimic the key characteristics of BPV from the posterior semicircular canal but can mimic the positional nystagmus of BPV from the horizon- tal semicircular canal.
  
  Vibration-Induced Nystagmus
  Vibration applied to the mastoid can often induce a typical peripheral vestibular nystag- mus in patients with compensated unilateral vestibular lesions.67,68 With vestibular neuritis the slow phase is nearly always directed toward the lesion side but with Meniere’s syndrome it can be directed to either side. Vibration may activate hair cells in the inner ear although the exact mechanism for vibration induced nystag- mus is poorly understood. In some cases of anterior semicircular dehiscence syndrome vibration over the suboccipital cranium will induce nystagmus in the plane of the anterior canal.69 In this case vibration activates the ante- rior semicircular canal just as noise or pressure
  
  changes activate the canal (see Fig. 16–3B and 3C in Chapter 16).
  
  Head-Shaking Nystagmus
  Patients with a compensated vestibular imbal- ance due to either peripheral or central lesions may develop a transient nystagmus after vigor- ous head shaking.70 With unilateral peripheral vestibular lesions, the abnormal side is in the direction of the slow phase. With central ves- tibular lesions, the direction of nystagmus is nonlocalizing. Sometimes vertical nystagmus is induced by horizontal head shaking.71 The results of vertical head shaking are more difﬁ- cult to interpret because some normal subjects will have transient vertical nystagmus after ver- tical head shaking.
  
  Hyperventilation-Induced Nystagmus
  Hyperventilation can induce a near-faint dizzi- ness in anyone, particularly in anxious patients, but hyperventilation-induced nystagmus is less common.72 Patients with compressive lesions of the vestibular nerve, such as with an acoustic neuroma or cholesteatoma, or with demyelination of the vestibular nerve root entry zone, such as with multiple sclerosis, may develop nystagmus after hyperventilation. Presumably metabolic changes associated with hyperventilation trigger the partially damaged nerve to ﬁre inappropriately. Hyper- ventilation-induced nystagmus has also rarely been associated with labyrinthitis or perilymph ﬁstula.
  OTHER OCULAR OSCILLATIONS ‌‌
  Dissociated Spontaneous Nystagmus
  Several different lesions of the posterior fossa can result in a spontaneous nystagmus with tor- sional, horizontal, and vertical components varying in each eye. The nystagmus is usually synchronized, however, in that the fast compo- nent occurs at exactly the same time in both eyes. Tumors, vascular disease, and demyeli- nating disease of the brain stem produce this form of dissociated nystagmus.73 Frequently the eye on the side of the lesion shows the larg- est amplitude oscillation. Monocular nystag- mus results from similar posterior fossa lesions; this unusual form of dissociated nystagmus also has been reported with such varied entities as congenital syphilis, meningitis, optic nerve glioma, cerebral trauma, unilateral amblyopia, and high refractive error.74,75 As expected, these patients are typically bothered by severe oscillopsia.
  Seesaw nystagmus is an unusual type of dis- sociated nystagmus in which one eye rhythmi- cally rises and intorts and the other eye falls and extorts. It may be congenital but most often is produced by acquired lesions near the optic chiasm, particularly those producing a bitemporal ﬁeld defect and decreased central visual acuity.76 Lesions associated with seesaw nystagmus include craniopharyngiomas, syrin- gobulbia, brainstem infarction, and diffuse choroiditis; compression of the midbrain teg- mentum may be the common denominator.24
  
  Voluntary Ocular Oscillations (Voluntary Nystagmus)
  Some normal subjects are able to produce rapid oscillations of the eyes at will, apparently by producing rapid sequenced saccades back and forth.77 Some cases may overlap with con- genital nystagmus.78 The main signiﬁcance of these ocular gymnastics is that they may be mistaken for pathologic nystagmus. High in frequency (90 to as high as 1380 cycles/min) and low in amplitude (2 to 5 degrees), these rapid horizontal movements cannot be main- tained for more than 20 to 30 sec before fatigue
  sets in. Several siblings in the same family may have the ability to produce voluntary ocular oscillations. Keyes79 reported two generations of the same family who could produce the eye movements, suggesting a dominant mode of inheritance.
  
  Convergence Retraction Nystagmus
  This dramatic ocular motor disorder results from lesions involving the diencephalic midbrain junction. When the patient attempts to make voluntary upward saccades or when involuntary upward saccades (fast components) are induced by an optokinetic or vestibular stimulus, the patient develops co-contraction of all extraocu- lar muscles and the eyes rhythmically retract and converge.80 (See Video 6–14). In other cases convergence nystagmus occurs without retrac- tion, apparently because of asynchronous adducting saccades.81 Convergence retraction nystagmus is usually associated with other signs of midbrain dysfunction (impaired upward gaze, pupillary abnormalities, accommodative spasm, retraction of the lids, and skew deviation), con- stituting the dorsal midbrain syndrome. This syndrome is most frequently produced by dys- germinomas of the pineal region but is also asso- ciated with other tumors and vascular lesions involving the tectal or pretectal area.
  
  Saccadic Intrusions
  Included under this category are square wave jerks, macrosquare wave jerks, macrosaccadic oscillations, ocular ﬂutter, and opsoclonus. The common feature is that unwanted saccades dis- rupt steady ﬁxation. Square wave jerks refer to small-amplitude involuntary saccades that take the eyes off the target, followed after a normal intersaccadic interval (200 msec) by a correc- tive saccade bringing the eyes back to the tar- get. Infrequent small square wave jerks can be seen in normal subjects, especially the young and elderly.82 Persistent large-amplitude square wave jerks (1 to 5 degrees) are abnormal but nonlocalizing. They are prominent with cerebellar lesions and with progressive supra- nuclear palsy and have been reported with dif- fuse cerebral lesions, Huntington’s disease, and schizophrenia.83,84 Macrosquare wave jerks
  (10 to 50 degrees) have been observed in mul- tiple sclerosis and olivopontocerebellar atro- phy. Macrosaccadic oscillations are typically seen in patients with saccade overshoot dysme- tria (i.e., those with cerebellar lesions). After reﬁxation, patients make a series of hypermet- ric saccades, apparently because they are unable to make a small enough saccade to bring the target onto the fovea. Ocular ﬂutter refers to a burst of to-and-fro horizontal saccades occurring either spontaneously or after a sac- cade to a target (See Video 6–15). This burst of saccades lacks the characteristic delay normally present between serial saccades. Ocular ﬂutter is typically seen with diffuse involvement of brainstem-cerebellar pathways, being particu- larly prominent in such varied disorders as Friedreich’s ataxia, brainstem encephalitis, and paraneoplastic syndromes.‌‌
  The most prominent saccadic oscillations are seen with opsoclonus.85 With this rare eye movement disorder, the eyes are constantly making random conjugate saccades of unequal amplitude in all directions. As with ocular ﬂutter, there is typically no intersaccade inter- val. The phenomenon occurs with several different types of CNS disease and probably represents a mixed group of eye movement disorders. The inappropriate saccades are most prominent immediately before or after a reﬁxation and are only slightly affected by loss of ﬁxation. One variety of opsoclonus prob- ably represents a continuum with square wave jerks and ocular ﬂutter. Other more dramatic varieties of opsoclonus have been reported in patients with brainstem encephalitis, as a remote effect of tumors (e.g., neuroblastoma), and in association with toxins (e.g., the pesti- cide kepone).24 These saccade disorders prob- ably represent a release of the brainstem sac- cade burst neurons from supranuclear control. Functional MRI showed activation of the deep cerebellar nuclei in two patients whose opsoclonus was markedly diminished with eye closure.86
  
  Ocular Bobbing
  Ocular bobbing consists of abrupt, nonrhyth- mic, conjugate, downward jerks of the eyes, followed by slow return to midposition.31 The abnormal movements are classically seen in comatose patients with intrinsic pontine lesions
  that also produce absent reﬂex horizontal eye movements, but they have also been reported with posterior fossa lesions that compress the pons and with metabolic encephalopathy.87 Inverse ocular bobbing or ocular dipping refers to a slow downward movement of the eyes fol- lowed by a rapid return to midposition. Reverse bobbing consists of a rapid deviation of the eyes upward followed by a slow return to the pri- mary position. These latter phenomena may be variations of ocular bobbing because all can be seen in the same subject at different times.88 As with typical ocular bobbing, they are usually seen with metabolic disorders or structural lesions of the pons.
  
  Palato-Ocular Myoclonus
  This is a rhythmic oscillation of the eyes associ- ated with synchronous oscillation of the palate. An associated rhythmic oscillation of die phar- ynx, larynx, mouth, tongue, diaphragm, extrem- ities, and intercostal muscles may also occur.89 The eye movements are typically pendular oscillations that are often vertical but may have a horizontal or torsional component. The fre- quency varies from 1 to 3/sec, and the move- ments may continue with loss of ﬁxation. Ocular myoclonus often disappears during sleep even though the palatal movements continue. Palato-ocular myoclonus is seen in association with lesions disrupting the connections between the cerebellar dentate nucleus, the red nucleus, and the inferior olivary nucleus (Guillain- MoDaret triangle). It most commonly accom- panies vascular lesions but also occurs with tumors and degenerative disease. When seen in association with vascular lesions, it often develops months after the brainstem or cere- bellar infarction. Intravenous scopolamine has been reported to abolish the ocular oscillations temporarily, but there is no good long-term treatment.90
  
  OCULAR TILT REACTION
  If a subject is tilted in the frontal plane (about the nasal occipital axis), the head reﬂexively tilts and the eyes counter-roll and skew toward the opposite side. The functional role of this reﬂex in visual stabilization during natural body
  
  Right labyrinth and
  pontomedullary
  
  Right ponto- mesencephalic
  
  Figure 6–7. Ocular tilt responses associated with lesions at different locations within the peripheral and central vestibular pathways. The ocular tilt reaction consists of a head tilt toward the side of the lower eye, a skew deviation with one eye higher than the other, and counterroll (torsion) of both eyes, with the top poles rolling toward the side of the lower eye. The ipsilateral eye is down with lesions of the labyrinth and pontomedtillary regions but it is up with lesions in the pontomes- encephalic region.
  
  movements is minimal, however, as the magni- tude of the compensatory head tilt and ocular counter-rolling is only about 10% of angular displacement of the head. The ocular tilt reac- tion is principally a labyrinthine reﬂex; it is independent of the position of the head, rela- tive to the body (indicating that neck position is not important). The ocular tilt reaction can be elicited by electrical stimulation of the rostral midbrain tegmentum in the region of the inter- stitial nucleus of Cajal.91 Clinically, the ocular tilt reaction has been seen in patients with peripheral labyrinthine lesions (a complication of stapedectomy), lesions of the lateral medulla (particularly Wallenberg’s syndrome), and with
  
  Lesions in these regions would, of course, result in an ocular tilt reaction in the opposite direction (Fig. 6–7). Paroxysmal tonic ocular tilt reactions have been reported in patients with multiple sclerosis and in a patient with a focal brainstem abscess.94,95 Such patients may respond to carbamazepine or baclofen.
  
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  26. Dannenbaum E, Paquet N, Chilingaryan G, Fung J. Clinical evaluation of dynamic visual acuity in subjects with unilateral vestibular hypofunction. Otol Neurotol. 2009;30(3):368.
  27. Schmäl F, Lübben B, Weiberg K, Stoll W. The minimal ice water caloric test compared with estab- lished vestibular caloric test procedures. J Vestib Res. 2005;15(4):215.
  28. Newman-Toker DE, Sharma P, Chowdhury M, Clemons TM, Zee DS, Della Santina CC. Penlight- cover test: a new bedside method to unmask nystag- mus. J Neurol Neurosurg Psychiatry. 2009;80(8):900.
  29. Rucker JC. An update on acquired nystagmus. Semin Ophthalmol. 2008;23(2):91.
  30. Jacobson GP, McCaslin DL, Kaylie DM. Alexander’s law revisited. J Am Acad Audiol. 2008;19(8):630.
  31. Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th ed. New York: Oxford University Press; 2005.
  32. Baloh RW, Spooner JW. Downbeat nystagmus: a type of central vestibular nystagmus. Neurology. 1981;31:304.
  33. Zee DS, Yamazaki A, Batter PH, Gucer G. Effects of ablation of ﬂocculus and parallocculus on eye move- ments in primates. J Neurophysiol. 1981;46:878.
  34. Halmagyi GM, Rudge P, Gresty MA, Sanders MD. Downbeating nystagmus. Arch Neurol. 1983;40:777.
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  36. Spooner JW, Baloh RW. Arnold-Chiari malformation: improvement in eye movements after surgical treat- ment. Brain. 1981;104:51.
  37. Fisher A, Gresty M, Chambers B, Rudge P Primary position upbeat nystagmus: a variety of central posi- tional nystagmus. Brain. 1983;106:949.
  38. Aschoff JC, Conrad B, Kornhuber HH. Acquired pen- dular nystagmus with oscillopsia in multiple sclerosis: a sign of cerebellar nuclei disease. J Neurol Neurosurg Psychiatry. 1974;37:570.
  39. Baloh RW, Yee RD, Honrubia V. Eye movements in patients with Wallenberg’s syndrome. Ann NY Acad Sci. 1981;374:600.
  40. Marti S, Straumann D, Büttner U, Glasauer S. A mod- el-based theory on the origin of downbeat nystagmus. Exp Brain Res. 2008;188(4):613.
  41. Cogan DG. Congenital nystagmus. Can J Ophthalmol. 1967;2:4.
  42. Dell’Osso LF, Schmidt D, Darolf RB. Latent, manifest latent, and congenital nystagmus. Arch Ophthalmol. 1979;97:1877.
  43. Yee RD, Wong EK, Baloh RW, Honrubia V. A study of congenital nystagmus: waveforms. Neurology. 1976;26:326.
  44. Yee RD, Baloh RW, Honrubia V Kim YS. A study of congenital nystagmus: vestibular nystagmus. J Otolaryngol. 1981;10:89.
  45. He X, Gu F, Wang Z, et al. A novel frameshift muta- tion in FRMD7 causing X-linked idiopathic congenital nystagmus. Genet Test. 2008;12(4):607.
  46. Fang S, Guo X, Jia X, Xiao X, Li S, Zhang Q. Novel GPR143 mutations and clinical characteristics in six Chinese families with X-linked ocular albinism. Mol Vis. 2008;14:1974.
  47. Self J, Lotery A. A review of the molecular genetics of congenital idiopathic nystagmus (CIN). Ophthalmic Genet. 2007;28(4):187.
  48. Baloh RW, Honrubia V, Konrad HR. Periodic alter- nating nystagmus. Brain. 1976;99:11.
  49. Keane JR. Periodic alternating nystagmus with down- ward beating nystagmus. A clinico-anatomic case study of multple sclerosis. Arch Neurol. 1974;30:399.
  50. Leigh RJ, Robinson DA, Zee DS. A hypothetical expla- nation for periodic alternating nystagmus: Instability in the optokinetic vestibular system. Ann NY Acad Sci. 1981;374:619.
  51. Halmagyi GM, Rudge P, Gresty AM, et al. Treatment of periodic alternating nystagmus. Ann Neurol. 1980;8:609.
  52. Gallagher BB, Baumel IP, Mattson RH, Wood-burg SG. Primidone, dipenylhydantoin and Phenobarbital. Aspects of acute and chronic toxicity. Neurology. 1973;23:145.
  53. Hogan RE, Collins SD, Reed RC, Remler BF. Neuro-ophthalmological signs during rapid intrave- nous administration of phenytoin. J Clin Neurosci. 1999;6(6):494.
  54. Baloh RW, Konrad HR, Dims D, Honrubia V. Cerebellar-pontine angle tumors. Results of quan- titative vestibulo-ocular testing. Arch Neurol. 1976;33:507.
  55. Lloyd SK, Baguley DM, Butler K, Donnelly N, Moffat DA. Bruns’ nystagmus in patients with vestibular schwannoma. Otol Neurotol. 2009;30(5):625.
  56. Hood JD. Further observations on the phenomenon of rebound nystagmus. Ann NY Acad Sci. 1981;374:352.
  57. Baloh RW, Yee RD, Honrubia V. Internuclear oph- thalmoplegia. I. Saccades and dissociated nystagmus. Arch Neurol. 1978;35:484.
  58. Cogan DG, Kubik SC, Smith WL. Unilateral inter- nuclear ophthalmoplegia: report of eight clinical cases and one post-mortem study. Arch Ophthalmol. 1950;44:783.
  59. Spooner JW, Baloh RW. Eye movement fatigue in myasthenia gravis. Neurology. 1979;29:29.
  60. Nylen CO. Positional nystagmus. A review and future prospects. J Laryngol Otol. 1950;64:295.
  61. Baloh RW, Honrubia V, Jacobson K. Benign positional vertigo: clinical and oculographic features in 240 cases. Neurology. 1987;37:371.
  62. Aw ST, Todd MJ, Aw GE, McGarvie LA, Halmagyi M. Benign positional vertigo: a study of its three dimen- sional spatio-temporal characteristics. Neurology. 2005;64:1897.
  63. Grand W. Positional nystagmus: an early sign of medulloblastoma. Neurology. 1971;21:1157.
  64. Gregorius FK, Crandall PH, Baloh RW. Positional vertigo in cerebellar astrocytoma. Report of two cases. Surg Neurol. 1976;6:283.
  65. Lin J, Elidan J, Baloh RW, Honrubia V. Direction changing positional nystagmus: incidence and mean- ing. Am J Otolaryngol. 1986;7:306.
  66. Baloh RW, Yue Q, Jacobson KM, Honrubia V. Persistent direction-changing positional nystagmus. Another variant of benign positional nystagmus? Neurology. 1995;45:1297.
  67. Park HJ, Shin JE, Lim YC, Shin HA. Clinical sig- niﬁcance of vibration-induced nystagmus. Audiol Neurootol. 2008;13(3):182.
  68. Dumas G, Perrin P, Schmerber S. Nystagmus induced by high frequency vibrations of the skull in total uni- lateral peripheral vestibular lesions. Acta Otolaryngol. 2008;128(3):255.
  69. White JA, Hughes GB, Ruggieri PN. Vibration- induced nystagmus as an ofﬁce procedure for the diag- nosis of superior semicircular canal dehiscence. Otol Neurotol. 2007;28(7):911.
  70. Hain TC, Spinder J. Head-shaking nystagmus. In: Sharpe JA, Barber HO, eds. The Vestibulo-ocular Reﬂex and Vertigo. New York: Raven Press; 1993.
  71. Strupp M. Perverted head-shaking nystagmus: two possible mechanisms. J Neurol. 2002;249(1): 118.
  72. Bance ML, O’Driscoll M, Patel N, Ramsden RT. Vestibular disease unmasked by hyperventilation. Laryngoscope. 1998;108:610.
  73. Cogan DG. Dissociated nystagmus with lesions in the posterior fossa. Arch Ophthalmol. 1963;70:121.
  74. Nathanson M, Bergman PS, Berker MB. Monocular nystagmus. An J Ophthalmol. 1955;40:685.
  75. Donin JF. Acquired monocular nystagmus in children.
    Can J Ophthalmol. 1967;2:212.
  76. Rambold H, Helmchen C, Straube A, Büttner U. Seesaw nystagmus associated with involuntary tor- sional head oscillations. Neurology. 1998;51:831.
  77. Shults WT, Stark L, Hoyt WF, Ochs AL. Normal saccadic structure of voluntary nystagmus. Arch Ophthalmol. 1977;95:1399.
  78. Lewis RF, Traish AS, Lessell S. Atypical voluntary nys- tagmus. Neurology. 2009;72(5):467.
  79. Keyes MJ. Voluntary nystagmus in two generations.
    Arch Neurol. 1973:29:63.
  80. Gay AJ, Brodkey J, Miller JE. Convergence retrac- tion nystagmus: an electromyographic study. Arch Ophthalmol. 1963:70:456.
  81. Ochs AL, Stark L, Hoyt WF, D’Amico D. Opposed adducting saccades in convergence retraction nystag- mus. Brain. 1979;102:497.
  82. Herishanu YO, Sharpe JA. Normal square wave jerks.
    Invest Ophthalmol Vis Sci. 1981;20:268.
  83. Fukazawa T, Tashiro K, Hamada T, Kase M. Multisystem degeneration: drugs and square wave jerks. Neurology. 1986;36:1230.
  84. Troost BT, Daroff RB. The ocular motor defects in pro- gressive supranuclear palsy. Ann Neurol. 1977:2:397.
  85. Wong A. An update on opsoclonus. Curr Opin Neurol. 2007;20:25.
  86. Helmchen C, Rambold H, Sprenger A, Erdmann C, Binkofski F. Cerebellar activation in opsoclonus. An fMRI study. Neurology. 2003;61:412.
  87. Bosch EP, Kennedy SS, Aschenbrener CA. Ocular bobbing: the myth of its localizing value. Neurology. 1975;25:949.
  88. Stark SR, Masucci EF, Kurlzke JF. Ocular dipping.
    Neurology. 1984;34:391.
  89. Tahmoush AJ, Brooks JE, Keltner JL. Palatal myo- clonus associated with abnormal ocular and extremity movements. Arch Neurol. 1972:27:431.
  90. Gresty MA, Ell JJ, Findley LJ. Acquired pendular nystagmus: its characteristics, localizing value and pathophysiology. J Neurol Neurosurg Psychiatry. 1982;45:431.
  91. Westheimer G, Blair M. The ocular tilt reaction – a brain stem oculomotor routine. Invest Ophthalmol. 1975;14:833.
  92. Brandt T, Dieterich M. Pathological eye head coordi- nation in roll: tonic ocular lilt reaction in mesenceph- alic and medullary lesions. Brain. 1987;1(10):649.
  93. Halmagyi GM, Gresty MA, Gibson WPR. Ocular tilt reaction with peripheral vestibular lesions. Ann Neurol. 1979;6:80.
  94. Hedges TR, Hoyt WF. Ocular tilt reaction due to an upper brain stem lesion: paroxysmal skew deviation, torsion, and oscillation of the eyes with head tilt. Ann Neurol. 1982;11:537.
  95. Oh SY, Choi KD, Shin BS, Seo MW, Kim YH, Kim JS. Paroxysmal ocular tilt reactions after mesodien- cephalic lesions: report of two cases and review of the literature. J Neurol Sci. 2009;277(1-2):98.
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  Chapter 7 ‌‌
  
  Laboratory Examination of the Vestibular
  System
  
  NYSTAGMOGRAPHY ‌
  Methods of Recording Eye Movements Interpreting the Recording
  Recording Pathologic Nystagmus Bithermal Caloric Test
  Tests of Visual–Ocular Control
  ROTATIONAL TESTING OF VESTIBULO-OCULAR REFLEXES
  Relationship between Stimulus and Response Results in Normal Subjects
  Results in Patients
  VISUAL–VESTIBULAR INTERACTION
  Methodology
  Results in Normal Subjects Results in Patients
  TESTS OF OTOLITH–OCULAR REFLEXES
  Ocular Counterrolling Eccentric Rotation
  Off-Vertical Rotation Linear Acceleration
  VESTIBULOSPINAL TESTING
  Static-Force Platforms
  Moving-Platform Posturography
  VESTIBULAR-EVOKED POTENTIALS
  Brain Stem and Cortical
  Vestibular Evoked Myogenic Potentials (VEMPs)
  
  NYSTAGMOGRAPHY
  Nystagmography is a method for recording nystagmus, although it can be used for record- ing any type of eye movement. One can quan- tify the slow-component velocity, frequency, and amplitude of spontaneous or induced nys- tagmus, and the changes in these measure- ments brought about by loss of ﬁxation (with eyes open in darkness).1 In addition, visually controlled eye movements (saccades, smooth pursuit, and optokinetic nystagmus) can be recorded and quantitatively assessed.
  
  Methods of Recording Eye Movements
  Electrooculography (or electronystagmogra- phy, ENG) is the simplest and still most readily
  available system used for nystagmography (Fig. 7–1).2,3 The potential difference between the cornea and retina, known as the corneal– retinal potential, acts as an electric dipole, ori- ented in the direction of the long axis of the eye. In relation to a remote location, an electrode placed in the vicinity of the eye becomes more positive when the eye rotates toward it and less positive when it rotates away from it. Recordings are usually made with a three-electrode system, using differential ampliﬁers. Two of the (active) electrodes are placed on each side of the eye, and the reference (ground) electrode is placed somewhere remote from the eye. The two active electrodes measure a potential change of equal amplitude but opposite direction. The difference in potential between these elec- trodes is ampliﬁed and then transferred to a recording device for a graphical representation. Because the differential ampliﬁers monitor the
  171
  
  Center Right Gaze Left Gaze
  –
  –
  –
  –
  –
  
  +
  +
  +
  +
  Electrodes + Amplifier
  Pen Recorder
  
  Figure 7–1. Electronystagmography. Electrode placement (top); Method for recording eye movements (bottom). See text for details.
  
  difference in voltage between the two active electrodes, remote electrical signals (electro- cardiographic or electroencephalographic, for example) arrive at the electrodes with approxi- mately equal amplitude and phase and are canceled out.
  Infrared video recording of eye movements (videonystagmography, VNG) is a newer, more ﬂexible eye movement recording system that is gradually replacing ENG in many clinical labo- ratories (Fig. 7–2).4 The infrared cameras used are ﬁtted into various types of goggles, which are then placed around the patient’s head. With some goggles, the cameras are placed directly in front of the eyes, which is ﬁne for recording eye movements in dark conditions (i.e., caloric and positional tests). To allow patients to better track targets (e.g., during saccade and smooth pursuit testing), other goggles were designed with the cameras mounted on top (thus out of the patient’s line of vision) and a reﬂective glass is used so that the eyes can be recorded. The infrared video camera is interfaced with a digi- tal computer. At regular intervals, images are stored by the computer for subsequent data analysis. Specialized digital signal–processing
  algorithms are then used to determine horizon- tal, vertical, and even torsional eye position.
  Magnetic search coils are another method of recording eye movements. This technique uses a contact lens embedded with two coils of wire, one that senses horizontal and vertical move- ments, and the other that senses torsional movements. When the subject sits in a mag- netic ﬁeld, voltages are induced in these search coils that can be used to measure eye position. The magnetic search coil technique is the gold standard technique for measuring eye move- ments because it allows measurement of eye rotations around all threes axes with high sensitivity and low noise.
  Each eye movement recording system has advantages and disadvantages. ENG is rela- tively inexpensive, easily administered, nonin- vasive, does not interfere with vision, and does not require head restraint. Furthermore, it is reasonably accurate even for the large- amplitude horizontal eye movements that are encountered during routine ENG testing. The disadvantages of ENG include the inability to measure torsional eye movements and rela- tively inaccurate measurement of vertical eye
  Video Cameras Video Cameras
  
  Reflective lenses
  
  Right Eye Left Eye
  
  5 10 15
  
  Figure 7–2. Videonystagmography. Two different examples of goggle systems, one with cameras mounted in front of the eyes and the other with cameras mounted on top of the goggles and out of the patient’s line of vision (top); example of appearance of video-recorded eyes (middle); example of videonystagmography caloric tracing and smooth pursuit tracing (bottom).
  
  movements, interference of eye blink artifacts, poor signal-to-noise ratio, and dependence on lighting conditions in the test room.5,6 Infrared video recordings have the advantage of accu- rately recording horizontal, vertical, and torsional eye movements.4 In addition to providing a digitized paper recording, there is a video recording that can be reviewed when there are questions about the paper recording, and it can also be used for teaching purposes. With video recordings there is a much faster setup time, as the goggles containing the video cameras are
  simply strapped on. Usually the computer ﬁnds and calibrates the eyes in less than a minute. With ENG, calibrations must be repeated fre- quently throughout the test battery, since the corneal–retinal potential ﬂuctuates, particu- larly if the lights are turned on and off. In addition, with the video system there is no interference from extraneous electrical signals from in- or outside the body. Disadvantages of the video systems include possible obstruction of vision by the video cameras, difﬁculty wear- ing eyeglasses, difﬁculty in keeping the camera
  system ﬁxed on the forehead, and difﬁculty with the digital tracking system in some patients with poor contrast between the pupil and iris. Eye blinks can interfere with the video record- ing systems, but VNG can be used to monitor eyelid dynamic disorders.7 The main disadvan- tage of the magnetic search coil technique is that it requires the use of a thick contact lens, which can cause discomfort for the patient or rarely corneal abrasion. Accordingly the mag- netic search coil technique is generally only used in research laboratories.
  With newer versions of VNG systems with high-frequency sampling rates, the degree of precision now rivals that of the magnetic search coil technique,8 so such systems are being incorporated into more research laboratories. Although increased precision of VNG and the magnetic search coil technique is a clear advan- tage over ENG in research studies,9 it remains uncertain whether these advantages over ENG enhance clinical diagnostic capabilities or can result in better patient outcomes.
  Ultimately, the performance of any of these techniques to record eye movements depends substantially on practical factors like the skills of the technician performing the test, the coop- eration of the patient, and the expertise of the clinician interpreting the test. If the test is not properly set up or instructions are not effec- tively communicated to the patient, then the results will be largely questionable. For the caloric test, the ear canals often need to be cleaned, the irrigation tube must be appropri- ately positioned, and the temperature of the water monitored. These are not difﬁcult tasks, but appropriate training, experience, and care are required. There are many patient factors (e.g., decreased alertness from sedating medi- cines, apathy, or severe nausea) that could result in an invalid test even when performed
  by a top technician. Finally, the clinician inter- preting the test must be familiar with these and other nuances of the test.
  
  Interpreting the Recording
  By convention, for horizontal recordings, eye movements to the right are displayed so that they produce upward pen deﬂection and those to the left produce downward pen deﬂection. For vertical recordings, upward and downward eye movements produce upward and downward deﬂections, respectively. For torsional eye movements, clockwise eye movements produce upward pen deﬂections while counterclockwise eye movements produce downward pen deﬂec- tion. Figure 7–3 illustrates the relationship between components of a typical beat of hori- zontal nystagmus. Values chosen for each component are those commonly seen with spon- taneous vestibular nystagmus recorded in the dark. The fast component moves to the left, so by convention the nystagmus is to the left (i.e., “left-beating”). A 10-degree fast component would have an average velocity (a/fd; a = ampli- tude, fd = fast duration) of approximately 100 degrees/sec. The slow-component velocity (a/sd; a = amplitude, sd = slow duration) is usu- ally much slower—in this case, 10 degrees/sec. It is approximately the product of the amplitude times frequency as long as the fast duration is small compared with the slow duration. Although the magnitude of each nystagmus measurement shown in Figure 7–2 can be calculated directly from the paper recording, such a procedure is tedious and therefore subject to error. Digital computers are ideally suited for making such measurements. Using a programmed algorithm, computers can calculate the amplitude, dura- tion, and velocity of each of the slow and fast
  
  R sc fc a
  L
  
  10°
  sd fd
  1 sec
  
  f = sd 1 fd vsc = a
  vsc  a·f if sd >> fd
  + sd
  Figure 7–3. Single beat of nystagmus recorded with electronystagmography. a, amplitude; f, frequency; fc, fast component; fd, fast duration; sc, slow component; sd, slow duration, vsc, velocity of slow component.
  components. Plots of the nystagmus slow- component velocity versus time are particularly useful for quantifying the magnitude of induced nystagmus (as will be shown later).
  Nystagmography can be used to evaluate any type of eye movement disorder, and the testing procedure should be ﬂexible enough to deal with any abnormality encountered. It is useful, however, to have a standard test battery that will at least screen all areas of potential abnor- mality (Table 7–1). In most clinical laborato- ries, the test battery includes (1) recording for pathologic nystagmus, (2) the bithermal caloric test, and (3) tests of visual–ocular control.
  
  Recording Pathologic Nystagmus
  The same systematic search for pathologic nys- tagmus outlined in the previous chapter should be conducted during the nystagmography examination. Recording with eyes open in darkness is more effective than using Frenzel glasses for identifying peripheral spontaneous and positional nystagmus. Approximately 20% of normal subjects have a low-velocity sponta- neous nystagmus (i.e., <4 degrees/sec) and as many as 75% have a low-velocity positional nystagmus when tested with eyes open in darkness.10,11 Apparently the vestibular system is unable to stabilize the position of the eyes when visual signals are removed.
  
  SPONTANEOUS NYSTAGMUS
  The effect of change in ocular position and ﬁxation on peripheral spontaneous nystagmus
  is illustrated with the ENG recordings in Figure 7–4. The patient was tested 3 days after and again 2 weeks after a left labyrinthectomy. On the initial recording, nystagmus was pres- ent even while ﬁxating on a target, although it was more prominent without ﬁxation. On the subsequent recording, nystagmus occurred only when the lights were turned off. This pattern is typical of an acute peripheral vestib- ulopathy of any cause. The nystagmus is exag- gerated with gaze in the direction of the fast component (Alexander’s law). As a general rule, nystagmus with ﬁxation (nystagmus seen on routine neurologic examination) disappears within 1 to 2 weeks after the occurrence of an acute peripheral vestibular lesion. By contrast, spontaneous nystagmus can be recorded in the dark for as long as 5 to 10 years after an acute peripheral vestibular lesion. In some patients, the spontaneous nystagmus emerges only with mental alerting tasks (e.g., when performing serial 7 subtractions from 100).12 Changes in head position with respect to gravity may alter the direction and magnitude of peripheral spontaneous nystagmus.
  Eye movement recordings can help differ- entiate congenital and central varieties of spon- taneous nystagmus from peripheral varieties. Spontaneous downbeating nystagmus is a com- mon central nystagmus pattern. The downbeat nystagmus shown in Figure 7–5a increases in frequency and amplitude with downward gaze, but it reversed direction with upward gaze. Loss of ﬁxation did not change the nystagmus frequency or amplitude (Fig. 7–5b). The spon- taneous vertical nystagmus was superimposed on attempted vertical pursuit (Fig. 7–5c).
  
  Table 7–1 Standard Nystagmography Test Battery
  Recording for Pathologic Nystagmus
  Fixation at midposition
  Fixation inhibited with eyes open in darkness (constant mental alerting) Gaze held 30° right, left, up, and down
  Rapid and slow positional changes
  Bithermal Caloric Test
  30°C and 44°C water infused into each ear, eyes open in darkness, constant mental alerting, allow at least 5 min between each infusion
  Visual Tracking Tests
  Saccades: 5°–40°, target can be series of dots or lights Smooth pursuit: target velocity 20°–40°/sec Optokinetic nystagmus: stripe velocity 20°–40°/sec
  Optokinetic after-nystagmus: lights turned off after 1 min constant velocity optokinetic nystagmus in each direction
  3 Days Post Labyrinthectomy
  14 Days Post Labyrinthectomy
  30° right 30° right
  10°
  
  15° right 5 sec
  
  Center
  
  15° left
  
  30° left
  
  Lights out
  Center
  Center
  
  30° left
  Lights out
  30° right
  
  Center
  
  30° left
  Figure 7–4. Peripheral spontaneous nystagmus (bitemporal horizontal ENG recording) taken 3 days and 14 days after the patient underwent a left labyrinthectomy. By 14 days, the nystagmus disappeared when in the light with ﬁxation but was still prominent in the dark when ﬁxation was inhibited.
  
  The waveform of the congenital nystagmus illustrated in Figure 7–6a changed in different horizontal gaze positions (from pendular to near sawtooth). When ﬁxation was inhibited by darkness, the nystagmus almost disappeared (Fig. 7–6b). Horizontal smooth pursuit was markedly impaired in both directions (Fig. 7–6c). By comparison, peripheral spontaneous nystagmus does not change direction with change in gaze position, does increase with loss of ﬁxation, and usually does not impair smooth pursuit. The slow component with acquired spontaneous nystagmus is typically
  linear, producing a sawtooth pattern, whereas the slow component with congenital nystagmus usually increases exponentially.13
  
  GAZE-EVOKED NYSTAGMUS
  The most common type of gaze-evoked nystagmus (drug-induced) has approximately equal ampli- tude in all directions of gaze. A large-amplitude, asymmetric gaze-evoked nystagmus is often seen with lesions of the cerebellar-pontine (CP) angle (so-called Bruns’ nystagmus).14 The lesion is usu- ally on the side of the large-amplitude nystagmus.
  
  (a)
  30° up
  (b)
  
  Lights off
  
  15° up
  
  Center
  
  15° down

5 sec

Pursuit down

10°

Pursuit up

Figure 7–5. Spontaneous downbeat nystagmus (monocular vertical ENG recordings). (a) Nystagmus increased on down- ward gaze and changed direction on upward gaze. (b) Loss of ﬁxation had little effect. (c) Nystagmus was superimposed on attempted vertical pursuit.

(a)

30° right

15° right 5 sec Center

(b)

Lights off Lights on

10°

15° left

(c)

Pursuit right

Pursuit left

30° left

Figure 7–6. Congenital nystagmus (bitemporal horizontal ENG recordings), (a) Waveform changed in different gaze posi- tions, (b) Nystagmus decreased with loss of ﬁxation, (c) Nystagmus was superimposed on attempted horizontal pursuit.

Rebound gaze-evoked nystagmus decays as the lateral gaze position is held (Fig. 7–7, upper trace) and recurs transiently after returning to the primary position, with fast components occurring in the direction of the return saccade (Fig. 7–7, lower trace).15

POSITIONAL NYSTAGMUS

Although benign paroxysmal positional nystag- mus can be readily identiﬁed on routine physi- cal examination, recording the nystagmus documents its stereotyped proﬁle. For this rea- son, we include the Dix-Hallpike positioning test as part of our nystagmography examina- tion; the technician also observes the nystag- mus while it is being recorded. Dix-Hallpike positioning can also be used to identify central positional nystagmus, which is typically down- beating. VNG is ideal for documenting vertical and torsional positional nystagmus patterns since the video recording can be reviewed. (Fig. 7–8).16 If ENG is used with only horizon- tal electrodes, then vertical or torsional nystagmus could be missed.17

As suggested earlier, persistent low velocity positional nystagmus is a common ﬁnding on nystagmography even in control subjects when recordings are made with eyes open in dark- ness. An average slow-phase velocity that exceeds 4 degrees/sec is considered abnormal, but nonlocalizing. Both direction-ﬁxed and direction-changing static positional nystagmus occur with peripheral and central vestibular lesions.18 Lack of suppression of the nystagmus with ﬁxation indicates a central lesion.

Bithermal Caloric Test

MECHANISM OF STIMULATION

Robert Barany received the Nobel Prize for proposing the mechanism of caloric stimula- tion of the vestibular system. The test uses a nonphysiologic stimulus (water or air) to induce endolymphatic ﬂow in the semicircular canals by creating a temperature gradient from one side of the canal to the other (Fig. 7–9).19,20 Irrigation of the external auditory canal with

Center 15°

Left 30°

Center

5 sec

Figure 7–7. Rebound nystagmus (horizontal bitemporal ENG recording). Nystagmus decays as the lateral gaze position is held and recurs on return to the primary position. The reverse occurred with gaze to the right.

–10

Eye Position (deg)

–20

–10

–20

		Horizontal

		Horizontal

–10

–20

Torsional

Vertical

5 10

15 20 25

Time (seconds)

Figure 7–8. Three-dimensional recording of benign paroxysmal positional nystagmus. Scleral search coil in right eye. Positive values indicate clockwise (as seen from the subject), up and right. Vertical lines indicate start and end of positioning maneuver. (Courtesy Michael Fetter, Tübingen, Germany).

water or air that is below or above body tem- perature transfers a temperature gradient from the external auditory canal to the inner ear by conduction. The horizontal semicircular canal develops the largest temperature gradient because it lies closest to the source of tempera- ture change. Because the vertical canals are relatively remote from the external ear, caloric stimulation of the vertical canals is unreliable. The endolymph circulates because of the dif- ference in its speciﬁc gravity on the two sides of the canal when the semicircular canal being investigated is in the vertical plane. Caloric testing of horizontal semicircular canal func- tion is usually performed with the patient in

same test is repeated with the patient lying on the abdomen, so that the horizontal canal is reversed in the vertical plane (i.e., the direction of the gravity vector with relation to the head is reversed), the direction of nystagmus induced by warm and cold stimulation is reversed.

Monkeys that have had their horizontal semicircular canals blocked with parafﬁn still have caloric-induced nystagmus, although

Ampullopetal deviation of cupula

Ampulla

Middle ear

the supine position, with head tilted 30 degrees up (placing the horizontal semicircular canals in the vertical plane; see Fig. 1–4c). With the warm caloric stimulus illustrated in Figure 7–9, the column of endolymph nearest the middle ear rises because of its decreased density. This

Crista 37°C

Utricle

44°C Water

Temp.

gradient

a External

b canal

causes the cupula to deviate toward the utricle (ampullopetal ﬂow) and produces horizontal nystagmus with the fast component directed toward the stimulated ear. A cold stimulus pro- duces the opposite effect on the endolymph column, causing ampullofugal endolymph ﬂow and nystagmus directed away from the

Horizontal semicircular canal

Gravity vector

44°C

Temp. 37°C

stimulated ear. These induced eye movements can be remembered with the mneumontic COWS—cold opposite, warm same. If the

Distance from external canal

Figure 7–9. Mechanism of caloric stimulation of the horizontal semicircular canal (see text for details).

lesser in magnitude than prior to surgery.21 Presumably, the spontaneous afferent nerve activity increases and decreases because of heating and cooling of the afferent nerve, respectively. Consistent with this interpreta- tion, the caloric-induced nystagmus in canal- blocked animals does not reverse direction when the gravity vector is reversed.21 This mechanism could also explain the unexpected ﬁnding of caloric-induced nystagmus in space, outside of earth’s gravity.22 Other mechanisms, including differential pressure effects from the temperature gradient and central otolith–canal interactions, have also been proposed to account for caloric responses in space.23 From a clinical point of view, however, gravity is the main driving force for the caloric response. The response can be effectively shut off (in instances in which the patient becomes extremely uncomfortable) simply by having the patient sit up and tilt the head about 30 degrees downward so that the horizontal canals are in the horizontal plane.24

The caloric test is the most widely used clin- ical test of the vestibulo-ocular reﬂex (VOR) for two major reasons: (1) each labyrinth can be stimulated individually and (2) the stimulus is easy to apply without requiring complex equipment. Several limitations of the test must be appreciated if one is to assess the results properly, however. The slow-component veloc- ity and duration of caloric-induced nystagmus are dependent not only on the relationship between the temperature gradient vector and the gravity vector but also on the blood ﬂow to the skin, presence of ﬂuid in the middle ear chamber, the physical distance between the tympanic membrane and the horizontal canal (longer distance leads to less temperature transfer), and heat conductivity of the temporal bone.25,26 If local blood ﬂow to the skin is decreased (from vasoconstriction due to pain or to anxiety), the maximum slow-component velocity of the response decreases (from decreased heat conductivity through skin), but its duration is prolonged (from delayed heat transfer). Patients with infection or ﬂuid in the middle ear and mastoid air cells may have an increased caloric response (increased maxi- mum slow component velocity) because the ﬂuid can increase heat conductivity from the external ear to the inner ear. Similarly, patients who have undergone mastoid surgery and reconstruction of their middle ear may have

increased responses due to a shortening of the conduction pathway. A thickened temporal bone, by contrast, would produce the opposite effect, because of decreased bone heat con- ductivity. Some of these factors no doubt underlie the large variability of caloric responses measured in normal subjects and explain the occasional unexpected increase or decrease in caloric response found in patients with tempo- ral bone disease. The caloric response can also be attenuated by small or narrow external audi- tory canals, or cerumen build-up within the external canal.

TEST METHODOLOGY

With the bithermal caloric test introduced by Fitzgerald and Hallpike,27 each ear is irrigated for a ﬁxed duration (30 to 40 sec) with a con- stant ﬂow rate of water that is 7° below body temperature (30°C) and 7° above body tem- perature (44°C). One must wait a minimum of 5 min from the end of one response to the next stimulus to avoid additive effects. The major advantages of this test methodology are

(1) both ampullopetal and ampullofugal endo- lymph ﬂow are serially induced in each horizontal semicircular canal, (2) the caloric stimulus is highly reproducible from patient to patient, and (3) the test is tolerated by most patients. The major limitation is the need for constant temperature baths and plumbing to maintain continuous circulation of water through the infusion hose. Patients with migraine may have an increased chance of hav- ing a migraine headache after caloric testing.28 The magnitude of caloric-induced nystag- mus is highly dependent on the degree of ﬁxa- tion permitted during the test procedure. Four different ﬁxation conditions have been used for caloric testing: (1) eyes open, ﬁxating; (2) eyes open, Frenzel glasses; (3) eyes open, total dark- ness; and (4) eyes closed. Without eye move- ment recording devices, obviously only the ﬁrst two conditions can be used. Comparison of these four conditions in normal subjects shows a consistently lower coefﬁcient of variation (standard deviation/mean) for response mea- surements when the test is performed with eyes open, either behind Frenzel glasses or in

total darkness.29

When caloric testing is performed with ﬁxation (as initially described by Fitzgerald and Hallpike), two separate systems are being

evaluated: the VOR and the smooth pursuit system (see Visual–Vestibular Interaction, Chapter 3). Some normal subjects are very good at suppressing caloric-induced nystagmus with ﬁxation29; others are not. Patients with impaired smooth pursuit (such as patients with cerebellar atrophy) may show no difference in caloric-induced nystagmus with or without ﬁxation.30 When measured with ﬁxation the responses in these patients will appear hyper- active when compared with those of subjects with a normal smooth pursuit system. Eye clo- sure and the associated upward deviation of the eyes can lead to suppression of both spontane- ous and induced nystagmus.29 It can also alter the nystagmus waveform, making it more difﬁ- cult to quantify with nystagmography. Patients with central nervous system (CNS) lesions often have a horizontal deviation of the eyes on closure, which can also change the waveform of induced nystagmus.31 To avoid these uncontrol- lable variables, caloric testing should be per- formed with eyes open (either in the dark or behind opaque goggles). For a brief period during the test, ﬁxation can be permitted to evaluate the nystagmus suppressing functional status of the smooth pursuit system.32

NORMATIVE DATA

The response to caloric stimulation can be assessed in several ways. The simplest method is to measure the duration of nystagmus after

each infusion, using a stopwatch. Prior to the development of eye movement recordings, this was the only way to quantify the bithermal caloric test. Using nystagmography, however, it is possible to record multiple response mea- surements accurately. Figure 7–10 illustrates an ENG recording of a normal caloric response. The subject was supine, the head elevated 30 degrees, and the eyes open behind Frenzel glasses in a darkened room. Two hundred ﬁfty milliliters of 44°C water was infused into the left ear during the 40 sec marked on the ﬁgure, resulting in ampullopetal endolymph ﬂow in the left horizontal semicircular canal, producing left-beating horizontal nystagmus. The nystag- mus began just before the end of stimulation, reached a peak approximately 60 sec post stim- ulus, and then slowly decayed over the next minute. Next to the ENG tracing, nystagmus slow-component velocity, slow-component amplitude, and frequency are plotted versus time. Each measurement demonstrates beat- to-beat variability, but the velocity of the slow components shows the least variability. Furthermore, a decrease in slow-component velocity is the most sensitive indicator of vestibular damage.

As suggested earlier, the absolute magnitude of caloric response depends on several physical factors unique to each subject that are unre- lated to actual semicircular canal function (e.g., blood ﬂow to the skin, ﬂuid in the middle ear, the physical distance between the tympanic

(a)

44° Caloric infusion

5 sec

15°

(b)

Slow Comp. Vel. (deg/sec)

Slow Comp. Ampl. (deg)

20 (c)

0 30 60 90 120

8 (d)

Frequency (beats/sec)

0 30

60 90 120

Seconds

Figure 7–10. Caloric response produced by infusion of 250 ml of 44°C water into the left ear of a normal subject.

(a) Bitemporal electronystagmographic recording. Horizontal bar indicates duration of infusion. Plots are of slow- component velocity (b), slow-component amplitude (c), and frequency (d) versus time, generated by a digital computer.

membrane and the horizontal canal, and heat

( ( ) 00

[2]

conductivity of the temporal bone). The maxi- mum slow-component velocity (MSCV) after a

R L44  R L30

caloric stimulus can be as low as 5 degrees/sec and as high as 75 degrees/sec and still be within the 95% conﬁdence interval for normal subjects.33 Because of this large intersubject variability, intrasubject measurements are more useful clinically (Fig. 7–11). The vestibu- lar paresis formula

compares the MSCV of nystagmus to the right with that of nystagmus to the left in the same subject. Dividing by the total response normal- izes the measurements to remove the large variability in absolute magnitude of normal caloric responses.

A caloric ﬁxation suppression index is

( ( )

100

[1]

obtained by having the patient ﬁxate on a target

R R44  L L44

during the middle of the response. Because the slow-component velocity of caloric-induced

compares the MSCV of right-sided (R) responses with that of left-sided (L) responses, and the directional preponderance formula

H O °C Nystagmus to R

nystagmus is constantly changing, it is impor- tant that the ﬁxation period occur near the time of maximum response to obtain the best esti- mate of ﬁxation suppression. The ﬁxation suppression index is deﬁned as (MSCV with ﬁxation ÷ MSCV without ﬁxation) × 100. With each of these formulas, the result is reported as a percentage of the total response.

In our laboratory, a vestibular paresis is deﬁned as >25% asymmetry between left-and

Normal

Left vestibular paresis

Right directional preponderance

30°

44°

30°

44°

30°

44°

Ear L R

R L R

L R

Nystagmus to L

right-sided responses, and a directional pre- ponderance as >30% asymmetry between left- and right-beating nystagmus, and a ﬁxation suppression index >70% is abnormal. These values are comparable to those reported by other investigators (many use >30% asymmetry to deﬁne a vestibular paresis), but it must be emphasized that each laboratory should estab- lish its own normal range because of the many methodologic variables discussed earlier.

Slow component velocity

RESULTS IN PATIENTS

Table 7–2 summarizes the abnormalities found in caloric testing, their meaning in terms of location of lesion, and the mechanism by which each abnormality is produced.

Peripheral Lesions

Assuming acceptable test conditions and per-

(40 sec) 1 2 3

Time (min)

Duration

of irrigation

formance (e.g., experienced technician, coop- erating patient, clean and symmetric external auditory canals), the ﬁnding of a signiﬁcant ves- tibular paresis with bithermal caloric stimula-

Figure 7–11. Normal and two common patterns of abnor- mal response to bithermal caloric testing. With a vestibu- lar paresis, the responses to cold (30°C) and warm (44°C) water are decreased on the same side. With a directional preponderance, the responses to warm water on one side and cold water on the opposite side are decreased.

tion suggests damage to the vestibular system that can be located anywhere from the end organ to the vestibular nerve root entry zone in the brain stem. By far, the most common cause of a caloric vestibular paresis is unilateral

Table 7–2 Interpreting the Results of Bithermal Caloric Testing

Result Location of Lesion Mechanism

Vestibular paresis Labyrinth, VIII nerve Decreased peripheral sensitivity Directional preponderance Not localizing Tonic bias in vestibular system

Hyperactive responses Cerebellum Loss of inhibitory inﬂuence on vestibular nuclei Dysrhythmia Cerebellum Loss of inhibitory inﬂuence on pontine nuclei Impaired ﬁxation suppression CNS pursuit pathways Interruption of visual signals on way to

oculomotor neurons

Perverted nystagmus Fourth ventricular region Disruption of vestibular commissural ﬁbers

peripheral vestibular disease. For the central vestibular system to be the source, the lesion would need to involve the eighth nerve root entry zone. In animal studies focal lesions in different vestibular nuclei did not produce a vestibular paresis. This is not to say that a cen- tral lesion cannot cause a vestibular paresis, but to simply say that a central lesion is much less likely. A recent study reported that 43% (10 out of 23) of patients with stroke (deﬁned as a relevant lesion with restricted diffusion on magnetic resonance imaging [MRI]) causing acute vertigo who underwent caloric testing had a vestibular paresis of >25%.34 In 22% (5 out of 23) of these stroke patients the ves- tibular paresis was severe (>75%). Because peripheral causes of vestibular paresis are much more common than central causes, the likelihood of a central cause is low particularly when there are no other central ocular motor abnormalities (e.g., bi-directional gaze evoked nystagmus) or other brainstem signs.

A directional preponderance on caloric testing occurs with peripheral end-organ and eighth nerve lesions and with CNS lesions (from brain stem to cortex).30 It indicates an imbalance in the vestibular system and is usually associated with spontaneous nystagmus: the velocity of the slow components of the spontaneous nystagmus adds to that of the caloric-induced nystagmus in the same direction and subtracts from that of the caloric-induced nystagmus in the opposite direc- tion.35 Occasionally, a directional preponderance will occur in patients without spontaneous nys- tagmus; most of these patients have peripheral lesions, although about 5% have central lesions.36 The need to distinguish between end-organ and eighth nerve lesions is a common clinical problem. Partial lesions of the eighth nerve should not, in theory, affect the duration of induced nystagmus, as it is related to the time course of cupular deﬂection and not to the ability

of the nerve ﬁbers to transmit action potentials. However, end-organ lesions involving the cup- ula and hair cells should affect both the MSCV and duration of the responses. Unfortunately, this turns out not to be a reliable way of differ- entiating end-organ from eighth nerve lesions. Lesions involving the eighth nerve can reduce the duration of nystagmus, whereas end-organ lesions (particularly in the early stages) frequently result only in decreased MSCV (the duration of response remains unaffected). The magnitude of loss is of some help in differentiat- ing nerve from end-organ lesions. A complete or nearly complete unilateral paralysis is more commonly associated with nerve lesions than with end-organ labyrinthine lesions.

The vestibular paresis and directional pre- ponderance formulas are of little use in evaluat- ing patients with bilateral peripheral vestibular lesions, because caloric responses are symmet- rically depressed. Because of the wide range of normal values for MSCV, the patient’s value may decrease severalfold before falling below the normal range. For example, a patient may have a MSCV of 7 degrees/sec for each side, values that are typically within the normal range. However, if that patient has other features indi- cating a bilateral vestibulopathy, then it can be assumed that the MSCV would have been sub- stantially higher if it was tested prior to the pre- sentation. Baseline and serial measurements in the same patient are needed if one hopes to identify early bilateral vestibular impairment, such as that produced by ototoxic drugs.

Central Lesions

As suggested earlier, patients with CNS lesions may exhibit a vestibular paresis on caloric test- ing if the lesion involves the root entry zone of the vestibular nerve.34 The most common neu- rologic disorders associated with this ﬁnding

are multiple sclerosis, lateral brainstem infarc- tion, and inﬁltrating gliomas. Each disease nearly always produces other brainstem signs, so the ﬁnding of a vestibular paresis is not likely to be misinterpreted as a sign of a peripheral vestibular disorder if the complete clinical pic- ture is carefully considered. A careful assess- ment is needed because central abnormalities could be subtle such as central oculomotor abnormalities (e.g., bi-directional gaze-evoked nystagmus). In rare cases, a massive brainstem infarction or diffusely inﬁltrating glioma leads to bilateral decreased caloric responses.

Lesions of the cerebellum can lead to increased caloric responses, possibly because of loss of the normal inhibitory inﬂuence of the cerebellum on the vestibular nuclei. Because of the wide range of normal caloric responses, however, it is unusual for any of the responses to exceed the upper normal range. Patients with the cerebellar atrophy syndromes demon- strate a wide range of caloric responses.37 Those with Friedreich’s ataxia often have bilaterally decreased responses because of associated atrophy of the vestibular nerve and ganglia, whereas those with a dominantly inherited spi- nocerebellar ataxia (SCA) syndrome could have decreased, normal, or even increased responses, depending on which areas of the medulla and pons are involved. Increased caloric responses, when they do occur, are usually found in patients with clinically pure cerebellar atrophy (e.g., SCA-6, see Chapter 18). Bilaterally reduced caloric responses are common in SCA-1 and SCA-3.38–40

An abnormal ﬁxation suppression index on caloric testing typically occurs with lesions involving the smooth pursuit system (from the parietal-occipital cortex to the pons and cere- bellum). Lesions of the midline cerebellum produce the most profound impairment of ﬁxa- tion suppression. When asymmetric, pursuit deﬁcits in one direction correlate with suppres- sion deﬁcits in the opposite direction.

Dysrhythmia refers to a marked beat-to-beat variability in caloric-induced nystagmus ampli- tude without any change in the slow-component velocity proﬁle. The cerebellum is important for controlling the amplitude of nystagmus fast components, and loss of this control with cere- bellar lesions may lead to a disorganized nystagmus pattern. Unfortunately, from a diag- nostic point of view, caloric dysrhythmia also occurs in normal subjects when they are tired and inattentive. As will be shown in the next

section, rotatory stimuli are better suited than caloric stimuli for examining the pattern of induced nystagmus.

Vertical or oblique nystagmus produced by caloric stimulation of the horizontal semicircu- lar canals is called perverted nystagmus. Normal subjects commonly exhibit a small vertical component on nystagmography recordings of caloricinduced nystagmus, but vertical compo- nents larger than the horizontal components are clearly abnormal.41 Perverted nystagmus with caloric stimulation has been reported with both peripheral and central lesions, the latter usually being in the region of the ﬂoor of the fourth ventricle (near the vestibular nuclei).42 Perverted caloric nystagmus occurs in rhesus monkeys after unilateral focal lesions occur in the rostral medial vestibular nucleus. Warm caloric stimulation on the intact side produces downward nystagmus, and cold stimulation produces upward diagonal nystagmus. These ﬁndings are probably due to a disturbance of the commissural ﬁbers between the vestibular nuclei.

Tests of Visual–Ocular Control

The central vestibulo-ocular connections are highly integrated with the visual-ocular stabi- lizing pathways, and both systems share the ﬁnal common pathway of the oculomotor neu- rons (see Comparison of Vestibular- and Visual- Induced Eye Movements in Chapter 3). If the efferent limb of the VOR arc is damaged, visu- ally controlled eye movements are also abnor- mal; but if the afferent limb of the reﬂex is damaged, visually controlled eye movements are usually normal. Because eye movement– recording techniques used for quantifying the VOR can also be used to quantify visually con- trolled eye movements, an important “bonus” of information is obtained with little increased effort. Table 7–3 summarizes the types of sac- cade, smooth pursuit, and optokinetic abnor- malities commonly associated with focal lesions of the nervous system.

SACCADIC EYE MOVEMENTS

Methods of Testing and Results in Normal Subjects

One can induce saccadic eye movements with a series of dots or lights separated by known

Table 7–3 Summary of Visual Ocular Control Abnormalities Produced by Focal Neurologic Lesions

Location of Lesion Saccades Smooth Pursuit and OKN Slow Phase

Cerebellopontine angle Ipsilateral dysmetriaa Progressive ipsilateral impairment

Diffuse cerebellar Bilateral dysmetria Bilateral impairment

Intrinsic brain stem Marked slowing, increased delay time Ipsilateral or contralateral impairment

Basal ganglia Mild slowing, hypometria,b increased delay time

Bilateral impairment

Frontoparietal cortex Difﬁculty inhibiting reﬂex saccades Ipsilateral impairment

aUnder- and overshoots.

bUndershoots only.

OKN, optokinetic nystagmus.

angular degrees, or with a dot of light generated on a screen and moved through a series of step- wise jumps of different amplitudes.43 The ENG recording in Figure 7–12A illustrates the high speed and accuracy of saccadic eye movements induced in a normal subject by a target moving in steps of random amplitude. Normal subjects consistently undershoot the target for jumps larger than 20 degrees, requiring a small cor- rective saccade to achieve the ﬁnal position. Overshoots of the target are rare. A character- istic delay time of approximately 200 msec occurs between each target jump and induced saccade.

Computer algorithms have been developed to rapidly quantify these saccade parameters.43 Saccades are easily identiﬁed on the basis of their characteristic velocity proﬁle. The rela- tionship between peak velocity and amplitude (the so-called main sequence) is nonlinear, with decreasing peak velocities occurring at higher amplitudes (Fig. 7–12B). For example, the average peak velocity for a 15 degrees sac- cade is 400 degrees/sec, whereas that for a 30 degrees saccade is 550 degrees/sec. Saccade accuracy is deﬁned as the ratio of the saccade amplitude divided by the target displacement amplitude times 100. The mean saccade accuracy

Right eye

Left eye

Target

15°

5 sec

800

deg/sec

600

400

200

Left eye

Right eye

40 20 0

20 40 40 20 0

Amplitude (deg)

20 40

Figure 7–12. Saccadic eye movements induced in a normal subject by a target moving in steps of random amplitude (3°–36°) and changing intervals between jumps (0.5–2.5 sec). (top) Monocular horizontal electronystagmographic record- ings. (bottom) Computer-generated plots of peak velocity versus amplitude for entire sequence (dotted lines represent normal mean ± standard deviation).

for normal subjects on the random saccade test is 88%. Overshooting of the target rarely occurs in normal subjects. The mean delay time on the same test is 186 msec.44

Results in Patients

Slowing of saccadic eye movements can occur with lesions anywhere in the diffuse central pathways involved in generating saccades. The most pronounced slowing occurs with lesions of the pretectal and paramedian pontine gaze centers, the oculomotor neurons, and the extraocular muscles. Lesions involving these pathways impair both voluntary and involun- tary saccades. Damage to the oculomotor neurons, oculomotor nerves, and extraocular muscles causes a slowing of saccades when the paretic muscle is the agonist required to gener- ate the sudden force necessary to move the globe rapidly. Saccade slowing identiﬁed on eye movement recording can occur before clinical examination reveals the presence of strabismus.45,46 Recordings have been particu- larly helpful for identifying early lesions of the medial longitudinal fasciculus (MLF), mani- fested by slowing of adducting saccades made by the medial rectus on the side of the lesion (Fig. 7–13).47,48 A characteristic saccade abnor- mality is seen with myasthenia gravis. Saccades begin with normal velocity, but within a short time the transmitters at the myoneural junc- tion are depleted, and the remainder of the saccade is markedly slow.49 In some patients with severe oculomotor dysfunction, only brief bursts of oculomotor ﬁring are possible before a complete block occurs. This results in the unusual situation in which a patient with almost complete absence of sustained eye movements can have small-amplitude, high-velocity sacca- des followed by a quick return to the primary position (so-called ocular quiver). These sac- cade abnormalities are usually rapidly reversed with intravenous Tensilon.50

Reversible saccade slowing is produced by fatigue and by ingestion of alcohol or tranquil- izers.51–53 This results from impaired synaptic transmission through the multineuronal net- works needed to generate the high-frequency ﬁring for horizontal and vertical saccades. Patients with Huntington’s disease and pro- gressive supranuclear palsy develop slowing of saccades, apparently due to diffuse degenera- tion of supranuclear pathways.54,55 Focal disease

of the pretectum or paramedian pontine retic- ular formation produces selective slowing of vertical and horizontal saccades, respec- tively.56,57 Lesions of one paramedian pontine center produce ipsilateral saccade slowing. The pretectal centers for upward and downward saccades are separate (downward ventral dor- sal to the upward center) but are so close together that lesions usually involve both. Destruction of the pretectal and pontine supra- nuclear saccade centers results in complete absence of saccadic eye movements (voluntary and involuntary). Patients with such a dysfunc- tion produce only a slow tonic deviation of the eyes with vestibular or optokinetic stimuli because of the absence of fast components (see Fig. 7–29c).57

Impaired saccade accuracy is most com- monly seen with cerebellar disorders.58,59 Overshooting of the target (saccade overshoot dysmetria) is most apparent, as overshoots rarely occur in normal subjects (See Video 7–1). The velocity of these inaccurate saccades is normal unless the brain stem is also involved. Of the cerebellar atrophy syndromes, saccade dysmetria is most prominent with Friedreich’s ataxia.60,61 Monocular overshoots in the abduct- ing eye are characteristic of MLF lesions (see Fig. 7–13). Disorders of the cortical and sub- cortical supranuclear centers also affect the accuracy of saccades.62,63 Patients with Parkinson’s disease exhibit delayed saccade reaction time and hypometria of voluntary sac- cades. Complete removal of one hemisphere or the presence of a large frontal parietal lesion results in hypometria of horizontal saccades made in the contralateral direction.64 Vertical saccades are unaffected. Animals with lesions of the frontal eye ﬁelds may have normal- appearing saccade metrics but have difﬁculty inhibiting reﬂex saccades.65 Patients with lesions of the frontal cortex and basal ganglia have sim- ilar difﬁculties.66,67 This can be demonstrated with the antisaccade test, in which a ﬁxation tar- get is illuminated in the periphery and the patient is instructed to make a saccade in the exact opposite direction. Normal subjects can reliably perform this task, but patients with lesions involving cortical and subcortical presac- cade structures often make unwanted saccades to the ﬁxation target before reﬁxating in the desired location.

Patients with acquired and congenital oculo- motor apraxia68 and ataxia telangiectasia69

Right eye

Left eye

Target

15°

5 sec L

800

deg/sec

600

400

200

Left eye

40 20 0

Right eye

20 40 40 20 0 20 40

Amplitude (deg)

Figure 7–13. Saccadic eye movements in a patient with bilateral medial longitudinal fasciculus lesion caused by multiple sclerosis. Recordings are as in Figure 7–12. Adducting saccades are markedly slow; abducting saccades have normal velocity but overshoot the target.

exhibit prolonged reaction time for the initia- tion of voluntary saccades and use a series of hypometric saccades to produce reﬁxations. Nystagmus fast components (involuntary sac- cades) are also abnormal, such that the eyes deviate in the direction of the slow component rather than in the direction of the fast compo- nent. To compensate for impaired voluntary saccades, these patients often use head thrusts to perform reﬁxation. Because their VOR is intact, the head thrusts produce con- troversive deviation of the eyes, necessitating an overshoot of the head thrusts to obtain ﬁxa- tion. Fixation is then maintained as the head is slowly returned on line with the target. The site of the anatomic defect that produces these abnormalities in voluntary saccades is unknown.

SMOOTH PURSUIT

Methods of Testing and Results in Normal Subjects

Examining physicians can test smooth pursuit eye movements by slowly moving their ﬁnger or a pencil back and forth and asking the patient to follow it as well as possible. The target should be moved as smoothly as possible and the movement should not be too fast (about 1/2 cycle/sec is an ideal rate). A more exact rela- tionship between the velocity of the target and

the eye is determined by using precise targets and eye movement recording. A pendulum hanging from the ceiling or a metronome pro- vides an inexpensive reproducible sinusoidally moving target. Precise control of the target can be achieved over a series of velocities by pro- jecting a dot onto a screen with a motor-con- trolled device. Figure 7–14b illustrates an ENG recording of horizontal smooth pursuit in a normal subject as he follows a sinusoidally moving dot on a white screen (0.3 Hz, maxi- mum amplitude 18 degrees). The accuracy of smooth pursuit can be quantiﬁed by repeatedly sampling eye and target velocity and plotting the two velocities against each other (see Fig. 7–14d). A computer algorithm makes the comparison between eye and target velocity after saccade waveforms have been removed.70 The slope of this eye target velocity relation- ship (in this case, 0.95) represents the gain of the smooth pursuit system. The mean gain determined from similar plots in 25 normal young subjects was 0.95 ± 0.07. Older normal subjects (>70 years of age) show marked vari- ability in pursuit ability, and therefore pursuit testing must be interpreted with caution in older patients.71 Also, smooth pursuit gain decreases with both increasing frequency and increasing velocity of the target. Each labora- tory must establish normative data for its stan- dard test protocol.

(a)

15°

5 sec R

(b)

15°

(c)

15°

(d)

(e)

16 Target

16 32 48 velocity

(deg/sec

Target

16 32 48 velocity

16 (deg/sec

Eye velocity (deg/sec)

Figure 7–14. Smooth pursuit of a target (a) moving with a sinusoidal waveform in a normal subject (b) and a patient with cerebellar atrophy (c). Bitemporal horizontal recording. Eye velocity is plotted against target velocity (both sampled 10 times/sec) after saccades have been removed for the normal subject (d) and patient (e).

Results in Patients

Patients with impaired smooth pursuit require frequent corrective saccades to keep up with the target, producing so-called cogwheel, or sacca- dic, pursuit (see Fig. 7–14c). As expected, the gain (given by the slope of the eye velocity–target velocity plot) of the smooth pursuit system is markedly decreased in such patients (see Fig. 7–14e). It must be emphasized, however, that normal subjects may intermix saccades with smooth pursuit movements, particularly if they are inattentive or fatigued, or if the target velocity exceeds the limit of their smooth pursuit system.72 Therefore, quantitative analysis of intersaccadic eye velocity is a more reliable way of assessing the accuracy of smooth pursuit than simply observ- ing the frequency of superimposed saccades.

Abnormalities of smooth pursuit are of lim- ited localizing value, as they occur with disor- ders throughout the CNS. Acute lesions of the peripheral labyrinth or vestibular nerve tran- siently impair smooth pursuit contralateral to the lesion when the eyes are moving against the slow component of spontaneous nystagmus.73 This asymmetry in smooth pursuit disappears within a few weeks despite the continued pres- ence of spontaneous nystagmus in darkness. Just as tranquilizing drugs, alcohol, and fatigue affect saccadic eye movements, they also impair smooth pursuit eye movements.74 Barbiturates may impair smooth pursuit before affecting sac- cadic eye movements, which suggests an increased sensitivity of the smooth pursuit system. Patients with diffuse cortical disease75 (degenerative or vascular), basal ganglia

disease54,76(Parkinson’sdiseaseandHuntington’s disease), or diffuse cerebellar disease37,58 consis- tently have bilaterally impaired smooth pursuit eye movements. Focal disease of one cerebellar hemisphere or one side of the brain stem usu- ally produces ipsilateral impairment of smooth pursuit, although large cerebellar pontine angle tumors are frequently associated with bilater- ally impaired smooth pursuit.14 Focal cortical lesions in the parietooccipital region impair ipsilateral smooth pursuit (Fig. 7–15a).77,78

OPTOKINETIC NYSTAGMUS

Methods of Testing and Results in Normal Subjects

The simplest optokinetic stimulus is a striped cloth that can be moved across the patient’s visual ﬁeld in each direction. While the patient stares at the cloth, the amplitude of induced nystagmus in each direction is compared. This type of test permits identiﬁcation of absent or markedly asymmetric optokinetic nystagmus (OKN). The test sensitivity is improved by using an optokinetic stimulus of known velocity and recording the induced nystagmus. Figure 7–16 shows such a recording of OKN induced by a striped drum completely surrounding a subject and moving at a constant velocity of 30 degrees/sec. At the arrow, the lights were turned off and optokinetic after-nystagmus (OKAN) was recorded. A plot of slow- component velocity is provided beneath the tracing. Typically, the OKN slow-component velocity approaches that of the drum velocity as

(a)

Target position

15º

Patient 1

Patient 2

1 sec

15º

(b)

Drum velocity

60º/sec

0º/sec

15º

60º/sec

Patient 1

Patient 2

15º

1 sec R

Figure 7–15. Right monocular recordings of horizontal smooth pursuit (a) and optokinetic nystagmus (OKN) (b) from two patients with left parietal lobe lesions.77 In A the patients tracked a laser dot moving in a sinusoidal fashion (left: 0.2 Hz, peak velocity 22.5°/sec; right: 0.4 Hz, peak velocity 45°/sec). In B a surrounding optokinetic drum moved in a sinusoidal pattern (0.05 Hz, peak velocity 60°/sec). Pursuit and OKN slow phases to the left were markedly impaired.

long as the drum velocity does not exceed 30 to 40 degrees/sec. As with smooth pursuit gain, the gain of OKN (slow-component velocity/ drum velocity) drops off with increasing fre- quency and drum velocities in normal subjects (Fig. 7–17).79 The OKAN velocity is more vari- able than OKN velocity even in young normal subjects. There is a rapid exponential dropoff followed by a gradual decay, as shown in Figure 7–16. The mean OKAN slow-component

velocity (after the initial rapid dropoff) and the mean OKAN duration in 20 normal subjects after 1 min of 30 degrees/sec optokinetic stim- ulation was 6.3 degrees/sec ± 4.5 degrees/sec and 23.75 sec ± 23.1 sec, respectively.79

Results in Patients

As a general rule, abnormalities of optokinetic slow components parallel abnormalities in

SCV (deg/sec)

b 5 sec

Lights out

15º

55 60 0 5 10

Time (sec)

Figure 7–16. Optokinetic nystagmus (OKN) induced by a surrounding striped drum moving at a constant velocity of 30°/sec. At the arrow the lights were turned off, and optokinetic after-nystagmus (OKAN) was recorded. a Bitemporal electronystagmographic recording. b Plot of slow-phase velocity (SCV) versus time.

Slow Phase Eye Velocity (deg/sec)

0 10 20 30 40 50 60 70 ‌

Optokinetic Drum Velocity (deg/sec)

Figure 7–17. Normal mean ± 1 standard deviation for horizontal optokinetic nystagmus slow-phase velocity at different drum velocities. , ramp acceleration from 0° to 70°/sec in 1 min; , constant velocity for 30 sec; , sinusoidal (0.05 Hz).

smooth pursuit, and abnormalities of fast components correlate with abnormalities of voluntary saccades.79 Symmetrically decreased slow-component velocity is produced by dif- fuse disease of the cortex, diencephalon, brain stem, and cerebellum.37,54,58,62,75 As with smooth pursuit, focal lateralized disease of the parietal occipital region, brain stem, and cerebellum result in impaired OKN when the stimulus moves toward the damaged side (see Fig. 7–15b).77,78 Lesions of the occipital lobe, although associated with a hemianoptic visual ﬁeld defect, are not associated with impaired smooth pursuit or OKN, presumably because each parietal lobe receives oculomotor signals from both occipital lobes. Some patients with severely impaired smooth pursuit exhibit a gradual buildup in OKN slow-component velocity.80 This is a feature of OKN normally seen in afoveate animals that have only a sub- cortical OKN system (see Chapter 3). Presumably, in normal humans the cortical pursuit system dominates the subcortical OKN system, so normal OKN exhibits features of normal pursuit. When the cortical pursuit sys- tem is lesioned, however, the remaining OKN may exhibit features of the subcortical system. Patients who are unable to produce saccadic eye movements produce only a slow tonic devi- ation of the eyes in the direction of an optoki- netic stimulus. Although patients with slow

saccades produce OKN, the waveform is rounded, and the amplitude and slow- component velocity are decreased. The delayed ending of the impaired fast component sub- tracts from the initial part of the slow compo- nent in the opposite direction. The many causes of saccade slowing were outlined in detail in the previous section.

Abnormalities of OKAN are typically seen with peripheral vestibular lesions.81 Unilateral lesions result in asymmetric OKAN (present only in the direction of the spontaneous nystagmus), whereas bilateral lesions (e.g., due to ototoxic drugs) result in diminished or absent OKAN in both directions.79

ROTATIONAL TESTING OF VESTIBULO-OCULAR REFLEXES

The determination of which vestibular subor- gans are stimulated by rotation of the head requires knowledge of three factors: (1) the axis of rotation, (2) the orientation of the skull (and thus the labyrinth) with respect to the rotation, and (3) the orientation of the rotation with respect to gravity (Fig. 7–18). Currently, rotational tests of the vestibulo-ocular reﬂexes concentrate on the horizontal semicircular canal ocular reﬂex (yaw, z-axis rotation) because

z-axis

Roll

Pitch

y-axis

x-axis

Yaw

Off-center rotation Off-vertical rotation

Figure 7–18. Deﬁnitions of different axes and orientations for rotational testing.

it is the easiest reﬂex to stimulate and record. Rotational tests of the vertical semicircular canals and otoliths are still in the developmen- tal stage and are not generally available in most clinical settings (Table 7–4).

Rotational testing of the horizontal semicir- cular canal offers several advantages over caloric testing. Multiple graded stimuli can be applied in a relatively short period of time, and the testing is usually well tolerated by patients.

Table 7–4 Vestibular Tests and the Suborgans They Stimulate

Test	Horizontal Canals	Vertical Canals	Otoliths
Conventional rotational chair	+
Upright pitch rotation		+	+
Onside pitch rotation		+
Static ocular counterrolling			+
Dynamic ocular counterrolling		+	+
Eccentric rotation	+		+
Off-vertical rotation	+		+
Linear track			+
Parallel swing			+

Unlike caloric testing, a rotational stimulus to the semicircular canals is unrelated to physical features of the external ear or temporal bone, so a more exact relationship between stimulus and response is possible. However, rotational stimuli affect both labyrinths simultaneously, in contrast to the selective stimulation of one labyrinth possible with caloric testing.

According to the pendulum model intro- duced in Chapter 2, the slow-component veloc- ity of rotational-induced nystagmus should be proportional to the deviation of the cupula, which, in turn, is proportional to the intensity of stimulation. As will be demonstrated in the following sections, this model’s applicability to different forms of rotational stimulation pro- vides a rational approach to the evaluation of clinical rotational testing.

Relationship between Stimulus and Response

PASSIVE WHOLE-BODY YAW ROTATION

With standard rotational chairs, the angular acceleration in the z-axis can be precisely con- trolled and multiple response measurements

can be accurately monitored. Figure 7–19 illus- trates the nystagmus responses of a normal subject to three common types of angular acceleration used in clinical laboratories. The subject was rotated in the z-axis with the eyes open in complete darkness while he performed continuous mental arithmetic to maintain alert- ness. Each stimulus produced a peak angular chair velocity of 120 degrees/sec.

As with caloric testing, maximum slow- component velocity is the response measure- ment most useful for quantifying testing. The coefﬁcient of variation (standard deviation divided by the mean) for maximum slow- component velocity after a rotational stimulus is about one-half the coefﬁcient of variation after a caloric.82 Even with this increased preci- sion, however, there is still large variation in the rotational responses of normal subjects. Factors such as stress, fatigue, level of mental alertness, and habituation all contribute to the variability (see Chapter 3). Complete darkness is needed so that the patient cannot ﬁxate on a target.

The slow-component velocity proﬁles (Fig. 7–19d–f) for each stimulus can be pre- dicted by the pendulum model discussed in Chapter 2. Note the similarity between these proﬁles and the time course of cupula devia- tion illustrated in Figure 2–15. An important

Chair velocity

EOG
Chair velocity

EOG
Chair velocity

10 sec

120

15º

120

Slow component velocity (deg/sec)

0 60


10	20	30	40	50


10	20	30	40	50

80 e

30 f

20 30 40 50

80 100

EOG

10 sec

15º

0 10 20 30 40 50

Seconds

Figure 7–19. Nystagmus recording (a–c) and slow-component velocity proﬁle (d–f) with three types of angular accel- eration, each resulting in a maximum velocity of 120°/sec. With the impulse stimulus (a) the change in velocity occurs in < 1 sec, with an acceleration of 140°/sec2. The sinusoidal stimulus (b) has a frequency of 0.05 Hz (20 sec/cycle) and a maximum acceleration of 38°/sec2. The constant acceleration stimulus (c) is 4°/sec2 for 30 sec (horizontal bitemporal electrooculorgraphic [EOG] recordings).

feature not addressed by the simple pendulum model is the adaptation phenomena (see Chapter 2). The step response best illustrates the effect of adaptation on induced nystagmus. Instead of slowly returning to the baseline as would be predicted by the pendulum model, the velocity of the slow component reverses direction and then slowly returns to the base- line (as shown in Fig. 7–19a, d). Reversals of this type consistently occur in normal subjects when the step change in angular velocity is >100 degrees/sec.83

Two types of measurements are typically used to quantify the response to these tradi- tional rotational stimuli: a magnitude (gain) and a timing (time constant or phase shift) measurement. The gain is deﬁned as the peak slow-phase eye velocity divided by the peak stimulus (chair) velocity. The time constant of the step response is deﬁned as the time required for the response to decay to 1/e or to 37% of the maximum value. For a sinusoidal test, the phase is typically measured by comparing the time of the maximum head velocity (measured by chair velocity) with the time of the maxi- mum slow-phase eye velocity. Consistent with models of the canal-ocular reﬂex, the maximum slow-phase eye velocity leads the maximum head velocity at low frequencies of sinusoidal rotation in normal subjects. The time constant (TCOR) of the canal-ocular reﬂex measured after

a step change in angular velocity is inversely

related to the phase lead () at low frequencies of sinusoidal rotation by84

in all three axes—yaw, pitch, and roll. Although expensive rotational devices are available for passively rotating the whole body at high accel- erations in all three planes, the tests can also be performed with passive head-on-body rotation by manually moving the head with small- amplitude thrusts in all three planes (as is done with the bedside head-thrust test).87 The eye movement recording system must be precise enough to measure the small-amplitude, high- velocity eye movements that are induced. The scleral search coil technique is a sensitive eye movement recording system that has been used to record these types of eye movements in research laboratories. With this system, the sub- ject is seated within a set of external reference magnetic ﬁeld generator coils and wears a con- tact lens that contains tiny “receiving” coils to record horizontal, vertical, and torsional eye posi- tion.88 Similar coils can be attached to the head to accurately measure head position. VNG systems that are tightly coupled to the head to prevent slippage are just becoming available.89 ENG is not sensitive enough and, of course, it can only accurately record horizontal eye movements.

The unique advantage of the high-acceleration test is that one can measure gain in the time domain early after the onset of the stimulus. Early gain measurements (<50 msec after the stimulus) reﬂect an almost pure vestibulo- ocular response, since visual and other modula- tory central inﬂuences occur later in the response. Another unique advantage of the high-acceleration test is that it is more sensitive than traditional low-acceleration testing for

TCOR  q

[3]

identifying the difference between ampullopetal and ampullofugal responses when there is a uni- lateral loss of function (see later discussion).

where  = 2F.

HIGH-ACCELERATION

SMALL-AMPLITUDE ROTATION

Brief high-acceleration impulses provide a unique assessment of the VOR not available with traditional stimuli.85,86 Accelerations >2000 degrees/sec2 are typically applied for <200 msec, leading to a head position change of 10 to 15 degrees. By contrast, most commercially avail- able motorized chairs have a weight-dependent peak acceleration <150 degrees /sec2. Because only a small amplitude of head displacement is produced, the head accelerations can be applied

ACTIVE HEAD ROTATION (AUTOROTATION)

Active head-only rotational testing is a method for assessing the VOR that can potentially be performed at the bedside or in the clinic with inexpensive, transportable equipment.90–92 Patients are taught to move their head back and forth in a sinusoidal pattern, typically in the range of 0.5 to 3 or 4 Hz. The test can theo- retically be performed in all three axes, although subjects ﬁnd it easiest to rotate their head in the yaw axis. To date, eye movements have mostly been recorded with ENG, but with this system only horizontal eye movements can be

accurately recorded. Auditory cueing is typically used to instruct the patient to perform the head rotations but somatosensory cues may provide an even better training stimulus.93 The test can be performed either at discrete sinusoidal fre- quencies or by a sweep of frequencies, although the latter stimulus may be more difﬁcult to train. Gain and phase measurements can be made after frequency analysis of the data; this analysis is similar to that performed with pas- sive whole-body rotation. Of course, at these higher frequencies, no nystagmus is recorded and the sensitivity of the eye movement record- ing system becomes more important. A major advantage of the autorotation test is that it pro- vides a measurement of gain for the VOR in the frequency range (>1 Hz) in which it nor- mally functions.94 Disadvantages include the following: patients may have difﬁculty perform- ing the movements,92 responses may vary with practice,92 poor test-retest inter-individual repeatability,95 and extravestibular inﬂuences such as preprogrammed compensatory eye movements and neck-ocular responses can help compensate for vestibular loss.96,97

Results in Normal Subjects

PASSIVE WHOLE-BODY YAW ROTATION

Step Changes in Angular Velocity

The main advantage of the step stimulus is that it provides a rapid assessment of the gain and the time constant of the canal-ocular reﬂex in each direction. Because the stimulus is brief, however, if subjects are not maximally alert or if they attempt to suppress the response, the ini- tial peak will be blunted and the estimate of gain, inaccurate. For this reason, several mea- surements should be averaged in each direc- tion. The results of a typical response to a step change in velocity in a normal subject are shown in Figure 7–20a. Slow-component velocity (log- arithmic scale) is plotted versus time; each dot represents the average slow-component veloc- ity over a 25-msec interval. Fast components have been removed. The gain (peak slow-com- ponent velocity/peak chair velocity) can be read directly from these plots. The time constant (TCOR) represents the time required for the

slow-component velocity to fall to 37% of its

peak value given by the slope of a regression

line ﬁtted to the data. The normal mean gain

and TCOR values calculated from similar plots in 20 normal subjects were 0.63 ± 0.18 and

12.2 ± 3.6 sec, respectively.84 These values are relatively stable over a wide range of step changes in velocity (0 to 250 degrees/sec), but both show a gradual decrease with larger- magnitude impulses (>120 degrees/sec).82,83

The variance associated with measurements comparing clockwise and counterclockwise responses in the same subject is less than the variance in response between subjects. A nor- malized difference formula, [(clockwise − counterclockwise) ÷ (clock wise + counter- clockwise)] × 100, is analogous to the directional preponderance formula used with caloric test- ing. Greater than 20% asymmetry on this nor- malized difference formula is considered abnormal in our laboratory.

Sinusoidal Changes in Angular Velocity

With sinusoidal rotational testing, the gain of the canal-ocular reﬂex can be measured at mul- tiple discrete frequencies after the subject has attained a steady-state response. It usually pro- vides a more accurate assessment of gain than is obtained with the step test. The main disadvan- tage is the more time that it takes to test a broad frequency range. Also, unlike the step test, sinusoidal testing measures only a single time constant (the low-frequency phase lead reﬂects the average time constant in both directions).

Two standard computer plots generated dur- ing sinusoidal rotational testing in a normal sub- ject are shown in Figure 7–21a. The subject was rotated at 0.05 Hz (peak velocity 60 degrees/ sec) with eyes open in the dark while perform- ing continuous mental alerting tasks. As with the step data shown in Figure 7–20, each dot repre- sents the average slow-component velocity over a 25-msec interval. The gain (peak slow-compo- nent velocity/peak chair velocity) in each direc- tion can be read directly from these plots, or an average gain can be calculated by performing a frequency analysis (Fourier analysis) on the data. From this analysis, one obtains the gain, dc bias, and phase relationship between the funda- mental of the slow-component velocity and the chair velocity.70 If the slow-component velocity data are symmetrical (as in normal subjects), the phase can be read directly from these plots by comparing the time of the maximum or the zero eye velocity with that of the chair velocity.

(a)

130

SCV

Gain = 0.78

TCOR = 12.0

CCW

Gain = 0.75

TCOR = 14.1

0 10 20 30

(b)

130

SCV

CW CCW

Gain = 0.50 Gain = 0.95

TCOR = 5.2 TCOR = 11.2

0 10 20 30 0 10 20 30

Time (seconds)

Figure 7–20. Plots of nystagmus slow-component velocity (SCV) (log scale) versus time after a step change in angular velocity (100°/sec acceleration 140°/sec2) in a normal subject (a) and a patient with an acute right peripheral vestibular lesion (b). Gain is peak SCV divided by change in chair velocity. TCOR is the slope of a regression line best ﬁt to the data. CCW, counter clockwise; CW, clockwise, (see text for details).

However, if the responses are asymmetric (as in Fig. 7–21b), an accurate assessment of phase can be obtained with a Fourier analysis of the data. The plot of slow-component velocity ver- sus stimulus velocity (Fig. 7–21, right) provides

a rapid visual assessment of dc bias and facilitates measurement of an average gain in each direction (i.e., the slope of the line in each direction). As with step-rotational stimuli, >20% asymmetry on the standard

Slow Component Velocity (deg/sec)

–40

(a)

Gain = 0.58

	DCBias = 1.2

	DCBias = 1.2

Phase = 8

Gain R = 0.64

L = 0.54

DCBias = 0

Normal

–80

–40

(b)

Gain = 0.54

	DCBias = 12.8

	DCBias = 12.8

Phase = 25

Gain R = 0.72

L = 0.37

DCBias = 9

Patient

–80

0 20

Time (sec)

40 80 40 0 –40 –80

Stimulus Velocity (deg/sec)

Figure 7–21. Plots of nystagmus slow-component velocity versus time (left) and versus chair velocity (right) during sinu- soidal angular rotation (0.05 Hz, 60°/sec peak velocity) in a normal subject (a) and a patient with an acute right peripheral vestibular lesion (b) (same patient as in Fig. 6–20). The gain, phase (lead) and dc bias (+ rightward bias) were determined from frequency analysis (Fourier analysis) of the data.

directional preponderance formula is consid- ered abnormal for all frequencies and ampli- tudes of stimulation.

The gain and phase of the canal-ocular reﬂex vary with frequency in normal subjects (Fig. 7–22),84 which is consistent with the pen- dulum model. Normal subjects exhibit an approximate 45-degree phase lead of eye veloc- ity relative to chair velocity at 0.01 Hz, but this phase lead is near zero by 0.2 Hz.

HIGH-ACCELERATION,

LOW-AMPLITUDE ROTATION

Typical responses to a high-acceleration impulse in all three planes in a normal subject are shown

in Figure 7–23.87 The impulses are passive, unpredictable, low-amplitude (10–20 degrees), high-acceleration 3000 to 4000 degrees/s2) head rotations (head thrusts) in yaw, pitch, and roll with the subject sitting upright. Head and eye position and velocity are almost equal and opposite (gain near 1.0) for yaw and pitch impulses, so there is relatively little change in gaze position. By contrast, the compensatory eye movement in the roll plane has a gain of about 0.8, so there is a gaze instability in this plane. This difference in normal gain in the three planes of rotation can be more readily seen in plots of eye velocity versus head veloc- ity shown in Figure 7–24 (top traces). In the yaw and pitch planes, the slope is near 1.0

1.0

Gain

0.1

0.05

Phase

–10

0.01

0.1 1.0

Frequency (Hz)

Figure 7–22. Plots of the gain and phase (mean ± 1 standard deviation) of the horizontal canal-ocular reﬂex as a function

of frequency in 10 normal subjects (), 20 patients with compensated unilateral vestibular lesions ( ), and 22 patients with bilateral peripheral vestibular lesions (). All subjects were tested with mental alerting in the dark. The unilateral patients

had absent caloric response on one side; the bilateral patients had symmetrically decreased response to caloric stimulation.85 The peak velocities at different frequencies were 0.0125 Hz, 100°/sec; 0.05 and 0.2 Hz, 60°/sec; 0.4 and 0.8 Hz 30°/sec.

Position (RV)

0.1

0.0

–0.1

–0.2

| 5º

Onset

Yaw Pitch

Roll

Head Eye

Gaze

125

Velocity (º/sec)

–125

–250

Right

0 100

200

0 100 200

Time (ms)

CCW

0 100 200

Figure 7–23. Head, gaze and eye positions and velocities in normal subjects during a yaw-right, pitch-up, and a roll- counterclockwise (GCW) head thrust. The eye signals are inverted for illustration. The arrows indicate the onset of head movement. Note the gaze instability with roll thrusts. (From Au ST et al. Head impulses reveal loss of individual semicircu- lar canal function. J Vestib Res. 1999;9:173–180, with permission.)

(gain near 1.0), whereas the slope is about 0.8 in the roll planes.

ACTIVE HEAD ROTATION

Most normal subjects can produce near-perfect compensatory eye movements in the frequency range of 1 to 4 Hz with active sinusoidal head movements (Fig. 7–25).96 When the scleral search coil technique is used to record eye movements in the horizontal and vertical planes, the gain measurements are close to 1.0 and phase changes are near zero over this wide frequency range (Fig. 7–26). Interestingly, the VOR gain from active head rotations is consistently higher than the gain from passive head rotations in this frequency range in normal subjects (Fig. 7–26). Normative data from studies using ENG to record eye move- ments have been more variable. Some investi- gators have found gains in excess of 1.1 in the high-frequency range and others have reported poor test–retest reliability of the gain measurements.95,97,98 Vertical gain and phase measurements are particularly unreliable with ENG, with a wide range of normative val- ues being reported. In our experience this test is overused and overinterpreted.

Results in Patients

UNILATERAL PERIPHERAL LESIONS

Patients who suddenly lose vestibular function on one side have asymmetric responses to rota- tional stimuli because of (1) a dc bias resulting from spontaneous nystagmus and (2) the differ- ence in response to ampullopetal and ampull- ofugal stimulation of the remaining intact labyrinth.84 These features are readily seen in passive yaw rotation data shown in Figures 7–20b and 7–21b. The patient was tested shortly after the acute onset of vertigo due to a right peripheral vestibular lesion (probable viral neu- rolabyrinthitis). At the time of testing, he exhib- ited a spontaneous left-beating nystagmus (eyes open in the dark) with an average slow-phase velocity of 10 degrees/sec. This spontaneous nystagmus added to rotational-induced nystag- mus in the same direction and subtracted from that in the opposite direction. The effects of this dc bias and of the asymmetry in response to ampullopetal and ampullofugal stimulation of the intact labyrinth are best illustrated in the plot of eye velocity versus stimulus velocity from sinusoidal rotation (see Fig. 7–21b, right side). The dc bias (the eye velocity at the point of Y-intercept) is equivalent to the average

200

100

–100

YAW

PITCH Y

ROLL X

–200

200

100

–100

–200

Eye Velocity (deg/sec)

200

100

–100

–200

200

100

–100

–200

200

100

–100

–200

Normal

LuPCOZ Y X

Z Y X

LuSD Z Y X

Z Y X

LuVD Z Y X

Z Y X

bVD Z Y X

Z Y X

Right Left Up Down CCW CW

–200 –100 0 100 200 –200 –100 0 100 200 –200 –100 0 100 200

Head Velocity (deg/sec)

Figure 7–24. Eye velocity as a function of head velocity during roll, pitch, and yaw head thrusts in a normal subject and in four patients with the following conditions: after left unilateral posterior canal occlusion (LuPCO); after left unilateral deafferentation of the superior branch of the vestibular nerve (LuSD); after left unilateral vestibular deafferentation (LuVD); and after bilateral vestibular deafferentation (bVD). The ten trials in each direction are displayed. CCW, counter- clockwise; CW, clockwise. (From Au ST et al. Head impulses reveal loss of individual semicircular canal function. J Vestib Res. 1999;9:173–180, with permission.)

slow-phase velocity of the spontaneous nystag- mus. The gain (slope) of the response with ampullopetal stimulation of the intact labyrinth is twice that with ampullofugal stimulation.

With compensation, the dc bias gradually disappears and the gain asymmetry between ampullopetal and ampullofugal stimula- tion decreases but does not disappear.99,100

(a)

Eye Velocity (deg/sec)

100

–50

–100

(b)

Head Velocity (deg/sec)

100

–50

–100

0 1.0 2.0 3.0 4.0 5.0 6.0

Eye Velocity (deg/sec)

–20

–40

–60

–80

–100

G = 1.04

0 1.0 2.0 3.0 4.0 5.0 6.0

–100

–50 0

50 100

Time (sec) Head Velocity (deg/sec)

Figure 7–25. Eye movements recorded with a scleral search coil during self-generated (active) head oscillations in the pitch plane. (a) head velocity, (b) Eye velocity data are ﬁtted to sinusoids (solid curves) for those cycles meeting the statisti- cal criterion for acceptance, while cycles rejected due to artifacts are indicated by horizontal bars. (c) The graph plots phase- corrected eye velocity against head velocity; the slope corresponds to gain (G). The two ﬂanking lines indicate boundaries of the region in which data points were accepted for analysis. (From Demer JL et al. Visual–vestibular interaction in humans during active and passive, vertical head movement. J Vestib Res. 1993;3:101, with permission.)

It remains most pronounced after high-intensity stimuli. These dynamic asymmetries in the canal-ocular reﬂexes can best be determined in the laboratory by using high-acceleration, small-amplitude impulses or high-frequency, high-acceleration sinusoidal rotations.86,87,101,102 Brief high-acceleration head thrusts in normal subjects result in little gaze instability, whereas in patients with a unilateral vestibular loss, accelerations toward the side of the lesion produce a prominent gaze shift in that direction because of the lack of a compensatory VOR response (Fig. 7–27a). This same gaze deviation phenomenon can be seen with high-frequency sinusoidal rotation; the deviation is most prominent at the highest fre- quencies when the head rotates toward the lesion side (Fig. 7–27b). Interestingly, this gaze deviation during ipsilesional rapid head movements is greater with passive rotation than with active head rotations, suggesting that with active rotations patients are able to compensate partially for the lack of a compen- satory VOR response. It follows that passive head rotations at high accelerations are best suited for identifying the dynamic

asymmetries associated with unilateral vestibu- lar lesions.101,102

By performing high-acceleration, small- amplitude head thrusts in all three planes, one can assess the function of the three pairs of semicircular canals (Fig. 7–24).86,87 For exam- ple, a patient who underwent blockage of the left posterior semicircular canal for treatment of benign paroxysmal positional vertigo showed a prominent decrease in VOR gain during upward pitch and counterclockwise roll head thrusts (Fig. 7–24, LuPCO). A patient with involvement of all three semicircular canals on the left side showed a prominent decrease in VOR gain with horizontal head thrusts to the left and approximate symmetrical decrease in gain with up-and-down pitch movements and a prominent decrease in gain with counterclock- wise roll (Fig. 7–24, LuVD). Thus, directional deﬁcits in response to ipsilesional head thrusts allows one to identify the individual semicircu- lar canal lesions. The abnormalities are best identiﬁed by measuring VOR gain close to peak head velocity, where the disinhibition input from the intact side approaches saturation values. Recall that inhibition is produced by

1.75

1.50

VOR Gain

1.25

1.00

0.75

0.50

0.0 1.0 2.0 3.0 4.0

Active VOR Passive VOR

Phase - deg

–1

–2

–3

–4

–5

0.0 1.0 2.0

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Figure 7–26. Vestibulo-ocular reﬂex (VOR) gain and phase from nine normal subjects tested at multiple single frequen- cies during passive and active head rotations in the pitch plane. Gain was greater during active head rotations than during passive rotations in the mid-frequency range. Phase was near zero for both types of rotation.

ampullofugal stimulation of the horizontal semicircular canals and ampullopetal stimula- tion of the vertical canals. In addition to the dynamic asymmetries in VOR responses in the planes of the three sets of semicircular canals, patients with unilateral peripheral vestibular lesions develop anomalous (out of the plane of rotation) eye movements that contribute to gaze instability and to complaints of oscillopsia.102 For example, vertical head thrusts in the pitch plane result in anomalous torsional eye move- ments due to loss of the normally balanced ver- tical canal inputs (Fig. 7–28). Normally the ver- tical canals on each side generate a torsional component that is perfectly balanced with pitch rotation so that no torsional eye movements

are observed. However, with a unilateral loss of vestibular function, aberrant torsional eye movements are generated during up-and-down head thrusts. These aberrant torsional eye movements could contribute to sensations of tilt often reported by patients with unilateral vestibular lesions.102

Patients with compensated unilateral periph- eral vestibular lesions show a characteristic pattern of decreased gain and increased phase lead at low frequencies of sinusoidal z-axis rota- tion (see Fig. 7–22).103 These changes appear to be ﬁxed in that they can be observed as long as 10 years after an acute unilateral peripheral vestibular loss.100 Their functional implications are minimal, however, as the visuomotor system

R L

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Figure 7–27. Gaze stability during horizontal head rotations in the light in a normal subject and in a patient with right peripheral vestibular loss (after a nerve section). a The head is passively moved in quick steps (thrusts) to the right and left. Gaze is stable in the control whereas in the patient there are prominent gaze shifts to the right with head thrusts to the right. b Active and passive sinusoidal rotations of the patient’s head show the same gaze instability with movements to the right, but the gaze instability is much greater with passive than with active (self-generated) movements. (From Foster CA et al. Defects of gaze stability in multiple axes following unilateral vestibular lesions. Exp Brain Res. 1997;116:501, with permission).

can compensate for the loss of vestibular func- tion in the low-frequency range.

BILATERAL PERIPHERAL LESIONS

Rotational stimuli are ideally suited for testing patients with bilateral peripheral vestibular lesions because both labyrinths are stimulated simultaneously and the degree of remaining function is accurately quantiﬁed.84,86,104,105 Because the variance associated with normal rotational responses is less than that associated with caloric responses, diminished function is

identiﬁed earlier. Furthermore, artifactually decreased caloric responses occasionally occur in patients with angular, narrow external canals or with thickened temporal bones. Because the intensity of rotational stimuli is unrelated to these physical features, rotational-induced nys- tagmus is normal in such patients. Frequently patients with absent response to bithermal caloric stimulation have decreased but record- able rotational-induced nystagmus, particularly at higher frequencies of sinusoidal rotation (see later discussion). The ability to identify remaining vestibular function—even if

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Figure 7–28. Aberrant torsional eye movements induced by self-generated, vertical head thrusts in a patient with a left-sided peripheral vestibular loss. a Clockwise (CW) torsional eye movements are more prominent during upward (ﬁrst arrow) than downward (second arrow) head movement. Gaze deviations were corrected with torsional quick phases (asterisks). b There are no torsional head movements during these vertical head thrusts to account for the torsional eye movement responses. CCW, counterclockwise. (From Foster CA et al. Defects of gaze stability in multiple axes following unilateral vestibular lesions. Exp Brain Res. 1997;116:501, with permission.)

minimal—is an important advantage of rota- tional testing, particularly when the physician is contemplating ablative surgery or monitor- ing the effects of ototoxic drugs. By using pre- cisely graded rotational stimuli on a serial basis, ototoxic effects are recognized earlier than by using the less-precise caloric stimulus.

Patients with bilateral peripheral vestibular loss show the same pattern of low-frequency gain and phase deﬁcits on sinusoidal testing (only more pronounced) observed in patients with compensated unilateral peripheral vestibu- lar lesions (see Fig. 7–22).106 Rarely, patients may have no response to rotation at frequencies below 0.05 Hz and yet have normal responses at higher frequencies.84 These ﬁndings have important clinical implications with regard to testing patients with suspected bilateral periph- eral vestibular disease. Given that the results of the bithermal caloric test reﬂect the results of low-frequency sinusoidal stimulation, the absence of caloric response does not indicate an absence of vestibular function. In fact, a patient could have absent caloric response yet normal response to traditional rotational testing at higher frequencies (up to 1 Hz). However, high- acceleration, small-amplitude head thrusts can be very sensitive for identifying bilateral periph- eral vestibular loss, particularly if one focuses on the ﬁrst 100 msec after the impulse.107 Central compensation mechanisms cannot make up for the loss of peripheral vestibular function in this time domain. Interestingly, patients who show minimal or no early VOR response after high- acceleration head thrusts can have reasonably good responses during sinusoidal head rotation at higher frequencies.107 These nonvestibular oculomotor responses are presumably gener- ated by using whatever residual vestibular func- tion remains and other sensory clues that are available. These nonvestibular compensatory eye movements are most pronounced with active head rotations, presumably because the patient can use information generated by the volitional head movements to improve the com- pensatory eye movements. This must be kept in mind, however, when using autorotational tests to screen for bilateral vestibular loss.

CENTRAL VESTIBULAR LESIONS

As with lesions of the peripheral vestibular structures, lesions of the central VOR pathways can lead to a decrease or an asymmetry in the

gain of rotational-induced nystagmus. Lesions involving the nerve root entry zone and vestib- ular nuclei may produce responses indistin- guishable from those produced by peripheral vestibular lesions. The spectrum of abnormali- ties associated with central lesions, however, is much more diverse than a simple decrease in the gain. The gain may be increased in some patients with cerebellar lesions.108 The highly organized pattern of the nystagmus produced in normal subjects may be disorganized, result- ing in so-called dysrhythmic nystagmus. If the production of fast components is impaired, the nystagmus waveform is distorted or there may be only a slow tonic deviation of eyes from side to side. In this case, high-acceleration impulses or high-frequency sinusoidal rotation are the only stimuli that can be used to measure VOR gain. Finally, central lesions often interfere with the integration of visual and vestibular sig- nals, producing abnormalities on tests of visual– vestibular interaction (see later discussion).

Low-frequency sinusoidal rotational stimuli are ideally suited for studying the pattern of induced nystagmus. Figure 7–29 illustrates the responses to sinusoidal rotation (eyes open in darkness) in (a) a normal subject, (b) a patient with cerebellar atrophy, (c) a patient with a left pontine lesion (astrocytoma), and (d) a patient with a bilateral lesion of the medial longitudi- nal fasciculus (MLF). In the normal subject the eyes alternately deviate in the direction of the fast component for each half-cycle of induced nystagmus. As discussed in Chapter 3, the eye position in the orbit for initiation of fast components is near the midline. Fast compo- nents (saccades) are generated in the parame- dian pontine reticular formation, and the cerebellum controls the amplitude of both vol- untary and involuntary saccades. In the patient with cerebellar atrophy (Fig. 7–29b), the nys- tagmus pattern is disorganized with fast com- ponents occurring in random fashion, causing marked beat-to-beat variability in amplitude. This type of abnormality has been termed dys- rhythmia and is commonly found in patients with all varieties of cerebellar lesions. Patients with dysrhythmic vestibular nystagmus also demonstrate dysmetria of voluntary saccades.

The patient with a left pontine lesion (see Fig. 7–29c) could not produce voluntary or involuntary saccades (fast components) to the left, so during the half-cycle that normally produces left-beating nystagmus, the eyes

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Figure 7–29. Electronystagmographic recordings of nystagmus response to sinusoidal rotation at 0.05 Hz, peak velocity 60°/sec in a normal subject (a) and in patients with cerebellar atrophy (b), left pontine glioma (c), and bilateral medial longitudinal fasciculus lesions caused by multiple sclerosis (d).

tonically deviated to the right. In patients with bilateral pontine lesions, the eyes tonically deviate to the right and left with each half-cycle of rotation because of the complete absence of fast components.57 One might mistakenly inter- pret this as a decreased or absent vestibular response.

In the patient with a bilateral MLF lesion (Fig. 7–29d), there is a dissociation in fast compo- nents between the two eyes. When either paretic adducting eye is required to make a fast compo- nent, the nystagmus beats are rounded because of a decrease in the frequency of action potentials arriving at the medial rectus motor neurons via the damaged MLF. Abducting fast components,

however, are normal because the abducting mus- cles (abducens nuclei) receive their innervation for fast components directly from the parame- dian pontine reticular formation with no involve- ment of the MLF. Frequently, the abducting fast components are actually too large. The oculomo- tor control centers attempt to overcome the block at the MLF by increasing the innervation sent from the paramedian pontine region to the ocul- omotor neurons.109,110 Because (according to Herring’s law) this increased innervation is sent equally to both medial and lateral rectus oculo- motor neurons, the difference in amplitude between adducting and abducting fast compo- nents is further magniﬁed.

VISUAL–VESTIBULAR INTERACTION ‌‌

The model introduced in Chapter 3 (Fig. 3–21) represented two general types of visual–vestibular interaction: one mediated via the “direct” (pur- suit) pathway and the other via the indirect (velocity storage) pathway. Because the direct pathway is dominant in humans, clinical tests have focused on pursuit–VOR interaction. In rare patients with selective lesions of the direct pathway, it is possible to demonstrate visual– vestibular interaction mediated via the indirect velocity storage pathway (see later discussion).

Methodology

Since the visual tracking systems function best at low frequencies and low velocities, visual– vestibular interaction is most prominent at low frequencies and low velocities. In the laboratory,

visual–vestibular interaction is typically tested by rotating the subject either sinusoidally or with a step change in velocity while (1) the surround- ing optokinetic drum is stationary (visualvestib- ulo-ocular reﬂex [VisVOR], a synergistic interaction of the visual and vestibular systems) or (2) the drum and chair are coupled so that they move together (ﬁxation suppression of the vestibulo-ocular reﬂex [VOR-FIX], an antago- nistic interaction between the visual and vestibular systems).111 Fixation suppression can also be tested by rotating the subject in the dark with a single ﬁxation light attached to the chair.

Results in Normal Subjects

Typical responses of a normal subject to low- frequency sinusoidal (0.05 Hz) optokinetic (OKN), vestibular (VOR), and visual-vestibular (VisVOR and VOR-FIX) stimulation are shown in Figure 7–30 (left). In each case, the peak stimulus velocity is 60 degrees/sec. At this low

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Normal Subject Right Peripheral Bilateral Peripheral Right

Left

OKN

VOR

VisVOR

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Figure 7–30. Plots of slow-phase velocity versus time from a low-frequency visual–vestibular test battery (see text for details) in a normal subject (left), a patient who underwent a right labyrinthectomy (center), and a patient with bilateral vestibulopathy secondary to ototoxic drugs (right) (0.05 Hz, peak velocity 60°/sec). OKN, optokinetic nystagmus; VisVOR, visual-vestibulo-ocular reﬂex; VOR, vestibulo-ocular reﬂex; VOR-FIX, ﬁxation suppression of VOR. (From Baloh RW, et al. Quantitative vestibular testing. Otolaryngol Head Neck Surg. 1984;92:1,45, with permission.)

frequency and peak velocity, the normal sub- ject has a VisVOR gain of 1.0 (i.e., the slow- phase eye velocity is equal and opposite to the head velocity) and a VOR-FIX gain of 0 (i.e., the subject is able to completely suppress the VOR with ﬁxation). The mean gain ± standard deviation for similar sinusoidal testing in 20 normal subjects is as follows: OKN 0.83 ± 0.13; VOR 0.50 ± 0.15; Vis-VOR 0.99 ± 0.05; VOR-

FIX 0.03 ± 0.02. At high frequencies (>1 Hz) and velocities (>50 degrees/sec), the OKN (and pursuit) gain decreases (e.g., see Fig. 7–17). Above 2 Hz, the VisVOR and VOR-FIX gain are approximately the same as the VOR gain (near 1.0).

Results in Patients

Patients with peripheral vestibular lesions have decreased and/or asymmetric VOR gain, but visual–vestibular responses are usually normal at low stimulus frequencies and velocities

(see Fig. 7–30, center and right). Even with a complete loss of vestibular function, the visuo- motor system can provide good ocular stability. At high frequencies and velocities, however, the VisVOR gain decreases if the VOR gain decreases.112

Three abnormal patterns of visual–vestibular interaction seen on low-frequency sinusoidal testing in patients with central lesions are shown in Figure 7–31.111 Patients with lesions involving the vestibular nucleus region (e.g., Wallenberg’s syndrome) exhibit prominent ocul- omotor abnormalities (see Stroke Syndromes, Chapter 14). With eyes open in the sitting posi- tion, there is a tonic pulling of the eyes toward the side of the lesion, resulting in spontaneous nystagmus with the fast phase toward the intact side. With eyes closed or with eyes open in darkness, the spontaneous nystagmus may change direction. The responses illustrated in Figure 7–31 (left) are from a 32-year-old man who had the acute onset of vertigo, nausea, vomiting, dysphagia, and falling to the left.

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Figure 7–31. Plots of slow-phase velocity versus time from a low-frequency visual–vestibular test battery in a patient with infarction of the left lateral medullary region (left), a patient with midline cerebellar atrophy (center), and a patient with a glioma in the deep parietal lobe on the left side (right) (0.05 Hz, peak velocity 60°/sec). OKN, optokinetic nystagmus; VisVOR, visual-vestibulo-ocular reﬂex; VOR, vestibulo-ocular reﬂex; VOR-FIX, ﬁxation suppression of VOR. (From Baloh RW, et al. Quantitative vestibular testing. Otolaryngol Head Neck Surg. 1984;92:145, with permission.)

On neurologic examination, he exhibited spon- taneous nystagmus to the right while ﬁxating, and to the left in the dark. He also presented with ipsilateral facial hypalgesia, Horner’s syn- drome, and extremity ataxia, and contralateral extremity hypalgesia. The OKN and VOR responses were asymmetric but in opposite directions, consistent with the changing direc- tion of the patient’s spontaneous nystagmus from light to dark. Despite the decreased OKN gain, the VisVOR gain was normal in both directions. Fixation suppression of VOR slow phases toward the side of the lesion was impaired. A similar pattern of abnormalities was found in six other patients with infarction in the lateral medulla.113

Patients with lesions involving the vestibulo- cerebellum are unable to modify vestibular responses with vision.114 This is illustrated by the patient data shown in Figure 7–31 (center),

As noted earlier, in patients with minimal or no sinusoidal VOR, VisVOR, and VOR-FIX, responses are almost identical (e.g., Fig. 7–31, center). These patients may show evidence of visual–vestibular interaction with impulse stim- uli, however. The patient with cerebellar atro- phy, whose data are shown in Figure 7–32, had absent pursuit and sinusoidal OKN but exhib- ited a gradual buildup in OKN after a step onset in drum velocity. The gain (initial peak eye veloc- ity/peak stimulus velocity) of the step responses was the same regardless of whether the patient received (1) a VisVOR stimulus (i.e., a step from 0 to 60 degrees/sec in the light with a

100

in which the VOR, VisVOR, and VOR-FIX gains are approximately the same (nearly 1.0) and the OKN gain is markedly decreased in both directions. This patient was a 31-year-old woman who complained only of unsteadiness and oscillopsia. The results of neurologic exam- ination were normal except for spontaneous downbeat nystagmus and truncal ataxia. Computerized tomography (CT) and magnetic resonance (MR) scanning documented atrophy of the midline cerebellum.

Lesions of the visuomotor pathways from the parieto-occipital cortex to the pons (i.e., those shown in Fig. 3–23) lead to impaired smooth pursuit and optokinetic slow phases toward the side of the lesion.77 The abnormal visual-ocular control does not impair VOR responses but does alter visual–vestibular inter- action. Typical responses to the four sinusoidal rotational test conditions in a patient with a deep parietal lobe lesion are shown in Figure 7–31 (right). This 21-year-old man developed bitemporal headaches and slowly progressive

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right facial and upper-extremity weakness. An angiogram identiﬁed a tumor blush in the left parietal region. A left parietal brain biopsy revealed a grade II astrocytoma. The OKN gain was normal to the right and markedly decreased to the left. The VOR gain was normal in both directions, but the patient was unable to inhibit VOR slow phases to the right with ﬁxation (i.e., the VOR-FIX gain was increased to the right). The VisVOR gain was slightly asymmetric, with lower gain to the left than to the right.

0 20 40

Time (sec)

Figure 7–32. Vestibulo-ocular reﬂex (VOR), ﬁxation sup- pression of VOR (VOR-FIX), and visual-VOR (VisVOR) responses to step rotational stimuli (0° to 60°/sec, 140°/sec2 acceleration) in a patient with cerebellar atrophy. The log of slow-phase eye velocity is plotted against time. For the VOR the chair was stopped in the dark, for the VOR-FIX the chair was stopped in the light, and for the VisVOR the chair was maintained at a constant velocity in the light with a stationary surround. (From Baloh RW, et al. Late cortical cerebellar atrophy. Brain. 1986;109:159, with permission.)

ﬁxed surround), (2) a VOR-FIX stimulus (i.e., stopping the rotating chair in the light with a ﬁxed surround), or (3) a VOR stimulus (i.e., start- ing or stopping the chair in darkness). However, the rate of decay in slow-phase velocity (i.e., the time constant) was prolonged after a VisVOR stimulus and shortened after a VOR-FIX stimu- lus, compared with the VOR stimulus. Thus, one type of visual–vestibular interaction (that medi- ated via the velocity storage pathway) was pre- served in a patient with absent smooth pursuit.‌‌

In summary, in addition to tests of the VOR, rotational testing includes tests of visual– vestibular interaction. Lesions of the periph- eral vestibular system typically impair only the VOR, whereas lesions of the CNS impair OKN and visual–vestibular interaction. The pattern of abnormal response can help localize lesions within the central pathways.

TESTS OF OTOLITH–OCULAR REFLEXES

Ocular Counterrolling

The otolith-ocular reﬂex produces torsional eye movements during static head tilts. Rotating the head toward the right shoulder causes the eyes to counterrotate to the left (see Chapter 3). Such rotation of the head in the coronal plane is called roll, and the counterrotation of the eyes is called ocular counterrolling.115,116 Dynamic roll movements also stimulate the vertical semicir- cular canals because of the angular acceleration of the movement, so when using roll stimulation a distinction should be made between static and dynamic ocular counterrolling.

The clinical use of ocular counterrolling has been hampered by difﬁculties both in stimulus delivery and in the measurement of response. In order to rotate someone in the coronal plane, the subject must be securely fastened to a cum- bersome device. In addition, the amount of torsional eye movement produced by a static tilt in the coronal plane is relatively small. For example, if the head is tilted 45 degrees, the eyes counterroll only about 7 degrees. Electrooculography is insensitive to this type of movement, so video recording or the magnetic scleral search coil must be employed.

Unilateral peripheral vestibular lesions can pro- duce asymmetries in static ocular counterrolling;

roll to the side of the lesion results in less coun- terrolling than roll away from the side of the lesion.117,118 With some types of central lesions one can see a roll rather than a counterroll response (i.e., the eyes rotate in the direction of head tilt).119,120 However, the responses are too variable to be a reliable test for identifying the side of a unilateral lesion.

Eccentric Rotation

Eccentric (off-center) rotation is delivered by seating a subject upright in a conventional rota- tional chair such that the head is away from the axis of rotation as if the head were placed at the end of the arm of a centrifuge (see Fig. 7–18). During angular acceleration with the head eccentric, the labyrinth is exposed to both rota- tional and linear (tangential and centrifugal) acceleration, and thus both the otolith organs and the horizontal semicircular canals are stim- ulated. Once a constant angular velocity is achieved, however, only the otoliths are stimu- lated. The net linear acceleration delivered to the subject is the vector summation of the lin- ear acceleration produced by the movement itself and the linear acceleration produced by gravity (See Fig. 1-3b). The advantages of eccentric rotation are that conventional rota- tional chairs (with minor modiﬁcations) and EOG methods can be used for this test.

With sinusoidal angular acceleration the dif- ference between eye movements induced with the head at the center of rotation and those with the head eccentric is the contribution of the oto- lith organs.121–123 An even simpler test of otolith function is to have the subject estimate the sub- jective vertical (with a vertical light bar) during constant velocity eccentric rotation.124,125 Unlike other tests of subjective vestibular sensation, the sensation of tilt experienced during eccen- tric rotation appears to be highly reproducible. Patients who have undergone a unilateral ves- tibular neurectomy experience less of a sensa- tion of tilt when the lesioned ear is outermost.124 The deﬁcit is maximum in the ﬁrst postopera- tive week but persists for at least 24 weeks.126

Off-Vertical Rotation

Off-vertical rotation is performed by seating the subject in a conventional rotational chair

and then tilting the entire apparatus, including the chair and subject (see Fig. 7–18).127,128 In this way, as the subject rotates, the head is con- tinually changing its orientation with respect to gravity. In the extreme case, in which the chair is tipped completely on its side (earth- horizontal axis, or so-called barbecue rotation), the subject is rotated from supine to lateral to prone to lateral, and so on.129,130 Once a con- stant velocity is achieved, only the otolith organs are stimulated (because the canals respond only to angular acceleration).‌‌

A major advantage of this type of otolith test is that a conventional rotatory chair can be used if the angle of inclination is kept small. Subjects can be placed into or moved from the appara- tus easily, and conventional EOG can record the eye movements because they are largely horizontal. A disadvantage is that the stimulus often produces nausea. Off-vertical constant velocity rotation in normal subjects induces two horizontal eye movement components: a bias and a modulation component.129,130 In patients with unilateral peripheral vestibular lesions, the bias component is diminished when the patient rotates toward the involved ear while the modulation component remains unchanged.131

Linear Acceleration

Another technique that has been used to study the otolith ocular reﬂex in the research labora- tory is to deliver a linear acceleration on a lin- ear track or a parallel swing.132–135 As with eccentric rotation, the otolith organs sense the net linear acceleration—that is, the vector summation of the linear acceleration induced by the device itself and that due to gravity. For the relatively simple case in which the subject is placed on the device facing the side as if looking out the side window of an automobile moving forward, a consistent horizontal eye movement (the linear VOR) can be recorded. For other head orientations vertical or torsional eye movements are induced, requiring eye movement recording techniques such as a magnetic scleral search coil or video system. Although patients with complete unilateral and bilateral vestibular loss consistently show a diminished linear VOR gain compared to controls,134,136,137 the test is not sensitive for identifying partial loss of vestibular function.

Furthermore, the asymmetry in the linear VOR gain after an acute unilateral vestibular lesion disappears within a few months.137

VESTIBULOSPINAL TESTING

Current tests of vestibular function concen- trate on the vestibulo-ocular system: the vestibulospinal system has been relatively neglected. A major reason for this neglect is that it is difﬁcult to assess the role of the ves- tibulospinal system in isolation of the other sensory systems.

Static-Force Platforms

The simplest method of recording human pos- tural sway employs a force plate. There are sev- eral devices of this type, each designed with the basic idea of recording the position of a subject’s center of mass during upright stance. In fact, these devices measure the position of the center of pressure (COP), which is a good estimate of the position of the center of mass if the body is moving slowly. The COP is mea- sured with force transducers in the force plate and then differentiated to give instantaneous sway velocity (Fig. 7–33).138 The major limita- tion of such devices relates to two factors:

the nervous system uses a combination of sensory modalities during the maintenance of upright stance, and (2) static force plates do not yield controlled stimulus–response mea- sures of vestibulospinal function and thus must rely on spontaneous movements of the body. This latter consideration is analogous to mak- ing assessments of the vestibulo-ocular system by simply monitoring eye position in the absence of vestibular stimulation. The mea- surement of postural sway might be useful as a screening test for imbalance, but the informa- tion it provides is nonspeciﬁc and probably not helpful for identifying vestibular lesions.138–140

Moving-Platform Posturography
Moving-force platforms have been designed to overcome the limitations of static-force plat- forms discussed above by (1) controlling the relative contributions of the visual, somatosensory,

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Figure 7–33. Examples of posturography raw data from a static and dynamic test in an older subject with eyes open and closed. Upper traces, sway position (center of pressure [COP]) in the anterior–posterior (AP) directions; lower traces, sway velocity in the anterior–posterior ) directions.

and vestibular inputs that are normally used to maintain upright posture; and (2) incorporat- ing stimulus–response measurements. By cou- pling the platform to the sway of the subject, it is possible to maintain the angle between the foot and the lower leg at a constant value, thereby reducing a major source of somatosen- sory input to the postural control system.141 A similar effect can be achieved by having the subject stand on a thick foam rubber pad. If the subject simultaneously closes the eyes or if the movement of the visual enclosure is cou- pled to body sway, the subject is also deprived of visual information about postural sway. In this way, the inﬂuence of the labyrinth on upright posture via the vestibulospinal system can be studied in a more or less isolated fash- ion.142 The disadvantage of this technique is that during postural sway many of the subor- gans of the vestibular labyrinth are simultane- ously stimulated, including the vertical semicir- cular canals and the otolith organs bilaterally. For this reason, moving-platform studies are incapable of providing an assessment of the individual suborgans of the vestibular labyrinth. In addition, these devices do not assess the subject’s strategy in moving other body parts and joints. Not surprisingly, patients with bilat- eral peripheral vestibular loss perform poorly on these tests when visual and somatosensory
signals have been effectively removed.140,143,144 However, preliminary reports that moving- platform posturography can identify sites of lesion or speciﬁc vestibular disorders have not been conﬁrmed. Dynamic posturography is not a diagnostic test but rather a method to quan- tify balance dysfunction under different sen- sory conditions (Fig. 7–34).145,146 It may be helpful for identifying people at risk for falling, although it is not clear if it is better at this than a careful clinical assessment.147 Posturography may also be helpful in distinguishing between organic and function balance disorders.148

VESTIBULAR-EVOKED POTENTIALS
Brain Stem and Cortical
The ability to record a human brainstem vestib- ular-evoked potential has obvious merits, as it would provide an objective measure of periph- eral vestibular function that would be indepen- dent of either the oculomotor or postural control systems. Despite the fact that short latency sensory-evoked potentials using auditory, visual, and somatosensory inputs have been developed and are in routine clinical use, vestibu- lar-evoked potentials are not routinely available.

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Figure 7–34. Mean sway velocity (vertical bar = 1 standard deviation) in young (black bars) and older (gray bars) controls and older patients with imbalance (striped bars) for the four standard posturography test conditions. AP, anterior–posterior; ML, medial–lateral. In the two graphs to left, the platform was still; in the two graphs to the right, the platform tilted up and down sinusidally about a central axis (0.10 Hz, 4° peak amplitude) (see Fig. 6–33).

One reason for this lack of development is related to the difﬁculty of delivering a vestibu- lar stimulus that is capable of triggering a coor- dinated volley of neural activity, a requirement for eliciting a measurable evoked potential.149 The vestibular equivalent of an auditory click, visual ﬂash, or somatosensory prick is a brief, abrupt, high-intensity rotational impulse with an angular acceleration in the range of 7000 degrees/sec2.
Prior research regarding human vestibular- evoked potentials has focused upon recording long-latency cortical potentials rather than brainstem–evoked potentials.150,151 The results of these studies are conﬂicting. It is still unclear whether the recorded potentials are speciﬁc for the vestibular stimulus. Short-latency ves- tibular-evoked potentials have been induced in animals and in humans149 using brief, high- acceleration head displacements, but because of the complex methodology required and the potential discomfort to the patients, this type of testing will not likely become available in the
clinical vestibular laboratory. Pulsed galvanic stimulation over the mastoid can induce a syn- chronized volley within the vestibular-cochlear nerve, but this stimulus is also uncomfortable and could even lead to potential nerve damage.

Vestibular Evoked Myogenic Potentials (VEMPs)
MECHANISM OF STIMULATION
Vestibular evoked myogenic potentials were ﬁrst recorded in the 1960s, but it wasn’t until the 1990s that the clinical application of this technique was appreciated.152–154 Animal stud- ies show that both air and bone conducted sound activates otolith afferents (utricular and saccular) but rarely semicircular canal afferents.155 Consistent with this observation it was shown that sound-evoked potentials recorded from electrodes over the sterno- cleidomastoid muscle in patients persisted
despite profound sensorineural hearing loss but disappeared after vestibular nerve sec- tion.156 The motor neurons of cervical ﬂexor muscles receive inhibitory input from the sac- cule and intramuscular recordings in the ster- nocleidomastoid muscle show that the initial positivity of the VEMP is produced by an inhi- bition of the underlying motor units.157,158 Based on this data there is a general consensus that cervical VEMPs (cVEMPs) are saccular and inferior vestibular nerve dependent. More recently it has been shown that VEMPs can also be recorded from electrodes placed near the eyes (ocular VEMPs or oVEMPs).159 These potentials are not due to eye movement or electro-oculographic potentials. Since the vast majority of otolith ocular connections originate from the utricle, oVEMPs could be useful for assessing utricular function.160 Consistent with this premise patients with vestibular neuritis (which typically involves just the superior divi- sion of the vestibular nerve) were found to often have normal cVEMPs but absent oVEMPs.161

TEST METHODOLOGY
For recording cVEMPs electrodes are placed over the most prominent part of the sterno- cleidomastoid muscles and reference elec- trodes are placed on the clavicles. The record- ingsmustbemadewhenthesternocleidomastoid muscles are contracting. The simplest way to achieve this is to have the subject raise their head while lying supine. Many different stimuli have been used, including air- and bone-con- ducted sounds, skull taps, and galvanic current, but the most commonly used stimulus in our laboratory is an air-conducted high-intensity (100 to 130 dB SPL) low-frequency tone burst with a center frequency of about 500 Hz (2 msec rise/fall time, 2 msec plateau). Since the myogenic evoked potentials are large in amplitude, usually more than 100 microvolts) only a small number need be averaged. Typically three stimulation sequences (rate of four per second) are given, each consisting of 64 tone bursts. To correct for interindividual/ interside/intertest variations in tonic muscle contraction, a separate channel is used to obtain a numerical value for background muscle tension (rectiﬁed EMG).
Standard methodology has not been devel- oped for recording oVEMPs, but the most
consistent potentials appear to be obtained from electrodes placed beneath the eyes and on the cheeks while the subject is instructed to look upward.162 The stimuli (e.g., tone burst) can then be introduced and the response recorded. Since oVEMPs are smaller in ampli- tude than cVEMPs, more averaging may be needed.

NORMATIVE DATA
The typical cVEMP consists of a positive/ negative wave labeled p13 and n23 based on the approximate latency and polarity (Fig. 7–35).163 cVEMP amplitude is linearly related with back- ground muscular tension, so the p13-n23 amplitude should be divided by the mean value of the rectiﬁed EMG. The response is much larger in the ear ipsilateral to the stimulus and is larger for tone bursts than for clicks (Fig. 7–35). Since the responses depend on normal sound transmission through the middle ear, patients with middle ear disease such as otosclerosis may have absent responses. Of particular importance, the p13-n23 amplitude of cVEMPs decreases with age so the test is less useful in older patients.163 Each laboratory should establish normative data, but in our lab- oratory greater than 50% amplitude asymme- try and absolute amplitude values below 100 microvolts are considered abnormal. We do not routinely use latency measurements.
Normative data have not been established for oVEMPs, but when the recording elec- trodes are placed beneath the eyes, contralat- eral responses are much larger than ipsilateral responses (i.e., the reﬂex is crossed). This is consistent with the crossed utriculo-ocular pathway.

RESULTS IN PATIENTS
Since cVEMPs reﬂect activity originating in the saccule and carried in the inferior vestibular nerve, vestibular lesions that damage the saccule and/or inferior vestibular cause abnormal cVEMPs. About 50% of patients with Meniere’s syndrome have a decreased or absent cVEMP on the involved side when tested between attacks.164,165 Furthermore, cVEMPs can be used to monitor the effect of intratympanic gentamicin injection for treatment of Meniere’s syndrome.166 cVEMPs are abnormal in about 55%–80% of patients with vestibular schwannomas.165,167,168
Right Ear Right Ear
500 Hz toneburst, 130 dB peSPL click, 100 dB HL

n23

p13

n23

p13

n23

p13

n23

p13
Right SCM

Left SCM

100 V 100 V

20 msec 20 msec
Figure 7–35. Vestibular evoked myogenic potentials (VEMPs) recorded from the right and the left sternocleidomas- toid (SCM) in response to sound stimulation to the right ear in a healthy individual. Sound stimuli were either 500 Hz tonebursts with an intensity of 130 dB peSPL or 100 dB HL clicks. The vertical dashed lines shows stimulus onset (the 20 millisecondsec prestimulus recordings were used for measuring background muscular tension). Although there are typical positive-negative VEMPs on the side ipsilateral to the sound stimulation, there is only a weak inverted response on the con- tralateral side. Note that VEMPs in response to tone bursts have longer latencies compared with those in response to clicks and amplitudes in response to tonebursts are larger than those in response to clicks. (From Brantberg K. Vestibular evoked myogenic potentials (VEMPs): usefulness in clinical neurotology. Semin Neurol. 2009;29:541 with permission.)

Stim Right (affected ear) Right SCM
Stim Left (healthy ear) Left SCM

130 SPL

p13
n23

5 ms 100 µv

p13

n23

100 SPL n23

p13
Figure 7–36. Vestibular evoked myogenic potentials (VEMPs) illustrate the typical hyperactive response and reduced threshold in a patient with superior semicircular canal dehiscence syndrome on the right side. Active electrodes were placed over the superior part of the sternocleidomastoid muscle (SCM), and the reference electrodes were placed near the mid-portion of the clavicle. High-intensity (100 to 130 dB sound pressure level [SPL]), low-frequency (500-Hz tone bursts, 2-ms rise/fall time, and 2-ms plateau) sounds were presented monaurally via TDH-49P headphones. Three stimulation sequences (rate of four per second) were given, each consisting of 64 tone bursts. The mean curves are shown below the three repetitions for each stimulus.
This is comparable to the rate of abnormal caloric responses. Theoretically the test should reﬂect which division of the vestibular nerve the tumor
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104. Markham CH, Diamond SG. Distinctive counter- rolling disruption caused by brainstem compres- sion. In: Kunze K, Zangemeister WH, Arlt A, eds. Clinical Problems of Brainstem Disorders. Stuttgart, Germany: Georg Thieme Verlag; 1986.
105. Gresty MA, Bronstein AM. Otolith stimulation evokes compensatory reﬂex eye movements of high velocity when linear motion of the head is combined with con- current angular motion. Neurosci Lett. 1986;65:149.
106. Crane BT, Viirre ES, Demer JL. T he human horizon- tal vestibulo-ocular reﬂex during combined linear and angular acceleration. Exp Brain Res. 1997;114:304.
107. Gresty MA, Bronstein AM, Barratt H. Eye movement responses to combined linear and angular head move- ment. Exp Brain Res. 1987;65:377.
108. Dai MJ, Curthoys IS, Halmagyi GM. Linear acceler- ation—perception in the roll plane before and after unilateral vestibular neurectomy. Exp Brain Res. 1989;77:315.
109. Böhmer A, Mast F. Chronic unilateral loss of otolith function revealed by the subjective visual vertical during off center yaw rotation. J Vestib Res. 1999;9:413.
110. Böhmer A, Mast F. The subjective visual vertical dur- ing off-center angular rotation: a parameter to reveal chronic unilateral loss of vestibular function? J Vestib Res. 1996;6:20.
111. Benson AJ. Modiﬁcation of the response to angular accelerations by linear accelerations. In: Kornhuber HH, ed. Handbook of Sensory Physiology: Vestibular System. Vol 6. Pt 2. Berlin, Germany: Springer- Verlag; 1974.
112. Stockwell CW, Turnipseed GT, Guedry FE. Nystagmus responses during rotation about a tilted axis. Pensacola, FL: Naval Aerospace Medical Research Lab; 1971.
113. Wall CD, Furman JM. Visual–vestibular interaction in humans during earth-horizontal axis rotation. Acta Otolaryngol (Stockh). 1990;109:337.
114. Furman, JM, Schor RH, Schumann TL. Off-vertical axis rotation: a test of the otolith–ocular reﬂex. Ann Otol Rhinol Laryngol. 1992;101:643.
115. Furman JMR, Wall C III, Kamerer DB. Earth hori- zontal axis rotational responses in patients with uni- lateral peripheral vestibular deﬁcits. Ann Otol Rhinol Laryngol. 1989;98:551.
116. Niven JI, Hixon WC, Correia MJ. Elicitation of hori- zontal nystagmus by periodic linear acceleration. Acta Otolaryngol (Stockh). 1966;62:429.
117. Buizza A, Schmid R, Droulez J. Inﬂuence of linear acceleration on oculomotor control. In: Fuchs AF, Becker V, eds. Progress in Oculomotor Research. New York: Elsevier/North Holland; 1981.
118. Baloh RW, Beykirch K, Honrubia V, Yee RD. Eye movements induced by linear acceleration on a paral- lel swing. J Neurophysiol. 1988;60:2000.
119. Bronstein AM, Gresty MA. Short latency compensa- tory eye movement responses to transient linear head acceleration: a speciﬁc function of the otolith–ocular reﬂex. Exp Brain Res. 1988;71:406.
120. Bronstein A, Gresty MA, Brookes GB. Compensatory otolithic slow phase eye movement responses to abrupt linear head motion in the lateral direction. Acta Otolaryngol Suppl (Stockh). 1991;418:42.
121. Lempert T, Gianna C, Brookes G, Bronstein A, Gresty M. Horizontal otolith–oculalr responses in humans after unilateral vestibular deafferentation. Exp Brain Res. 1998;118:533.
122. Baloh RW, Fife TD, Zwerling L, et al. Comparison of static and dynamic posturography in young and older normal people. J Am Geriatr Soc. 1994;42:405.
123. Baloh RW, Corona S, Jacobson KM, Enrietto JA, Bell
  T. A prospective study of posturography in normal older people. J Am Geriatr Soc. 1998;43:438.
124. Baloh RW, Jacobson KM, Beykirch K, Honrubia
  V. Static and dynamic posturography in patients with vestibular and cerebellar lesions. Arch Neurol. 1998;55:649.
125. Nashner LM. A model describing vestibular detec- tion of body sway motion. Acta Otolaryngol (Stockh). 1971;72:429.
126. Nashner LM, Black FO, Wall C III. Adaptation to altered support and visual conditions during stance: patients with vestibular deﬁcits. J Neurosci. 1982;2:536.
127. Allum JHJ, Pfaltz CR. Visual and vestibular contribu- tions to pitch sway stabilization in the ankle muscles of normals and patients with bilateral peripheral ves- tibular deﬁcits. Exp Brain Res. 1985;58:82.
128. Black FO, Wall C III, Nashner LM. Effect of visual and support surface references upon postural con- trol in vestibular deﬁcit subjects. Acta Otolaryngol (Stockh). 1983;95:199.
129. Baloh RW, Jacobson KM, Enrietto JA, Corona S, Honrubia V. Balance disorders in older people: quan- tiﬁcation with posturography. Otolaryngol Head Neck Surg. 1998;119:89.
130. Furman JM, Baloh RW, Kamran B, et al. Assessment: posturography. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1996;46:1763.
131. Piirtola M, Era P. Force platform measurements as predictors of falls among older people: a review. Gerontology. 2006;52:1.
132. Gianoli G, McWilliams S, Soileau J, Belafsky P. Posturographic performance in patients with the potential for secondary gain. Otolaryngol Head Neck Surg. 2000;122:11.
133. Elidan J, Sohmer H. Vestibular tests in evolution. III. Vestibular evoked potentials. In: Baloh RW, Halmagyi GM, eds. Disorders of the Vestibular System. New York: Oxford University Press; 1996: 274.
134. Hofferberth B. Evoked potentials to rotatory stimula- tion. Acta Otolaryngol Suppl (Stockh). 1984;406:134.
135. Pirodda E, Ghedini S, Zanetti MA. Investigations into vestibular-evoked responses. Acta Otolaryngol (Stockh). 1987;104:77.
136. Bickford RG, Jacobson JL, Cody DT. Nature of aver- age evoked potentials to sound and other stimuli in man. Ann NY Acad Sci. 1964;112:204.
137. Colebatch JG, Halmagyi GM. Vestibular evoked potentials in human neck muscles before and after unilateral vestibular deafferentation. Neurology. 1992;42:1635.
138. Ferber-Viart C, Dubreuil C, Duclaux R. Vestibular evoked myogenic potentials in humans: a review. Acta Otolaryngol (Stockh). 1999;119:6.
139. Curthoys IS, Kim J, McPhedran SK, Camp AJ. Bone conducted vibration selectively activates irregular pri- mary otolithic vestibular neurons in the guinea pig. Exp Brain Res. 2006;175(2):256.
140. Colebatch JG, Halmagyi GM, Skuse NF. Myogenic potentials generated by a click-evoked vestibu- locollic reﬂex. J Neurol Neurosurg Psychiatry. 1994;57(2):190.
141. Uchino Y, Sato H, Sasaki M. Sacculocollic reﬂex arcs in cats. J Neurophysiol. 1997;77(6):3003.
142. Colebatch JG, Rothwell JC. Motor unit excitabil- ity changes mediating vestibulocollic reﬂexes in the sternocleidomastoid muscle. Clin Neurophysiol. 2004;115(11):2567.
143. Todd NP, Rosengren SM, Aw ST, Colebatch JG. Ocular vestibular evoked myogenic poten- tials (OVEMPs) produced by air- and bone-cond ucted sound. Clin Neurophysiol. 2007;118(2): 381.
144. Todd NP, Rosengren SM, Colebatch JG. A utricu- lar origin of frequency tuning to low-frequency
  vibration in the human vestibular system? Neurosci Lett. 2009;451(3):175.
145. Iwasaki S, Chihara Y, Smulders YE. The role of the superior vestibular nerve in generating ocular vestib- ular-evoked myogenic potentials to bone conducted vibration at Fz. Clin Neurophysiol. 2009;120(3): 588.
146. Rosengren SM, Aw ST, Halmagyi GM, Todd NP, Colebatch JG. Ocular vestibular evoked myogenic potentials in superior canal dehiscence. J Neurol Neurosurg Psychiatry. 2008;79(5):559.
147. Brantberg K. Vestibular evoked myogenic potentials (VEMPs): usefulness in clinical neurotology. Semin Neurol. 2009;29(5):541.
148. de Waele C, Huy PT, Diard JP, Freyss G, Vidal PP. Saccular dysfunction in Meniere’s disease. Am J Otol. 1999;20(2):223.
149. Murofushi T, Shimizu K, Takegoshi H, Cheng PW. Diagnostic value of prolonged latencies in the ves- tibular evoked myogenic potential. Arch Otolaryngol Head Neck Surg. 2001;127(9):1069.
150. Helling K, Schönfeld U, Clarke AH. Treatment of Ménière’s disease by low-dosage intratympanic gentamicin application: effect on otolith function. Laryngoscope. 2007;117(12):2244.
151. Patko T, Vidal PP, Vibert N, Tran Ba Huy P, de Waele C. Vestibular evoked myogenic potentials in patients suffering from an unilateral acoustic neu- roma: a study of 170 patients. Clin Neurophysiol. 2003;114(7):1344.
152. Suzuki M, Yamada C, Inoue R, Kashio A, Saito Y, Nakanishi W. Analysis of vestibular testing in patients with vestibular schwannoma based on the nerve of origin, the localization, and the size of the tumor. Otol Neurotol. 2008;29(7):1029.
153. Ushio M, Iwasaki S, Chihara Y. Is the nerve origin of the vestibular schwannoma correlated with vestibular evoked myogenic potential, caloric test, and auditory brainstem response? Acta Otolaryngol. ePub ahead of print, November 26, 2008.
154. Murofushi T, Halmagyi GM, Yavor RA, Colebatch JG. Absent vestibular evoked myogenic potentials in vestibular neurolabyrinthitis. An indicator of infe- rior vestibular nerve involvement? Arch Otolaryngol Head Neck Surg. 1996;122(8):845.
155. Kim HA, Hong JH, Lee H. Otolith dysfunction in vestibular neuritis: recovery pattern and a predictor of symptom recovery. Neurology. 2008;70(6):449.
156. Brantberg K, Bergenius J, Tribukait A. Vestibular- evoked myogenic potentials in patients with dehis- cence of the superior semicircular canal. Acta Otolaryngol. 1999;119(6):633.
157. Watson SRD, Halmagyi GM, Colebatch JG. Vestibular hypersensitivity to sound (Tullio phe- nomenon): structural and functional assessment. Neurology. 2000;54(3):722.
158. Brantberg K, Verrecchia L. Testing vestibular-evoked myogenic potentials with 90-dB clicks is effective in the diagnosis of superior canal dehiscence syndrome. Audiol Neurootol. 2009;14(1):54.
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Chapter 8 ‌‌‌‌

Clinical Evaluation of Hearing

TYPES OF HEARING DISORDERS
Conductive Sensorineural
Central Hearing Disorders BEDSIDE TESTS OF HEARING BEHAVIORAL AUDIOMETRY
The Audiogram
Speech Recognition Tests Stenger Test
IMPEDANCE AUDIOMETRY

TYMPANOMETRY
The Acoustic Reﬂex
AUDITORY-EVOKED RESPONSES
Electrocochleography
Brainstem Auditory-Evoked Response
GENERATING POTENTIALS TEST METHODOLOGY RESULTS IN PATIENTS
CENTRAL AUDITORY SPEECH TESTS SUMMARY OF AUDITORY TEST RESULTS

TYPES OF HEARING DISORDERS
Hearing disorders can be classiﬁed as conduc- tive, sensorineural, and central, based on the anatomic site of lesion. A battery of audiologi- cal tests can help localize the lesion within the anatomical pathways.1,2

Conductive
Conductive hearing loss results from lesions involving the external or middle ear. The tympanic membrane and ossicles act as a trans- former amplifying airborne sound and efﬁ- ciently transferring it to the inner ear ﬂuid (see “Middle Ear” in Chapter 2). If this normal pathway is obstructed, transmission may occur across the skin and through the bones of the skull (bone conduction), but at the cost of con- siderable energy loss.
The most common cause of conductive hear- ing loss is impacted cerumen in the external auditory canal. This benign condition is often ﬁrst noticed after bathing or swimming, when water closes the remaining tiny passageway.
The most common serious cause of conductive hearing loss is inﬂammation of the middle ear, or otitis media. Either infected (suppurative oti- tis) or noninfected (serous otitis) ﬂuid accumu- lates in the middle ear, impairing the conduc- tion of airborne sound. Otosclerosis produces progressive conductive hearing loss by immobi- lizing the stapes with new bone growth in front of and below the oval window. Other causes of conductive hearing loss include large tympanic membrane perforations, trauma, congenital malformations of the external and middle ears, and tumors of the temporal bone.

Sensorineural
Sensorineural hearing loss results from lesions of the cochlea and/or the auditory division of the eighth cranial nerve.3 The spiral cochlea mechanically analyzes the frequency content of sound. For high-frequency tones, only sensory cells in the basal turn are activated, whereas for low-frequency tone maximum stimulation occurs at the apex, even though all or nearly all sensory cells are activated with loud sounds.
219
Therefore, with lesions of the cochlea and its afferent nerve, hearing levels for different fre- quencies are often unequal, and the timing (phase) relationship between different fre- quencies may be altered. Patients with sen- sorineural hearing loss often have difﬁculty hearing speech that is mixed with background noise and may be annoyed by loud speech.‌‌
Distortion of sound is common with sen- sorineural hearing loss. A pure tone may be heard as noisy, rough, or buzzing, or it may be distorted so that it sounds like a complex mixture of tones. Binaural diplacusis occurs when the two ears are affected unequally so that the same frequency has a different pitch in each ear; that is, the patient hears different sounds in each ear. Monaural dipla- cusis occurs when two tones or a tone and noise are heard simultaneously in one ear. With recruitment there is an abnormally rapid growth in the sensation of loudness as the intensity of a sound is increased so that faint or moderate sounds cannot be heard, whereas there is little or no change in the loudness of loud sounds.
Sudden unilateral deafness is a common syn- drome with ill-deﬁned pathophysiology.4 Probably most cases are due to viral infections involving either the cochlea or auditory nerve.5 Viral infections can be part of a systemic viral illness such as measles, mumps, and infectious mononucleosis or an isolated infection of the labyrinth or eighth nerve without systemic symptoms. Mumps is a particularly common cause of unilateral hearing loss in school-aged children. Other common causes of acute uni- lateral hearing loss are head trauma and vascu- lar occlusive disease.
Relapsing unilateral sensorineural hearing loss associated with tinnitus, ear fullness, and vertigo is typical of Meniere’s syndrome. Ototoxic drugs produce a bilateral subacute hearing loss, and acoustic neuromas (vestibular schwannomas) characteristically produce a slowly progressive unilateral sensorineural hearing loss. The chronic progressive bilateral hearing loss associated with advancing age is called presbycusis. It may include conductive and central dysfunction, but the most consis- tent effect of aging is on the sensory cells and neurons of the cochlea.5 Genetic disorders account for the majority of cases of sensorineu- ral hearing loss in children (see “Hereditary Disorders” in Chapter 18).
Central Hearing Disorders
Central hearing disorders result from lesions of the central auditory pathways: the cochlear and dorsal olivary nuclear complexes, inferior col- liculi, medial geniculate bodies, and auditory cortex in the temporal lobes and their intercon- necting afferent and efferent ﬁber tracts. As a rule, patients with central lesions do not have impaired hearing levels for pure tones, and they understand speech if it is clearly spoken in a quiet environment. If the listener’s task is made more difﬁcult with the introduction of background or competing messages, perfor- mance deteriorates in patients with central lesions more than in normal subjects. Lesions involving the nerve root entry zone or cochlear nucleus can result in unilateral hearing loss for pure tones (e.g., demyelination or infarction of the lateral pontomedullary region). Because at least 50% of afferent nerve ﬁbers cross central to the cochlear nucleus, this is the most central structure in which a lesion can result in a uni- lateral hearing loss.

BEDSIDE TESTS OF HEARING
A quick test for hearing loss in the speech range is to observe the response to spoken commands at different intensities (whisper, conversation, shouting).6 The examiner stands behind the patient to prevent lip reading and occludes and masks the non-test ear by moving a ﬁnger back and forth in the patient’s external ear canal. Finger rubs at different intensities and dis- tances from the ear have been shown in a rigor- ous study to be a rapid, reliable, and valid screening test for hearing loss in the frequency range of speech.7 If a patient can hear a faint ﬁnger rub stimulus at a distance of 70 cm (approximately one arm’s length) from one ear, then a hearing loss on that side—as deﬁned by a gold standard audiogram threshold of >25 dB at 1000, 2000, and 4000 Hz—is highly unlikely. On the other hand, if a patient cannot hear a strong ﬁnger rub stimulus at 70 cm, then a hear- ing loss on that side is highly likely.7 Tuning fork tests permit a rough assessment of the hearing level for pure tones of known frequency. Clinicians can use their own hearing level as a reference standard. The Rinne test compares the patient’s hearing by air conduction with that
by bone conduction. The fork (256 or 512 Hz) is ﬁrst held against the mastoid process until the sound fades. It is then placed 1 inch from the ear. Normal subjects can hear the fork longer by air than by bone conduction. If bone con- duction is greater than air conduction, a con- ductive hearing loss is suggested. The Weber test compares the patient’s hearing by bone conduction in the two ears. The fork is placed at the center of the forehead or on a central inci- sor and the patient is asked where he or she hears the tone. Normal subjects hear it in the center of the head, patients with unilateral con- ductive loss hear it on the affected side, and patients with unilateral sensorineural loss hear it on the side opposite the loss. Though these tuning fork tests can be useful in some clinical settings, they are not considered to be reliable or valid screening tests.6‌‌

BEHAVIORAL AUDIOMETRY
Audiometry typically consists of a battery of tests, the differential results of which provide site-of-lesion information.1 It typically begins with pure-tone threshold testing to compare a subject’s hearing sensitivity to norms at selected frequencies (the audiogram).
The Audiogram
Pure tones are deﬁned by their frequency and their intensity. To quantify the magnitude of hearing loss, normal hearing levels have been established. These levels approximate the inten- sity of the faintest sounds that can be heard by normal ears. A patient’s hearing level (HL) is the difference in decibel (dB) between the faintest pure tone that the patient can hear and the normal reference level given by the stan- dard, where 0 dB HL is the sound pressure level (SPL) at which listeners with normal hearing are able to perceive the signal 50% of the time. Brief-duration tones at selected frequencies are presented by earphones (air conduction) and a vibrator pressed against the mastoid portion of the temporal bone (bone conduction). The results of air and bone conduction testing are plotted on a graph from which the magnitude of the sensitivity loss (in dB) as a function of fre- quency is determined (Fig. 8–1). A simple way to summarize the severity of hearing loss is to calculate the pure tone average (PTA) = the average hearing level at 500, 1000, and 2000 Hz. For example, if the hearing level is 40 dB, 50 dB, and 60 dB at 500, 1000, and 2000 Hz, respectively, then the PTA is 50 dB, considered a moderate hearing loss (Table 8–1).

Frequency in Hz
125 250 500 1000 2000 4000 8000
Hearing level in dB re ANSI, 1969
Hearing level in dB re ANSI, 1969
0
10
20
30
40
50
60
70
80
90
100
110
125 250 500 1000 2000 4000
0
10
20
30
40
50
60
70
80
90
100
110
8000

Air
Bone
Right ear

Left ear

Air
Bone
Right ear

Left ear

(with masking)

Figure 8–1. Pure-tone audiogram: left ear, normal; right ear, conductive hearing loss due to otosclerosis.
Table 8–1 Severity of hearing loss based on the pure tone average (PTA)
Normal 0-25 dB
Mild Hearing Loss 26-40 dB
Moderate Hearing Loss 41-55 dB Moderate Severe Hearing Loss 56-70 dB Severe Hearing Loss 71-90 dB
Profound Hearing Loss >90 dB
PTA = Average of hearing levels at 500, 1000 and 2000 Hz.

With a conductive hearing loss, air conduction is impaired while bone conduction remains nor- mal (i.e., an air-bone gap on the audiogram, Fig. 8–1, right ear). Measurement of bone conduc- tion requires careful masking of the nontest ear. Masking involves introducing airborne noise into the nontest ear to eliminate cross-hearing via
bone conduction. There is a <5 dB attenuation between the two ears for a bone conduction receiver placed on any part of the skull. Therefore, a nonhearing ear may appear to have nearly nor- mal hearing via bone conduction if the normal ear is not properly masked. The best masking sound for pure tones is a narrow band of white noise centered about the pure tone being tested. Lesions producing sensorineural hearing loss impair both air and bone conduction, often with changing pure tone levels at different fre- quencies. Although the audiogram does not provide speciﬁc diagnostic information to iden- tify the site of lesion, certain patterns suggest speciﬁc diagnoses. Typical audiograms seen in patients with four common causes of sen- sorineural hearing loss are shown in Figure 8–2. None of these patterns is pathognomonic of a given disorder, but they occur often enough to
be of diagnostic value.

Frequency in Hz
A 125
0
10
20
30
40
50
60
Hearing level in dB re ANSI, 1969
Hearing level in dB re ANSI, 1969
70
80
90
100
110
250 500 1000 2000 4000 8000

B 125 250 500 1000 2000 4000 8000
0
10
20
30
40
50
60
70
80
90
100
110
C 125 250 500 1000 2000 4000 8000
0
10
20
30
40
50
60
70
80
90
100
110
D 125 250 500 1000 2000 4000 8000
0
10
20
30
40
50
60
70
80
90
100
110
Figure 8–2. Audiograms illustrating four common patterns of sensorineural hearing loss. (A) Notched pattern of noise- induced hearing loss. (B) Downward sloping pattern of presbycusis. (C) Low-frequency trough of Meniere’s syndrome. (D) V-pattern of congenital hearing loss.
Speech Recognition Tests ‌‌
Two categories of tests are used to determine the patient’s ability to hear and understand speech: (1) the speech reception threshold and
speech discrimination.
The speech reception threshold (SRT) is the intensity at which the patient can correctly repeat 50% of highly familiar two-syllable words (e.g., airplane, cowboy, sidewalk). The SRT is an estimate of the minimum level of conversation that a person can hear. It provides a check on the validity of the pure- tone audiogram, as it should agree (±5 dB) with an average of the two best pure-tone thresholds in the speech range (500 to 2000 Hz). It is not a test of discrimination, but it does provide information about a patient’s abil- ity to recognize and respond to speech. Occasionally, a patient who is profoundly deaf or aphasic cannot repeat words. In such cases a speech detection threshold (SDT) is obtained by having the patient respond to a speech signal.
The speech discrimination test is a measure of the patient’s ability to understand speech when it is presented at a level that is easily heard. For this test, the patient is usually pre- sented with 50 phonetically balanced monosyl- labic words at a comfortable listening level (typically 35 to 40 dB above the SRT). Each word is presented with a carrier phrase, such as “you will say ” or “say the word ” The test is scored as a percentage of the correct responses (e.g., 49 out of 50 correct = 98% speech discrimination). In patients with eighth nerve lesions, speech discrimination can be severely reduced even when pure-tone levels are normal or near normal, whereas in patients with cochlear lesions, discrimination tends to be proportional to the magnitude of hearing loss.8

Stenger Test
The Stenger test is helpful for determining whether a patient is deliberately exaggerating or feigning a hearing loss.9 It is based on the psychophysical observation that a tone pre- sented to both ears in the same phase at differ- ent intensities above threshold is perceived only in the ear with better hearing. Tones are presented simultaneously to both good and
suspect ears. The signals are turned on together and the patient is asked to respond as long as the tone is on. As long as the tone is below the actual threshold in the suspect ear, the patient will hear the sound in the other ear and respond. If the tone in the suspect ear is then increased above its true threshold, the patient will either fail to respond or show confusion, being unaware of the sound in the good ear and not wanting the examiner to know that he hears the sound in the suspect ear. A patient with true unilateral loss will of course only hear the sound presented in the good ear and quickly respond. Although screening tests are usually done at one intensity, a more complete test can be done at multiple intensities or using the same procedure with spondee words. Of course, the Stenger test works only with a unilateral loss, as a minimum 20 dB threshold difference is required at the test frequency.10

IMPEDANCE AUDIOMETRY
Impedance may be deﬁned as the resistance of a given system to the ﬂow of energy. Acoustic impedance refers to the resistance of the mid- dle ear system to the passage of sound. Its reciprocal, acoustic compliance, refers to the ease of sound transmission through the middle ear system. In simpliﬁed terms, acoustic imped- ance is related to the elasticity and stiffness of the middle ear conduction system. Acoustic impedance measurements are based on the principle that energy that is not absorbed by the ear is reﬂected.11 By measuring the differ- ence between the intensity of a sound going into the external auditory canal and that reﬂected from the tympanic membrane, one can estimate the impedance (or compliance) of the middle ear system.
Acoustic impedance measurements are made by a probe tip hermetically inserted into the ear canal. The probe tip contains three openings: (1) one for air pressure generation and measurement, (2) one for probe tone gen- eration, and (3) one for pickup of sound waves reﬂected off the tympanic membrane. A sche- matic drawing of the impedance measurement system is shown in Figure 8–3. With this sys- tem the difference between generated and reﬂected sound is systematically measured at different external ear pressure levels.

Probe tone generation ‌‌

Loudspeaker

Sound generator 220 Hz
Air pressure generation and measurement
Air pump

Intensity knob

Manometer

Rectifier

Rectifier

AMP

AMP
Compliance change meter

Probe

DC source (18 V)
DC source (18 V)
SPL & compliance sensing & measurement

Microphone (sound reflecting off
tympanic membrane to microphone pickup)

Figure 8–3. Schematic drawing of acoustic impedance measuring system (see text for details). SPL, sound pressure level. (From Goodhill V. Ear Diseases, Deafness and Dizziness. Harper & Row, Hagerstown, 1979, with permission.)
TYMPANOMETRY
Tympanometry is a method for evaluating changes in acoustic impedance by producing systematic changes in air pressure in the exter- nal ear canal. A plot of compliance change ver- sus air pressure (the tympanogram) is made by ﬁrst introducing a positive pressure into the external canal (usually equivalent to +200 mm of water) and then decreasing the pressure to approximately −200 mm of water (although the negative range can be extended to −600 mm of water). As the pressure is changed, compliance will change if the conduction system is normal. The shape of the normal tympanogram resem- bles a teepee (Fig. 8–4). The peak of the teepee represents the point of maximum com- pliance at which the air pressure in the middle ear equals the air pressure in the external audi- tory canal. Tympanometry can provide useful information about (1) mobility of the tympanic membrane, (2) perforations of the tympanic membrane, (3) pressure within the middle ear, and (4) patency and dynamic function of the eustachian tubes. Artifactual responses can result from inappropriate placement of the probe (against the canal wall or into impacted cerumen) or from an inadequate seal.
Four characteristic abnormal tympanographic patterns should be recognized (see Fig. 8–4).12
A restricted tympanogram implies normal mid- dle ear pressure and limited compliance relative to normal mobility. It is typically seen in advanced cases of otosclerosis, lateral ﬁxation of the ossicular chain, tympanic membrane ﬁbro- sis, and middle ear tympanosclerosis. A hyper- mobile tympanogram indicates a ﬂaccid tym- panic membrane. It occurs with ossicular chain discontinuity and with partial atrophy of the tympanic membrane. A ﬂat tympanogram means that there is little or no change in middle ear compliance when ear pressure is varied in the external ear canal. This pattern is more commonly seen with secratory otitis media but can also be seen with congenital malforma- tions of the middle ear and occlusion of the external ear canal by cerumen, epithelium, and foreign bodies. Finally, with a retracted tym- panogram, the maximum compliance occurs at negative pressures greater than −100 mm of water. It implies a negative middle ear pressure with a retracted tympanic membrane. This pat- tern is most commonly seen with poor Eustachian tube function.

The Acoustic Reﬂex
The acoustic reﬂex refers to contraction of the stapedius muscle in response to a loud sound.
5 A B

Compliance change
Compliance change
0

5

5 C D

0

5 ‌
–300

–100 0 +100 +300 –300 –100 0 +100 +300
Air pressure, mm H2O
Figure 8–4. Four characteristic abnormal tympanograms. (A) Restricted. (B) Hypermobile. (C) Flat. (D) Retracted. Blue area, normal range.

It is measured by monitoring the change in acoustic impedance in response to a loud sound introduced into either ear. The stapedius mus- cle contracts bilaterally, regardless of which ear is stimulated. Contraction of the stapedius muscle produces stiffening of the tympanic membrane and thus an increase in acoustic impedance. This results in an attenuation of sound transmitted to the cochlea by about 10 dB. In a normal subject the acoustic reﬂex will be observed when a pure-tone signal is pre- sented between 70 and 90 dB above hearing level (median value 82 dB), and when a white noise stimulus is presented at 65 dB above hearing level.
Patients with conductive hearing loss often have an absent acoustic reﬂex because the lesion prevents a change in compliance with stapedius muscle contraction. An air bone gap as small as 5 dB may obscure the acoustic reﬂex. Acoustic reﬂex testing is particularly useful for identify- ing a false or so-called intralabyrinthine conduc- tive hearing loss (see Semicircular Canal Dehiscence Syndrome, Chapter 16). A normal acoustic reﬂex in a patient with an apparent con- ductive hearing loss suggests the likelihood of superior semicircular dehiscence. The acoustic reﬂex can also be useful for identifying the site of lesion for different types of sensorineural hearing loss. With cochlear lesions the acoustic reﬂex often can be demonstrated at a sensation
level <60 dB above the auditory pure-tone threshold. This is another form of abnormal loudness growth or recruitment. A cochlear hearing loss must be severe before the acoustic reﬂex is lost. An absent reﬂex is rarely associated with a cochlear hearing loss <50 dB, and only when the hearing loss exceeds 85 dB is the reﬂex absent in 50% of patients. By contrast, patients with eighth nerve lesions often have either nor- mal hearing or only mildly impaired hearing (<20 dB), yet they have an abnormal acoustic reﬂex. The reﬂex may be absent, exhibit an ele- vated threshold, or exhibit abnormal decay. Reﬂex decay is present if the amplitude decreases to one-half of its original size within 10 sec of tonal stimulation. However, the test has not been proven to be a highly accurate test for discriminating between these causes, or even identifying an eighth nerve lesion.32

AUDITORY-EVOKED RESPONSES
The advent of averaging by computer made it possible to collect and analyze a variety of evoked electrical potentials from the auditory system.14,15 Repetitive sounds are delivered to the external ear and an “averaged” series of speciﬁc brain wave potentials are recorded with disk electrodes for up to 500 msec after
signal onset. The latencies (relative to signal onset) of each of the potentials are used as the most reliable means by which generator sources for the potentials are identiﬁed. Electrical events in the cochlea (so-called electrococh- leography) can best be monitored by an elec- trode inside the external canal or from a tran- stympanic electrode on the cochlear promontory.16,17 A series of waves in the ﬁrst 5 msec after the stimulus reﬂects the cochlear microphonics and the compound cochlear action potential (Fig. 8–5).18 Other evoked potentials from the auditory nerve and central nervous system (CNS) can be recorded with differential scalp electrodes.19 One electrode is placed at the vertex (the positive electrode) and another on the earlobe or mastoid (the negative electrode) ipsilateral to the acoustic stimulation. A third electrode (contralateral mastoid or earlobe) serves as the ground. Acoustic signals are presented via earphones, or bone vibrator and responses are ampliﬁed, ﬁltered, and averaged. The early (0 to 10 msec) evoked responses reﬂect the far-ﬁeld represen- tation of electrical events generated at points from the periphery (eighth nerve action poten- tial) to the level of the brain stem. The ﬁve to seven waves in the ﬁrst 10 msec are referred to as the brainstem–evoked response. The mid- dle latency responses (12 to 50 msec) have received less systematic study but probably reﬂect electrical activity in the upper brain stem and in the primary and nearby secondary auditory projection areas. The late evoked responses (50 to 300 msec) reﬂect cortical electrical activity.‌‌
Electrocochleography
Up to the present, this technique has been most useful for identifying cochlear responses in infants or in very young children who are unable to cooperate with behavioral testing.20 A rough estimate of the cochlear response at multiple frequencies and intensities can be obtained. Of course, the presence of these responses does not indicate that the subject actually “hears”; rather, it documents that electrical activity is being generated within the cochlea. The presence of cochlear microphonics and summating potentials (see Fig. 8–5) in the absence of a compound action potential suggests a denervated cochlea. Electrocochleography is useful in conjunction with brainstem auditory-evoked responses (BAER) in adults when one is attempting to identify whether a hearing loss is cochlear or retrocochlear. The presence of a normal elec- trocochleogram in a patient with an absent BAER suggests an auditory neuropathy.21 Absence of both can occur with either cochlear or retrocochlear lesions. Electrocochleography is also used to assess the likelihood of Meniere’s syndrome, though it is not a very accurate test (see Chapter 11).

Brainstem Auditory-Evoked Response
As noted above, the BAER reﬂects the far-ﬁeld representation of electrical events occurring in the eighth nerve and brain stem.15 It is highly reproducible in a given subject, and the latency of the various waves shows little variation
1
1
N
Stimulus

N
N
CM
2
among normal subjects.22 With rare exceptions, the BAER is not affected by inattention to the stimulus, alterations in the level of conscious- ness, or drugs. For this reason it can be used to test the integrity of the peripheral and brain- stem auditory pathways in patients who cannot cooperate with subjective auditory testing (e.g., infants, comatose patients).23
0 1 2 3 4 5
msec
Figure 8–5. Electrical response of the cochlea to a tone burst. An electrode near the round window records the cochlear microphonic potential (CM) and a compound action potential (N1 and N2). (Adapted from Sohmer H, Feinmesser M. Electrocochleography in clinical audiologi- cal diagnosis. Arch Otorhinolaryngol (Berl). 1974;206:91.)
GENERATING POTENTIALS
A schematic drawing of a BAER and the neural centers that are thought to generate each component of the response is shown
Milliseconds
0 1 2 3 4 5 6 7 8 9 10

60 dBHL 1.9 3.0 4.1 5.2
+
+
Cz
5.9 7.6 9.2
5.8
IV
V
0.1 µV units
0.1 µV units
II III
I
VII
VI
Central acoustic n.‌‌‌
Lateral lemniscus
z
z
C – Cochlea, acoustic n. terminals
Cochlear nucleus, Superior olivary complex
Inferior colliculus
Medial geniculate
Auditory radiations
Figure 8–6. Normal brain stem auditory evoked response evoked by clicks of 60 dB HL (60 dB above normal hearing threshold) at a rate of 10/sec. Normal mean latencies for waves I through VII are shown on the time scale (the intermedi- ate latency, 5.8 msec, between waves IV and V, is the mean peak latency of a fused wave IV/V when present). The neural centers thought to be responsible for generating each wave are shown at the bottom. (Adapted from Stockard JJ, Stockard JE, Sharbrough FW. Detection and localization of occult lesions with brain stem auditory responses. Mayo Clin Proc. 1977;52:761.)
in Figure 8–6.31 Wave I (average latency 1.9 msec) results from activation of the eighth nerve terminals within the cochlea, whereas wave II (average latency 3.0 msec) results from activation of the central portions of the eighth nerve. The remainder of the waves are gener- ated by the brainstem auditory nuclei and path- ways.24,25 Although a useful working tool, this schematic electroanatomic correlation is an oversimpliﬁcation. Clearly, each vertex-positive and vertex-negative potential after wave I reﬂects simultaneous activity in multiple brain- stem loci. The more caudal generators, such as the eighth nerve, cochlear nuclei, and superior olivary complex, contribute to the response beyond waves II and III. By the time waves VI and VII appear, the summation of potentials from the different neural centers is so complex that the concept of single principle contribu- tors to individual waves no longer applies.

TEST METHODOLOGY
The standard stimulus for eliciting a BAER is a click caused by a very short (<1 msec) pulse.
This signal produces a spectrally diffused acoustic stimulus, with most of the energy con- centrated in the high frequencies (around 1–4K Hz with most of the commercially available speakers). The absolute latency of the BAER waves is dependent on the intensity of the click stimulus. The BAERs to unﬁltered clicks pre- sented at various intensity levels from a normal subject are shown in Figure 8–7. Wave V is most robust, often being identiﬁable at only 10–20 dB above hearing level. At 60 dB above hearing level, all waves are identiﬁable. Such latency intensity functions provide a basis for estimating the degree of hearing loss in patients who cannot cooperate with standard pure-tone behavioral testing.26 Because of this latency- intensity relationship, however, BAERs must be interpreted with caution in patients with severe conductive or cochlear hearing loss (particularly if it involves high frequencies).

RESULTS IN PATIENTS
In practice, only waves I, III, and V are used to deﬁne response abnormalities. Waves II, IV,
V
IV
200 nV I II III
VI

dB SL 70

50

Right ear
II III
I
IV - V

30 0 2
Left ear I
10
4 6 8 10
IV - V
III

0 5 10 15
msec
Figure 8–7. Brain stem auditory evoked responses in a
normal subject that are induced by clicks at varying inten-
sity levels (10 to 70 dB sensation level [SL]).

VI, and VII are sufﬁciently variable in the nor- mal population to preclude their routine use in deﬁning response abnormalities on the basis of a single recording. Often waves IV and V fuse into a single complex, which is designated as wave IV/V. Because wave I disappears before wave IV/V with decreasing stimulus intensity (e.g., see Fig. 8–7), the absence of wave IV/V in the presence of wave I suggests a retrocochlear lesion. The absence of all waves, on the other hand, often reﬂects a peripheral lesion (con- ductive or cochlear) or a technical problem.27 If peak I occurs at normal latency, then prolonga- tion of the I–III or I–IV/V interval suggests a lesion of the eighth nerve or brain stem.‌
In clinical neurotology BAERs have been used mostly in (1) evaluating the cause and reversibility of coma, (2) assessing the likeli- hood of multiple sclerosis (MS), and (3) assessing the likelihood of a structural lesion involving the eighth nerve (e.g., vestibular schwannomas) (Fig. 8–8).25 Because BAERs are relatively resistant to metabolic insults, they can help differentiate between metabolic and structural causes of brainstem dysfunction. The presence of an intact BAER in a patient with global brainstem dysfunction on neurologic examination suggests the possibility of a meta- bolic, reversible cause of coma. The absence of waves III and/or V in the presence of wave I, however, suggests widespread structural dam- age of the brainstem and implies a poor prog- nosis.28,29 The complete absence of a BAER may have a similar poor prognosis but requires
0 2 4 6 8 10
Time in msec
Figure 8–8. Brain stem auditory evoked responses in a patient with a left acoustic neuroma. Dashed lines indicate repeat test. Wave I occurs at normal latency on both sides, but the I–III and I–V intervals are prolonged on the left side.

more cautious interpretation, as there may be other explanations for the lack of response (technical or otologic problems).
In patients suspected of having MS who present with lesions outside of the brain stem (e.g., optic nerve or spinal cord), an abnormal BAER supports the likely diagnosis (the impor- tant second lesion).27,30 Obviously, if the initial lesion involves the brain stem, the ﬁnding of an abnormal BAER provides little additional information. In the past brainstem auditory- evoked responses were used to screen for ves- tibular schwannomas but with the improved resolution and reduction in costs of MR imag- ing the BAER can no longer be recommended for primary screening for these tumors (see Chapter 15).32

CENTRAL AUDITORY SPEECH TESTS
Patients with lesions of the central auditory pathways usually have normal pure-tone hearing levels. Routine speech tests are also usually normal because speech contains a great deal of redundancy. Within the central auditory
pathways, redundancy is enhanced by the mul- tiple crossings and interactions. One of the few diagnostically useful central audiologic ﬁndings is the reduced ability of patients with temporal lobe lesions to discriminate speech in the ear contralateral to the lesion when the task is complicated by distorting the speech.33 Apparently, by making the speech less redun- dant, heavier demands are placed on the inte- grating, synthesizing function of the auditory cortex.
There are several varieties of central audi- tory speech tests currently in use, each involv- ing methods of presenting distorted speech. Portions of the frequency spectrum of speech can be ﬁltered, the speech can be time com- pressed, it can be presented at very low intensi- ties, and the speech can be interrupted at irregular intervals. Dichotic stimulation involves presenting two different messages to each ear.34 Both monosyllabic and spondee words can be used. As with distorted speech tests, when a temporal lobe lesion exists, the ear contralateral to the lesion performs poorer than the ear ipsilateral to the lesion.‌

SUMMARY OF AUDITORY TEST RESULTS
Hearing loss for pure tones is typically divided into conductive and sensorineural;
central lesions rarely produce such hearing loss (Table 8–2). Conductive and sensorineu- ral loss can usually be differentiated with an audiogram based on the finding of an air- bone gap with the former and a characteris- tic frequency intensity profile with the latter. The causes of a conductive hearing loss can be differentiated with tympanometry. There are several test results that help distinguish between a cochlear and retrocochlear sen- sorineural hearing loss. Speech discrimina- tion is relatively preserved with a cochlear loss, whereas it is impaired early and dispro- portionately to any pure tone loss with a sensorineural loss. Loudness recruitment is commonly seen with a cochlear loss, whereas tone decay is a common feature of a sen- sorineural loss. Abnormalities of the stapedius reflex and BAER provide an objective differentiation between cochlear and retrocochlear lesions. With cochlear hearing loss these measurements remain normal unless the loss is profound. On the other hand, the stapedius reflex and BAER are usually abnormal with only mild to moderate hearing loss due to retrocochlear damage. Central hearing disorders may show abnormalities of the late waves of the BAER or of cortical-evoked responses or in discriminating speech when the task is com- plicated by distorting the content of the speech.

Table 8–2 Summary of Auditory Test Results with Lesions at Different Locations
SENSORINEURAL
Test Conductive Cochlea Nerve Central
Speech
discrimination
Normal Relatively preserved
Abnormal early Normal
Tympanometry Abn: restricted,
hypermobile, ﬂat
Normal Normal Normal
Stapedius reﬂex Absent Normal Absent or decay Normal
BAER Normal Normal Absent, delayed I–III, I–V
Delayed III–V
Special tests — Loudness recruitment

Abn, abnormal.
Tone decay Dichotic listening, alter- nating speech, ﬁltered speech
REFERENCES
1. Katz J, Medwetsky L, Burkard RF, et al. eds. Handbook of Clinical Audiology. 6th ed. Baltimore: Lippincott Williams & Wilkins; 2009.
2. Kileny PR, Zwolan TA. Diagnostic and rehabilitative audiology. In: Cummings CW, Flint PW, Haughey BH, et al. eds. Otolaryngology Head and Neck Surgery. 4th ed. St Louis, MO: CV Mosby; 2005.
3. Arts HA. Sensorineural hearing loss: Evaluation and management in adults. In: Cummings CW, Flint PW, Haughey BH, et al. eds. Otolaryngology Head and Neck Surgery. 4th ed. St Louis, MO: CV Mosby; 2005.
4. Rauch SD. Idiopathic sudden sensorineural hearing loss. N Engl J Med. 2008;359:833.
5. Schuknecht HL. Pathology of the Ear. 2nd ed. Philadelphia: Lea & Febiger; 1993.
6. Bagai A, Thavendiranathan P, Detsky AS. Does this patient have hearing impairment? JAMA. 2006;295:416.
7. Torres-Russotto D, Landau WM, Harding GW, Bohne BA, Sun K, Sinatra PM. Calibrated ﬁnger rub auditory screening test (CALFRAST). Neurology. 2009;72(18):1595.
8. Jerger J, Jerger S. Diagnostic signiﬁcance of PB word functions. Arch Otolaryngol. 1971;93:573.
9. Durmaz A, Karahatay S, Satar B, Birkent H, Hidir
  Y. Efﬁciency of Stenger test in conﬁrming pro- found, unilateral pseudohypacusis. J Laryngol Otol. 2009;123(8):840.
10. Kintsler DP, Phelan JG, Lavender RB. Efﬁciency of the Stenger and speech Stenger tests in functional hearing loss. Audiology. 1972;11:187.
11. Jerger J, Jerger S, Maulden L. Studies in impedance audiometry. I. Normal and S-N ears. Arch Otolaryngol. 1972;96:513.
12. Liden G, PedersonJL, Bjorkman G. Tympanometry.
  Arch Otolaryngol. 1970;92:248.
13. Jerger J, Anthon L, Jerqer S, et al. Studies in imped- ance audiometry. III. Middle ear disorders. Arch Otolaryngol. 1974;99:165.
14. Kileny PR, Young KE, Niparko JK. Acoustic and elec- trical assessment of the auditory pathway. In: Jackler RK, Brackmann DE, eds. Neurotology. St. Louis, MO: CV Mosby; 1993.
15. Stone JL, Calderon-Arnulphi M, Watson KS, et al. Brainstem auditory evoked potentials–a review and modiﬁed studies in healthy subjects. J Clin Neurophysiol. 2009;26(3):167.
16. Sohmer H, Feinmesser M. Cochlear action poten- tials recorded from the external ear in man. Ann Otol Rhinol Laryngol. 1967;76:427.
17. Margolis RH, Rieks D, Fournier EM, Levine SE. Tympanic cochleography for diagnosis of Meniere’s disease. Arch Otolaryngol Head Neck Surg. 1995; 121:44.
18. Sohmer H, Feinmesser M. Electrocochleography in clinical audiological diagnosis. Arch Otorhino-laryngol (Berl). 1974;206:91.
19. Møller AR, Janetta PJ. Neural generators of the audi- tory brainstem response. In: Jacobson JT, ed. The Auditory Brainstem Response. Boston: College-Hill Press; 1985.
20. Northern JL, Downs MP. Hearing in Children. Baltimore: Williams & Wilkins; 1978.
21. Vlastarakos PV, Nikolopoulos TP, Tavoulari E, Papacharalambous G, Korres S. Auditory neuropathy: endocochlear lesion or temporal processing impair- ment? Implications for diagnosis and management. Int J Pediatr Otorhinolaryngol. 2008;72(8):1135.
22. Musiek FE, Kibbe-Michal K, Ceurkink NA, et al. ABR results inpatients with posterior fossa tumors and nor- mal pure tone hearing. Otolaryngol Head Neck Surg. 1986;94:568.
23. Wilkinson AR, Jiang ZD. Brainstem auditory evoked response in neonatal neurology. Semin Fetal Neonatal Med. 2006;11(6):444.
24. Møller AR, Janetta PJ, Møller MB. Neural generators of brain stem evoked potentials. Results from human intracranial recordings. Ann Otol Rhinol Laryngol. 1981;90:591.
25. Walsh P, Kane N, Butler S. The clinical role of evoked potentials. J Neurol Neurosurg Psychiatry. 2005;76(suppl 2):ii,16.
26. Don M, Eggermont JJ, Brachmann DE. Reconstruction of the audiogram using brain stem responses and high-pass noise masking. Ann Otol Rhinol Laryngol. 1979;88(suppl 57):1.
27. Coats AC. Human auditory nerve action potentials and brain stem evoked responses. Arch Otolaryngol. 1978;104:799.
28. Coldie WD, Chiappa KH, Young RR, Brooks EB. Brain stem auditory and short somatosensory evoked responses in brain death. Neurology. 1981;31:248.
29. Hall JW, Mackey-Hargadine JR, Kim EE. Auditory brain stem response in determination of brain death. Arch Otolaryngol. 1985;111:613.
30. Paludetti G, Ottaviani F, Gallai V, et al. Auditory brain stem responses (ABR) in multiple sclerosis. Scand Audiol. 1985;14:27.
31. Stockard JJ, Stockard JE, Sharbrough FW. Brain stem auditory evoked potentials in neurology: methodology, interpretation, and clinical application. In: Aminoff MJ, ed. Electrodiagnosis in Clinical Neurology. New York: Churchill Livingstone; 1986.
32. Fortnum H, O’Neill C, Taylor R, et al. The role of magnetic resonance imaging in the identiﬁcation of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness and natural history. Health Technol Assess. 2009;13(18):iii, ix, 1.
33. Berlin C, Lowe-Bell S, Janetta P, Kline D. Central auditory deﬁcits after temporal lobectomy. Arch Otolaryngol. 1972;96:4.
34. Denes H, Cariezel F. Dichotic listening in crossed aphasia. Arch Neurol. 1981;38:182.
PART
3
‌

Diagnosis and Management of Common Neurotologic
Disorders

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Chapter 9 ‌‌

Infectious Diseases

ACUTE OTITIS MEDIA AND OTOMASTOIDITIS
Diagnosis and Management ‌
CHRONIC MASTOIDITIS AND CHOLESTEATOMA
Diagnosis Management
BACTERIAL LABYRINTHITIS
Diagnosis Management PETROSITIS
Diagnosis Management
INTRACRANIAL EXTENSION OF EAR INFECTIONS
Routes of Spread Meningitis Epidural Abscess
Lateral Sinus Thrombophlebitis Brain Abscess

Otitic Hydrocephalus Diagnosis Management
MALIGNANT EXTERNAL OTITIS
Diagnosis Management
VIRAL INFECTIONS OF THE INNER EAR
Clinical Syndromes Diagnosis
Viral versus Other Causes of Peripheral Cochleovestibular Loss
Management
SYPHILITIC INFECTIONS OF THE EAR
Diagnosis Management
TUBERCULOSIS AND MYCOTIC INFECTIONS OF THE INNER EAR
Tuberculous Mastoiditis Mycotic Mastoiditis Basilar Meningitis

Bacterial infections involving the audio-vestibular structures result from the spread of an infec- tion from another region of the body, typically the middle ear or the meninges. As with most bacterial infectious disorders, the advent of antibiotics substantially changed the preva- lence and scope of complications from infec- tious diseases. Prior to antibiotics, it was not uncommon for the common variety of middle ear infection, otitis media, to evolve into a chronic infection that eventually eroded into the inner ear. However, with antibiotics it is now quite rare for this to occur. Thus, at this point viral infections—or at least presumed viral infections—are the most common type
of infectious process involving the audio- vestibular system.
In this chapter we discuss infectious diseases that can involve the audio-vestibular system.

ACUTE OTITIS MEDIA AND OTOMASTOIDITIS
Infection of the middle ear (otitis media) is the most common disease treated with antibiotics in the United States. Because the air cavity of the middle ear is in direct communication with the mastoid air cells, infection can spread

233
Upper respiratory tract infection

Acute tubotympanitis

Secretory otitis media
Secretory otitis media
Acute otitis media
Acute otitis media
Acute otomastoiditis

Polypoid granuloma
Polypoid granuloma
Chronic otomastoiditis

Perilymph fistula
Labyrinthitis
Perilymph fistula
Labyrinthitis

Cholesteatoma
Cholesteatoma
Figure 9–1. Patterns of progression of middle ear infections.

throughout the pneumatized parts of the tem- poral bone (see Fig. 2–2). Typical patterns of progression of middle ear infections are sum- marized in Figure 9–1. The most common complication of otitis media is mastoiditis.1
Eighty percent of children between the ages of 1 and 6 years have at least one bout of acute otitis media.2 The symptoms typically include unilateral otalgia, fever, and hearing loss. Vertigo is not a common symptom since the infection in uncomplicated cases is restricted to the middle ear. The peak incidence occurs during the ﬁrst year of life, reaching an inci- dence rate of almost 50% and then gradually decreasing to an incidence rate of <10% beyond age 6.3 With acute otitis media, there is a middle-ear effusion that can be determined by the appearance of the tympanic membrane (i.e., fullness or bulging of the membrane along with cloudiness or redness), pneumatic otos- copy, or tympanometry. Spontaneous perfora- tion can occur, allowing the purulent effusion to drain into the external ear (i.e., otorrhea). Following resolution of the acute infection, a serous or mucinous effusion can persist for months (i.e., chronic otitis media with effusion). Persistent pain and swelling behind the ear may indicate mastioditis.4 However, the incidence of mastoiditis is very low (< 1%) even among

patients with acute otitis media managed initially with observation rather than antibiot- ics.5 The majority of patients who develop mas- toiditis are receiving antibiotic therapy for acute otitis media, so antibiotics are not a safe- guard against developing acute mastoiditis.

Diagnosis and Management
The diagnosis of acute otitis media rests on ﬁnd- ing the characteristic changes in the tympanic membrane in a patient complaining of acute otalgia and hearing loss. The most common organisms associated with acute otitis media worldwide are Streptococcus pneumoniae, Hemophilus inﬂuenza, Moraxella catarrhalis, and group A Streptococcus.6 Once the clinical diagnosis is made, the patient can either be managed with observation and conservative management when the case is uncomplicated (mild otalgia and fever <39°C) or with antibi- otic therapy, typically amoxicillin.5 An observa- tion period is reasonable because in some cases the cause will be viral rather than bacterial and because randomized placebo-controlled trials have shown that most patients do well even without antibiotics.5,7 If there is clinical wors- ening or no improvement in 48 to 72 hours,
then antibiotics should be initiated. If the infection fails to resolve within a few days of antibiotic therapy, then the antibiotic is typi- cally changed to amoxicillin-clavulante. If acute otitis media persists, then a myringotomy can be performed to obtain a sample of the ﬂuid for culture and also to treat otalgia. The antibiotics are then adjusted on the basis of the results of culture. Signs of acute mastoiditis include pos- tauricular swelling, erythema, tenderness, and protrusion of the auricle. The causative organ- isms in acute mastoiditis are often different from those causing acute otitis media. Since potential drug-resistant staphylococcus and pneumococcus infections are common with mastoiditis, obtaining a specimen for culture is important for directing antibiotic treatment.8‌‌

CHRONIC MASTOIDITIS AND CHOLESTEATOMA
Chronic mastoiditis results from an untreated or nonresponsive acute mastoiditis or otitis media.2,3 Pathology is characterized by thick- ened edematous mucosa with obliteration of the mastoid air cell lumen, perivascular ﬁbro- sis, and osteitis. Chronic obstruction of the mastoid antrum leads to irreversible changes in the mucosa and bone of the mastoid. Polypoid granulomas composed of hyperplastic mucosa may ﬁll the mastoid antrum, extend into the middle ear, and extrude through a tym- panic membrane perforation into the external auditory canal.
Another consequence of chronic otitis media is a cholesteatoma, which is a collection of ker- atinized squamous epithelium that can invade the middle ear and other pneumatized areas of the temporal bone through the tympanic mem- brane.9 The term cholesteatoma is a misnomer because it does not contain cholesterol and is not a neoplasm. Cholesteatomas usually develop in the epitympanic space of the middle ear following a perforation in the pars ﬂaccida region of the tympanic membrane (see Fig. 6–1B). From here they extend posteriorly into the antrum, into the central mastoid tract, or inferiorly into the middle ear to erode the ossi- cles and bony labyrinth, producing a mixed conductive sensorineural hearing loss and ver- tigo. The mechanism by which a cholesteatoma erodes bone is not entirely clear, but it is not a
simple pressure necrosis. Ultra-structural stud- ies in humans and experimental studies in ani- mals suggest that the bone resorption is caused primarily by activation of multinucleated osteo- clasts in the bone.10 Ultimately, a cholestea- toma may erode through the temporal bone into the intracranial cavity, producing central nervous system (CNS) symptoms and signs.
Cholesteatomas themselves are prone to recurrent infection, because they contain kera- tin debris enclosed in a tissue space. The bacte- ria seen with chronic cholesteatomas are dif- ferent from those seen with acute otitic infections, with the most common aerobe being Pseudomonas aeruginosa, followed by Staphylococcus aureus.11 The most common anaerobes are Proteus and bacteroides. When acutely infected, cholesteatomas can rapidly cause bone destruction. With chronic mastoidi- tis and cholesteatoma formation, a ﬁstula may develop in the bony labyrinth, producing an artiﬁcial communication between the peri- lymph and the middle ear.12 The ﬁstula can be caused by either progressive rarefying osteitis or erosion by the cholesteatoma. Patients with a perilymph ﬁstula experience severe episodes of vertigo when they sneeze or cough because the sudden change of pressure in the middle ear is transmitted directly to the inner ear.

Diagnosis
Patients with chronic mastoiditis typically pres- ent with painless purulent otorrhea. Otoscopic examination of the tympanic membrane may reveal evidence of a perforation, particularly in the pars ﬂaccida region, and a cholesteatoma or granuloma may be visible in the epitympanic region of the middle ear. The otoscopic appear- ance of a cholesteatoma can be quite variable. The typical attic retraction cholesteatoma appears as a “pearly tumor” in the posterior superior portion of the tympanic membrane. In other cases, a cholesteatoma develops at the margin of a perforation and migrates into the middle ear. Cholesteatomas sometimes appear behind or within an intact tympanic membrane (so-called primary cholesteatomas). Rarely, a cholesteatoma is not seen otoscopically but is discovered at the time of mastoid surgery. A perilymph ﬁstula can be identiﬁed on examina- tion by transiently changing the pressure in the external canal using a pneumatic bulb attached
Figure 9–2. Computed tomography scan of the temporal bone in a patient with a cholesteatoma eroding the wall of the horizontal semicircular canal (A) and the facial canal (B). Arrows point toward area of bony erosion. FC, facial canal; HC, horizontal semicircular canal; IAC, internal auditory canal; V, vestibule.‌‌
to the otoscope (see Chapter 6). With a positive ﬁstula test the patient develops vertigo and nystagmus lasting 10 to 20 sec. The nystagmus can be in either direction but usually is in the same direction with both positive and negative pressure. Computed tomography (CT) scan- ning of the temporal bone may reveal a non- pneumatized or poorly pneumatized mastoid, haziness of air spaces, or bony erosion from a cholesteatoma or osteitis (Fig. 9–2). One can also identify erosion of the bony wall of the horizontal semicircular canal or the facial canal.

Management
Initial management is directed at medical treat- ment of the chronic infection.3,13 Chronic oto- mastoiditis that is unresponsive to medical management requires surgical eradication of all diseased tissue. A complete transcortical mastoidectomy is performed with attention to establishing good communication from the mastoid into the middle ear space. A bony ﬁs- tula requires microsurgical removal of the lesion and closure with either perichondrium or fascia. Damage to the ossicular chain can usually be repaired.
BACTERIAL LABYRINTHITIS
Labyrinthitis refers to an inﬂammatory process of the labyrinth. Bacterial infections initially affect the otic capsule from which they extend into the perilymphatic space and ultimately involve the membranous labyrinth. There are two types of labyrinthitis associated with acute and chronic bacterial infections of the tempo- ral bone: (1) serous or toxic labyrinthitis, in which bacterial toxins or chemical products invade the inner ear; and (2) suppurative laby- rinthitis, in which bacteria invade the inner ear. The former often leads to only subtle symptoms such as an insidious high-frequency sensorineu- ral hearing loss, whereas the latter typically leads to a profound combined auditory and vestibular loss with little or no recovery.
Serous labyrinthitis is a common complica- tion of acute or chronic middle ear infections. With acute otitis media, small molecules such as bacterial toxins or inﬂammatory mediators such as cytokines and nitric oxide rapidly dif- fuse through the round window into the scala tympani.14 Acute and chronic inﬂammatory cells also inﬁltrate the round window, and a ﬁne seroﬁbrinous precipitate forms just medial to the round window membrane. The toxins and inﬂammatory mediators may penetrate the
basilar membrane and invade the endolymph at the basal turn of the cochlea. Such changes could explain the high incidence of high- frequency sensorineural hearing loss in patients with chronic otitis media.15 A more rapid onset of serous labyrinthitis results in a more com- plete sensorineural hearing loss along with ves- tibular symptoms, including episodic vertigo and unsteadiness.16
The most common port of entry of bacteria into the inner ear (i.e. suppurative labyrinthi- tis) is from the spinal ﬂuid in patients with meningitis (which may or may not be a compli- cation of middle ear infection).17 Children with bacterial meningitis are particularly susceptible to developing suppurative labyrinthitis with residual severe hearing loss occurring in about 11%.18 The prevalence of residual vestibulopa- thy has not been well deﬁned. Patients with bacterial meningitis develop labyrinthitis when bacteria enter the perilymphatic space by way of the cochlear aqueduct or internal auditory canal. Meningogenic bacterial labyrinthitis is usually bilateral, whereas direct invasion from a chronic otitic infection is almost always uni- lateral. The most common route for a direct bacterial invasion of the labyrinth is via a horizontal semicircular canal ﬁstula from a cholesteatoma. Endolymphatic hydrops can be a sequela of both serous and suppurative labyrinthitis.19‌

Diagnosis
Acute suppurative labyrinthitis has become relatively rare since the introduction of antibi- otics because patients at high risk of develop- ing it (e.g., those with meningitis or severe middle ear infections) are typically started on treatment early in the course of the infection before extension to the inner ear occurs. Symptoms to indicate involvement of the inner ear include the sudden onset of severe vertigo, nausea, vomiting, and unilateral or bilateral hearing loss. The diagnosis of bacterial labyrin- thitis in association with acute or chronic ear infections is based on ﬁnding the characteristic symptoms and signs of inner ear dysfunction. As noted earlier, serous labyrinthitis most com- monly produces a slowly progressive, insidious high-frequency sensorineural hearing loss, which may be discovered only with audiomet- ric testing. Suppurative labyrinthitis produces
a much more fulminant course, with both audi- tory and vestibular loss. Intermediate clinical pictures are not uncommon, however, and it may be impossible to differentiate between a toxic and suppurative labyrinthitis on the basis of the symptoms alone. Bacterial labyrinthitis should be considered in any patient with acute or chronic ear infection or meningitis who develops a sudden or progressive sensorineural hearing loss and vestibular symptoms. A posi- tive ﬁstula test suggests that the chronic inner ear infection has eroded into the horizontal semicircular canal.

Management
Management of labyrinthitis is directed at the associated infection of the middle ear, mastoid, and, if present, meninges. Any patient with acute or chronic bacterial ear disease associ- ated with sudden or rapidly progressive inner ear symptoms should be hospitalized and the primary source (typically otitis media or men- ingitis) should be identiﬁed. The appropriate course of antibiotics should then be started.13 If mastoiditis occurs, then surgical intervention to eradicate the middle ear and mastoid infection is often required after a few days of antibiotic treatment. If bacterial meningitis is diagnosed, then corticosteroids as adjuvant therapy can reduce the incidence of long-term hearing loss.18,20 In a rat model of meningitis-associated hearing loss, antioxidant therapy plus antibiot- ics was more effective in preventing hearing loss than antibiotics alone.21 If the labyrinthitis and meningitis are secondary to chronic ear infection, a labyrinthectomy might be indicated if the meningitis fails to respond to adequate medical treatment. A resistant or recurrent meningitis may result from unrecognized posterior fossa epidural abscesses with dural perforation or from congenital direct commu- nications with the cerebrospinal ﬂuid (CSF).

PETROSITIS
Infections involving the perilabyrinthine bone may extend into the apical regions of the petrous bone, producing petrositis. Although only about 30% of petrous bones are pneuma- tized into the petrous apex, when infection
does spread into this region, management can be difﬁcult because drainage is more restricted and the proximity of the apical air cells to dip- loic spaces predisposes to osteomyelitis.13,22 Because of these problems, petrositis is com- monly associated with both bacterial labyrin- thitis and with intracranial extension of the infection.‌‌

Diagnosis
The main symptom of an indolent infection in the petrous bone is a deep, boring pain. With infection in the perilabyrinthine region, pain is often referred to the occipital, parietal, or temporal regions. With infection conﬁned to the petrous apex, pain is referred to the deep retro-orbital area. In 1904, Gradenigo described a classic triad associated with lesions of the petrous apex: (1) deep retro- orbital pain, (2) paralysis of the ipsilateral lat- eral rectus muscle from involvement of the abducens nerve as it crosses the petrous bone, and (3) otitic infection with purulent discharge from the ear.23 The syndrome may be associ- ated with vertigo and hearing loss, either from a concomitant bacterial labyrinthitis or from involvement of the eighth nerve in its bony canal. Radiologic evidence for infection of the petrous apex can be difﬁcult to establish even with high-resolution CT and magnetic reso- nance imaging (MRI). The difﬁcultly with radiologic diagnosis is that abnormalities in this region can be missed, and ﬂuid accumula- tion in the petrous apex can be a benign ﬁnding even earning the label “leave alone lesions.”24–26

Management
Management is usually a combined medical– surgical approach. After appropriate antibiotic therapy, the mucosal and bone infection must be removed. Surgically, one usually begins with a radical mastoidectomy and dissection along the cell tracts to the petrous bone. Osteomyelitis of the petrous apex and cranial base can be life threatening. The surgical goal is to remove the maximum amount of infected temporal bone while preserving the seventh and eighth cranial nerves and the labyrinth.27
INTRACRANIAL EXTENSION OF EAR INFECTIONS
Extension of infection from the temporal bone into the cranial cavity demands rapid diagnosis and effective therapy to prevent permanent neurologic sequelae or death. Complications can result directly from either acute otitis media and mastoiditis or with chronic otomas- toiditis and bone destruction. In a patient with an otitic infection who is febrile and continues to complain of severe ear and mastoid pain or headache despite appropriate antibiotic ther- apy, intracranial extension of the infection should be considered. Localized neurologic signs frequently do not develop until late in the disease process, and the diagnosis should be considered before focal signs develop.
Although the incidence of morbidity and mortality with CNS complications of ear infec- tions has markedly decreased since the antibi- otic era, these disorders have not disappeared and still remain a major problem in the twenty- ﬁrst century. In a recent review of 3364 patients with bacterial otitis media admitted to a ter- tiary referral university hospital, 422 (12.5%) presented with complications (extracranial/ intracranial ratio 1:1).1 Mastoiditis was the most common extracranial complication and lateral sinus thrombophlebitis the most common intracranial complication. In those with com- plications the mortality rate was 1.4% and the morbidity rate 3.8%.

Routes of Spread
Infection within the temporal bone can reach the intracranial space via three routes: (1) direct extension, (2) hematogenous spread, and
thrombophlebitis. Extracranial subpe- riosteal abscesses, intracranial extradural abscesses, and sigmoid sinus thrombophlebitis almost always result from a direct extension of the temporal bone infection. Subdural and brain abscesses may also result from direct extension along the soft tissue planes through the petromastoid canal to the poste- rior fossa or along the petrosquamous suture line to the middle fossa. There is a rich network of veins in and around the temporal bone, and these veins directly communicate with extra- cranial, intracranial, and cranial diploic veins.

Thrombophlebitis of any of these veins may spread to the others, resulting in osteomyelitis of the calvaria or brain abscess at some distance from the temporal bone. Meningitis, particu- larly in young children, typically results from hematogenous dissemination. The frequent association between acute otitis media, pneu- monia, and meningitis is probably due to the fact that all three diseases result from a sys- temic bacterial infection that has entered via the upper respiratory tract. Chronic bacterial otomastoiditis produces meningitis by direct extension through bone and dura or through the inner ear via a labyrinthine ﬁstula produced by a cholesteatoma.

Meningitis

Meningitis secondary to ear disease is primarily a disease of infants with acute otitis media.28 As a general rule, the bacteria causing the menin- gitis are similar to those causing the acute ear infection. With chronic ear infections and cholesteatoma, however, multiple microorgan- isms may be involved in the meningitis. Recurrent meningitis associated with middle ear infections suggests a CSF ﬁstula, with

pneumoniae being the most common organ- ism responsible.29

Epidural Abscess
A potential intracranial complication of chronic otitic infections is extradural abscess, a collection of purulent ﬂuid between the dura mater and bone of the middle or posterior fossa.19,29 The dura mater is usually an effective barrier, and the infection remains localized outside the nervous system. Extradural abscesses are frequently asymptomatic and are discovered incidentally on CT or during mas- toidectomies for acute or chronic disease.30 Extradural abscesses in the middle fossa may become large and compress the temporal lobe, whereas abscesses in the posterior fossa remain small because of the tight attachments of the dura. The initial symptoms of fever, severe headache, and vomiting without focal neuro- logic signs can create a diagnostic and thera- peutic dilemma.
Lateral Sinus Thrombophlebitis
Of the three dural sinuses intimately connected with the temporal bone, the lateral sinus is most commonly affected by acute or chronic temporal bone infection.31 Inﬂammation in the extradural space adjacent to the lateral sinus causes a local phlebitis and formation of a mural thrombus. The thrombus enlarges within the lumen of the vessel and may occlude it or become infected. A bland or infected throm- bus may propagate in either direction and become organized. When infected, septic emboli are released into the bloodstream, caus- ing septicemia and its systemic manifestations (i.e., fever, chills). When the cerebral veins are involved, the patient may develop focal or gen- eralized seizures.

Brain Abscess
Although the overall incidence of otitic brain abscesses has decreased due to early treatment with antibiotics, atypical brain abscesses in immunocompromised patients are becoming more common.32 As noted earlier, brain abscesses associated with ear infections pre- dominantly originate from venous throm- bophlebitis rather than direct extension through the dura mater.33 The temporal lobe is most commonly involved, followed by the cerebel- lum. Both aerobic and anaerobic organisms are found in pure or mixed cultures within brain abscesses. Multiple organisms are found in more than half of the cases.34 Surprisingly, although H. inﬂuenza and Pseudomonas spe- cies are common organisms with ear infections, they are rare with brain abscesses.
Neurologic signs associated with temporal lobe abscess are often subtle, particularly in an immunocompromised patient or if the patient has received inadequate antibiotic therapy.35 An upper-quadrant hemianopia can result from involvement of the optic radiations on either side, and when the abscess is in the dominant hemisphere, speech may be abnormal. Usually some weakness of the contralateral face and arm occurs, but gross paralysis is rare. The signs of a cerebellar abscess are usually more prominent. The patient complains of severe neck stiffness and holds the head rigid in a tilted position. Neurologic examination reveals
ataxia, dysrhythmia, and dysmetria of the ipsi- lateral extremities, and the gait is markedly ataxic—if the patient is able to walk at all. Asymmetric gaze-evoked nystagmus is usually present with larger amplitude directed toward the side of the abscess. As the disease pro- gresses, the speech becomes thick and slurred and swallowing difﬁculty develops.

Otitic Hydrocephalus
In 1931, Symonds36 coined the term otitic hydrocephalus to describe the syndrome of increased intracranial pressure without evi- dence of meningitis or brain abscess in patients with chronic ear infections (i.e., pseudotumor cerebri). Symonds later hypothesized that the
brain edema resulted from thrombosis of the superior sagittal sinus, leading to impaired CSF resorption. More recent MRI studies show that thrombosis of the lateral venous sinus alone can impede venous draining and produce a rise in CSF pressure.37 Complications include chronic headaches and visual loss due to optic nerve compression.38

Diagnosis
An intracranial complication of an otitic infec- tion should be considered in any patient with a known ear infection who continues to com- plain of severe pain and headache despite appropriate antibiotic therapy (Fig. 9–3). The presence of fever, neck rigidity, and a positive

History

Persistent pain and drainage despite appropriate antibiotics

Examination

Persistent fever and neck stiffness Meningismus
Focal neurologic signs

CT scan with contrast

Negative

MRI MRV

Negative

LP

Positive

Positive

Positive
Mastoiditis Cholesteatoma Petrositis Abscess
Venous thrombosis

Small epidural or subdural effusion Cerebritis
Venous thrombosis

Meningitis Epidural effusion Cerebritis
Meningitis Epidural effusion Cerebritis
Negative

Continued observation
Continued observation
Figure 9–3. Algorithm for the diagnosis of intracranial complications of ear infections. CT, computerized tomography; LP, lumbar puncture; MRI, magnetic resonance imaging; MRV, magnetic resonance venography.
Kernig’s or Brudzinski’s sign supports the ini- tial impression. As noted earlier, focal neuro- logic signs develop late in the course, even with localized brain abscesses, so one must have a high degree of suspicion based on the clinical presentation. After a detailed history and a careful physical examination, a CT scan with contrast is the initial diagnostic test. The CT scan will show bone erosion, collections of pus within the intracranial cavity, and can identify thrombosis of the venous sinuses.13 It can miss small collections of extradural or subdural pus and early stages of brain abscess formation, however, which might be identiﬁed with MRI. Venous thrombosis is best identiﬁed by MRI with venography (MRV).31 If a mass lesion has been ruled out, a lumbar puncture is performed for analysis of the CSF. The characteristic proﬁle of bacterial meningitis (pleocytosis, decreased glucose, and increased protein) is readily identiﬁed. More subtle changes (mono- cytic pleocytosis and mildly increased protein) can be seen with collections of pus in the epi- dural spaces or with brain abscess. The ﬁnding of increased intracranial pressure without a structural lesion suggests the possibility of a sinus thrombosis.‌‌

Management
Treatment of the intracranial complications secondary to ear infections is directed along two lines: (1) eradication of the infection with appropriate antibiotics and (2) establishing adequate drainage and excision of infected tis- sue when necessary.13 Complications due to acute otitis media are usually effectively con- trolled by a myringotomy and adequate paren- teral antibiotics. Complications associated with bone destruction from chronic otitis media and mastoiditis usually require some type of mastoidectomy along with parenteral antibiot- ics. As a general rule, when there is a collection of pus within the intracranial cavity, treatment is directed ﬁrst to reduce intracranial pressure—usually by evacuating the empyema. Appropriate management of meningitis con- sists of ﬁrst identifying the offending organism, beginning appropriate intravenous antibiotics, and periodic monitoring of the progress by lumbar puncture.39 Otitic hydrocephales typi- cally requires long-term CSF drainage with a ventriculoperitoneal shunt.38
MALIGNANT EXTERNAL OTITIS
Otitis externa, usually a benign disorder, can lead to a debilitating disease called malignant external otitis in elderly diabetic patients.40,41 It typically begins with a nonspeciﬁc infection of the external canal, resulting in complaints of pain, drainage, and fullness of the ear. The pain becomes severe and continuous as the infec- tion spreads to contiguous soft tissues and adja- cent bony structures. The invading organism is almost always P. aeruginosa. The organism invades the junction of the cartilaginous and osseous portions of the external auditory canal and spreads to the temporo-occipital bones. The most common neurologic sequela is involvement of the facial nerve in the fallopian canal or at the stylomastoid foramen.42 Occasionally, multiple cranial nerves are com- pressed extradurally, and in rare cases, the infection spreads across the dura to produce a purulent meningitis.

Diagnosis
Diagnosis rests on ﬁnding the characteristic granulation tissue in the external canal along with a positive culture for P. aeruginosa (Fig. 9–4). A CT scan of the temporal bone may reveal (1) a soft tissue mass in the external canal, (2) clouding of the mastoid air cells, (3) sequestra of the bony canal, (4) erosion of bony structures at the base of the skull, and (5) soft tissue masses within the parapharynx and nasopharynx.43 Initial ﬁndings on CT can often predict the likely clinical course.44 An MRI is useful on follow-up to identify soft tissue evo- lution and meningeal enhancement.45

Management
Initial local treatment consists of removal of all accumulated debris and granulation tissue from the external canal and instillation of a gentamicin wick (gentamicin sulfate drops on 1/2-inch gauze packing) in the external canal. This, along with strict control of the underlying diabetes, can be sufﬁcient treatment in some patients with early stages of disease. In patients with more advanced disease, including bony erosion, or in those who fail to respond promptly to this initial therapy, a bone scan is indicated
External otitis with extuberant tissue in a diabetic patient

Biopsy and culture

Malignant external otitis

Computed tomography (CT)

Initial therapy:
Persistence
- Debridement
- Gentamicin wick
- Strict control of diabetes
Initial therapy:
Persistence
- Debridement
- Gentamicin wick
- Strict control of diabetes
No bone erosion ‌

Bone scan

Osteitis, osteomyelitis

Initial therapy plus:
- Parenteral antibiotics
- Surgery (sequestrectomy, drain abscesses)
- Continue until local disease clears

Bone erosion, abscesses

combination of auditory and vestibular symp- toms. They may be part of a systemic viral illness such as measles, mumps, and infectious mono- nucleosis, or more commonly it is an isolated infection of the labyrinth and/or eighth nerve without systemic involvement. In the latter case, the infecting agent is rarely identiﬁed, but an iso- lated viral infection of the inner ear is presumed based on the typical self-limited clinical course and prior pathologic evidence to support the link between the sudden onset of hearing loss and/or vertigo and a viral infection.46 Similar assump- tions about a viral etiology are made with idio- pathic facial nerve palsy (i.e., Bell’s palsy), which is also a typically self-limited cranial neuritis.

Of the thousands of infants born deaf every year, about 20% of cases are thought to be the result of congenital viral infections.47 CMV infections are most common.48 In adults, two relatively common presumed viral disorders are vestibular neuritis and sudden sensorineu- ral hearing loss (SSNHL) or “sudden deaf- ness.”49,50 Despite this strong suspicion of a viral origin for these common neurotologic syndromes, proof of a viral pathophysiology in individual cases is rare. Epidemiologic evi- dence supports a viral cause in most patients with either sudden deafness or acute prolonged vertigo. A large percentage of such patients report an upper respiratory tract illness within 1 to 2 weeks prior to the onset of symptoms. Both syndromes occur in epidemics, may affect several members of the same family, and erupt more commonly in the spring and early summer.51–53A list of the viruses that have been clinically associated with cases of deafness and/

Figure 9–4. Algorithm for the management of malignant external otitis. (Adapted from Smith PG, Lucente FE. External ear: Infections. In: Cummings CW, Fredrickson JM, Harker LA, Krause CJ and Schuller DE (eds). Otolaryngology—Head and Neck Surgery, CV Mosby, St. Louis, 1986, with permission.)

to assess the possibility of osteitis or osteomy- elitis. If positive, the patient will require long- term parenteral antibiotic therapy dependent on the microbial ﬁndings and local cleansing and debridement, as required (Fig. 9–4).

VIRAL INFECTIONS OF THE INNER EAR

Viral infections of the inner ear can present with sudden deafness, acute vertigo, or with some

or vertigo is given in Table 9–1.54 In most cases, however, proof that these viruses caused the symptoms is circumstantial.

Table 9–1 Viruses Clinically Associated with Hearing Loss and/or Vertigo

Cytomegalovirus Hepatitis

Rubella Adenovirus

Mumps Inﬂuenza

Rubeola Parainﬂuenza

Varicella-zoster Poliomyelitis

Herpes simplex Coxsackie

Epstein-Barr Lymphocytic choriomeningitis

Variola Yellow fever

Adapted from Davis and Johnson.54

Figure 9–5. Pathologie ﬁndings in a patient with vestibular neuritis. Sections through comparable areas of Scarpa’s ganglia on the normal side (A) and the side with absent caloric response (B) stained with toluidine blue. Only a few small neurons remain in B (bar = 100 µm). (From Baloh RW et al. Vestibular neuritis: clinical pathological correlation. Otolaryngol Head Neck Surg. 1996;114:586–592, with permission.)

Possibly, the most convincing evidence for a viral cause of these auditory and vestibular syndromes comes from the temporal bone studies of Schuknecht and colleagues.46,52,55 These and other investigators have reported pathologic evidence for isolated viral involvement of the cochlea and auditory nerve in patients with sudden deafness and of the vestibular end organs and vestibular nerve in patients with isolated sudden vertigo (Fig. 9–5).56,57 The atrophy of the nerves and end organs is identical to that associated with well-documented viral disorders (such as mumps or measles).58 In all of these cases the vasculature was intact; there was no evidence of a vascular cause for the sudden deafness or vertigo.

Clinical Syndromes

HERPES ZOSTER OTICUS

A clear example of a viral syndrome involving the eighth nerve is herpes zoster oticus (also known as the Ramsay Hunt syndrome).59 Presumably, the zoster virus remains dormant in the ganglia associated with the seventh and eighth nerves and is reactivated during a period of lowered immunity. The patient initially develops a deep burning pain in the ear followed a few days later by vesicular eruption in the external auditory canal and concha. At some time after the onset of pain, either before or after the vesicular eruption, the patient may develop hearing loss, vertigo, and

facial weakness. About half have cochleoves- tibular symptoms and facial paralysis and half have just facial paralysis.60 The pathologic ﬁnd- ings in patients with herpes zoster oticus con- sist of perivascular, perineural, and intraneural round cell inﬁltration in the seventh nerve and in both divisions of the eighth nerve.61

VESTIBULAR NEURITIS

Vestibular neuritis is typically manifested by the gradual onset of vertigo, nausea, and vomit- ing over several hours.62 Occasionally patients have prodromal dizzy spells for a day or so before onset.63 The symptoms usually reach a peak within 24 hr and then gradually resolve over several weeks. During the ﬁrst day there is severe truncal unsteadiness and imbalance to the point that falling toward the affected side when trying to walk is common.64 Patients also often report difﬁculty focusing because of the spontaneous nystagmus. In most patients the course is self-limited with complete func- tional recovery within 3 months.65 There are important exceptions to this rule, however. Occasionally patients—particularly the elderly—will have intractable dizziness that persists for years.66 Recurrences are relatively rare.67 A small percentage of these patients will have multiple recurrent episodes of vertigo leading to a profound bilateral vestibulopathy (so-called bilateral sequential vestibular neuri- tis).68 The episodic vertigo is eventually replaced by persistent disequilibrium and oscillopsia.

Experimental studies in animals have shown that several viruses will selectively infect the vestibularnerveandlabyrinth.54,69 Furthermore, differential susceptibility to viral infection and antigen expression has been observed in differ- ent cell types within the inner ear.70 Herpes simplex virus type 1 (HSV-1) can produce selective involvement of the vestibular nerve and labyrinth when inoculated into the ear of a guinea pig.69 The HSV is a DNA-containing virus that establishes a latent infection in neu- rons by incorporating part of its DNA into the nucleus of the neuron. Although the molecular mechanisms involved in the establishment and maintenance of latency and reactivation from the latent state are only partially understood, part of the HSV genome, called LAT for latency-associated transcript, can be identiﬁed in latently infected cells using molecular

hybridization methods. Presumably, LAT codes for a protein that blocks the replication cycle of the latent virus at some early point so that the infected cells are not damaged and are able to maintain the latent state. Since reactiva- tion of a latent HSV-1 infection in the genicu- late ganglion is thought to be a common cause of Bell’s palsy,71 reactivation of a latent HSV-1 infection in Scarpa’s ganglia might be the cause of vestibular neuritis. HSV-1 has been identi- ﬁed in Scarpa’s ganglia72,73and in the vestibular labyrinth74 of autopsied adults without a prior history of vertigo, but there is still no conclu- sive proof that reactivation of latent HSV-1 virus is the cause of vestibular neuritis.

A unique feature with most cases of vestibu- lar neuritis is selective damage to the superior part of the vestibular labyrinth with sparing of the inferior part. Since the posterior semicircu- lar canal remains functional, patients often develop benign paroxysmal positional vertigo as a sequela even though they have no remain- ing horizontal or anterior semicircular canal function. Rotational studies with measurement of three-dimensional eye movements in patients with vestibular neuritis indicates that the posterior semicircular canal is typically spared even though anterior and horizontal semicircular canal function is absent.75,76 How the presumed viral etiology can lead to selec- tive involvement of the superior vestibular labyrinth is unknown. There is an anastamosis between the facial nerve and the superior ves- tibular nerve, but HSV-1 is found equally in the superior and inferior vestibular ganglia.77 A few cases have been reported in which selec- tive involvement of the inferior division of the vestibular nerve appeared to be the cause.73,78,79 In these cases, the caloric responses were normal (indicating normal horizontal canal function, and thus intact superior vestibular nerve) but the VEMP response—a method to measure the function of the saccule and thus inferior vestibular nerve—was abnormal, or an impulse test in the plane of the posterior canal was abnormal.76,78,79 The clinical presentation of inferior vestibular neuritis remains ill- deﬁned, however. Though one would expect a spontaneous downbeating and torsional nys- tagmus in the acute phase, none of the reports claiming a diagnosis of inferior vestibular neuritis describe this pattern of nystagmus.76,78,79 In fact, most reported cases of inferior vestibular

neuritis report no nystagmus at all, even in the acute phase and even after provocative tests.76,78,79 In addition, some of the cases reported are very nonspeciﬁc presentations rather than the typical sudden and constant acute vestibular syndrome presentation.78

SUDDEN SENSORINEURAL HEARING LOSS (SUDDEN DEAFNESS)

Although the term sudden deafness is com- monly used, the hearing loss due to viral infec- tion usually comes on over several hours and may even extend over several days.46,80 The loss is usually unilateral, often profound, and may be permanent, although it reverses at least par- tially in most cases. It returns to normal in more than 50% of patients (with or without treatment).81 Prognosis is best when the hear- ing loss is mild and begins to recover within 2 weeks. Severe hearing loss (>90 dB), advanced age, and presence of vertigo are poor prognos- tic factors. Tinnitus and fullness in the involved ear are common.82

As with vestibular neuritis a viral cause is likely with most cases of sudden deafness, although it is rare that a viral cause can be proven in an individual case.83 Several viruses will selectively infect the cochlea and spiral ganglia in animal models.84,85 Latent HSV1 has been identiﬁed in the spiral ganglia of autop- sied adults without a history of hearing loss85 so like vestibular neuritis reactivation of a latent herpes infection may be a cause of sudden deafness.

Diagnosis

The diagnosis of Herpes zoster oticus rests on ﬁnding the characteristic cutaneous eruptions about the auricle and external ear canal. A spe- ciﬁc diagnosis can be made using either direct ﬂuorescent antigen assay (DFA) or polymerase chain reaction (PCR). For DFA testing, a vesi- cle should be unroofed and then the base of the lesion rubbed with a cotton-tipped swab. The swab is then rubbed on a glass slide and sent for DFA testing.86 For PCR testing, either vesicular ﬂuid can be collected or material from the swab can be used.87,88 PCR can also be performed using saliva, CSF, or crusts or

skin scrapings from maculopapular lesions. Although the herpetic external otitis is self- limiting, the seventh and eighth nerve damage is often profound and nonreversible. An MRI with contrast will often show diffuse enhance- ment of the seventh and eighth cranial nerves.89,90

The diagnosis of vestibular neuritis or sud- den deafness rests on ﬁnding the characteristic clinical presentation and audio-vestibular sys- tem examination ﬁndings in the absence of neurologic symptoms and signs (See Video 6–2, Video 6–3, Video 6–4, Video 6–5, and Video 6–6). Routine otologic examination is usually unremarkable, and CT scanning of the tempo- ral bone reveals only a normal-appearing bony labyrinth. Occasionally, the eighth nerve or membranous labyrinth will be enhanced after contrast on MRI, but this only indicates inﬂam- mation of unknown cause. Serologic studies can demonstrate that a virus infected the patient, but they do not prove that the infec- tious agent caused the inner ear damage. Furthermore, isolation of an infectious agent from the nasopharynx or other tissue other than the membranous labyrinth does not prove a causal relationship between the virus and the inner ear disease. Although a few viruses have been cultured directly from perilymph samples in infected ears, this is not a practical method for routine diagnosis of viral infections of the inner ear.54

Vestibular neuritis presents with signs of both canal and otolith dysfunction.91,92 Nearly all have a unilateral caloric paresis, a positive head-thrust sign, and tilt of the subjective visual vertical. Between 30% to 50% have a decreased vestibular evoked myogenic potential (VEMP) on presentation. Otolith-related test abnormal- ities improve more rapidly than canal-related abnormalities, and patients with a persistently positive head-thrust sign at follow-up are more likely to continue to complain of dizziness than patients in whom the head-thrust sign returns to normal.92 Patients with vestibular neuritis may have hearing loss in the ultrahigh- frequency range, which suggests that the audi- tory end organ may be involved to a minor degree even though it is clinically silent.93,94 With sudden deafness the hearing loss tends to be most prominent in the high frequencies, a ﬁnding consistent with neuropathologic studies demonstrating the greatest degree of damage

in the basilar turn of the cochlea.80 Brainstem auditory-evoked (BAER) studies are usually normal, consistent with a cochlear site of pathology. Vestibular abnormalities have been identiﬁed on electronystagmography (ENG) in patients with sudden deafness but without associated vestibular symptoms.95

Viral versus Other Causes of Peripheral Cochleovestibular Loss

Viral infections of the inner ear must be dif- ferentiated from other forms of labyrinthitis (bacterial and syphilitic) and from acute laby- rinthine ischemia and from perilymph ﬁstula (Table 9–2). As noted earlier, bacterial labyrin- thitis is typically associated with acute and chronic otomastoiditis, which should be easily identiﬁed on examination of the ear and with CT of the temporal bone, or meningitis. Suppurative labyrinthitis invariably results in a fulminate profound loss of both auditory and vestibular function, usually with only

minimal recovery. Serous labyrinthitis may produce only a high-frequency sensorineural hearing loss if the toxic products remain con- ﬁned to the basilar region of the cochlea. Syphilitic labyrinthitis might initially be con- fused with viral neurolabyrinthitis, but the for- mer leads to recurrent episodes of vertigo and hearing loss, usually progressing to severe bilat- eral dysfunction over a period of months. Unlike the gradual onset of symptoms over hours with viral syndromes, infarction of the labyrinth results in a sudden profound loss of auditory and vestibular function—often in a setting of prior episodes of transient ischemia within the vertebrobasilar system (see Chapter 14). Infarction of the labyrinth, lateral brain stem, or cerebellum should be considered a potential cause in patients who present with acute onset vertigo and imbalance. The proba- bility of having a vascular etiology drops sub- stantially when the symptoms are isolated audio-vestibular symptoms,96 and it becomes remarkably low when the key examination fea- tures also suggest a peripheral etiology.64

Table 9–2 Differential Diagnosis of Acute Peripheral Vestibulopathy

History Examination Laboratory

Viral

neurolaby- rinthitis

Bacterial labyrinthitis

Syphilitic labyrinthitis

Labyrinthine ischemia

Perilymph ﬁstula

Developing over hours, resolving over days, prior ﬂu-like illness

Abrupt onset, associated hearing loss, prior ear infections

Recurrent episodes, associated tinnitus and hearing loss, prior congenital or acquired syphilis

Abrupt onset, usually associated neurologic symptoms, prior vascular disease

Abrupt onset associated with head trauma, barotrauma, or sudden strain during heavy lifting, coughing, or sneezing; chronic otomastoiditis with cholesteatoma

Normal except for signs of acute unilateral vestibular loss

Signs of otitis media or meningitis

May be stigmata of congenital syphilis, rarely associated signs of neurosyphilis

May be signs of brain stem or cerebellar infarction

Positive ﬁstula test, may be chronic otitis with tympanic membrane perforation

ENG: caloric hypoexcitability Audio: may show ultrahigh-

frequency loss

ENG: absent caloric response Audio: profound sensorineural

hearing loss CSF: pleocytosis

ENG: caloric hypoexcitability Audio: low-frequency loss Serology: positive FTA-ABS CSF: usually normal

ENG: absent caloric response Audio: profound sensorineural

hearing loss

Neuroimaging: may show brain infarction

ENG: caloric hypoexcitability Audio: usually sensorineural loss CT of temporal bone may show

erosion from cholesteatoma

CSF, cerebrospinal ﬂuid; CT, computed tomography; ENG, electronystagmography; FTA-ABS, ﬂuorescent treponemal antibody absorption (test).

The key examination features that suggest a vestibular nerve localization include a unidirec- tional spontaneous nystagmus and a correspond- ing positive head-thrust test. Red ﬂags that raise the suspicion for a vascular etiology include any other neurologic symptoms or signs, severe truncal ataxia (unable to sit unassisted), and a clinical history indicating high risk for stroke.64

Like viral infections of the inner ear, peri- lymph ﬁstulae can present with hearing loss, vertigo, or a combination of auditory and ves- tibular symptoms. With the latter, however, the onset is usually abrupt, and there is nearly always a precipitating event, such as head trauma, barotrauma, or a sudden strain during heavy lifting, coughing, or sneezing. Perilymph ﬁstulae are particularly common in patients who have undergone stapedectomy for otoscle- rosis. Most perilymph ﬁstulae are self-limited, so it is presumed that the ﬁstulae heal. Indications for exploratory surgery include ongoing symptoms suspicious for a perilymph ﬁstulae (episodes induced by coughing or sneezing) and/or a positive ﬁstula test (see Chapter 16).

Management

During the acute stages of herpes zoster oticus, warm, moist compresses applied locally can provide symptomatic relief, although often sys- temic analgesics are required. Based on treat- ment of zoster infections in other parts of the body a combination of high-dose corticoster- oids (e.g., prednisione 60 mg/d with taper over 10–14 days) and antiviral drugs (e.g., valacycol- vir 1 g three times a day for 7–10 days) are typically used for treatment.97 However, there remains uncertainty because of a lack of ade- quate trials98 in Ramsay Hunt syndrome and also because the beneﬁcial effects of corticos- teroids and antivirals in the most common her- pes zoster disorder (i.e., shingles) is the time to pain recovery and time to skin lesion healing, without evidence of a beneﬁcial long-term out- come.97 In Ramsay Hunt syndrome the most important outcomes are facial nerve recovery and recovery of audio-vestibular function.

The management of patients who present with an isolated episode of auditory and vestibu- lar loss is controversial because the pathophysi- ology is often uncertain. As suggested earlier, unless there is convincing evidence to suspect a

vascular or nonviral infectious cause, the patient’s symptoms should be managed as a pre- sumed viral neurolabyrinthitis. Symptomatic treatment with antivertiginous and antiemetic medications are useful to treat acute vertigo with nausea and vomiting (see Chapter 19). Vestibular physical therapy is appropriate for patients with acute vestibular neuritis, though most of the randomized trials of vestibular phys- ical therapy were conducted in patients with surgical lesions or groups of mixed or vaguely stated etiologies99 (see Chapter 20). Steroids have been recommended for their anti- inﬂammatory effect based on a few controlled studies.100–104 One large randomized placebo- controlled trial of oral corticosteroids and valcy- clovir (2 by 2 factorial design) found that on average patients treated with corticosteroids within 3 days of onset had a superior improve- ment in vestibular recovery as measured by the surrogate outcome of caloric response at 12 months compared to placebo.102 Valcyclovir did not demonstrate an average beneﬁcial effect. However, it is not known if corticosteroids improve functional outcome since functional outcome was not assessed in this trial and many patients with a chronic caloric asymmetry are asymptomatic. High doses of prednisone or methylprednisone are given for 3 days to a week and then rapidly tapered. A course of corticoste- riods is also generally recommended for patients with sudden deafness though adequate trials are lacking.105,106 Interest has increased in the use of intratympanic (IT) corticosteroids injection in sudden sensorineural hearing loss, particularly when used as a “salvage” therapy following failed oral treatment,107,108 but large and rigorous trials are still necessary to establish the effect. Numerous so-called vasodilating regimens have been proposed, but they would have little effect on the presumed viral pathophysiology. Although many patients with vestibular neuritis are left with a permanent loss of vestibular function (as documented by serial caloric examinations), the CNS is able to adapt to the vestibular loss, and residual symptoms are usually minimal once the compensation has occurred (see Chapter 20).

Although antiviral agents such as cytosine arabinase and acyclovir have been used for treating systemic viral illnesses in children, it is unclear whether the hearing loss that is often associated with disorders such as cytomegalovi- rus and rubella infections is altered by such treatment.55

SYPHILITIC INFECTIONS OF THE EAR ‌‌

Involvement of the eighth nerve and/or laby- rinth can be an early or late manifestation of both congenital and acquired syphilis. About one in three patients with congenital syphilis develops otologic manifestations. Although the number of new cases of congenital syphilis pro- gressively declined from 1930 to 1968, the inci- dence of new cases appears to have stabilized since 1968. From 1981 through 1989, the over- all incidence of syphilis in the United States increased by 34%.109 More recently the inci- dence of syphilis is again on the rise due to widespread human immunodeﬁciency virus (HIV) infections.110 Syphilitic infections pro- duce auditory and vestibular symptoms by two different pathophysiologic mechanisms: (1) meningitis with involvement of the eighth nerve and (2) osteitis of the temporal bone with associated labyrinthitis.111,112 The former typi- cally occurs as an early manifestation of acquired syphilis, whereas the latter occurs as a late manifestation of both congenital and acquired syphilis. With early congenital syphi- lis there may be a lymphocytic inﬁltration of both the membranous labyrinth and eighth nerve, leading to profound bilateral deafness. Spirochetes have been demonstrated in tem- poral bones obtained at autopsy in such patients. With early acquired syphilis, the pre- dominant pathologic ﬁnding is basilar meningi- tis affecting the eighth nerve, particularly the auditory branch. The hearing loss typically occurs with the rash and lymphadenopathy of secondary syphilis. It is usually abrupt in onset, tends to be bilateral, and is rapidly progressive. Vestibular symptoms are often absent. Patients demonstrate symptoms and signs of meningi- tis, including headache, stiff neck, cranial nerve palsies, and optic neuritis. With late syphilis most patients have a combination of hearing loss, tinnitus, and vertigo.113

Both congenital and acquired syphilitic infec- tions produce temporal bone osteitis and laby- rinthitis as a late manifestation. The congenital variety is approximately three times as common as the acquired variety.114 The time of onset of congenital syphilitic labyrinthitis is anywhere from the ﬁrst to seventh decades, with the peak incidence in the fourth and ﬁlth decades, whereas acquired syphilitic labyrinthitis rarely occurs before the fourth decade and has a peak

incidence in the ﬁfth and sixth decades. The congenital variety is often associated with other stigmata of congenital syphilis, such as intersti- tial keratitis, Hutchinson’s teeth, saddle nose, frontal bossing, and rhagades. Of these associ- ated signs, interstitial keratitis is by far the most common, occurring in approximately 90% of patients.114 Pathologic changes in the labyrinth are similar in the congenital and acquired vari- ety, consisting of inﬂammatory inﬁltration of the membranous labyrinth and osteitis of all three layers of the otic capsule.19 A combination of hydrops of the membranous labyrinth and atrophy of the cochlear and vestibular end organs resembles the pathologic ﬁndings in idiopathic Meniere’s syndrome.

The natural history of syphilitic labyrinthitis is a slow, relentless progression to profound or total bilateral loss of vestibular and auditory function.115,116 This progression is marked by episodes of sudden deafness and vertigo and ﬂuctuation in the magnitude of hearing loss and tinnitus.

Diagnosis

Infants with congenital syphilis exhibit a pro- found bilateral sensorineural hearing loss along with extensive damage to multiple organs (Table 9–3). The hearing loss associated with early acquired syphilis may be the only mani- festation of a basilar meningitis, or it may be associated with headaches, stiff neck, and mul- tiple neurologic ﬁndings. The rash of second- ary syphilis may precede or accompany the onset of hearing loss. A CSF examination is invariably abnormal with a pleocytosis and ele- vated protein.112 The CSF venereal disease research laboratory (VDRL) test may or may not be positive.

The diagnosis of syphilitic labyrinthitis as a late manifestation of either congenital or acquired syphilis is based on the ﬁnding of a positive serum ﬂuorescent treponemal anti- body absorption (FTA-ABS) test in a patient with the typical clinical history of ﬂuctuating hearing loss and vertigo (see Table 9–3).117 The serum VDRL is positive in only about 75% of cases, making it an unreliable test for syphilitic labyrinthitis.114 As noted earlier, patients with congenital syphilitic labyrinthitis often have associated stigmata of congenital syphilis, whereas patients with the acquired variety may

Table 9–3 Differential Features of Different Otologic Manifestations of Syphilis

EARLY LATE

Congenital Acquired Congenital Acquired

Pathophysiology Inﬂammation of

membranous labyrinth and eighth nerve

Meningitis with involvement of eighth nerve

Temporal bone osteitis and petrositis with secondary degeneration of membranous labyrinth leading to endolymphatic hydrops

Hearing loss Congenital deafness Abrupt onset,

bilateral, progressive

Begins unilateral, ﬂuctuating, progresses to bilateral over months; associated tinnitus and ear pressure

Vertigo No Infrequent Episodic (hours) with ﬂuctuating hearing loss

Age of peak incidence

At birth 20–30 years 30–50 years 40–60 years

Associated features ‌

Infection involving multiple organs

Rash of

secondary syphilis

Interstitial keratitis, other stigmata of congenital syphilis

Other

features of tertiary syphilis

Cerebrospinal ﬂuid

Usually abnormal (pleocytosis, elevated protein, VDRL ±)

Usually normal Usually normal

Treatment IV aqueous penicillin, 20 million U/day ×

2 weeks

IM benzathine penicillin, 2.4 million U, weekly × 3 months; prednisone 30–60 mg qod, 3–6 months, slow tapering

IM, intramuscular; IV, intravenous; VDRL, venereal disease research laboratory (test).

have other clinical symptoms and signs of ter- tiary syphilis. The CSF examination is usually normal in both the congenital and acquired varieties of syphilitic labyrinthitis.113

Management

Penicillin is still the treatment of choice for the otologic manifestations of syphilis, although the optimal regimen for each variety remains uncertain.116 Because CSF infection accompa- nies the early manifestations of both congenital and acquired syphilis, high-dose intravenous penicillin seems appropriate. Prognosis follow- ing treatment is poor in the early congenital form, but it is excellent in the early acquired variety. Complete recovery of both hearing and vestibular function usually occurs with the latter.112

For the late manifestations of both congeni- tal and acquired syphilitic labyrinthitis, the combination of steroids and penicillin appears to be superior to penicillin alone.115,116 Numerous penicillin regimens have been used, with the most popular being benzathine penicillin

(2.4 million units) given weekly for 6 weeks to 3 months. Along with the penicillin, predni- sone, beginning at a dose of 60 mg/day on an alternate day regimen, is given for 3 months, followed by a slow tapering. If symptoms recur during the tapering, a more long-term mainte- nance dosage of prednisone may be required. Most patients can be expected to stabilize or improve on this therapeutic regimen.115

TUBERCULOSIS AND MYCOTIC INFECTIONS OF THE INNER EAR

Tuberculous Mastoiditis

The tuberculosis pandemic along with the development of resistant strains has become a global public health problem.118 Tuberculous mastoiditis accompanies both pulmonary and nonpulmonary infections, presumably because of hematogenous spread. In contrast to bacte- rial infections, tuberculosis of the temporal bone runs an indolent course and usually pro- duces little pain.119 The classical presentation is

multiple perforations of the tympanic mem- brane, ear discharge, and progressive hearing loss. The foul-smelling otorrhea, when cul- tured, typically shows nonspeciﬁc mixed organ- isms. It may mimic chronic otomastoiditis with cholesteatoma formation because there is often tympanic membrane perforation and promi- nent granulomatous tissue. A CT scan of the temporal bone shows an irregular, punched- out lesion resembling a cholesteatoma. Tuberculosis mastoiditis can usually be differ- entiated from bacterial mastoiditis by the pres- ence of soft tissue in the entire middle ear cavity, preservation of mastoid air cells without sclerosis, and soft tissue extension or mucosal thickening in the external ear canal.120 Diagnosis rests on culturing tuberculosis from the otorrhea or by histologic examination of the mastoid granulomatous tissue. Management consists of antituberculous drugs and surgical eradication of the lesion.

Mycotic Mastoiditis

characteristic CSF proﬁle of lymphocytic pleocytosis, elevated protein, and decreased glucose. Often, there are associated systemic symptoms and signs, including multiple pulmonary lesions. Mycobacterium tuberculosis may be seen on acid-fast smears and cultured from the CSF. The diagnosis of fungal menin- gitis relies on identifying the appropriate anti- gen in the CSF.

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O. Enteroviruses and sudden deafness. CMAJ. 2003;168(11):1421.
Nomura Y, Hara M, Kurata T Experimental herpes simplex virus and cytomegalovirus labyrinthitis. Acta Otolaryngol Suppl (Stockh). 1989;457:57.
Fukuda S, Furuta Y, Takasu T, et al. The signiﬁcance of herpes viral latency in the spiral ganglia. Acta Otolaryngol Suppl (Stockh). 1994;514:108.
Dahl H, Marcoccia J, Linde A. Antigen detection: the method of choice in comparison with virus isolation and serology for laboratory diangnosis of herpes zoster in human immunodeﬁciency virus-infected patients. J Clin Microbiol. 1997; 35:347.
Vazquez M, LaRussa PS, Gershon AA, et al. The effec- tiveness of the varicella vaccine in clinical practice. N Engl J Med. 2001;344:955.
Harbecke R, Oxman NM, Arnold BA, et al. A real time PCR assay to identify and discriminate among wild type and vaccine strains of varicella-zoster virus and herpes simplex virus in clinical specimen, and comparison with the clinical diagnosis. J Med Virol. 2009;81:1310.
Kuo MJ, Drago PC, Proops DW, Chavda SV. Early diagnosis and treatment of Ramsay Hunt syndrome: the role of magnetic resonance imaging. J Laryngol Otol. 1995;109:777.
Berretini S, Bianchi MC, Segnini G, et al. Herpes zoster oticus: correlations between clinical and MRI ﬁndings. Eur Neurol. 1998;39:26.
Faralli M, Molini E, Ricci G, et al. Study of vestibu- lar evoked myogenic potentials in unilateral vestibu- lopathy: Otolithic versus canal function testing. Otol Neurotol. 2006;27(8):1115.
Kim HA, Hong JH, Lee H, et al. Otolith dysfunction in vestibular neuritis: recovery pattern and a predictor of symptom recovery. Neurology. 2008;70(6):449.
Bergenius J, Borg E, Audio-vestibular ﬁndings in patients with vestibular neuronitis. Acta Otolaryngol (Stockh). 1983;906:389.
Rahko T, Karma P. New clinical ﬁnding in vestibular neuritis: high frequency audiometry hearing loss in the affected ear. Laryngoscope. 1986;96:198.
Wilson WR, Laird N, Kavesh DA. Electronystagmographic ﬁndings in idiopathic sud- den hearing loss. Am J Otolaryngol. 1982;3:279.
Kerber KA, Brown DL, Lisabeth LD, Smith MA, Morgenstern LB. Stroke among patients with diz- ziness, vertigo, and imbalance in the emergency department: a population-based study. Stroke. 2006;37:2484.
Whitley RJ. A 70 year old woman with shingles: review of herpes zoster. JAMA. 2009;309:73.
Uscategui T. Doree C, Chamberlain IJ, Burton MJ. Antiviral therapy for Ramsay Hunt syndrome in adults. Cochrane Database Sys Rev. 2008:CD006851.
Strupp M, Arbusow V, Maag KP, Gall C, Brandt T. Vestibular exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology. 1998;51:838.
Wilson W, Byl FM, Laird N. The efﬁcacy of steroids in the treatment of idiopathic sudden hearing loss: a double-blind clinical study. Arch Otolaryngol. 1980;106:772.
Ariyasu L, Byl FM, Sprague MS, Adour KK. The beneﬁcial effect of methylprednisone in acute ves- tibular vertigo. Arch Otolaryngol Head Neck Surg. 1990;116:700.
Strupp M, Zingler VC, Arbusow V, et al. Methylprednisolone, valacyclovir, or the com- bination for vestibular neuritis. N Engl J Med. 2004;351(4):354.
Shupak A, Issa A, Golz A, Margalit Kaminer, Braverman I. Prednisone treatment for vestibular neuritis. Otol Neurotol. 2008;29(3):368.
Walker MF. Treatment of vestibular neuritis. Curr Treat Options Neurol. 2009;11(1):41.
Rauch SD. Clinical practice. Idiopathic sudden sen- sorineural hearing loss. N Engl J Med. 2008;359: 833.
Wei BP, Mubiru S, O’Leary S. Steroids for idio- pathic sudden sensorineural hearing loss. Cochrane Database Sys Rev. 2006:CD003998.
Plontke SK, Lowenheim H, Mertens J, et al. Randomized, double blind, placebo controlled trial on the safety and efﬁcacy of continuous intratym- panic dexamethasone delivered via a round window catheter for severe to profound sudden idiopathic sensorineural hearing loss after failure of systemic therapy. Laryngoscope. 2009;119(2):359.
Ho HG, Lin HC, Shu MT, Yang CC, Tsai HT. Effectiveness of intratympanic dexamethasone injection
in sudden-deafness patients as salvage treatment.
Laryngoscope. 2004;114:1184.
Rolfs RT, Nakashima AK. Epidemiology of primary and secondary syphilis in the United States, 1981 though 1989. JAMA. 1990;264:1432.
Mishra S, Walmsley SL, Loutfy MR, Kaul R, Logue KJ, Gold WL. Otosyphilis in HIV-coinfected indi- viduals: a case series from Toronto, Canada. AIDS Patient Care STDS. 2008;22(3):213.
Karmody C, Schuknecht H. Deafness in congenital syphilis. Arch Otolaryngol. 1966;83:18.
Saltiel P, Melmed CA, Portnoy D. Sensorineural deafness in early acquired syphilis. Can J Neurol Sci. 1983;10:114.
Yimtae K, Srirompotong S, Lertsukprasert K. Otosyphilis: a review of 85 cases. Otolaryngol Head Neck Surg. 2007;136(1):67.
Morrison AW. Management of Sensorineural Deafness. Boston: Butterworh; 1975.
Steckelberg JM, McDonald TJ. Otologic involvement in late syphilis. Laryngoscope. 1984;94:753.
Amenta CA, III, Dayal VS, Flaherty J, Weil RJ. Luetic endolymphatic hydrops: diagnosis and treatment. Am J Otol. 1992;13:516.
Hughes GB, Rutherford I. Predictive value of sero- logic tests for syphilis in otology. Ann Otol Rhinol Laryngol. 1986;95:250.
Nicolau Y, Northrop C, Eavey R. Tuberculous otitis in infants: temporal bone histopathology and clinical extrapolation. Otol Neurotol. 2006;27(5):667.
Jeanes A, Friedmann I. Tuberculosis of the middle ear. Tubercle, J Br Tuber Assoc. 1960;41:109.
Rho MH, Kim DW, Kim SS, Sung YS, Kwon JS, Lee SW. Tuberculous otomastoiditis on high-resolution temporal bone CT: comparison with nontuberculous otomastoiditis with and without cholesteatoma. AJNR Am J Neuroradiol. 2007;28(3):493.
Olalla I, Ortin M, Hermida G, et al. Autologous peripheral blood stem cell transplantation in a patient with previous invasive middle ear mucomycosis. Bone Marrow Transpl. 1996;18:1183.
Slack CL, Watson DW, Abzug MJ, Shaw C, Chan KH. Fungal mastoiditis in immunocompromised children. Arch Otolaryngol Head Neck Surg. 1999;125(1): 73.
Yaramis A, Girkan F, Elevli M, et al. Central nervous system tuberculosis in children: a review of 214 cases. Pediatrics. 1998;102:E49.

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Chapter 10 ‌‌

Benign Positional Vertigo

HISTORICAL BACKGROUND CAUSES OF BENIGN POSITIONAL

VERTIGO ‌

POSTERIOR CANAL VARIANT OF BENIGN POSITIONAL VERTIGO

Clinical Features Pathophysiology

Diagnosis Management

OTHER VARIANTS OF BENIGN POSITIONAL VERTIGO

Horizontal Canal Benign Positional Vertigo Anterior Canal Benign Positional Vertigo Mimics of Benign Positional Vertigo

Benign positional vertigo (BPV), also called benign positioning vertigo and benign paroxys- mal positional vertigo, is a common inner ear disorder resulting from abnormal stimulation of the semicircular canals (usually the poste- rior). The direction of the provocative move- ment and the appearance of the induced eye movements (nystagmus) identify the involved canal(s). The abnormal stimulation is due to the presence of detached otoconia (canaliths) moving in the canal endolymph under the inﬂuence of gravity. In order for positional ver- tigo to occur, two events must happen: (1) oto- conia must be dislodged from the utricular macule, and (2) the head must be held in a critical position that allows the otoconia to enter a semicircular canal. BPV is not a disease; rather, it is a syndrome that can have multiple causes of the detached otoconia.

HISTORICAL BACKGROUND

The basic features of BPV and the associated paroxysmal positional nystagmus were ﬁrst described in a single patient by Bárány in 1921,1 but it was not until 1952 that Dix and Hallpike described the provocative positioning

maneuver and clearly deﬁned the clinical syndrome.2 Bárány speculated that the parox- ysmal positional nystagmus was caused by a lesion of the otolith organs, as it was induced by a change in head position relative to gravity. Dix and Hallpike came to a similar conclusion after reviewing the clinical features of 100 patients with BPV and identifying unilateral degeneration of the utricular macule at necropsy in a typical case.

In 1961, Schuknecht reviewed the temporal bone specimens from three patients who had been reported to have BPV and was struck by the remarkable similarity of the pathologic changes.3 Each had a selective degeneration of the superior part of the labyrinth, including the superior branch of the vestibular nerve, the utricle, and the crista of the horizontal and anterior semicircular canals. He concluded that in each case the damage to the labyrinth resulted from occlusion of the anterior vestibu- lar artery, the branch of the internal auditory artery that supplies these organs. Schuknecht felt that the paroxysmal positional nystagmus that occurred in these cases must have origi- nated from the posterior semicircular canal since it was the only peripheral sensory organ capable of generating nystagmus that was still functioning. He did not feel that the intact

255

saccular macule was capable of generating nystagmus.

With this hypothesis in mind, Schuknecht attempted to produce paroxysmal positional nystagmus in four cats by cutting off the blood supply in the left anterior vestibular artery.3 Each animal developed the expected acute vestibular syndrome with horizontal nystagmus and imbalance in the immediate postoperative period. These symptoms gradually subsided over several days. One of the animals, however, developed typical benign paroxysmal positional nystagmus 3 months after the operation, which persisted until termination of the experiments at 7 months. Schuknecht theorized that loose otoconia from the degenerating utricular mac- ule came in contact with the cupula of the pos- terior semicircular canal, causing it to move in the plane of the canal after position changes.

In 1969, Schuknecht found basophilic depos- its on the cupulae of the posterior semicircular canals in two patients who manifested isolated BPV without any other ear symptoms prior to death from unrelated disease (Fig. 10–1).4 The deposits were present on the side that was undermost when the paroxysmal positional nystagmus was induced. These ﬁndings sup- ported his earlier hypothesis and, even though he observed particles in the canal in addition to those attached to the cupula, he coined the term cupulolithiasis.

The cupulolithiasis theory of Schuknecht gained general acceptance, but there were fea- tures of the characteristic paroxysmal positional nystagmusthatwerenotadequatelyexplained— the transient duration and the fatigability with repeated positioning. If the particles are adherent to the cupula, transient duration and

A Deposit

on cupula

Normal cupula

Left

Superior division

Saccule

Inferior division

Macule of the utricle

Right

Deposit on the cupula of the posterior semicircular canal

Figure 10–1. Basophilic deposits on the cupula in benign positional vertigo. A Histopathological section through the crista of the posterior semicircular canals of a patient who exhibited typical benign paroxysmal positional nystagmus in the head- hanging left position prior to death from unrelated causes. Attached to the cupula is a granular, basophilic staining deposit. B Drawing illustrating relationship between the macule of the utricle and the ampulla of the posterior semicircular canal when the head is erect. (From Schuknecht HF. Pathology of the Ear. Harvard University Press, Cambridge, 1993, with permission.)

fatigability would not be expected. In his initial report,3 Schuknecht suggested that the otoco- nial debris might dislodge from the cupula and ﬂoat away, allowing the cupula to return to its normal position, and that the particles might become dispersed within the endolymph with repeated positionings. However, when his sub- sequent postmortem studies showed that the otolithic debris was ﬁrmly attached to the cup- ula of the posterior semicircular canal, he felt that these possibilities were less likely.4‌‌

In the late 1970s, McClure began to experi- ment with mechanical models of the inner ear to see if these problems could be resolved. His simple model consisted of a water bottle repre- senting the utricular chamber and two attached rounded tubes representing the posterior and anterior semicircular canals. He placed mer- cury in the canals to represent the otoconial debris and noted that repeated positional changes from sitting to head-hanging position caused the mercury to enter the utricle. He recognized that freely ﬂoating debris in the posterior semicircular canal could readily explain both the paroxysmal nature of the nys- tagmus and the fatigability. In 1979, along with Hall and Ruby5, McClure published his model and suggested that benign paroxysmal posi- tional nystagmus could be divided into two types: type A, a nonfatigable form caused by debris adherent to the cupula (i.e., cupulo- lithiasis), and type B, a more common fatigable form caused by free-ﬂoating particles in the endolymph, canalithiasis. This work served as the theoretical basis for the subsequent use of positional exercises and positional maneuvers to treat BPV.

Epley did not distinguish between cupulo- lithiasis and canalithiasis but rather suggested that debris was both attached to the cupula and free ﬂoating in the canal in most cases of BPV.6 He recognized that debris moving within the narrow semicircular canal would be much more effective in deviating the cupula than an equal amount of debris ﬂoating within the ampulla next to the cupula. He saw the analogy of the bolus of particles acting as a piston mov- ing within the narrow conﬁnes of the semicir- cular canal, which, according to Pascal’s formula, would lead to a magniﬁed force acting on the cupula. Epley argued that if this bolus of debris could move so easily with position change, it should be possible to move it around and out of the posterior semicircular canal and

into the utricle with appropriate positional changes. In a case series report in 1992, he reported that a simple particle repositioning maneuver cured most patients with BPV.7 Later, randomized placebo-controlled (sham positional maneuvers) trials conﬁrmed the treatment effect of what has become known as the Epley maneuver.8

At about the same time of Epley’s original reports, Parnes and McClure described a sur- gical procedure for blocking the posterior semicircular canal with a bony plug that was highly effective in curing intractable cases of BPV.9 During the process of exposing the membranous labyrinth of the posterior semicircular canal for the plugging operation, Parnes and McClure observed a chalky white substance within the endolymph of the posterior semicircular canal. Their obser- vation supported the canalithiasis model pro- posed by Hall et al.5 and was consistent with the success of Epley’s particle repositioning maneuver.

CAUSES OF BENIGN POSITIONAL VERTIGO

The ﬁrst event that must happen for BPV to occur is that otoconia must be free ﬂoating in the utricule. However, in most cases, there is no easily explainable reason for why the otoco- nia are released. The attacks of positionally triggered vertigo are not typically preceded by a speciﬁc event. However, the prevalence of the disorder dramatically increases with increasing age so that release of the otoconia could be an effect of the aging process. Osteopenia and osteoporosis are also more common in patients with idiopathic BPV than in controls, suggesting that abnormal calcium metabolism is an important etiological factor.10–12 Both osteopenia and BPV are more common in women and older people. In osteopenic rats, otoconia have decreased density and increased size compared to con- trols so the otoconia may be more easily dislodged.13 Furthermore, degeneration of otoconia is seen in older rats regardless of osteopenia.14

Another important association with BPV is migraine. Migraine is more common in patients with idiopathic BPV than in controls

particularly in patients under the age of 50.15,16 The reason for this association is not clear, but it is possible that migranous vasospasm could lead to dislodged otoconia.‌‌

Head trauma is the most common identiﬁ- able cause for dislodging otoconia. The most common cause of head trauma is motor vehicle accidents followed by common falls.17 BPV after head trauma tends to be more severe and more protracted than BPV from other causes. Infection and ischemia of the inner ear are the next most common causes for free-ﬂoating oto- conia. In animal models, brief periods of isch- emia result in prominent release of otoconia from the utricular macule (see Anatomy of Otolith Organs, Chapter 2). Nearly half of patients with vestibular neuritis have BPV as a sequela (see Chapter 9). Vigorous exercise such as aerobics, mountain biking, and swim- ming are associated with recurrent BPV.18–20 Presumably repeated abrupt accelerations can dislodge otoconia. Surgeries involving drilling of the temporal bone such as with cochlear implants can dislodge otoconia and predespose to BPV.21

The second event that must happen for BPV to occur is the otoconial debris must enter a semicircular canal. Free-ﬂoating otoconia in the utricle are not believed to cause symptoms. It is only when the otoconia enter a semicircu- lar canal that symptoms occur. Because of its position in the head the posterior semicircular canal is most vulnerable. Loose otoconia in the utricle will fall into the posterior semicircular canal and become trapped if the head is held backward below the horizontal plane for a few minutes. This explains why BPV often ﬁrst occurs after situations such as going to a hair- dresser, a dentist, or ﬁxing a leaky kitchen sink. People with certain occupations, such as auto mechanics and plumbers, are particularly prone to developing recurrent BPV. It is not too farfetched to assume that otoconial debris is ﬂoating freely within the endolymph in nearly everyone, particularly older people.22 It is just a matter of whether the head is held in the criti- cal position long enough for the particles to drop into the posterior semicircular canal. Benign positional vertigo commonly occurs after surgical procedures regardless of the nature or location of the surgery. Initially this was thought to result from some metabolic changes associated with the trauma of surgery or from the anesthesia, but more likely the BPV

is secondary to prolonged positioning with the head back in people who already have free- ﬂoating debris in the vestibule. Positioning for dental and radiological procedures is another common precipitating factor for BPV.23,24 Interestingly BPV occurs more commonly on the right side compared to the left, possibly because people tend to sleep more on the right side than the left.25,26

POSTERIOR CANAL VARIANT OF BENIGN POSITIONAL VERTIGO

Clinical Features

By far the most common variety of BPV is that associated with debris in the posterior semicir- cular canal (PC-BPV).27 Patients develop brief episodes of vertigo and nystagmus (usually last- ing <30 sec) with position change: typically when turning over in bed, getting in and out of bed, bending over and straightening up, or extending the neck to look up.28 (See Video 6–12 and Video 6–13) Importantly, the vertigo of BPV is triggered by certain position changes. Any patient with vertigo will report worsening of the vertigo in certain positions, but patients with BPV will report that the vertigo is triggered by the position change. “Top shelf vertigo,” in which a patient experiences an episode of vertigo while reaching for something on a high shelf, is nearly always due to PC- BPV. Since the most common provocative movements for inducing PC-BPV occur in bed or when getting in and out of bed, patients report that the vertigo is severe in the morning and tends to disappear once they are up. The common report of having attacks mostly in the morning may also be because the particles have had a chance to accumulate in one part of the canal while the patient is lying still sleeping. Turning the head from side to side while erect does not induce nystagmus because this movement does not stimulate the posterior semicircular canal. Often after a ﬂurry of episodes, patients com- plain of more prolonged nonspeciﬁc dizziness (a motion-sick sensation) that may last hours or even persist throughout the day. Vertigo can awaken the patient; presumably, positional ver- tigo occurs when they turn over while sleeping, and some patients experience severe nausea

and vomiting, which can be even more bother- some than the vertigo.

As the name implies, BPV is a benign disor- der meaning that it is not progressive and in most cases will eventually remit spontane- ously.29 However, spontaneous remission can take months or longer, and there are some patients who report having symptoms for many years and are only cured after a canalith repositioning maneuver. In a longitudinal cohort study of patients who presented to an Otolaryngology clinic, the mean time to symp- tom resolution was 39 days with a wide standard deviation of 47 days.29 In a population- based telephone survey study, patients with BPV reported a mean symptom duration of 2 weeks (range 0.5 days to 104 weeks), with about one-third reporting symptoms more than 1 month.30,31 The duration of symptoms in con- trol groups of randomized trials was generally more than 1 month for about 80% of the patients.32 The “benign” label also cannot be mistaken to mean that the symptoms are trivial. Patients with BPV have an increased incidence of falls, depression, and impairment of daily activities.33–35 During periods of symptomatic BPV, 24% of patients reported giving up driv- ing a car and 18% avoided leaving their home.31 Also reﬂecting the burden of BPV on patients, in the population-based study nearly 80% of BPV patients reported a visit to a medical doc- tor.31 More than half of patients with PC-BPV have at least one recurrence after a remis- sion.15,27,31 In some patients, bouts of PC-BPV are intermixed with variable periods of remis- sion over many years.

In their initial description of the syndrome in 1952, Dix and Hallpike found evidence of ear disease in approximately two-thirds of their 100 patients with BPV.2 When the ear disease was unilateral, the nystagmus was usually induced when the abnormal ear was under- most. Subsequent reports conﬁrmed the benign nature of the disorder but suggested that most cases were unassociated with identiﬁable lesions.28,36,37 Despite its common occurrence, there have been relatively few reports of large series of patients with BPV.

We reviewed the clinical features of 240 cases of BPV, each with a typical clinical his- tory and the stereotyped paroxysmal positional nystagmus.28 The mean age of onset was 54 years (range 11 to 84 years). The two largest diagnostic categories were posttraumatic and

Table 10–1 Diagnoses in 240 Patients with Benign Paroxysmal Positional Vertigo28

Idiopathic 118

Post-traumatic 43

Viral neurolabyrinthitis 37

Basilar vertebral insufﬁciency 11

Meniere’s disease 5

Postsurgery (general) 5

Postsurgery (ear) 5

Ototoxicity 4

Luetic labyrinthitis 2

Chronic otomastoiditis 2

Other 8

postviral (Table 10–1). Patients with the for- mer had the onset of BPV within 3 days of well- documented head trauma. Patients in the viral group reported a prior episode of acute vertigo gradually resolving over 1 to 2 weeks. In 25 of 37 postviral patients, there was an associated sudden hearing loss that improved as vertigo subsided, although most patients were left with a residual unilateral sensorineural hearing loss. The associated hearing loss suggests that the viral process targeted the labyrinth (i.e., “laby- rinthitis”) rather than the more common tar- get, the vestibular nerve (i.e., “vestibular neuri- tis”). Episodes of BPV can begin as soon as 1 week and long as 8 years after the acute viral syndrome. Most patients reported a cold or ﬂu- like illness within 2 weeks of the acute vertigi- nous episode. Eleven patients reported typical symptoms of vertebrobasilar insufﬁciency (in addition to vertigo) prior to the onset of BPV. In these cases, the BPV could have resulted from ischemic damage to the labyrinth. It is important to recognize that these episodes of positional vertigo in such patients do not indi- cate recurrent vascular ischemia.

Females outnumbered males by a ratio of 1.6:1, combining all diagnostic categories. This ratio was approximately 2:1 if only the idio- pathic and miscellaneous groups were consid- ered. Other investigators have reported an even higher female-to-male preponderance with idiopathic BPV.37 The age of onset peaked in the sixth decade in the idiopathic group, in the fourth and ﬁfth decades in the postviral group, and was evenly distributed over the sec- ond to sixth decades in the posttraumatic group.

Pathophysiology

As noted earlier, the most likely explanation for PC-BPV is canalithiasis involving the posterior semicircular canal.7,38,39 With the patient sitting upright, a clot of calcium carbonate crystals forms at the most dependent portion of the posterior canal (Fig. 10–2A). Movement of the head back and to the side in the plane of that posterior canal (such as with the standard positioning test) causes the clot to move in an ampullofugal direction, producing ampullofu- gal displacement of the cupula due to the “plunger” effect of the clot moving within the narrow canal (Fig. 10–2B). Fatigability with repeated positioning is explained by dispersion of particles from the clot, making the plunger less effective. Reactivation of the positional vertigo after prolonged bed rest is also explained as the particles reform into a clot. The induced

vertigo and nystagmus are brief in duration because once the clot reaches its lowest posi- tion in the canal with respect to the earth’s sur- face, the cupula returns to its primary position with its usual time constant determined pri- marily by cupular elasticity. The typical latency of about 5 seconds before onset of nystagmus is explained by the delay in setting the clot into motion. It also explains why slow positioning does not induce vertigo or nystagmus, as the clot would move slowly along the undermost wall of the canal without producing a plunger effect.

Probably the most convincing argument for the canalithiasis theory is the dramatic response of PC-BPV to positional maneuvers designed to move the clot around the posterior semicircular canal into the utricle.7,27 By rotating the subject about the plane of the posterior canal, the clot moves from a position next to the cupula, as

A B C

Horizontal

Utricle Anterior

Posterior

Horizontal

Posterior

Clot

Horizontal

Posterior

D E

Anterior Horizontal

Horizontal

Posterior

Endolymphatic duct

Figure 10–2. Pathophysiology of the posterior canal variant of benign positional vertigo. In the sitting position (A) the clot of calcium carbonate crystals lies at the bottom-most position within the posterior canal. Movement to the head-hanging position (B) causes the clot to move away from the cupula, producing an excitatory burst of activity in the ampullary nerve from the posterior canal (ampullofugal displacement of the cupula). Rolling across to the opposite side in the plane of the posterior canal (C and D) causes the clot to enter the common crus of the posterior and anterior semicircular canals. Finally, when the patient sits up (E) and the clot falls into the utricle. (Adapted from Epley JM. The canalith reposition- ing procedure: For treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 1992;107:199, with permission).

shown in Figure 10–2A, into the utricle as shown in Figure 10–2E. It is of particular note that when the patient is moved from the initial head-hanging position (which induced the nys- tagmus) to the opposite head-hanging position (with the abnormal ear up), an identical burst of positioning nystagmus often occurs, in both cases with the upper pole of the eye beating toward the abnormal ear. This phenomenon is readily explained by following the movement of the clot around the posterior semicircular canal, which in each case produces ampullofugal dis- placement of the posterior canal cupula. If the debris were attached to the cupula as suggested by the cupulolithiasis theory, one would expect the nystagmus to change direction in the oppo- site head-hanging position.

Diagnosis

The diagnosis of PC-BPV rests on ﬁnding the characteristic paroxysmal positional nystagmus in a patient with a typical history of positional vertigo. The nystagmus is induced by rapidly moving the patient from the sitting to head- hanging position as originally described by Dix and Hallpike (see Fig. 6–6 in Chapter 6). It is important to prepare the patient in advance by explaining that the goal is to induce positional vertigo and that the patient must cooperate by keeping the eyes open and avoid blinking as much as possible. The typical nystagmus has tor- sional and vertical components. The eyes beat upward (toward the forehead) with the upper poles beating toward the ground (thus an upbeat- torsional nystagmus is seen).40,41 The vertical component is larger in the contralateral eye and the torsional component is larger in the ipsilat- eral eye, consistent with the known excitatory connections from the posterior semicircular canal to the eye muscles (see Fig. 3–8c in Chapter 3). A reverse nystagmus (downbeat and torsional) of lesser magnitude usually occurs if the patient is brought directly back up from the head-hanging position to the sitting position, a ﬁnding which is also highly supportive of free-ﬂoating particles in the canal because sit- ting up reverses the movement of the particles in the canal, thus triggering nystagmus in the reverse direction. The nystagmus triggered in the head-hanging position fatigues (decreases with repeated positioning) in more than 90% of patients, but there are occasional patients with

otherwise typical BPV and nystagmus who do not show fatigue with repeated positioning. There is usually a latency from the time the head-hanging position is achieved to the onset of positioning nystagmus but, as with fatigability, it is not an absolute feature. The presence of posi- tioning nystagmus correlates with the clinical symptoms. Unless the patient is tested during a period when he or she is having acute episodes of vertigo, the positioning nystagmus may not be observed. Patients with BPV may have negative positional testing if the particles are dispersed within the canal rather than coalescent as a clot. With the development of particle reposition- ing maneuvers designed to remove debris from the posterior semicircular canal, treating the patients with these maneuvers also serves to conﬁrm the diagnosis.27 Once the typical posi- tioning nystagmus is induced, we proceed with a positional maneuver to cure the condition (see later discussion). If the positioning nystag- mus and symptoms are gone after completing

the maneuver, the diagnosis was correct.

Since BPV can generally be diagnosed and cured at the time of the ofﬁce visit, ancillary testing is rarely indicated. Laboratory tests are generally not helpful for the diagnosis of BPV. Patients with recurrent BPV might be screened for osteopenia, although it is unproven whether correcting osteopenia decreases the likelihood of recurrent BPV. ENG and VNG are not help- ful since there is usually a minimal horizontal component to record and the prominent tor- sional component cannot easily be recorded. VNG allows one to actually view the nystagmus so that the torsional component can be appre- ciated, but the pattern of nystagmus is readily identiﬁable at the bedside without the need for VNG. The characteristic nystagmus is easily observed visually even if the patient attempts to ﬁxate (i.e., there is no need for Frenzel lenses or infrared video recordings). MRI of the brain is not indicated, but high resolution MRI of the inner ear might be informative for visualizing the otoconia debris and canal structure in very rare atypical or refractory cases.42,43

Management

Once BPV is diagnosed, a simple explanation of the nature of the disorder and its favorable prognosis can help relieve the patient’s anxiety. Because of the dramatic nature of the episodes

of vertigo, many patients believe that they have a life-threatening disorder such as a tumor or stroke, and they need to be reassured that they have a benign inner ear disorder. It is impor- tant to be aware, however, that although it is a benign disorder, recurrences are common. Episodes of positional vertigo typically occur in ﬂurries and about half of the patients will have at least one exacerbation after an initial remis-

sion.31 The likelihood of a recurrence should be explained to patients so they are not unduly frightened if it occurs.

We typically perform a particle repositioning maneuver designed to liberate the clot from the posterior semicircular canal immediately after the diagnosis is conﬁrmed with the Dix-Hallpike positioning test. We use a modiﬁed Epley maneuver, shown in Fig. 10–3.

Figure 10–3. Modiﬁed Eply maneuver for treating the posterior canal variant of benign positional vertigo. After turning the head toward the affected side (right side in this case) the patient moves from a sitting to head hanging position (The Dix-Hallpike test, 1–2); once the nystagmus and vertigo have subsided the patient rolls across to the opposite side, nose facing the ground, all in one motion (2–4); ﬁnally after about 30 seconds the patient returns to the sitting position (4–5). (From Fife TD et al. Quality Standards Subcommittee, American Academy of Neurology. Practice parameter: therapies for benign paroxysmal positional vertigo (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2008;70:2067 with permission).

2 3

Figure 10–4. Modiﬁed Seymont maneuver for treating the posterior canal variant of benign positional vertigo. After turn- ing the head toward the unaffected side (left side in this case) the patient moves from a sitting to right lateral position (1–2); while maintaining the head in the same position the patient moves across to the opposite lateral position, in the plane of the right posterior canal (2–3); after vertigo and nystagmus subsides the patient returns to the sitting position. (From Fife TD et al. Quality Standards Subcommittee, American Academy of Neurology. Practice parameter: therapies for benign paroxysmal positional vertigo (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2008;70:2067 with permission).

(See Video 10–1) The Semont maneuver (Fig. 10–4) may be equally effective, although there have been fewer controlled studies using this maneuver.32 The key feature of the particle repositioning maneuvers is to move the patient in the plane of the posterior semicircular canal to allow the clot of debris to rotate around the canal and enter the utricle.

The Epley maneuver is among the most efﬁcacious interventions in all of clinical medicine. The maneuver has been tested in numerous randomized placebo (i.e., sham pro- cedures) controlled trials. Trial quality has been rigorously scrutinized independently by the Cochrane Collaboration,8 the American Academy of Neurology Quality Standards Subcommittee,32 a multidisciplinary guideline development panel chosen by the American Academy of Otolaryngology–Head and Neck Surgery Foundation,44 and other independent groups.45,46 The summary results of all the valid randomized controlled trials indicate that the Epley maneuver has a large effect size in treating patients with BPV. In these studies, 61%–80% of patients treated with the maneu- ver had resolution of BPV compared with only

10%–20% of patients in the control groups with outcomes measured from 1 day to 1 month. These effect sizes translate into a “number needed to treat” (NNT) of 1.43 to 2.44. The NNT is a statistical measure that indicates the number of patients that had to have treatment to achieve the beneﬁcial outcome in one patient. Thus, approximately two patients with BPV require treatment with the Epley maneu- ver to eliminate the symptoms in one patient; this is among the largest effect sizes achievable in clinical medicine, and it is particularly impressive considering that the outcome used was elimination of symptoms (i.e., cure of symptoms) as opposed to only an improvement in symptoms.

Despite the large effect size of the Epley maneuver for BPV, the maneuver appears to be substantially underutilized in routine prac- tice. Of patients with BPV who presented to a physician, only 27% reported undergoing diag- nostic positional testing (i.e., the Dix-Hallpike test) and only 10% underwent a particle repo- sitioning maneuver of any type.31

It is doubtful that physicians are just instruct- ing patients to avoid provocative positions and await spontaneous resolution because about

75% of patients with BPV who present to a physician end up having at least one diagnostic test ordered, including imaging studies, ves- tibular tests, an audiogram, and blood tests.31,47 Although most patients are cured after a single particle repositioning maneuver, the cure rate is improved by repeating the proce- dure until no vertigo or nystagmus occurs in any position. Occasionally a patient will develop severe nausea and have to be rescheduled and premedicated with a vestibular suppressant drug. Although not routinely recommended, occasionally, vibration applied to the mastoid region is useful if, rather than a burst of nystag- mus with position change, the patient develops a slow, persistent nystagmus, suggesting that the otolithic debris is stuck to the wall of the semicircular canal or to the cupula and not freely moving. A sign that the modiﬁed Epley maneuver is going to be successful is the pro- duction of a second identical burst of positional nystagmus when the patient is moved from the initial head-hanging position across to the opposite head-hanging position.48 This indi- cates that the particles are moving along in the canal in the correct direction toward the utri- cle. If, on the other hand, a burst of nystagmus in the reverse direction occurs when moving from one head-hanging position to the other, the particles are most likely moving in the wrong direction back toward the cupula, a sign that the particle repositioning maneuver will be unsuccessful. When this occurs, the patient most likely elevated the head while rolling over from the head-hanging position to the other side because this can cause the particles to move back in the opposite direction because of gravity. It is critical that the head stay down during this phase of the positioning maneuver. When returning to the sitting position at the end of the particle repositioning maneuver, patients may have a brief but severe burst of vertigo (falling sensation) as late as 30 min after assuming the position.49 This delayed vertigo in the sitting position presumably occurs as the bolus of otolithic debris drops out of the common crus of the posterior and anterior semicircular canals into the utricle. Rarely, patients will develop a persistent vertigo and nystagmus after returning to the sitting posi- tion. This phenomenon might result from a jamming of the otolithic debris (a canalith jam) when migrating from a wider to narrower seg- ment, such as from the ampulla to the canal or

at the bifurcation of the common crus to the posterior and anterior canals.7 Repeating the particle repositioning with vibration applied to the skull (i.e., mastoid region of affected side) will usually break up the “canalith jam” and cure the BPV.

What happens to the particles once they enter the utricle? When the otoconia are sepa- rated from the gelatinous layer of the otolith membrane, they can dissolve in the endolymph ﬂuid, be taken up into the membrane by the process of phagocytosis, or simply remain free ﬂoating within the endolymph. The calcium concentration of the endolymph seems to be critical for determining whether the otolithic debris will dissolve.50 Otolith debris may not be cleared in patients who have recurrent attacks of BPV. As noted earlier, osteopenia and osteo- porosis are more common in patients with recurrent BPV than in patients with de novo BPV.12

After performing a particle repositioning maneuver, we recommend that patients avoid all extreme head-back positions such as those mentioned earlier. Other restrictions, such as having the patient sleep propped up for a few nights or wearing a cervical neck collar, do not improve the outcome.51Antivertiginous medi- cations such as meclizine or promethazine have relatively little use in the management of patients with BPV because the acute attacks are not suppressed by these drugs; moreover, the particle repositioning maneuver is much more effective in controlling the condition. For the very rare patient with prolonged refractory BPV, one might still consider a surgical proce- dure such as the singular neurectomy or the canal plugging procedure.9,52,53 The main com- plication of these procedures is a sensorineural hearing loss, which may occur in as many as 10% of patients.

Patients who have multiple recurrences of BPV can be taught to perform the particle repositioning maneuver on their own.55,56 We regularly give our patients a diagram for per- forming the maneuver on a bed at home (e.g., Figs. 10–3 and 10–4). One study compared the efﬁcacy of self-treatment with a modiﬁed Epley maneuver and a modiﬁed Semont maneuver and found that the response rate was signiﬁ- cantly greater with the modiﬁed Epley maneu- ver.56 Although minor complications such as those described earlier can occur, none of them is serious and most are cured by simply

repeating the maneuver. Patients can pre- sedate themselves and often they feel more comfortable performing the maneuver on their own in the controlled environment of their bedroom. Vibration applied to the mastoid is rarely required,57 but a simple neck massage vibrator can be used if one is available. Of course, one key point that cannot be ignored is that the particle repositioning maneuver (i.e., Epley maneuver or Semont maneuver) only works for treating PC-BPV. It is of no use for treating other causes of vertigo.‌‌

OTHER VARIANTS OF BENIGN POSITIONAL VERTIGO

As noted earlier, the most common type of BPV occurs when otoconial debris are within the posterior semicircular canal, probably because this is the canal in which it is most easily trapped. However, the otoconia can enter either one of the other canals and patients do present clini- cally with BPV from these canals. After poste- rior canal BPV, the next most common variant is horizontal canal BPV. Anterior canal BPV is much less common. The clinician must also add a bit more caution when making the diagnosis of either the horizontal or anterior canal vari- ants of BPV because the patterns of nystagmus seen with these variants can be similar to pat- terns of positional nystagmus caused by lesions in the central nervous system.58,59 This is differ- ent than the clinical scenario with posterior canal BPV because the characteristic pattern of nystagmus in posterior canal BPV (i.e., a burst of upbeat, torsional nystagmus lasting <30 sec- onds, and then having the nystagmus convert to downbeat torsional nystagmus if the patient is brought directly back up to the sitting position) is not a pattern expected or ever reported to be caused by a central lesion. For the PC-BPV variant, further adding to the conﬁdence in the bedside diagnosis is the fact it is readily cured at the bedside. On the other hand, horizontal canal BPV can at times be difﬁcult to make an immediate impact at the bedside.

The horizontal and anterior canal variants have clinical syndromes that resolve on average more quickly than the posterior canal variant,29 likely because the debris in these canals more readily falls back out based on the anatomy. Although, in rare cases the otolithic debris in

these variants can become attached to the cupula, producing true cupulolithiasis.

It is also possible for otoconia to enter multiple canals at once, particularly after head trauma,60 which leads to more challenging approach to repositioning.

Lastly, these other variants of BPV can be produced after performing the particle reposi- tioning maneuver for the typical posterior canal variant. For example, as the debris is moved from the posterior semicircular canal, it can enter the anterior canal from the common crus or it can enter the horizontal canal after it falls into the utricle (Fig. 10–5).

Horizontal Canal Benign Positional Vertigo

The clinical history of horizontal canal BPV is similar to that of the posterior canal variant, although there are important differences.61–63 With both syndromes, positional vertigo com- monly occurs in bed, particularly when patients turn over from one side to the other. Patients with PC-BPV, however, develop vertigo when getting in and out of bed and when bending down and straightening up or extending the head backward to look up. In contrast, patients with horizontal canal BPV develop vertigo pri- marily when turning over in bed or when turn- ing the head to the side when lying back in an easy chair. Occasionally, patients with horizon- tal canal BPV experience episodes of vertigo when turning the head to the side while sitting or walking. Remissions and exacerbations com- monly occur with both types of BPV, but exacerbations are typically shorter in duration with the horizontal canal variant than with the posterior canal variant, 29,64 though recurrences may be more common in the horizontal canal variant.54 With horizontal canal BPV, patients can develop two patterns of positionally trig- gered nystagmus (i.e., “geotropic” or “apogeo- tropic”) depending on whether the canaliths are in the anterior segment or the posterior segment of the horizontal canal.

GEOTROPIC NYSTAGMUS

When the canaliths are in the posterior seg- ment (or “long arm”) of the horizontal canal, patients will develop a paroxysmal, horizontal direction–changing nystagmus that beats

Anterior canal ampulla

Horizontal canal

Horizontal canal ampulla

Utricle Saccule

clot moves to the bottom of the canal in the lateral position, returning to the supine posi- tion results in a movement of the clot back to its original position and a burst of nystagmus in the opposite direction. Furthermore, rotation of the head to the opposite side causes the clot to move in the opposite direction and produces ampullofugal displacement of the cupula and geotropic nystagmus.

Unlike PC-BPV, the horizontal canal variant has only minimal latency and no fatigability. With PC-BPV, latency is explained by a delay in move-

Posterior

canal Debris

Vestibule

ment of the calcium carbonate clot and fatigabil- ity by dispersion of the calcium carbonate particles with repeated positioning. There may

Figure 10–5. Drawing of the vestibular labyrinth showing

the proposed path of debris as it moves out of the posterior semicircular canal and into the anterior or horizontal canal (dashed line and arrows).

toward the ground (so-called geotropic nystag- mus) when the head is turned to the side while they are lying supine (the nystagmus will also be triggered by a body roll to the side). Thus, when the head is turned to the left side, a left- beating nystagmus is triggered. Then, when the head is turned toward the right side, a right-beating nystagmus is triggered. The nys- tagmus lasts about a minute. Though it occurs with the head to either side, it is nearly always stronger on one side (the abnormal side). The debris enters the canal side of the horizontal semicircular canal when the patient lies supine. When the head is rapidly turned to the abnor- mal side, the mass is accelerated downward in the canal. The deceleration that occurs once the lateral position is reached would normally rapidly return the cupula to the center position and there would be no post-positioning nystag- mus. Because of the continued effect of gravity on the freely ﬂoating clot, however, it contin- ues to move downward in the canal toward the ampulla until it reaches the bottom of the canal in that lateral position. Movement of the clot within the canal results in an ampullopetal deviation of the cupula and a burst of nystag- mus beating toward the ground. When the clot stops moving, the cupula returns to the primary position, with the normal time constant. The longer duration of horizontal canal variant BPV compared to the posterior canal variant is explained by the longer time constant of the horizontal vestibulo-ocular reﬂex (VOR) than that of the vertical VOR.65 Once the free-ﬂoating

be a viscous plug or gel in the horizontal canal, rather than a clot of calcium carbonate crystals, which could explain the lack of fatigability.61

APOGEOTROPIC NYSTAGMUS

The second pattern of nystagmus that occurs with otoconia in the horizontal canal is the “apogeotropic” (i.e., away from the ground) pattern that is caused by otoconia in the ante- rior segment of the canal.66 This again can result from otoconia adherent to the cupula (cupulolithiasis) or free ﬂoating in the anterior segment of the canal (canalithitiasis). When patients have otoconia in these regions of the horizontal canal, a head turn to the left side while lying supine triggers a right-beating (thus away from the ground, “apogeotropic”) nystag- mus. Turning the head to the right side will trigger a left-beating nystagmus. The dynamics of the buildup and decay of nystagmus depends on whether the debris is free ﬂoating or attached to the cupula and the dynamics of the horizontal VOR. When the debris is attached to the cupula, the stimulus is constant accelera- tion, which causes a gradual buildup of slow- phase velocity determined by the dominant time constant, deﬁned as the time it requires for the response to reach 63% of maximum. An average time constant of the horizontal VOR in normal subjects is in the range of 12–20 sec. The gradual decay in slow-phase velocity after reaching a peak response can be explained on the basis of central VOR adaptation.

TREATMENT OF HORIZONTAL BPV

Unlike treatment for the posterior canal variant, there are no high-level randomized controlled

5 7

Figure 10–6. Maneuver for treating the horizontal canal variant of benign positional vertigo. While lying supine with the head turned toward the affected ear (right side in this case) the patient rolls across toward the unaffected side (1–3); the patient then continues the roll by moving through the prone position to the right lateral position (3–5); ﬁnally the patient returns to the sitting position (6–7). (From Fife TD et al. Quality Standards Subcommittee, American Academy of Neurology. Practice parameter: therapies for benign paroxysmal positional vertigo (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2008;70:2067 with permission).

trials of positional treatments for the horizontal canal variant.32 However, there are several different positional treatments that suggest efﬁcacy in cohort and case series designs. In general, it is easier to treat HC-BPV when the otoconia are in the posterior segment (render- ing geotropic positional nystagmus) because the particles are closer to the exit of the canal to the utricle and because they are less likely to be adherent to the cupula. In fact, when the patient is identiﬁed as having apogeotropic nys- tagmus, the ﬁrst goal in repositioning is gener- ally to move the otoconia from the anterior segment to the posterior segment, thus convert- ing the apogeotropic nystagmus to a geotropic nystagmus.

For patients with geotropic pattern of nys- tagmus, one commonly used maneuver is the “barbeque” maneuver (Fig. 10–6). With the

“barbeque” maneuver, the patient is rotated in the plane of the horizontal canal.67–69 The patient starts in the supine position and is rolled 90 degrees to the normal side (the side with lesser nystagmus), then in 90-degree steps to prone, to the abnormal side, and back to the supine. Another maneuver gaining acceptance is the Gufoni maneuver. With the Gufoni maneuver70 the patient is rapidly moved from the sitting position (feet forward) to a head lat- eral position (normal ear down). The head is held in this position for about 2 minutes until the geotropic nystagmus disappears. The head is then quickly turned to the side, nose down toward the ground. After 2 minutes the patient returns to the starting position. (See Video 10–2) Finally, the “forced prolonged position” is another option. With the “forced prolonged position” the patient is instructed

to sleep overnight with the normal ear down,71 which allows the otoconia to naturally fall out of the affected canal. The forced prolonged position is typically selected if the other maneu- vers are not effective or if the patient is not tolerating the other maneuvers.

When the pattern of nystagmus is apogeo- tropic, performing the barbeque maneuver toward the affected side can convert the nys- tagmus to geotropic.72 The Gufoni maneuvers can also do this.73 Once the nystagmus is con- verted, the typical treatments for geotropic can be used. More than half of patients with apo- geotropic BPV were cured by having them lie on the side of weakest nystagmus for 2 nights.74 Barbaque rotation and the Gufoni maneuver (toward the side with weaker nystagmus) can also get the debris to move from the anterior to posterior arm and out of the horizontal canal.72,73

Anterior Canal Benign Positional Vertigo

Rarely patients with a typical history of BPV, particularly after head trauma, exhibit a tor- sional downbeat nystagmus rather than the usual torsional upbeat nystagmus on the standard Dix-Hallpike positional test.28,75,76 The positioning nystagmus otherwise has all of the typical features of posterior canal BPV— the most important of these features is the brief duration, since persistent downbeat nystagmus is a central nervous system sign. With the stan- dard Dix-Hallpike test, turning the head to the right and lowering the patient into the head- hanging right position activates the right poste- rior semicircular canal and the left anterior semicircular canal. Since the ampullae are on the opposite ends of these two vertical canals, this positional change results in ampullofugal movement (excitation) of endolymph in the posterior semicircular canal and ampullopetal movement (inhibition) of the endolymph in the contralateral anterior canal. Thus, if there were debris in the anterior canal of the contralateral ear, it would be driven back toward the cupula rather than away from the cupula, as occurs in the posterior semicircular canal. Once the ﬁnal position is reached, however, debris within the canal would move downward away from the cupula of the anterior canal since the

ampullary segments of both anterior canals point downward in the head-hanging positions. The direction of the torsional component of the positioning nystagmus indicates which ear is the origin of the nystagmus.76,77 If the upper pole of the eye beats away from the ground toward the uppermost ear, then it originates from the anterior canal of the uppermost ear. If it beats toward the ground, then it originates from the anterior canal of the undermost ear. The standard particle repositioning maneuver used for treating PC-BPV on the same side is also successful for treating the anterior canal variant of BPV.76

Mimics of Benign Positional Vertigo

BPV is by far the most common cause of brief recurrent attacks of positional vertigo. But it is important to know that any patient with con- stant or prolonged vertigo will report worsening of the symptom with certain position changes. For example, if a patient has vestibular neuritis and presents with severe and constant vertigo, the patient will typically report feeling much better lying still and much worse with any movement. This history is frequently misinter- preted as a positional vertigo syndrome.

It is also important to know that positionally triggered nystagmus can be a central nervous system ﬁnding. The most common pattern of a central positional nystagmus is a persistent downbeating nystagmus, which can be misin- terpreted as nystagmus from anterior canal BPV.58 The next most common central pattern of positional nystagmus is a horizontal direction changing nystagmus, which can be identical to the patterns of nystagmus seen with horizontal canal BPV.59 Thus, when man- aging a patient with ﬁndings suggestive of either anterior or horizontal canal BPV but when the patient is not able to be effectively treated over a reasonable time frame or if there are any important inconsistencies, then a cen- tral lesion should be considered. The most common central lesions that mimic anterior and horizontal canal BPV are Chiari malforma- tions, tumors or other structural lesions involv- ing the cerebellum or peri-forth ventricular regions, or neurodegenerative disorders involv- ing the cerebellum (i.e., spinocerebellar ataxia syndromes).

Fortunately, the pattern of nystagmus seen with PC-BPV is not a pattern at all typical of a central lesion. To our knowledge there

Uneri A. Migraine and benign paroxysmal positional vertigo: an outcome study of 476 patients. Ear Nose Throat J. 2004;83(12):814.
Gordon CR, Levite R, Joffe V, Gadoth N. Is post-

has been no convincing report of a central lesion causing all the characteristic features of PC-BPV (i.e., a burst of upbeat torsional nys- tagmus in the head-hanging position with the duration of nystagmus being less than 30 sec- onds). Any reports that suggest this occurrence are much more likely to be an example of a common disorder (i.e., PC-BPV) co-occurring with a rare central lesion.

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Zucca G, Valli S, Valli P, Perin P, Mira E. Why do benign paroxysmal positional vertigo episodes recover spontaneously? J Vestib Res. 1998;8:325.
Fyrmpas G, Demitrios R, Bettina HA, et al. Are pos- tural restrictions after an Epley maneuver unneces- sary? First results of a controlled study and review of the literature. Auris Nasus Larynx. 2009;36(6):637.
Pournaras I, Kos I, Guyot JP. Benign paroxysmal posi- tional vertigo: a series of eight singular neurectomies. Acta Otolaryngol. 2008;128(1):5.
Leveque M, Labrousse M, Seidermann L, Chays
1. Surgical therapy in intractable benign paroxys- mal positional vertigo. Otolaryngol Head Neck Surg. 2007;136(5):693.
Sakaida M, Takeuchi K, Ishinaga H, Adachi M, Majima Y. Long-term outcome of benign paroxysmal positional vertigo. Neurology. 2003;60(9):1532.
Tanimoto H, Doi K, Katata K, Nibu KI. Self-treatment for benign paroxysmal positional vertigo of the pos- terior semicircular canal. Neurology. 2005;65(8): 1299.
Radtke A, von Brevern M, Tiel-Wilck K, Mainz- Perchalla A, Neuhauser H, Lempert T. Self- treatment of benign paroxysmal positional vertigo: Semont maneuver vs Epley procedure. Neurology. 2004;63(1):150.
Ruckenstein MJ, Shepard NT. The canalith reposi- tioning procedure with and without mastoid oscillation for the treatment of benign paroxysmal positional ver- tigo. ORL J Otorhinolaryngol Relat Spec. 2007;69(5): 295.
Yabe I, Sasaki H, Takeichi N, et al. Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6). J Neurol. 2003;250:440.
Johkura K. Central paroxysmal positional vertigo: iso- lated dizziness caused by small cerebellar hemorrhage. Stroke. 2007;38:e26; 2007;78:710.
Tomaz A, Ganança MM, Ganança CF, Ganança FF, Caovilla HH, Harker L . Benign paroxysmal posi- tional vertigo: concomitant involvement of differ- ent semicircular canals. Ann Otol Rhinol Laryngol. 2009;118(2):113.
McClure JA. Horizontal canal BPV. J Otolaryngol. 1985;14:30.
Pagnini P, Nuti D, Vannuchi P. Benign paroxys- mal positional vertigo in the horizontal canal. ORL J Otorhinolaryngol Relat Spec. 1989;51:161.
Baloh RW, Jacobson K, Honrubia V. Horizontal semi- circular canal variant of benign positional vertigo. Neurology. 1993;43:2542.
Chung KW, Park KN, Ko MH, et al. Incidence of hori- zontal canal benign paroxysmal positional vertigo as a function of the duration of symptoms. Otol Neurotol. 2009;30(2):202.
Baloh RW, Richman L, Yee RD, Honrubia V. The dynamics of vertical eye movements in normal human subjects. Aviat Space Environ Med. 1983;54:32.
Baloh RW, Yue Q, Jacobson KM, Honrubia V. Persistent direction-changing positional nystagmus: another variant of benign positional nystagmus? Neurology. 1995;45:1297.
Lempert T. Horizontal benign positional vertigo [let- ter]. Neurology. 1994;44:2213.
Baloh RW. Reply to the letter by Lempert: horizontal benign positional vertigo. Neurology. 1994;44:2214.
Escher A, Rufﬁeux C, Maire R. Efﬁcacy of the bar- becue manoeuvre in benign paroxysmal vertigo of the horizontal canal. Eur Arch Otorhinolaryngol. 2007;264(10):1239.
Francesco R, Francesco D, Salvatore G, Gautham K, Rosalia G, Riccardo S. Management of benign paroxysmal positional vertigo of lateral semicircu- lar canal by Gufoni’s manoeuvre. Am J Otolaryngol. 2009;30(2):106.
Nuti D, Agus G, Barbieri M, Passali D. Management of horizontal–canal paroxysmal positional vertigo. Acta Otolaryngol (Stockh). 1998;118:455.
Appiani GC, Catania G, Gagliardi M, Cuiuli G. Repositioning maneuver for the treatment of the
apogeotropic variant of horizontal canal benign par- oxysmal positional vertigo. Otol Neurotol. 2005; 26(2):257.
Boleas-Aguirre MS, Perez N, Batuecas-Caletrio A. Bedside therapeutic experiences with horizontal canal benign paroxysmal positional vertigo (cupulolithia- sis). Acta Otolaryngol. ePub ahed of print, May 20, 2009:1.
Chiou WY, Lee HL, Tsai SC, Yu TH, Lee XX. A single therapy for all subtypes of horizontal canal positional vertigo. Laryngoscope. 2005;115(8):1432.
Jackson LE, Morgan B, Fletcher JC, Jr., Krueger WW. Anterior canal benign paroxysmal positional
vertigo: an underappreciated entity. Otol Neurotol. 2007;28(2):218.
Tusa R, Herdman S. Assessment and treatment of anterior canal benign paroxysmal positional vertigo using the canalith repositioning maneuver (CRM). Neurology. 1997;48:A384.
Imai T, Takeda N, Ito M, Nakamae K, Sakae H, Fujioka H, Kubo T. Three-dimensional analysis of benign paroxysmal positional nystagmus in a patient with anterior semicircular canal variant. Otol Neurotol. 2006;27(3):362.

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Chapter 11 ‌‌‌‌

Endolymphatic Hydrops (Meniere’s Syndrome)

BACKGROUND OCCURRENCE CLINICAL FEATURES PATHOPHYSIOLOGY ANIMAL MODELS ETIOLOGY

Genetics

Migraine and Meniere’s Syndrome

Infection/Autoimmune

DIAGNOSIS

Audiometric Testing Vestibular Testing Imaging MANAGEMENT

Medical Management Surgical Management

BACKGROUND

When Prosper Meniere described a series of patients with hearing loss and vertigo in 1861, he was not attempting to deﬁne a disease but rather to convince his medical colleagues that vertigo could be a symptom of damage to the inner ear.1,2 Prior to this time, vertigo was con- sidered to be a cerebral symptom and was lumped together with epileptic seizures and stroke under the rubric of “apoplectiform cere- bral congestion,” a condition thought to result from overﬁlling of blood vessels in the brain.2 To support his argument, Meniere described the autopsy ﬁndings in a young girl who died 5 days after experiencing the sudden onset of hearing loss and vertigo. Meniere observed a red plastic material, in the child’s inner ear, a bloody exudate ﬁlling the semicircular canals. In retrospect, this likely represented a case of acute leukemia with hemorrhage into the inner ear. It provided convincing evidence that dam- age to the semicircular canals of the inner ear could cause vertigo. It would take almost another century before English and Japanese

researchers independently reported hydrops of the inner ear in autopsy specimens from patients with the typical symptom triad of modern-day Meniere’s disease.3,4 However, because of Meniere’s description of the young girl’s autopsy in his classical paper, the concept that Meniere’s disease was caused by hemorrhage into the inner ear persisted well into the twen- tieth century. Meniere was not suggesting that the patients he described with episodic vertigo and ﬂuctuating hearing loss had the same dis- ease as the young girl with sudden deafness and vertigo. He was simply trying to make the point that vertigo and hearing loss commonly occur together with inner ear disease.

The clinical proﬁle of Meniere’s disease evolved over the years from a nonspeciﬁc description of just about any combination of hearing loss and vertigo to a characteristic clin- ical triad of ﬂuctuating hearing loss, tinnitus, and vertigo. Once a characteristic pathology— endolymphatic hydrops—was discovered in the late 1930s,3,4 the next question was whether patients with the typical clinical proﬁle consistently showed this pathology. As more

273

and more pathological specimens have been reported, the answer to this question is, usually but not always.5–8 Complicating matters fur- ther, endolymphatic hydrops can be found in ears from patients without the typical symp- toms of Meniere’s disease and, occasionally, even in patients without ear symptoms.8–10 Furthermore, it has become apparent that Meniere’s syndrome and the characteristic inner ear pathology can be produced by several different etiologies, including infections (syph- ilitic, bacterial, and viral) and after traumatic and metabolic injuries to the inner ear. Some suggest using the term Meniere’s syndrome to describe the broad spectrum of disorders with the characteristic clinical triad regardless of cause, while restricting the use of Meniere’s disease to describe only those cases without an identiﬁable cause (idiopathic). However, as we will see, there are undoubtedly multiple etiolo- gies for the idiopathic group so that the separa- tion between Meniere’s syndrome and Meniere’s disease is arbitrary and likely to change constantly. For this reason, we prefer the general term Meniere’s syndrome to describe the classical clinical proﬁle of ﬂuctuat- ing hearing loss, tinnitus, and vertigo. When a cause can be determined, it can be described as Meniere’s syndrome due to infection or autoimmune disease, for example, and if no cause can be found, Meniere’s syndrome of unknown cause.‌‌

OCCURRENCE

It is difﬁcult to obtain accurate measures of the prevalence and incidence of Meniere’s syn- drome because of problems with a deﬁnitive diagnosis and patient selection. In 1984, Wladislavosky-Wasserman et al.11 reviewed the data of the Mayo Clinic in Rochester, Minnesota, and estimated a prevalence of 218 per 100,000 and an incidence of 15 per 100,000. In 2005, Shojaku et al.12 reported an average annual prevalence and incidence of 34.5 and 5.0, respectively, per 100,000 population in the Nishikubiki district of Japan. Figures for the incidence of Meniere’s syndrome in European countries varies from a low of 4 per 100,000 in Finland13 to as high as 157 per 100,000 in Britain.14 A recent study from Germany found a population prevalence of 0.12%.15 It affects

all races and is recognized in all countries. Kitahara et al.16 found that black Americans were affected only about half as often as white Americans. Although some studies have found a female preponderance among Meniere’s patients, others have not, and the slight differ- ences that have been reported can probably be attributed to patient selection. A Swedish study of 356 patients with advanced Meniere’s syn- drome found a preponderance of males over females,17 whereas a Japanese study found a slight female preponderance.18

There is general agreement that Meniere’s syndrome is a disease of middle age.19 The mean age of onset is remarkably consistent around the age of 40, with the mean age at diagnosis being closer to 50. Meniere’s syn- drome can occur in children, but it is rare. Initial audiograms in children often show a high-frequency hearing loss rather than the low-frequency loss seen in adults.20 In the material from the Mayo Clinic study, no patients with Meniere’s syndrome were under the age of 15 years.11

There is a good deal of confusion and con- troversy regarding when and how often Meniere’s syndrome becomes bilateral. Thomas and Harrison21 followed 610 cases of Meniere’s syndrome and noted that those cases that were destined to become bilateral invari- ably developed within 5 years of presentation. In contrast, Friberg and colleagues22 monitored 161 patients with repeated examinations and noted an almost linear increase in the number of bilateral cases from only a few percent at onset to almost 50% in those who had been fol- lowed for as long as 30 years. In another study with long-term follow-up, Kitahara et al.23 reported development of bilateral involvement in 41% of cases. In the Mayo Clinic study, about a third of patients developed bilateral involvement.11 Complicating matters further, the contralateral ear may show audiometric changes without overt symptoms.24,25

A major problem in interpreting all of these studies on the epidemiology of Meniere’s syn- drome is the lack of uniform criteria for diag- nosis and the likelihood that many different etiologies are being included in the patient groups being studied. For example, it is possi- ble that certain causes of Meniere’s syndrome might be more prevalent in one sex than the other, have a different racial distribution, and be more likely to become bilateral. Until there

are diagnostic markers that identify speciﬁc categories of Meniere’s syndrome, it will be very difﬁcult to obtain accurate statistics regarding the epidemiology of the disease.‌‌

CLINICAL FEATURES

Typically, an attack of Meniere’s syndrome begins with a sensation of fullness and pressure along with decreased hearing and tinnitus in one ear. Vertigo rapidly follows, reaching a maximum intensity within minutes and then slowly subsides over the next several hours. The patient is usually left with a sense of unsteadiness and dizziness for days after the acute vertiginous episode. In the early stages the hearing loss is completely reversible, but in later stages a residual hearing loss remains. Tinnitus may persist between episodes but usually increases in intensity immediately before or during the acute episode. It is typi- cally described as a roaring sound (the sound of the ocean or a hollow seashell sound). After vomiting the patient prefers to lie in bed without eating until the acute symptoms pass. Such episodes occur at irregular intervals for years, with periods of remission unpredictably intermixed.26,27 Eventually, severe permanent hearing loss develops and the episodic nature spontaneously disappears (“burnt-out phase”).7 However, some patients can continue to be bothered by severe dizziness even after a 20-year disease history.28‌

Variations from this classic picture are com- mon, particularly in the early stages of the disease process, but the diagnosis remains uncertain unless the combination of ﬂuctuating hearing loss and vertigo occurs. Isolated epi- sodes of vertigo or hearing loss often precede the characteristic combination of symptoms by months or even years. Although so-called ves- tibular Meniere’s and cochlear Meniere’s have been proposed as variations of the classic syn- drome, clinical–pathologic correlation of iso- lated vestibular and auditory disorders with selective endolymphatic hydrops of the vestib- ular and auditory labyrinth is lacking. A small percentage of patients with sudden deafness— particularly if there is associated vertigo—will later develop typical symptoms of Meniere’s syndrome, so-called delayed endolymphatic hyrdrops.29 Some patients with well-documented

Meniere’s syndrome experience abrupt epi- sodes of falling to the ground without loss of consciousness or associated neurologic symp- toms. These episodes have been called otolithic catastrophes by Tumarkin30 because of his sus- picion that they represented acute stimulation of the otoliths from the hydrops. Patients often report feeling as though they were pushed to the ground by some external force.31 These epi- sodes can be confused with drop attacks seen with vertebrobasilar insufﬁciency and may suggest an inaccurate diagnosis in a patient with otherwise typical symptoms and signs of Meniere’s syndrome.32

With delayed endolymphatic hydrops, the patient reports a long history of hearing loss, often since early childhood, followed years later by typical symptoms and signs of endo- lymphatic hydrops.33,34 The hydrops can develop in either ear. When it develops in the ear with longstanding hearing loss, the vertigo attacks may not be accompanied by ﬂuctuating hear- ing loss and tinnitus, confusing the diagnosis. Schuknecht34 speculated that the initial hear- ing loss results from a viral infection that also produces subclinical damage to the resorptive mechanism (in either ear). Hydrops develops years later as the balance between endolymph secretion and resorption is disrupted. Delayed hydrops might also result from an autoimmune process triggered by antigens released from the previously damaged inner ear or from genetic causes of unilateral hearing loss.35,36

PATHOPHYSIOLOGY

As indicated earlier, the principal pathologic ﬁnding in patients with Meniere’s syndrome is an increase in the volume of endolymph associ- ated with distension of the entire endolym- phatic system (Fig. 11–1).3,4,7 The membranous labyrinth progressively dilates until the saccu- lar wall makes contact with the stapes footplate and the cochlear duct occupies the entire vestibular scala. The cochlear and vestibular end organs and nerves show modest pathologic changes. Interestingly, even the contralateral ears show signiﬁcantly more damage than the inner ears of controls.37 Membranous labyrinth herniations and ruptures are common, the latter frequently involving Reissner’s mem- brane and the walls of the sacculus, utriculus,

Figure 11–1. Dilated membranous labyrinth in Meniere’s syndrome. The drawing was made from a three-dimensional model developed from serial sections of the ear of a patient with Meniere’s syndrome. (Adapted from Schuknecht HF. Pathology of the Ear. Lea & Febiger, Philadelphia, 1993, with permission.)

and ampullae. Occasionally, a rupture is fol- lowed by complete collapse of the membra- nous labyrinth.

Althoughthepathologicchangesin Meniere’s syndrome have been well described, the mech- anism for its ﬂuctuating symptoms and signs are still not completely understood. Some of the ﬂuctuating symptoms with Meniere’s syn- drome probably result from mechanical deformation of the end organ, which is revers- ible as the endolymphatic pressure decreases. The characteristic hearing loss can be explained by increased pressure at the apex of the cochlear duct leading to displacement of the basilar membrane and altered auditory thresholds.38,39 The dramatic sudden falling attacks initially described by Tumarkin are likely due to sud- den deformation or displacement of one of the otolith organs.30,31 In addition to mechanical effects on the sensorineural elements of the inner ear, increases in endolymphatic pressure can cause symptoms by altering blood ﬂow to the inner ear.39 Experimental and clinical data support the notion that pressure changes in the inner ear can induce ischemia that either tran- siently or permanently damages the sensory cells in the auditory and vestibular organs.40 Furthermore, hydrops can affect the neural regulation of inner ear blood ﬂow. Hypoxic changes within the ear could lead to changes in chemistry and resting potentials, which could explain reversible episodes of auditory and ves- tibular dysfunction. Prolonged ischemia would lead to permanent damage to the sensorineural elements.40

Another possible explanation for the epi- sodes of hearing loss and vertigo is ruptures in the membranes separating endolymph from perilymph, producing a sudden increase in potassium concentration in the latter.7 If the perilymph space of animals is infused with a potassium solution, the bioelectric activity of the labyrinthine receptors is inhibited.41 When the artiﬁcial infusate is stopped, potassium is slowly cleared from the perilymph, and laby- rinthine function returns to normal in 2 to 3 hr (the typical duration of a Meniere’s attack). However, the stereotyped episodes of vertigo, tinnitus, and low-frequency hearing loss would be difﬁcult to explain on the basis of random ruptures in the membranous labyrinth.

As discussed in Chapter 2, there are conﬂict- ing theories regarding the mechanisms in regu- lating endolymph volume.42 The longitudinal ﬂow theory, initially proposed by Guild, holds that endolymph is secreted by the stria vascu- laris in the cochlea and dark cells in the ves- tibular labyrinth, and the endolymph gradually ﬂows toward the endolymphatic duct and sac where it is resorbed. The radial theory assumes a local transverse and active diffusion process between endolymph and perilymph through- out the labyrinth. Finally, the dynamic theory is a combination of the two, whereby endo- lymph volume is determined by both a radial ionic diffusion and a slow longitudinal bulk process. Endolymphatic hydrops could result from an increase in production or a decrease in the resorption of endolymphatic ﬂuid. An increased production of endolymph could

result from an increase in active transport of cations (sodium, potassium, and calcium) with their anionic pair (chloride) as well as water into the endolymph to maintain osmolality and electroneutrality.39 Since the stria vascularis of the cochlea and the dark cells of the vestibular labyrinth are the sites of maximum ion trans- port and maximum energy consumption, they are likely candidates for the site of overproduc- tion of endolymph resulting in hydrops. The adrenal hormone aldosterone controls the level of membrane-bound Na/K ATPase of the stria vascularis and dark cells.43–45 And, in turn, it controls secretion of potassium ions and endo- lymph production. Increased aldosterone lev- els induced by diet or stress could be a trigger for inducing Meniere’s attacks.42 The vasopres- sin–aquaporin 2 system is also important for water homeostasis in the inner ear just as it is in the kidney.46,47 Plasma vasopressin levels are elevated during Meniere’s attacks48 and vaso- pressin type 2 receptors are up-regulated in surgical specimens of inner ears from patients with Meniere’s syndrome.49 Whether this sys- tem is involved in the pathogenesis of Meniere’s syndrome is yet to be determined.‌‌‌‌

Movement of solutes along the scala media toward the endolymphatic duct and sac has been shown to be an extremely slow process.42 While the bulk ﬂow of water and ions across the endolymphatic sac is minimal, the sac has been shown to be important in the extraction of debris and breakdown of macromolecules as well as secretion of macrophages and immune cells. Lesions that obstruct the endolymphatic duct or sac can cause typical symptoms of Meniere’s syndrome.50

ANIMAL MODELS

Endolymphatic hydrops can be reliably pro- duced in animals by either decreasing endo- lymph absorption or increasing secretion. Since the initial studies in guinea pig by Kimura and Schuknecht,51 endolymphatic hydrops has been produced in several animal species by surgical obliteration of the endolymphatic duct and sac.52,53 Injecting foreign substances such as lipopolysaccharides into the middle ear can also produce hydrops possibly by inducing endolymphatic sac dysfunction.54 Over- production models include injecting cholera

toxin into the inner ear55 and long-term admin- istration of alderosterone or vasopressin.56,57 A problem with all of these animal models is that they produce hydrops and hearing loss but no attacks of vertigo. Thus, they may be producing the interictal phase of Meniere’s syndrome but not the ictal phase. Recently, Takumada et al. produced a mouse model with episodic vestib- ular dysfunction by using a combination of intratympanic injections of lipopolysaccharides and intraperitoneal injections of aldersterone.53 Intratympanic injections of epinephrine caused episodes of vestibular dysfunction in these ani- mals but not in controls or in animals that just received lipopolysaccharides or aldosterone. This suggests that an additional “stressor” is required to trigger episodes of vestibular dys- function with endolymphatic hydrops.

ETIOLOGY

Genetics

As noted earlier, the incidence of Meniere’s syndrome varies between populations in differ- ent continents, suggesting that genetic factors may be important in the pathophysiology. Between 5% to 15% of patients with Meniere’s syndrome report a ﬁrst-degree relative with Meniere’s syndrome.58,59 Morrison et al. reported 46 families from the United Kingdom with at least two affected family members (27 families with two affected members, 12 fami- lies with three affected members, 6 families with four affected members, and 1 family with ﬁve affected members).58 The mode of trans- mission was most consistent with autosomal dominant with reduced penetrance. Frykholm et al.60 reported a large Finnish family with Meniere’s syndrome in ﬁve generations. A genome-wide linkage scan of the family identi- ﬁed ﬁve candidate regions with a lod score greater than one. Two additional Finnish fami- lies with autosomal dominant Meniere’s syn- drome were analyzed for linkage to these regions and a cumulative lod score of 3.5 was obtained for a single region on chromosome 12p.61 Two of the three families shared a

1.7 Mb haplotype in the region, suggesting a common ancestral origin. However, so far no mutations have been found on chromosome 12p. Since mutations in the COCH gene can

produce a syndrome that is similar to Meniere’s syndrome, two groups screened the COCH gene for mutations in patients with Meniere’s syndrome but found no mutations.62,63 Single nucleotide polymorphism (SNP) analysis of candidate genes found associations between Meniere’s syndrome and variants in the potassium channelgenes KCNE1 and KCNE364 and host cell factor C1 gene,65 but these ﬁnd- ings have not been replicated in other patient populations.‌‌

Migraine and Meniere’s Syndrome

Speculation on an association between migraine and Meniere’s syndrome dates back to the ini- tial description by Meniere.1,2 Numerous stud- ies have found an increased prevalence of migraine in patients with Meniere’s syndrome compared to controls.66,67 Whether migraine mimics Meniere’s syndrome or causes Meniere’s syndrome is yet to be determined. Since there is a major genetic component to migraine, the small percentage of patients with familial Meniere’s syndrome could have an inherited migraine/Meniere’s syndrome.68 We compared the clinical features of patients with Meniere’s syndrome and migraine with those who had Meniere’s syndrome alone.69 Age of onset was earlier and bilateral symptoms and signs were signiﬁcantly more common in migraine/Meniere’s syndrome compared with Meniere’s syndrome alone. Forty percent of patients with migraine/Meniere’s syndrome had a family history of episodic vertigo compared to 2% of patients with Meniere’s syndrome alone. Inherited metabolic abnormalities shared by brain and inner ear could explain the combina- tion of brain and ear symptoms in patients with migraine/Meniere’s syndrome.

Infection/Autoimmune

Bacterial, viral, and syphilitic infections can lead to endolymphatic hydrops and typical symptoms and signs of Meniere’s syndrome. The hydrops presumably results from damage to the ﬂuid resorption mechanism due to inﬂammation and scarring of the endolym- phatic duct and sac. Paparella and Djalitian found that 75 of 194 temporal bones from patients with a history of otitis media showed

typical pathological features of endolymphatic hydrops.70 Bacterial endotoxins placed on the middle ear of chinchillas permeate the round window and cause inﬂammatory cell recruit- ment, strial swelling, and sensory cell degen- eration.71 Overt or subclinical viral infections could damage the resorptive mechanisms of the inner ear, leading to an eventual decom- pensation in the balance between secretion and absorption of endolymph.7,72 Infections in utero may lead to developmental hypoplasia of the endolymphatic duct and sac predisposing to later development of Meniere’s syndrome. Autoimmune injury to the endolymphatic sac may play an important role in the pathogenesis of Meniere’s syndrome.73 The endolymphatic sac is the only site that contains immuno- competent cells in the inner ear and is capable of mounting an active immune response if appropriately stimulated.

DIAGNOSIS

Audiometric Testing

The key to the diagnosis of Meniere’s syndrome is to document ﬂuctuating hearing levels in a patient with the characteristic clinical history. A shift of more than 10 to 15 dB at two differ- ent frequencies is required.74 In the early stages, the sensorineural hearing loss typically affects only the low frequencies (low-frequency trough) (Fig. 11–2). This is followed by a “peaked pattern” with a prominent low- frequency hearing loss, best hearing at 2000 Hz, and a fall-off again in the higher frequencies.75,76 The ﬂuctuation in hearing levels is usually most prominent in the low frequencies. Speech dis- crimination is relatively preserved and recruit- ment often occurs consistent with a cochlear site of dysfunction. Brainstem auditory-evoked response (BAER) and stapedius reﬂex mea- surements are typically normal. Otoacoustic emissions are often abnormal in patients with Meniere’s syndrome, particularly as the disease evolves.77 If the hearing loss is >30 or 40 dB at a given frequency, then the otoacoustic emis- sions are absent at that frequency, consistent with a cochlear origin for the hearing loss. Smaller amplitude otoacoustic emissions in the opposite “normal ear” may be an early indica- tor of bilateral involvement.78

125 250 500 1000 2000 4000 8000

Hearing level in dB

100

110

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SRT - 20 dB

Discrim - 100%

100

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SRT - 35 dB

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125 250 500 1000 2000 4000 8000

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125 250 500 1000 2000 4000 8000

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Figure 11–2. Series of audiograms from a patient with Meniere’s disease. This patient’s hearing loss was initially ﬂuctuant. With time, the loss became permanent and progressive. SRT, speech reception threshold.

Electrocochleography (ECoG) is a clinical test that was developed to aid in the diagnosis of Meniere’s syndrome, and the test has also added insights about the underlying pathophys- iological process.79 With ECoG, the cochlear microphonic (CM), summating potential (SP), and the eighth nerve compound action poten- tial (AP) are measured in response to brief acoustic stimulation (clicks, tone pips, and tone bursts) (see Fig. 8–5 in Chapter 8). Summating potential is superimposed on CM during steady-state pure-tone stimulation such as with a tone burst. It can be positive or negative depending on the frequency and intensity of the pure tone. The AP is the synchronized response of the auditory nerve to the transient acoustic stimulation. In patients with Meniere’s syndrome, the SP/AP ratio (amplitude or area under the curve) is often increased, largely because of an increase in SP. Large SPs are rarely seen with other types of sensorineural hearing loss, so the ﬁnding is relatively speciﬁc for Meniere’s syndrome.75 On the other hand,

an abnormal ECoG is not very sensitive for Meniere’s syndrome. About a third of patients with deﬁnite Meniere’s syndrome have normal ECoGs.80 An elevated SP/AP ratio is helpful for identifying patients with sudden low frequency hearing loss who will go on to develop Meniere’s syndrome.29,81 Overall, ECoG is not widely used as a clinical tool because it has not proved to be a valid tool for discriminating endolym- phatic hydrops from other causes of recurrent dizziness at the time of clinical uncertainty.

Many patients with Meniere’s syndrome note that their symptoms ﬂuctuate with the amount of ﬂuid intake. Dehydration of the patient, most commonly achieved with the glycerol test, can transiently reverse the low-frequency hearing loss in many patients with Meniere’s syndrome (particularly those who are experiencing ﬂuctuating hearing loss).75 This test has not received general acceptance, however, because some patients (<10%) will develop severe headaches with or without nausea and vomiting during the testing.

Other dehydrating agents such as urea, furo- semide, or mannitol have fewer adverse effects, but they are also less effective in elevating plasma osmolality. A minimum increase in osmolality of 10 millios-moles/kg is necessary for a valid test. The test is typically conducted with an oral dosage of glycerol of 1.5 ml/kg body weight in the fasting state together with an equal volume of water and a ﬂavoring agent. The maximum dehydration occurs about 90 min after the glycerol is ingested, which is the best time to check for a change in hearing on audiometry. One must monitor blood osmo- lality since, even with this standard dosage, between 10% and 15% of patients will not reach the critical change in osmolality. A posi- tive glycerol test requires a 15 dB pure-tone change and/or a 15% discrimination gain. A small percentage of patients actually have a worsening of hearing after glycerol, possibly because of glycerol entering the scala media and attracting ﬂuid and thereby increasing the degree of hydrops.‌‌

Vestibular Testing

Electronystagmography may reveal a periph- eral spontaneous nystagmus and either a ves- tibular paresis or directional preponderance on caloric testing. The degree of caloric paresis increases with the duration of disease, eventu- ally stabilizing at approximately 50% of the normal functional level. In one study, after 7 years of follow-up, 65% of patients had a reduced response, rising to 75% after 20 years.82 A complete loss of caloric responses is unusual with Meniere’s syndrome. Both VEMP and head-thrust tests can be abnormal with Meniere’s syndrome, but abnormalities on these tests are less frequent than caloric abnor- malities.83,84 It is more typical that the head- thrust test is normal with Meniere’s syndrome unless a destructive procedural has been per- formed.85 During an acute attack of Meniere’s syndrome, the nystagmus may be directed toward the involved ear, but this “wrong- direction nystagmus” may be a reversal phe- nomena due to central compensation, since if the episodes are monitored from the begin- ning, they typically begin with nystagmus in the opposite direction (i.e., fast component toward the good ear).86

Imaging

Radiologic studies of the temporal bones in patients with Meniere’s syndrome may show narrowing of the endolymphatic duct or decreased pneumatization of the temporal bone.87 However, these features are also seen in normal subjects and therefore are of limited value in the diagnosis of Meniere’s syndrome. On computed tomography (CT) scan, the endolymphatic duct and sac may be more dif- ﬁcult to visualize in patients with Meniere’s syndrome than in controls, but this is not a reli- able enough ﬁnding to be of diagnostic value. Contrast enhancement of the endolymphatic duct and sac on magnetic resonance imaging (MRI) has been reported in a few patients with Meniere’s syndrome, but again, this is not a consistent ﬁnding.88 MRI (3T) of endolymph and perilymph after intratympanic administra- tion of gadolinium is a promising although invasive technique for identifying endolym- phatic hydrops.88–90

MANAGEMENT

Medical Management

SYMPTOMATIC TREATMENT OF ACUTE SPELLS

Because the cause of Meniere’s syndrome is usually unknown, treatment is empiric. Medical management consists of symptomatic treatment of the acute spells (Table 11–1, also see Table 19–2 in Chapter 19) and long-term prophylaxis with salt restriction and diuretics. Phenergan at 25 to 50 mg, orally or via suppository, is usually effective for relieving the acute vertigo, nausea, and vomit- ing. It should be taken as soon as possible, pref- erably during the prodrome if there are reli- able warning symptoms. Intravenous diazepam or droperidol may be required for severe attacks with repeated vomiting. Meclizine is often adequate for milder attacks. Antiemetics such as prochlorperazine (Compazine) are sometimes useful if nausea and vomiting are severe. Hearing can be improved with aids that can be manually adjusted as hearing ﬂuctuates.91

Table 11–1 Dosage and Effects of Commonly Used Antivertiginous Medications

Class

Drug

Dosage

Sedation

Anti- emetic Actions

Dryness of Mucous

Membranes

Extra- pyramidal Symptoms

Anticholinergic

Scopolamine

0.6 mg orally

+++

−

q4–6 h or

0.5 mg transdermally q3d

Monoamingergic Amphetamine 5 or 10 mg

orally q4–6h

Ephedrine 25 mg orally q4–6h

− + + +

− + + –

Antihistamine Meclizine

(Antivert)

Dimenhydrinate (Dramamine)

Promethazine (Phenergan)

25 mg orally q4–6h

25–50 mg orally or IM q4–6h or 25–100 mg suppository q8h

+ + + −

++ ++ + −

Phenothiazine Prochlorperazine 5 or 10 mg orally + +++ + +++

(Compazine)

Benzodiazepine Diazepam

(Valium)

IM, intramuscularly; IV, intravenously.

PROPHYLAXIS

or IM q6h or 25 mg suppository q12h

5 or 10 mg orally, IM, or IV

q4–6h

+++ + − −

patients. We have seen patients who had had

No high-level evidence has demonstrated an average beneﬁcial effect of medical interven- tions for Meniere’s disease. The main problem is that there is a lack of high-quality randomized trials rather than negative results from adequate trials. Importantly, there are several options for medical management that are very reasonable to try even though high-level evidence is lack- ing, because these treatments have a very low risk of harm to patients and also very low cost.

One of the ﬁrst options to consider is an aggressive low-salt diet. The mechanism by which a low-salt diet may decrease the fre- quency and severity of attacks with Meniere’s syndrome is unclear, but there is some empiric evidence for its efﬁcacy.92,93 Though no average beneﬁcial effect has been demonstrated by randomized controlled trials,94 a low-salt diet seems to have a dramatic effect in some

severe disabling episodes on a weekly basis have prolonged remissions (years) on a low-salt diet. Other patients show little or no improve- ment, possibly reﬂecting the multifactorial pathogenesis of Meniere’s syndrome, though differences in adherence to the diet or placebo effects are also possible explanations. Since there are no common risks associated with a low-salt diet (other than inconvenience to the patient), we recommend salt restriction as the ﬁrst step in any patient felt to have Meniere’s syndrome. An adequate trial of a low-salt diet is restricting the salt to about 1 to 2 g/day for a minimum of 2 to 3 months, which is not an easy task. If a good response is obtained, then the level of salt intake can be gradually increased while symptoms and signs are carefully moni- tored. Fluid and food intake should be regu- larly distributed throughout the day, and binges

(particularly foods with high sugar and/or salt content) should be avoided. Occasionally, patients will notice that certain foods (e.g., alcohol, coffee, chocolate) may precipitate attacks. Diuretics (e.g., hydrochlorothiazide, 50 mg two times a day) may provide additional beneﬁt in some patients, although there also have been no adequately controlled studies to demonstrate an average beneﬁcial effect.95 When attacks reliably occur at the time of the menstrual period, a diuretic can be started 4–5 days before menses and discontinued after menses. Acetazolamide is a carbonic anhydrase inhibitor that has long been used to lower ocu- lar pressure with glaucoma. Some patients on acetazolamide report an improvement in symp- toms. How it potentially works in Meniere’s syndrome is unknown, although it may decrease endolymph production. Acetazolamide is also known to decrease cerebrospinal ﬂuid (CSF) secretion and was shown to decrease the osmotic pressure of the inner ear in experi- mental endolymphatic hydrops in guinea pigs.96 An average trial dose of acetazolamide for treating Meniere’s syndrome is 250 mg twice a day.97 Prophylactic use of betahistine has also been reported to decrease the frequency of Meniere’s attacks in an open, nonmasked trial,98 but as with other medical treatment options adequate trial data are lacking.99

Surgical Management

SHUNTS

Two different types of surgery have been used for treating Meniere’s syndrome: endolym- phatic shunts and destructive procedures. Although shunts are logical, based on the pre- sumed pathophysiology of Meniere’s syndrome, several factors limit the probability of achieving a functional shunt with this disorder.100 The most popular shunt procedure at the present time is used to drain the endolymphatic sac to the mastoid cavity. A major conceptual prob- lem with this procedure is that pathologic stud- ies of temporal bones in patients with Meniere’s syndrome show evidence of blockage of the endolymphatic pathways proximal to the endo- lymphatic sac. Furthermore, Schuknecht91 pointed out that any drain device that is implanted in the endolymphatic sac will almost certainly become rapidly encapsulated in

ﬁbrous tissue. Revision operations and tempo- ral bone studies in patients who have had shunts implanted have shown ﬁbrous encapsulation of shunt devices. Not surprisingly, there are con- ﬂicting reports regarding the clinical efﬁcacy of these surgical shunt procedures.101,102

PRESSURE PULSE TREATMENT

Recently a minimally invasive device was intro- duced for the treatment of Meniere’s disease. The device, called the Meniett device, uses a pulse generator to provide positive pressure into the ear canal. A tympanostomy tube is required so that the pressure is transferred into the middle ear. The idea for this sort of treat- ment was based on observation that changes in ambient pressure improve Meniere’s disease symptoms103; however, the mechanism by which the external pressure works to reduce vertigo attacks is not clear. One theory is that the intermittent pressure could decrease endo- lymphatic ﬂuid volume by forcing outﬂow into the endolymphatic sac. A randomized con- trolled trial of the Meniett device found a ben- eﬁcial effect in patients who had at least two vertigo attacks per month for the 2 months prior to enrollment.104 The results indicate that the control group had vertigo attacks on 13% of the days over the 4 months, whereas the treat- ment group had vertigo attacks on 7% of the days (p = 0.048). However, all of the beneﬁt of the device was seen in the ﬁrst 3 months because in the fourth month the frequency of vertigo attacks in the control group dropped down to that of the treatment group. The authors of a longer term follow-up study of the device argue that there is a beneﬁcial effect out to 2 years, but this study was uncontrolled, had a high dropout rate, and also problems with compliance with the device.105 As a result, pres- sure pulse treatment may have an important impact in reducing the frequency of vertigo attacks, but the effect appears to be moderate and also limited to only several months. This is a common theme in Meniere’s disease treat- ment since the natural history of the disorder is that vertigo episodes decrease in frequency over time.

DESTRUCTIVE PROCEDURES

The rationale for destroying the labyrinth in treatment of Meniere’s syndrome is that the

nervous system is better able to compensate for complete loss of vestibular function than for partial loss that is ﬂuctuating in degree. Ablative procedures can be a particularly good option in patients with unilateral involvement who have no functional hearing on the dam- aged side. This is because a unilateral severe hearing loss is the most valid indicator of the affected side and also because one of the most concerning risks of the procedure (i.e., hearing loss) is no longer a factor. Obviously, ablative procedures should not be considered if the abnormal side is not well deﬁned or if an impor- tant level of uncertainty still exists about the cause of the vertigo attacks. Severe vertigo is expected during the immediate posttreatment period, but most patients who follow a struc- tured vestibular exercise program can return to normal activity within 1 to 3 months (see Chapter 20).106 Ablative procedures generally should be avoided in elderly patients because the elderly have great difﬁculty adjusting to the vestibular imbalance.

A chemical labyrinthectomy can be achieved by introducing an ototoxic drug into the middle ear, where it will be absorbed into the inner ear via the round window or the angular ligament of the round window.107 Initially, streptomycin was used, but more recently gentamicin has been the drug of choice. The advantages of this procedure are that it can be done as an outpa- tient with minimal discomfort and the ototoxic effects can be titrated over multiple treatments so that the patient may gradually compensate for the unilateral vestibular loss with only mild dizziness symptoms. The main disadvantage is the marked variability in the rate of entry of the ototoxic drug into the inner ear in different patients and thus more heterogeneity in the clinical response compared with surgical labyrinthectomy. Some patients receiving gentamicin injections may show a severe oto- toxic effect after one or two doses, whereas

with some deﬁciencies in the design or report- ing of the trial.

The two main types of destructive surgery are labyrinthectomy and vestibular nerve sec- tion. Labyrinthectomy is useful only when there is no functional hearing on the damaged side since any remaining hearing cannot be spared with this procedure. The purpose of a labyrinthectomy is to remove the neural epi- thelium of the vestibular end organs.110 Sectioning the vestibular nerve, or vestibular neurectomy, has the advantage of preserving hearing in patients with salvageable residual cochlear function, but the risks of complication are greater than with labyrinthectomy.111 Again, adequate randomized clinical trials of either of these procedures are lacking. Though dramatic and immediate reductions in the frequency of vertigo attacks have been demonstrated in case series reports,112 the patients selected for these procedures are generally at the severe stages of the disorder and thus may not be far off from the late stage of the disorder when the fre- quency of the vertigo attacks drops substantially based on the natural history of the disorder. As a result, it may be that destructive surgical pro- cedures improve the time to remission of ver- tigo attacks but not the long-term outcome.

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Gates GA, Verrall A, Green JD, Tucci DL, Telian SA. Meniett clinical trial: long-term follow-up. Arch Otolaryngol Head Neck Surg. 2006;132:1311.
Takemori S, Ida M, Umezu H. Vestibular train- ing after sudden loss of vestibular functions. ORL J Otorhinolaryngol Relat Spec. 1985;47:76.
Hone SW, Nedelski JM. Selective chemical ablation as treatment for Meniere’s disease. In: Harris JP, ed. Meniere’s Disease. The Hague, Netherlands: Kugler Publications; 1999.
Stokroos R, Kingma H. Selective vestibular ablation by intratympanic gentamicin in patients with unilat- eral active Ménière’s disease: a prospective, double- blind, placebo-controlled, randomized clinical trial. Acta Otolaryngol. 2004;124(2):172.
Postema RJ, Kingma CM, Wit HP, Albers FW, Van Der Laan BF. Intratympanic gentamicin therapy for control of vertigo in unilateral Menire’s disease: a prospective, double-blind, randomized, placebo- controlled trial. Acta Otolaryngol. 2008;128(8): 876.
Glasscock ME, Davis ME, Hughes GB, Jackson GG. Labyrinthectomy versus middle fossa vestibular nerve section in Meniere’s disease. Ann Otol Rhinol Laryngol. 1980;89:318.
Silverstein H, Arruda J, Rosenberg S. Vestibular neurectomy. In: Harris JP, ed. Meniere’s Disease. The Hague, Netherlands: Kugler Publications; 1999.
Glasscock ME, Thedinger BA, Cueva RA, Jackson CG. An analysis of the retrolabyrinthine vs. the ret- rosigmoid vestibular nerve section. Otolaryngol Head Neck Surg. 1991;104:88.

Chapter 12 ‌‌‌‌

Migraine

BACKGROUND CLINICAL FEATURES

Migraine without Aura Migraine with Aura Migrainous Vertigo Basilar Migraine

Migraine and Meniere’s Syndrome Migraine Equivalents PATHOPHYSIOLOGY

Genetics

Spreading Wave of Depression

Vasomotor Abnormalities

DIAGNOSIS

Migraine without Aura Migraine with Aura

Migraine Aura without Headache Basilar Migraine

Migrainous Vertigo

MANAGEMENT

Symptomatic and Abortive Treatment Prophylactic Treatment

BACKGROUND

Migraine is a complex multigenetic disorder that renders one susceptible to vascular and chemical changes in the brain that can lead to many different symptoms.1 The hallmark fea- ture of the disorder is severe attacks of head- aches. However, migraine is also characterized by many other features, including dizziness, visual phenomenon, hypersensitivities to sen- sory stimuli, nausea, paresthesias, and even frank focal weakness in some cases.

Dizziness symptoms are among the most common symptoms reported by migraineurs. In some cases, the dizziness symptom is best characterized as a sensitivity to motion, a symp- tom that most patients with migraine are sus- ceptible to throughout their lives. Other times, patients use “dizziness” to label a vague and nonspeciﬁc symptom such as disorientation or difﬁculty focusing on a task. However, the diz- ziness of migraine can also be true and severe room-spinning vertigo. Migraine, in fact, is the great mimicker of all causes of vertigo because symptoms of it can closely resemble the attacks

of Meniere’s syndrome, benign positional ver- tigo, and even vestibular neuritis.

The association of migraine and dizziness extends back to the nineteenth century when Livening noted their connection in his classic book On Megrim: Sick Headaches and Some Allied Health Disorders.2 However, only in recent years has vertigo been recognized as a common migraine symptom. So-called migrain- ous vertigo or migraine-associated vertigo (ver- tigo caused by migraine) affects about 1% of the general population and about 10% of patients seen in dizziness clinics and in migraine clinics.3 The vertigo attacks can occur during the head- ache, but most often the attacks occur during headache-free intervals.4 Although the clinical association between migraine and dizziness is well documented, it is difﬁcult to prove a causal relationship between migraine and dizziness or, for that matter, between migraine and any of the other transient symptoms that accompany it. For example, scintillating scotoma is a well- known accompaniment of migraine and is uni- versally accepted as a migrainous phenomenon, yet its pathophysiologic link with headache is

287

still unknown after hundreds of years of clinical association. The nonspeciﬁc, highly varied nature of dizziness makes the relationship between migraine and dizziness even more dif- ﬁcult to characterize. Recent advances in our understanding of the genetics and pathophysiol- ogy of migraine provide new hope for improved understanding of the link between patients with periodic headaches and dizziness.5‌‌

CLINICAL FEATURES

Migraine without Aura

Migraine without aura can probably best be described as a “sick headache.” Vague pro- dromal symptoms precede it, but aura phe- nomena are absent. The headache, unilateral or bilateral, builds slowly in intensity and may go on for several days. Nausea, vomiting, diar- rhea, chills, and prostration can all accompany the headache. Nonspeciﬁc dizziness is a com- mon complaint, and patients frequently report visual blurring and a sense of unsteadiness dur- ing the entire headache phase. Vertigo can occur before, during, or entirely separate from the episodes of headache.4,6

There is still debate as to whether migraine without aura and migraine with aura are dis- tinct syndromes, different manifestations of the same disorder, or part of a continuum. Patients can have both types of headaches (with and without aura), and not infrequently, both types of migraine run in the same family (see later discussion). The headache phases of both types of migraine are almost identical, and the same treatments are usually effective in controlling both types of migraine. Conversely, certain epi- demiological characteristics, overall familial aggregation, and varying pathophysiologic ﬁnd- ings suggest the possibility that these two types of migraine represent separate entities.7,8

Migraine with Aura

The aura with migraine typically precedes the onset of a severe, throbbing, unilateral head- ache. The aura symptoms slowly progress over several minutes, last 15 to 60 minutes, and then gradually abate. In a small percentage of patients, however, onset is more abrupt.

The headache begins as the aura diminishes, usually reaching its peak in about an hour and then gradually subsiding over the next 4 to 8 hours. Nausea and vomiting typically accom- pany the onset of the head pain.

The migraine aura consists of transient neu- rologic dysfunction, often with visual distur- bances, but also commonly includes prominent vertigo or somatosensory symptoms. Both posi- tive and negative visual phenomena occur. The latter include complete blindness, hemianopsia or quadrantanopsia, tunnel vision, altitudinal defects, monocular blindness, or one or more scotomata. Positive phenomena are more com- mon and may consist of stars, sparkling lights, unformed ﬂashes of light (photopsia), geomet- ric patterns, or a jagged, sparkling zig-zag (teichopsia or fortiﬁcation spectra). Although usually black and white, the visual phenomena can be in color. The positive and negative visual phenomena are combined in the so-called scin- tillating scotoma. Patients describe a hole in their vision with a sparkling border. The sco- toma will begin in one hemiﬁeld but gradually enlarge and move across to involve the other hemiﬁeld, with the leading edge being a zig- zag of sparkling lights.9

Somatosensory symptoms, particularly par- esthesias, are another common aura manifesta- tion. Numbness, tingling, or both may affect the hands, lower face, or half of the body. A characteristic feature of migrainous paresthe- sias is a migration of the numbness as it gradu- ally spreads over the face or extremity, some- times migrating from face to extremity on the same side or sometimes crossing over to the face and extremity on the opposite side. In a small percentage of patients, the paresthesias will simultaneously appear in multiple sites or be localized to a small area such as a single digit, lip, or cheek. When focal neurologic symptoms such as hemianopsia or unilateral paresthesias occur in an aura, they usually occur on the side opposite that of the headache. Only about 12% of patients with migraine regularly experience aura with their headache, but as many as two- thirds have occasional attacks with aura.13

Migrainous Vertigo

Overall, episodic vertigo occurs in about 25% of unselected migraine patients.11 The vertigo attacks can occur during the headache, but

most often the attacks occur during the head- ache-free interval. Only about a quarter of patients reliably experience headaches with their vertigo.10 Migrainous vertigo can be spon- taneous or positional and attacks typically last from minutes to days.10,12 If examined during an attack patients may show spontaneous or positional nystagmus (either in isolation or in combination) and the nystagmus can have either central or peripheral features.13 Complicating matters further, benign posi- tional vertigo is more common in patients with migraine than in the general population (see Chapter 10).14 Migrainous positional vertigo can be differentiated from benign positional vertigo by (1) short-duration symptomatic epi- sodes, (2) migrainous symptoms during epi- sodes, and (3) atypical positional nystagmus.15

Auditory symptoms are generally considered to be less common than the vestibular symp- toms of migraine. Phonophobia is probably the most common auditory symptom associated with migraine, occurring at some time in more than two-thirds of patients, usually in associa- tion with headache.16 Most patients with migrainous vertigo have normal audiometric ﬁndings.17 Several investigators have identiﬁed ﬂuctuating low-frequency hearing levels in patients with migraine, which are typical of those seen in patients with Meniere’s syndrome.16,18,19 These episodes are most com- monly seen in young women around the time of their menstrual period and are usually com- pletely reversible. In the case of Meniere’s syn- drome, a progressive loss of hearing is required. Migraine has also been identiﬁed as the cause of sudden hearing loss that persists.20,21 Such patients report the abrupt onset of a profound hearing loss and may show some gradual improvement, but they are often left with a severe unilateral sensorineural hearing loss. Some patients with sudden hearing loss report a prior history of ﬂuctuating hearing in the same ear and many develop persistent tinnitus. Hearing loss and tinnitus can also be symptoms of migrainous infarction.22

Basilar Migraine

Basilar migraine is a subtype of migraine with aura characterized by recurrent headaches, usu- ally localized to the occipital region, preceded by multiple neurological symptoms localized to

Table 12–1 Most Common Symptoms in 49 Patients with Basilar Migraine

Symptom Cases (%)

Headache (usually occipital)	96
Nausea	83
Vomiting	71
Vertigo	63
Gait ataxia	63
Paresthesias (usually bilateral)	61
Dysarthria	57
Weakness (usually bilateral)	55
Tinnitus	26
Impaired hearing	20
Double vision	16

the posterior fossa (Table 12–1).23,24 The aura consists of posterior fossa symptoms such as vertigo, ataxia, dysarthria, and tinnitus along with visual phenomena consistent with ischemia in the distribution of the posterior cerebral arteries. Motor and sensory symptoms, such as circumoral or extremity paresthesias, weakness, and drop attacks, are occasionally seen as well. When vertigo occurs it usually has an abrupt onset and lasts 5 to 60 minutes. The headache following the aura is usually unilateral occipital or frontal, but it can occur anywhere, especially in children.

Basilar migraine affects about 10% of patients suffering from migraine with aura.24 One must be alert for the possibility of basilar migraine in any patient presenting with transient vertigo and other posterior fossa symptoms.25 In some individuals, the headache is not severe and is adequately managed by aspirin, sleep, or mild analgesics and sedatives. Some of these patients are unaware that migraine is the cause of their headaches and are much more concerned about the aura. If vertigo is prominent, the patient may not mention the headache, think- ing it is unimportant. Similarly, other transient manifestations may be given less importance than that given the vertigo. Such patients may be misdiagnosed as having a peripheral labyrin- thine disease if the physician is not alert to the possibility of basilar migraine.

Migraine and Meniere’s Syndrome

Speculation on a relationship between migraine and Meniere’s syndrome dates back to the initial

description of the syndrome by Prosper Meniere in 1861.26 He noted that both conditions com- monly manifested episodes of vertigo, ﬂuctuat- ing hearing levels, and recurrent vomiting. Although many subsequent authors have also speculated on the relation between migraine and Meniere’s disease, there is still no generally accepted mechanism to explain the connec- tion.27–29 Diagnostic criteria have been estab- lished for both migraine and Meniere’s disease, but some of the criteria overlap. For example, the key diagnostic feature for Meniere’s syndrome is a ﬂuctuating, low-frequency sensorineural hearing loss that many clinicians consider pathognomonic for Meniere’s syn- drome. As noted earlier, however, ﬂuctuating low-frequency hearing loss can occur in patients with migraine. Although headache is the most common symptom of migraine, visual aura or episodes of vertigo can occur without headache. Therefore, even when using strict diagnostic cri- teria, it may not always be possible to separate the two conditions on clinical grounds alone.

Although most authors agree that there is an increased prevalence of migraine in patients with Meniere’s syndrome compared with the general population, the overall percentage of Meniere’s patients with migraine varies from study to study.30 A recent study that used cur- rent criteria for the diagnosis of migraine and Meniere’s syndrome found a lifetime preva- lence of migraine (with or without aura) of 56% in patients with Meniere’s syndrome compared to 25% in controls.31 Furthermore, 45% of patients with Meniere’s syndrome experienced at least one migrainous symptom (headache, photophobia, aura) with their Meniere’s attacks. Genetic factors are likely important for both disorders since migraine and Meniere’s syndrome tend to cluster in families.32 In three sets of twins in these families one twin had migraine and Meniere’s syndrome while the other twin had migraine and migrainous ver- tigo (without auditory symptoms).

Numerous studies have documented that migraine can lead to permanent auditory and vestibular deﬁcits.4,33–35 Since Meniere’s syndrome can develop in an ear previously damaged by infection or trauma, another explanation for the association between migraine and Meniere’s syndrome is the devel- opment of endolymphatic hydrops in an ear previously damaged by migraine. For example, the vasospasm could lead to ischemic damage

to the endolymphatic duct and/or sac, resulting in impaired ﬂuid circulation and the eventual development of hydrops. One would then expect a gradual progression of the disease typ- ical of Meniere’s syndrome of any cause.

Migraine Equivalents

BENIGN PAROXYSMAL VERTIGO OF CHILDHOOD

Basser36 described an episodic disorder in chil- dren under the age of 4 years that he called benign paroxysmal vertigo. A completely nor- mal child suddenly becomes frightened, cries out, clings to the parent, or staggers as though drunk, and exhibits pallor, diaphoresis, and often vomiting. Symptoms are accentuated by head movements, and sometimes nystagmus and torticollis are observed. Some children report a true spinning sensation, but most have difﬁculty describing what they are experienc- ing. The spells typically last for several minutes. Afterward, the child is immediately normal and can resume playing as though nothing has happened.

Vertigo spells typically begin before the age of 4 years and occur up to several times a month. After several years, they decrease in number and often gradually disappear. Many children have no further spells after the age of 7 or 8. The cause of benign paroxysmal vertigo of childhood is unknown, although most have a positive family history of vertigo or migraine.37 Follow-up studies of patients with typical benign paroxysmal vertigo during childhood show that nearly all patients eventually develop other features typical of migraine.38,39

VESTIBULAR MENIERE’S SYNDROME

In their initial recommendations on criteria for the diagnosis of Meniere’s disease, the American Academy of Ophthalmology and Otolaryngology Committee on Hearing and Equilibrium deﬁned vestibular Meniere’s syn- drome as recurrent attacks of vertigo without associated auditory symptoms. It was assumed that most of these patients would progress to manifest all of the symptoms of classical Meniere’s syndrome. However, because there are so many causes for recurrent episodic ver- tigo other than Meniere’s syndrome, more

recently the American Academy of Otolaryn- gology Head and Neck Surgery Committee on Hearing and Equilibrium recommended dis- carding the term vestibular Meniere’s disease. Rassekh and Harker28 followed up 38 patients with a diagnosis of vestibular Meniere’s syn- drome using a standard questionnaire. Seventeen of the 38 no longer fulﬁlled the cri- teria for the diagnosis of vestibular Meniere’s syndrome at follow-up. Of these, eight went on to develop unilateral Meniere’s syndrome and seven became asymptomatic. Of the 21 patients who continued to meet the criteria for vestibu- lar Meniere’s syndrome, 17 (81%) had migraine headaches. Overall, this study suggests that only a small percentage of patients who present with recurrent episodes of vertigo typical of vestibular Meniere’s syndrome go on to develop the classical symptom triad of Meniere’s syn- drome, whereas the majority are associated with migraine.

BENIGN RECURRENT VERTIGO OF ADULTHOOD

Slater40 and Moretti et al.41 described patients who, between the ages of 7 and 55 years, began to experience repeated episodes of vertigo, nausea, vomiting, and diaphoresis. The attacks often occurred on awakening in the morning, being particularly common around menses in women. Duration varied from a few minutes to as long as 3 to 4 days, with the vertigo becom- ing primarily positional toward the end of the spell. Nearly all patients were asymptomatic between spells. During episodes, there were no auditory symptoms, speciﬁcally no hearing loss, tinnitus, or ear pressure or fullness. Most patients either had migraine themselves or a strong family history of migraine. Furthermore, the episodes of vertigo had several features in

common with migraine, including precipitation by alcohol, lack of sleep, emotional stress, and a female preponderance.

We studied the families of 24 adults who presented to our clinic with benign recurrent vertigo and who reported a family history of similar attacks of vertigo.42 All probands under- went diagnostic evaluation to exclude identiﬁ- able causes of recurrent vertigo and they completed a standardized medical question- naire pertaining to episodic vertigo and the fea- tures of migraine. This questionnaire was also sent to all relatives of the probands who agreed to participate. Of 220 relatives who returned questionnaires, 37% reported BRV and 50% met the diagnostic criteria for migraine (Table 12–2). By contrast, only one of 43 (2%) unre-

lated spouses reported BRV and 10 of 43 (23%) met the diagnostic criteria for migraine. More than two-thirds of relatives with BRV met the diagnostic criteria for migraine and the majority reported that they had a typical migraine headache with at least some of their episodes of vertigo. Both benign recurrent vertigo and migraine showed a female prepon- derance (more than 2 to 1). Familial benign recurrent vertigo appears to be a migraine syn- drome, probably inherited in an autosomal dominant fashion with decreased penetrance in men.

OTHER MIGRAINOUS PHENOMENA

In young children the manifestations of migraine are protean, and headache is not always present.43 Migraine equivalents may appear as cyclic vomiting, attacks of abdominal pain, or even ophthalmoplegia. As the child matures, these nonspeciﬁc and other puzzling symptoms may cease and be supplanted by more typical paroxysmal head pain.

Table 12–2 Incidence of Vertigo and Migraine in Probands, First Degree Relatives (Parents, Siblings, Children), All Relatives, and Unrelated Spouses

	Totala	Benign recurrent vertigo	Migraine	Both
Probands	24	24 (100%)	20 (83%)	20 (83%)
First degree relatives	111	44 (40%)	51 (46%)	31 (28%)
All relatives	220	82 (37%)	110 (50%)	59 (27%)
Unrelated spouses	43	1 (2%)	10 (23%)	0 (0%)

a Those who returned questionnaires. (From Oh AK, Lee H, Jen JC, Corona S, Jacobson KM, Baloh RW. Familial benign recurrent vertigo. Am J Med Genet. 2001;100:287 with permission.)

Symptoms of migraine equivalents can also begin in adulthood. Isolated episodes of scintil- lating scotomas are not uncommon after the age of 40. Fisher44 reported 60 patients with what he called “transient migrainous accompa- niments,” which were attacks of paresthesias, aphasia, dysarthria, paresis, and diplopia with or without the visual manifestations of migraine. None of these patients had headache. Normal angiography, long-term follow-up, and, in a few cases, necropsy, suggested a migrainous syndrome despite the absence of associated headaches.‌‌

PATHOPHYSIOLOGY

Genetics

Although it is clear that some varieties of migraine are inherited, it is not clear whether migraine is a single syndrome or a variety of syndromes, some of which are inherited and some of which are not.45 The situation is analo- gous to the epilepsy syndromes. Some seizure syndromes are inherited and genetic factors are important for most types of epilepsy, but anyone can have a seizure with adequate prov- ocation. Similarly, several inherited syndromes are associated with migraine headache, and genetic factors are important in determining the threshold for migraine headaches, but structural lesions such as vascular malforma- tions and vasculopathies can trigger migraine headaches in anyone. Genotype heterogeneity has already been established for several migraine syndromes. These syndromes are deﬁned based on the presence of hemiplegic episodes or other aura symptoms that accom- pany migraine headaches. Within such fami- lies, however, some members may have only migraine headaches, indicating that there is also phenotypic heterogeneity. Not surpris- ingly, since headache is the least speciﬁc symp- tom of the different migraine syndromes, the genetic basis for migraine without aura has been more difﬁcult to establish.

Numerous studies over the years have docu- mented familial aggregation of migraine, and some neurologists have suggested that a posi- tive family history should be part of the diag- nostic criteria.46,47 In nearly all studies, the inci- dence of a positive family history in patients

with migraine headaches was signiﬁcantly greater than in controls. The incidence of a positive family history varied from approxi- mately 40% to 90% compared with approxi- mately 5% to 20% in controls. The percentage of positive family histories tended to be greater in those studies in which family members were individually interviewed than in studies that relied on questionnaires or on the recall of the proband. Studies in monozygotic and dizygotic twins have also supported a strong genetic component for migraine, particularly for migraine with aura. Also, the fact that the prev- alence of migraine in African and Asian popu- lations is lower than in European and North American populations favors a major genetic component. Studies of migrainous vertigo show the same familial aggregation seen in other migraine syndromes.48–50

RARE MIGRAINE SYNDROMES WITH KNOWN GENETIC CAUSES

The recent identiﬁcation of the genes for sev- eral rare subtypes of migraine may provide the ﬁrst true molecular insight into migraine pathophysiology. Within families with these relatively rare syndromes, some members will have only MO or MA, suggesting that these more common migraine syndromes may have a similar pathophysiologic mechanism.

Familial hemiplegic migraine (FHM) is an autosomal dominant disease characterized by headache attacks preceded by or accompanied by episodes of hemiplegia, sometimes lasting days.51 Within reported families with FHM, some affected members have interictal nystag- mus, ataxia, essential tremor, and seizures. MA and episodes of hemiplegia may alternate within individuals and co-occur within families. Based on this observation, Russell and Olesen52 concluded that the pathophysiology and etiol- ogy of FHM and other more common uncom- plicated migraine variants may be similar. By contrast, after comparing clinical features of patients with MA and patients with FHM, Thomsen et al.53 concluded that hemiplegic migraine is a separate entity from MA. Haan et al.54 suggested the FHM may be a hereditary form of basilar migraine. They studied aura symptoms in 83 patients from six unrelated families with FHM and found that 55 of the patients reported symptoms that met the International Headache Society (IHS) criteria

for basilar migraine. Consistent with this inter- pretation, angiography performed during an FHM attack showed spasm of the basilar artery.

So far, mutations in two genes have been identiﬁed in FHM: CACNA1A55 and ATP1A2.56 Both of these genes code for the transmem- brane component of a neuronal ion channel. Although there is overlap in clinical features, most families with FHM due to mutations in CACNA1A have progressive ataxia and interic- tal nystagmus,55,57 while the families reported with mutations in ATP1A2 had associated epi- leptic seizures.56 All of the mutations in CACNA1A associated with FHM have been missense mutations.57 Nonsense mutations in the same gene produce a related disorder, epi- sodic ataxia type 2 (EA-2), which is also associ- ated with migraine headaches.55,58 In some families there can be an overlap between epi- sodes of hemiplegia and episodes of ataxia.59 In families with mutations in either FHM gene, some members can have just MO or MA as the only manifestation.56,57

Some families with FHM are not linked to either the CACNA1A locus on chromosome 19p or the ATP1A2 locus on chromosome 1q.60 Terwindt et al.61 screened the CACNA1A gene for mutations in 27 patients with sporadic hemiplegic migraine and found only two muta- tions (one patient had ataxia and interictal nys- tagmus, while the other had no cerebellar signs). Jen et al.62 screened 19 patients with hemiplegic migraine (8 familial and 11 spo- radic) for mutations in CACNA1A and ATP1A2 and found only a single mutation in CACNA1A in one of the sporadic cases (who also had cer- ebellar ataxia). Of the approximately 40 FHM familieswithidentiﬁedmutationsin CACNA1A, about half had the T666M mutation. Most of the patients with the T666M mutation also have symptoms and signs of cerebellar ataxia, although there is a broad clinical spectrum.63 Likely mutations in several other genes will be identiﬁed, particularly in cases of sporadic hemiplegic migraine.

CANDIDATE GENES FOR COMMON MIGRAINE SYNDROMES

Within families with known mutations in CACNA1A or ATP1A2, some members have just MO or MA. Furthermore, linkage studies performed in a few large families with MO or

MA inherited in an autosomal dominant fashion found linkage to the 19p and 1q loci of these two genes.64,65 However, Kim et al.66 and Wieser et al.67 could not ﬁnd mutations in CACNA1A in patients with these common migraine syndromes. Jen et al.62 screened

50 probands from families with migraine (7 basilar migraine, 25 MO, 18 MA) and did not ﬁnd any mutation in either CACNA1A or ATP1A2. Based on this preliminary data, it does not appear that CACNA1A or ATP1A2 is important for the common migraine syndromes.

One way to explain the heterogeneity of migraine syndromes is to postulate a group of defects in genes that code for a family of pro- teins with similar properties and functions. The family of ion channels is appealing because many of the migraine syndromes share the clinical features of known inherited ion channel disorders (Table 12–3). A defective ion channel could explain the local buildup of extracellular potassium that initiates the spreading wave of depression in migraine (see later discussion). Since ion channels in the inner ear are critical for maintaining the potassium-rich endolymph and neuronal excitability, a defective ion channel shared by the brain and inner ear could lead to a reversible hair cell depolarization and auditory and vestibular symptoms. Further- more, many of the well-known triggers for migraine symptoms, including stress and menstruation, could result from hormonal inﬂuences on the defective ion channels. Finally prophylactic drugs such as beta blockers, calcium channel blockers, aceta- zolamide, and tricyclic amines might work by stabilizing abnormal ion channels. Acetazol- amide may work in episodic ataxia type 2 by changing cerebellar pH and stabilizing calcium channels.68

Table 12–3 Clinical features shared by known inherited ion channel disorders

Autosomal dominant inheritance Reduced penetrance

Periodic symptoms

Episodes triggered by stress, exercise May have no interictal ﬁndings Response to acetazolamide

Spreading Wave of Depression

Probably the most characteristic of migraine symptoms is the classic visual aura. It typically begins with a small scintillating scotoma that gradually enlarges over 20 to 30 minutes. There is convincing evidence that the visual aura is secondary to a spreading wave of cortical depression beginning at the occipital pole, which gradually spreads across the cortex before stopping at the central sulcus.69 Although decreased cerebral perfusion is associated with the spreading wave of depression, it is probably a secondary phenomenon rather than a primary process.70 The spreading wave of cortical depression is associated with a marked accu- mulation of extracellular potassium that must be cleared before neural activity can return to normal. Although the exact mechanism for the spreading wave of depression is not known, most agree that the initial event is local buildup of potassium in the extracellular space.

Nearby synaptic terminals then depolarize in response to the high extracellular potassium, and both excitatory and inhibitory neurotrans- mitters are released. This release in turn leads to the opening of subsynaptic channels, result- ing in further ionic exchange between the intracellular and extracellular ﬂuids. During the spreading wave of depression, neurons are completely silent for approximately 1 minute and they then slowly recover their predepres- sion level of ﬁring. The rate of movement of the spreading wave of depression across the visual cortex (measured with functional mag- netic resonance imaging [MRI]) nicely corre- lated with the rate of enlargement of the scintillating scotoma observed by patients.71 A spreading wave of cortical depression was observed on positron emission tomography (PET) in a patient having a typical migraine headache without aura.72

Consistent with a basic neuronal defect, patients with migraine have cortical abnormali- ties not only during their attacks but also in the interictal period. Paroxysmal slowing on interictal electroencephalographs (EEG) is commonly seen in migraine, and the classical association of migraine and epilepsy is well documented.73 Interestingly, identical paroxys- mal slowing on EEG is seen in patients with EA-2. Magnetic resonance spectroscopy shows decreased interictal energy metabolism in the cortex of patients with migraine with or

without aura.74,75 Single-photon emission com- puted tomography (SPECT) and other tech- niques for measuring cerebral blood ﬂow have shown areas of regional hypoperfusion, not only during migraine attacks but also in the interictal phase.76 These changes were found in migraine without visual aura, with visual aura, and with episodes of hemiplegia. Acetazolamide reversed these interictal areas of hypoperfu- sion in all three classes of migraine patients.

How does the spreading wave of depression and associated increase in extracellular potas- sium lead to a typical migraine headache? Trigeminal nerve ﬁbers surrounding pial arter- ies on the ventral surface of the brain could be depolarized by the high potassium concentra- tion.77 This in turn would lead to the release of neurotransmitters such as substance P and cal- citonin gene–related peptide (CGRP) by both orthodromic and antidromic conduction. The result is an increase in vascular permeability, dilatation of cerebral vessels, and a local inﬂam- matory response further activating pain- provoking ﬁbers of the trigeminal vascular sys- tem. Thus, the headache of migraine could be a secondary phenomenon, the end result of a local increase in extracellular potassium con- centration. Many of the drugs used for prophy- lactic treatment of migraine have been shown to suppress the cortical spreading wave of depression in an animal model of migraine.78

Vasomotor Abnormalities

Vasomotor abnormalities have long been con- sidered in the pathophysiology of migraine symptoms. Vasodilatation of extracranial ves- sels accompanies the typical migraine head- ache. Vasospasm occurs in some intracranial vessels with migraine, although there is contro- versy regarding its role in the production of symptoms. Although vasospasm is associated with the classical migraine visual aura, most likely, vasospasm results from a metabolic defect slowly spreading across the cerebral cortex and is secondary to hypometabolism. Vasospasm is more likely a cause of retinal migraine.79 Some patients experience episodes of monocular blindness, and when examined during these episodes there is vasospasm of retinal arteries. Furthermore, such patients respond to antispasmodic agents.80,81 Sudden episodes of hearing loss and/or vertigo

associated with migraine could be explained by the vasospasm of the cochlear and/or vestibular branches of internal auditory artery.‌‌

It is interesting to note that MRI studies in migraine patients found an increased preva- lence of small white matter hyperintensities, particularly involving the cerebellum and brain stem, compared to non-migraine control sub- jects.82–84 (Fig. 12–1).Though these are nonspe- ciﬁc ﬁndings, a leading hypothesis is that these

lesions reﬂect ischemia which could be related to vasospasm.

DIAGNOSIS

The diagnosis of migraine is relatively easy when headaches are the major feature and there is a strong family history. In patients in

Figure 12–1. Cerebellar lesions in patients with migraine from the CAMERA study. Corresponding magnetic resonance T2-weighted (left) and ﬂuid-attenuated inversion-recovery images (right) showing cerebellar infarct-like lesions (arrows) in four representative cases. (Kruit et al. Brain. 2005;128:2068-2077, with permission)

whom headache is less prominent or in patients with migraine equivalents, the diagnosis can be missed if one is unaware of the diversity of this syndrome.

Migraine without Aura

The criteria for the diagnosis of migraine with- out aura, established by the IHS, are summa- rized in Table 12–4.85 The patient must have had at least ﬁve headache attacks that meet the criteria and other causes of headache must be ruled out. If they meet all but one criteria they are designated as probable migraine. No labo- ratory or radiological ﬁndings are speciﬁc for migraine. The physical and neurological exami- nations are normal and serve primarily to exclude other causes of headache. A classic migraine attack typically has ﬁve phases: a prodrome (e.g, depression, cognitive dysfunc- tion, food craving), aura (e.g, visual, sensory, or motor phenomena), headache (usually unilat- eral and throbbing), resolution (when pain wanes), and recovery.86 None of these phases is obligatory for the migraine diagnosis, however. Symptoms (severity, duration, nature of pro- drome or aura) also vary substantially between individuals. Thus, the diagnosis of migraine is based on a combination of sequentially occur- ring symptoms in paroxysmal attacks. Motion sickness is often the ﬁrst symptom of migraine

Table 12–4 Diagnostic Criteria for Migraine without Aura

At least ﬁve attacks fulﬁlling B–D
Headache lasts 4–72 hr (untreated)
Headache has at least two of the following features:
Unilateral Pulsating
Moderate or severe (inhibits or prohibits daily activities)
Aggravated by walking, stairs, or similar physical activities
During headache at least one of the follow- ing:
Nausea and vomiting Photophobia and phonophobia
Other causes of headache have been ruled out

Source: Adapted from International Headache Society.85

in children and has been recommended for inclusion as another minor criterion for the diagnosis.87

Migraine with Aura

The IHS Headache Classiﬁcation Committee deﬁned migraine with aura as “an idiopathic recurring disorder manifesting with attacks of neurological symptoms unequivocally localiz- able to cerebral cortex or brain stem, usually gradually developed over 5 to 20 min and usu- ally lasting less than 60 min.”85 Visual symp- toms, including the classic scintillating scotoma and fortiﬁcation spectra, are the most com- monly recognized aura phenomena, but somatosensory and vestibular symptoms are probably equally common.

Migraine Aura without Headache

Although less common, migraine aura without headache is of particular interest from a neurotologic point of view. The occurrence of migraine aura without headache has been rec- ognized for many years, although this contin- ues to be a difﬁcult concept for both patients and physicians to deal with. Some patients will have isolated aura symptoms at one point in their life and typical migraine headaches at another point. In some patients the aura symp- toms occur alone on occasion and with typical headaches on other occasions. Some have only aura symptoms and never experience a head- ache. Terms such as migraine equivalent and migraine accompaniment have been used to describe these isolated aura symptoms, but a diagnosis is difﬁcult to arrive at without the presence of typical headaches at some time during the course.

Basilar Migraine

In 1961, Bickerstaff described a subset of migraine with aura characterized by a combi- nation of symptoms that he felt reﬂected isch- emia within the distribution of the basilar artery.88 Most of Bickerstaff’s patients were adolescent girls, but subsequent reports have conﬁrmed that basilar migraine can occur in both sexes at any age. Vertigo, tinnitus, and

decreased hearing are common symptoms with basilar migraine and could confound the dif- ferential diagnosis between basilar migraine and Meniere’s syndrome since these same symptoms are characteristic of the latter dis- ease. The IHS criteria for the diagnosis of basi- lar migraine require an aura that contains two or more of the symptoms listed in Table 12–1.85 Patients with isolated episodes of vertigo do not meet the criteria for basilar migraine.

Migrainous Vertigo

The IHS currently does not have criteria for the diagnosis of migrainous vertigo. However, Neuhauser and Lempert have suggested crite- ria that are becoming generally accepted.3,6 The criteria include the following: (1) recur- rent vertigo attacks, (2) migraine according to IHS criteria, (3) migrainous symptoms during at least two vertiginous attacks (headache, pho- tophobia, phonophobia, or aura symptoms), and (4) vertigo cannot be attributed to another disorder. Patients who meet criteria 1, 2, and 4, but not 3 are considered probable migrainous vertigo. Using these criteria in a screen of the general population in Germany, Neuhauser et al.10 concluded that migrainous vertigo is underdiagnosed and has considerable personal and health-care impact.‌

MANAGEMENT

Treatment of migraine can be divided into three general categories: symptomatic, abor- tive, and prophylactic. Some drugs are useful in ameliorating the symptoms of the acute attack, others can abort an attack if taken just after the onset, and still others are effective in reducing the frequency and severity of attacks or eliminating their occurrence entirely.

Before embarking on drug treatment of migraine, it is important to recognize that there are many common triggers for migraine symp- toms (Table 12–5). It is often helpful to have the patient keep a log of his or her migraine attacks, noting any possible triggers that might be regularly associated with the attacks. Though rigorous clinical trials are lacking, knowledge of triggers and focusing on general lifestyle fac- tors can go a long way in reducing the burden

Table 12–5 Common Factors that Trigger Migraine Symptoms

Stress, emotional upset

Hormones: menstruation, oral contraceptives, pregnancy

Sleep deprivation

Food: red wines, fermented cheeses, chocolate, coffee

Eating disorders: fasting, binges

of migraine symptoms in many patients. The general lifestyle factors that are important include stress management, good quality sleep, awareness of food-related factors, and cardio- vascular exercise. As a general rule, migraineurs have fewer symptoms when following a regi- mented schedule to ensure all of these factors are adequately addressed. These factors are perhaps more important for the management of migrainous vertigo than for migraine head- aches because there are no good trials of the effect of abortive or prophylactic medication treatment for migrainous vertigo, whereas there are adequate trials demonstrating the efﬁcacy of medicines to manage migraine headaches. Although we presume similar mechanisms cause headaches and vertigo, we cannot presume the same beneﬁt of these medications.

Symptomatic and Abortive Treatment

Symptomatic and abortive treatment for migrainous symptoms largely depends on which symptoms the patient is most bothered by. Headache symptoms, by far, have the most research to support the use of medicines, and society guidelines have been published. 89 The treatments available for acute attacks of migraine headaches include serontonin recep- tor agonsists (i.e, triptans), antiemetics, analge- sics, and combination preparations.

Clinical trials of abortive therapies for head- aches have also demonstrated that the medi- cines can reduce other symptoms of migraine attacks, including hypersensitivities (photopho- bia and phonophobia) and nausea. 90 However, no good clinical trial data exist to support the effect of abortive therapies for migraine vertigo. Only one randomized controlled trial

has been published on the treatment of migrainous vertigo with a triptan medication, but this trial had substantial limitations mainly stemming from the very few subjects enrolled.91 In this trial, 3 out of 8 patients randomized to zolmitriptan met the endpoint of vertigo symp- tom improvement at 2 hours, compared with 2 out of 9 patients taking placebo. Thus, the number of participants was much too small to make any conclusions about the effect of zol- mitriptan.

Symptomatic treatment of the vertigo attacks has also not been well studied speciﬁcally in migraine vertigo. As a result, migraine vertigo is managed symptomatically the same way that vertigo in general is managed. Antivertiginous and antiemetic medications are useful in reduc- ing the severity of the symptom (see Tables 19–2 and 19–3 in Chapter 19). Promethazine at 25 or 50 mg, orally or via suppository, is par- ticularly effective for the relief of both vertigo and nausea. Drugs in this class also have a sed- ative effect, which is probably one of the main reasons for a positive effect in patients with severe vertigo. However, the sedating effect typically limits the use of these medicines for less severe attacks. The decrease in gastric motility that occurs during migraine attacks can decrease the absorption of oral drugs as well as contribute to the nausea and vomiting. Metoclopramide (Reglan) promotes normal gastric motility and may improve absorption of oral drugs.

Prophylactic Treatment

Many studies of prophylactic treatments have demonstrated an average improvement in headache severity and frequency in patients with migraine headaches89 (Table 12–6). But, as with abortive and symptomatic treatments, no good trials of prophylactic agents have been conducted to measure the effect on vertigo attacks in a population of patients with migraine vertigo. As a result, we do not know whether migraine prophylactic medications are beneﬁ- cial in patients with migraine vertigo.

A general sentiment exists in clinical care that migraine prophylactic medicines can be effective in reducing the frequency and severity of migraine vertigo attacks, but this sentiment is based on anecdotes and observa- tional studies. In the absence of data from rig- orous clinical trials, it is a large—and poten- tially dangerous—leap to assume that a therapy is effective.

All of the prophylactic treatment studies in migraine vertigo have profound shortcomings. In fact, no control groups were even used in any of the prophylactic treatment studies iden- tiﬁed in a recent review on migraine vertigo.92 Not using control groups is a major shortcom- ing because of the natural tendency for symp- toms such as vertigo attacks to improve over time in the absence of any treatment. In fact, close to 50% (9 out of 19) of the patients expe- rienced spontaneous remission (i.e, no attack

Table 12–6 Common Drugs for Treating Migraine

Class Actions Sample Drugs

Serotonergic 5HT1 agonist Sumatriptan

5HT2 antagonist Dihydroxyergotamine

5HT reuptake inhibitor Methysergide, amitriptyline, ﬂuoxetine

Dopaminergic DRD2 antagonist, ion channel stabilization Prochlorperazine,a metoclopramidea Beta blockers 5HT2 antagonist Propranolol, atenolol

Calcium channel blockers

Non-steroidal

anti-inﬂammatory

Ion channel stabilization, neuronal protection, DRD2 antagonist

Prostaglandin suppression, neurogenic

inﬂammation

Flunarizine, nimodipine Aspirin, naproxen, ibuprofen

Anticonvulsants Ion channel stabilization, neuronal

inhibition

Valproate, gabapentine, topiramate

Carbonic anhydrase inhibitors

Ion channel stabilization Acetazolamide

aCan be used for both symptomatic and prophylactic treatment.

or very mild attacks) in the trial of zolmitriptan for migraine vertigo attacks.91 The authors spe- ciﬁcally point out that three of these patients had 10 or more attacks of vertigo within 12

Lempert T, Neuhauser H. Epidemiology of ver- tigo, migraine and vestibular migraine. J Neurol. 2009;256(3):333.
Cutrer FM, Baloh RW. Migraine-associated dizziness.
months prior to enrollment but then did not have even a single attack during the following 15 to 24 months. If no control group is used, then any “intervention” could appear to have a
Headache. 1992;32:300.
Baloh RW, Jen JC. Genetics of familial episodic ver- tigo and ataxia. Ann NY Acad Sci. 2002;956:338.
Neuhauser H, Lempert T. Vestibular migraine. Neurol Clin. 2009;27(2):379.
Rasmussen BK. Epidemiology of migraine. In:
treatment effect, which of course is the reason placebo-controlled trials are necessary.
When an important level of uncertainty exists about the potential beneﬁts of a therapy, then
Olesen J, Tfelt-Hansen P, Welch KMA, et al. eds. The Headaches. 3rd ed. Philadelphia: Lippincott, Williams and Wilkins; 2006.
Rasmussen BK, Olesen J. Migraine with aura and
the impact of the potential harms naturally increases. The main potential harms of migraine prophylactic agents include side effects and the associated costs of the medicines.
Despite the evidence void, physicians must
migraine without aura: an epidemiological study.
Cephalalgia. 1992;12:221,186.
Manzoni GC, Farina S, Lafranchi M, Solari A. Classic migraine—clinical ﬁndings in 164 patients. Eur Neurol. 1985;24:163.
Neuhauser HK, Radtke A, von Brevern M, et al.
still make treatment decisions in current patients presenting with migraine vertigo. Prophylactic migraine medications are reason- able options when patients are suffering from recurrent migraine vertigo attacks. But the ﬁrst
Migrainous vertigo: prevalence and impact on quality of life. Neurology. 2006;67(6):1028.
Kayan A, Hood JD. Neuro-otological manifestations of migraine. Brain. 1984;107:1123.
Brantberg K, Trees N, Baloh RW. Migraine-associated vertigo. Acta Otolaryngol. 2005 Mar;125(3):276.
von Brevern M, Zeise D, Neuhauser H, Clarke AH,
area of emphasis should be for patients to search for and reduce triggers, and also to focus on the general lifestyle measures that can impact symptoms. It is when attacks persist despite these general measures that trials of prophylactic medicines are reasonable, though patients should be clearly informed about the limitations of these medicines and also about
Lempert T. Acute migrainous vertigo: clinical and oculographic ﬁndings. Brain. 2005;128(pt 2):365.
Ishiyama A, Jacobson KM, Baloh RW. Migraine and benign positional vertigo. Ann Otol Rhinol Laryngol. 2000;109(4):377.
von Brevern M, Radtke A, Clarke AH, Lempert T. Migrainous vertigo presenting as episodic positional vertigo. Neurology. 2004;62(3):469.
Harker LA. Migriane-associated vertigo. In: Baloh
the optimal use of them.
For the same reasons already mentioned, there is no strong evidence to support the use of one typical prophylactic agent over another. One option for selecting prophylactic medica-
RW, Halmagyi GM, eds. Disorders of the Vestibular
System. New York: Oxford University Press; 1996.
Battista RA. Audiometric ﬁndings of patients with migraine-associated dizziness. Otol Neurotol. 2004;25(6):987.
Parker W. Migraine and the vestibular system in
tions in individual patients is to base the choice of agent on the presence of comorbidities. Thus, patients with hypertension could be started on a beta-blocker or verapamil; patients with depression or anxiety could be started on a
adults. Am J Otol. 1991;12:25.
Olsson JE. Neurotologic ﬁndings in basilar migraine.
Laryngoscope. 1991;101(suppl 52):1.
Lipkin AF, Jenkins HA, Coker NJ. Migraine and sud- den sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 1987;113:325.
Viirre ES, Baloh RW. Migraine as a cause of sudden

tricyclic amine or serotonin reuptake inhibitor; and patients with epilepsy could be started on one of the antiseizure agents (i.e, valproic acide, topiramate). In patients with benign recurrent vertigo, acetazolamide is also an option.

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Chapter 13 ‌‌

Immune-Mediated Diseases

AUTOIMMUNE INNER EAR DISEASE

Background Pathophysiology Clinical Features Diagnosis Management ‌

PARANEOPLASTIC IMMUNE DISORDERS

Background Pathophysiology Clinical Features

Diagnosis Management MULTIPLE SCLEROSIS

Background Pathophysiology Clinical Features Diagnosis Management

The immune system is implicated in many neu- rologic diseases. There are some primary immune-based neurologic diseases, such as multiple sclerosis and myasthenia gravis, and also many secondary immune-based diseases, including paraneoplastic syndromes. In pri- mary immune-mediated diseases the cause is typically not known, but genetic and environ- mental factors undoubtedly play a role. On the other hand, in secondary immune-based dis- eases a known inciting event occurs, typically an infection, cancer, or environmental stimu- lus, in the setting of genetic susceptibility. Immune-mediated disorders are important to identify because in many cases effective thera- pies are available. In the absence of adequate therapeutic trials, identifying an immune response can at least direct therapeutic approaches for what can otherwise be severely disabling deﬁcits.

In this chapter, we focus on the immune- mediated syndromes that can involve the peripheral audio-vestibular system and also the central vestibular system.

AUTOIMMUNE INNER EAR DISEASE

Background

The endolymphatic sac is the key structure for immunoregulation within the inner ear.1 Ultra- structural studies have identiﬁed lymphocytes and macrophages within the endolymphatic sac and a surrounding network of lymphatic vessels containing these mononuclear cells.2 Injection of exogenous antigens into the inner ear of a guinea pig is as effective for initiating systemic immunity as intraperitoneal injection. When an antigen is placed into the inner ear of animals that have been immunized against the antigen, immuno- competent cells inﬁltrate the ear and there is local production of antibody.3,4 The inner ear is dam- aged during the immune response, even though the antigen is not expressed in the inner ear. Surgical ablation of the endolymphatic sac or blockade of the endolymphatic duct markedly curtails the immunological response and inner

303

ear damage.5 Lymphocytes engaged in the immune response within the inner ear are recruited from the circulation, presumably via the spiral modiolar vein. With this secondary immune response, there is activation of spiral modiolar vein endothelium, release of cytokines such as interleukin-2, and up-regulation of adhesion molecule expression.6

The inner ear is also capable of mounting an immune response against one of its own anti- gens. Several groups have immunized mice, rats, and guinea pigs with speciﬁc inner ear antigens and produced inner ear damage.7–11 The histopathology of the inner ear in these ani- mals shows degenerative changes with mono- nuclear cell inﬁltration. Antibodies directed against several different inner ear proteins have been identiﬁed in these animals, but so far, pas- sive transfer of injury with these antibodies has not been produced. Sensitized lymphocytes, however, can produce inner ear damage and sensorineural hearing loss after passive transfer to other animals.11–13 Although there are still many unanswered questions regarding these animal models of immune-mediated inner ear damage and how they translate to humans, they clearly show that the inner ear can be damaged either directly by attack on inner ear proteins or indirectly by a general immune response against an irrelevant antigen.

In 1958 Lehnhardt14 was the ﬁrst to suggest that bilateral deafness might be caused by anti- cochlear antibodies. In 1979, McCabe described the clinical syndrome of autoimmune inner ear disease.15 He reported a series of patients with rapidly progressive bilateral sensorineural hear- ing loss often associated with vertigo or imbal- ance. There was histopathologic evidence com- patible with vasculitis in a temporal bone biopsy from one patient and evidence of cell-mediated immune responses to inner ear membranous tissue from several other patients. The most convincing evidence of immune-mediated damage, however, was the response to corticos- teroids and cytotoxic drug therapy. Subsequently, there have been numerous simi- lar case reports of patients with this clinical proﬁle who often show good response to immu- nosuppression with corticosteroids and other cytotoxic agents. However, the effect of corti- costeroids was variable in an open-label study (about 58% [67/116] of those enrolled met the criteria for improved hearing after initiating corticosteroid treatment), and there was no

average beneﬁcial effect of a cytotoxic agent (methotrexate) in one large randomized clinical trial.16 Autoantibodies have been identiﬁed in some patients, but, as in the case of the animal models, it is unclear whether the antibodies are involved in the pathogenesis or are simply an epiphenomenon (see later discussion).

Pathophysiology

A wide range of multisystem autoimmune dis- orders can involve the inner ear (Table 13–1). With these disorders, there appears to be an episodic breakdown in immunologic tolerance to self-molecules. These autoimmune diseases are thought to result from a defect in a cell sur- face protein on T cells required for the intra- thymic death of autoreactive T lymphocytes. The defective protein prevents negative selec- tion of autoreactive T cells so that there are excessive numbers of circulating autoreactive T cells. In a mouse model with this T cell surface protein defect (the MRL mouse), cochlear damage occurs in the early stages of the systemic illness.17,18

There are three major mechanisms by which an immune-mediated disease can damage the inner ear: (1) deposition of antigen antibody immune complexes in the tissue; (2) autoanti- bodies directed against inner ear antigens; and

(3) inﬁltration and destruction of inner ear tissue by speciﬁc cytotoxic T cells. A wide range of non-organ-speciﬁc autoimmune disorders presumably damages the inner ear via the ﬁrst mechanism.16 Temporal bone specimens from patients with polyarteritis nodosa, systemic

Table 13–1 Systemic Immunologic Disorders that Involve the Inner Ear15

Vasculitis Syndromes Polyarteritis nodosa Wegener’s granulomatosis Bechet’s syndrome Cogan’s syndrome

Connective Tissue Diseases Systemic lupus erythematosus Sjögren’s syndrome Rheumatoid arthritis

Vogt-Koyanagi-Harada syndrome Relapsing polychondritis Ulcerative Colitis

lupus erythematosus, and Wegener’s granulo- matosis show evidence of small vessel vasculitis with inﬂammation and ischemic changes. Endolymphatic hydrops has been found in some specimens, possibly secondary to the inﬂammatory changes. Cogan’s syndrome,19 which is characterized by interstitial keratitis and inner ear involvement, may blur the dis- tinction between organ-speciﬁc and non– organ-speciﬁc inner ear immune-mediated dis- ease.20,21 Lunardi et al.22 used pooled IgG immunoglobulins from patients with Cogan’s syndrome to screen a random peptide library to identify disease-relevant autoantigens. They found an immunodominant peptide with a sequence similar to the cell-density enhanced protein tyrosine phosphatase-1 (DEP-1/ CD148) that is expressed on the sensory epi- thelia of the inner ear and on endothelial cells. Antibodies directed against the “Cogan pep- tide” were able to transfer the disease to other animals and mice or rabbits immunized with the Cogan’s peptide or a different peptide from DEP-1/CD148; the animals developed hearing loss and interstitial keratitis. Furthermore, antibodies against the Cogan peptide cross- reacted with a structural protein of the reovirus type III, suggesting the possibility of molecular mimicry as a disease mechanism. About 50% of patients with Cogan’s syndrome report an upper respiratory infection prior to the onset of disease.

Central to the notion of an organ-speciﬁc immune disease is that antibodies or immune cells are directed at a speciﬁc inner ear antigen. Numerous clinical studies have examined cel- lular and humoral immune reactivity to a vari- ety of inner ear tissues from humans and ani- mals with immune-mediated inner ear disease.23 Cellular immune assays using lymphocyte migration inhibition and lymphocyte transfor- mation have produced some positive ﬁndings, but these assays are technically demanding and are not very sensitive.24 Detection of serum antibodies directed at inner ear antigens is a much simpler procedure and thus has potential to lead to a clinically useful laboratory test. Many patients with the typical syndrome of idiopathic bilateral progressive sensorineural hearing loss ﬁrst described by McCabe have antibodies in their serum that bind a 68 kDa protein on Western blot analysis.25–27 This 68 kDa protein is not species speciﬁc, since it is detectable using human, bovine, and guinea

pig inner ear tissue, and it is not even organ speciﬁc, since it is present in many other tis- sues. There is now convincing evidence that the antigen recognized by these antibodies is heat-shock protein 70 (HSP-70), a highly con- served molecule that is up-regulated during times of stress.28,29 Whether HSP-70 located in the inner ear is the target of these antibodies or simply shares an epitope with the true target antigen is unknown. However, the level of these anti-HSP-70 antibodies correlates both with the activity of disease and the steroid responsiveness of the disease.29 The HSPs are ubiquitous in all normal cells and are desig- nated as chaperone proteins because of their role in aiding protein folding. Since they are up-regulated in response to injury or stress, antibodies directed against them may be a sec- ondary phenomenon unrelated to the underly- ing cause of injury.30

Numerous investigators have shown that serum from some patients with immune-medi- ated inner ear disease contains antibodies directed against speciﬁc inner ear structures, using immunoﬂuorescence.31 However, there has been no consistent pattern of staining and no speciﬁc cellular or subcellular structure consistently stained. Disher and colleagues30 noted that patient sera containing antibodies directed against the 68 kDa protein produced a characteristic punctate “wine glass” staining pattern of the supporting cells in the guinea pig organ of Corti. Such a staining pattern was never seen with control sera. These authors concluded that, because of the localized stain- ing pattern, it was unlikely that HSP-70 was the primary target of these autoantibodies. Baek et al.32 found that patients with autoim- mune inner ear disease had a high frequency of circulating T cells producing interferon gamma or IL-5 in response to recombinant cochlin, the most abundant inner ear protein. Patients also showed signiﬁcantly elevated cochlin-speciﬁc serum antibody titers compared to controls or patients with other causes of hearing loss. Cochlin expression is largely conﬁned to the inner ear and mutations in the COCH gene that codes for cochlin causes progressive cochlear and vestibular pathology.

So far there have been only a few histopatho- logic studies of temporal bone specimens from patients with inner ear-speciﬁc immunologic disease. Schuknecht33 reported inﬁltration of lymphocytes, plasma cells, and macrophages in

Figure 13–1. Spiral modiolar vein of patient with auto- immune inner ear disease showing perivascular round cell inﬁltration (A) and new bone formation (B) in an area of intense inﬂammation (Courtesy, Harold F Schuknecht MD).

the endolymphatic and perilymphatic spaces and within the tympanic lamellae and spiral ligaments (Fig. 13–1). Osteoneogenesis and ﬁbrous tissue were present in the scala tympani adjacent to the round window and dense bone formation surrounded the spiral modiolar vein and modiolus. There were also focal mononu- clear inﬁltrates in the cochlear and vestibular nerve trunks. Although hydrops was also pres- ent, the pathology was distinct from that of typ- ical Meniere’s disease. These ﬁndings are also typical of those observed in experimental ani- mals undergoing chronic antigen stimulation.

Clinical Features

SYSTEMIC IMMUNE-MEDIATED DISEASES WITH INVOLVEMENT OF THE INNER EAR

Systemic lupus erythematosus (SLE) is the pro- totypical immune complex disease. Both sudden

unilateral and progressive bilateral sensorineu- ral hearing loss have been well documented with SLE.34,35 In a case series of female SLE patients, 57.5% (23/40) had impaired hearing, particularly in the low frequencies.36 In some cases, ﬂuctuating low-frequency hearing loss along with episodic vertigo suggests the diagnosis of endolymphatic hydrops. The most consistent inner ear pathology is a vasculitis, presumably caused by deposition of circulating immune complexes in the walls of blood ves- sels.37 In theory at least, the inner ear—just like the kidney—is a prime target in SLE because there are antigenic similarities between the stria vascularis and the glomerular basement mem- brane and both structures show deposits of immune complexes.38

Polyarteritis nodosa (PN) is a necrotizing vasculitis of small muscular arteries that com- monly involves the inner ear; hearing loss is occasionally the initial symptom.24,39 Patients can have hearing loss for several years before the systemic features of polyarteritis become evident. Obliterative vasculitis of the labyrin- thine artery can result in ischemic necrosis of the entire labyrinth. Wegener’s granulomatosis is another vasculitic syndrome characterized by necrotizing granulomas primarily within the upper respiratory tract, lung parenchyma, and kidneys. Although both acute and chronic sen- sorineural hearing loss occur with Wegener’s granulomatosis, a conductive hearing loss due to otitis media is a more common ﬁnding.40 Behçet’s disease is a rare vasculitic syndrome characterized by aphthous ulcers, genital ulcers, and iritis or uveitis. Auditory and ves- tibular symptoms due to inner ear involvement are common at any time during the course.41 A small percentage of patients with Sjogren’s syndrome have a progressive bilateral hearing loss presumably secondary to inﬁltration of the inner ear by autoreactive T cells.42

As noted earlier, Cogan’s syndrome is typi- ﬁed by audiovestibular symptoms and recur- rent nonsyphilitic interstitial keratitis.19–21 Initially, the clinical picture is indistinguishable from Meniere’s syndrome with episodic vertigo and ﬂuctuating hearing loss, but the course is more fulminant, typically rapidly leading to deafness if untreated. Although the disorder can begin with either eye or ear involvement, both organs are usually involved within 1 year of onset. Cogan’s syndrome has features of both non–organ-speciﬁc and organ-speciﬁc immune-mediated disease. In most cases, there

is evidence of a systemic vasculitis with deposi- tion of immune complexes. Some patients will develop a systemic illness resembling polyar- teritis nodosa. In most, however, only the ear and eye are involved.

Inner ear involvement occurs in about 50% of patients with relapsing polychondritis.24 This rare condition is characterized by recurrent episodes of inﬂammatory necrosis of cartilage.43 Conductive hearing loss is also common because of swelling and degeneration of carti- lage in the middle ear.44 Autoantibodies directed against collagen type 2 and type 9 and other cartilage components have been identi- ﬁed with this disorder, but it is unclear whether the inner ear damage is due to vasculitis or to these collagen autoantibodies.

AUTOIMMUNE INNER EAR DISEASE

The typical presentation of immune-mediated inner ear disease is a rapidly progressive bilat- eral sensorineural hearing loss that extends beyond the arbitrary 72 hr typical of sudden sensorineural hearing loss.15,45 Moscicki and colleagues26 deﬁned the following criteria for the disorder: (1) bilateral sensorineural hearing threshold of 30 dB at any frequency, and

(2) evidence of progression in at least one ear on two serial audiograms performed 3 months apart (progression being deﬁned as a threshold loss of 15 dB at one frequency or 10 dB at two or more consecutive frequencies). Fluctuating hearing loss qualiﬁes if there is also progression as deﬁned by the criteria. Most investigators have found a female preponderance, although others have not.29,46 Immune-mediated inner ear disease typically begins in the 30s and 40s, although there is a wide range of age of onset from childhood into the eighth decade. Vestibular symptoms typically occur in about 50% of patients. Most commonly, there are episodes of vertigo with or without episodes of ﬂuctuating hearing loss. Occasionally, patients show just a deterioration in balance due to bilateral progressive vestibular loss, which can be identiﬁed at the bedside with the head-thrust test. Whether a subset of patients has just bilateral vestibular loss without hearing loss is unclear, although to date, no convincing patients with this syndrome have been reported. Arbusow et al.47 found autoanti- bodies directed at inner ear antigens in 8 of 12 patients with idiopathic bilateral vestibul- opathy and normal hearing, but autoantibody

levels did not correlate with clinical activity and 3 of these patients treated with immunosup- pressive therapy showed no beneﬁt. Deutschlander et al.48 found antilabyrinthine or nervous tissue-speciﬁc serum antibodies in 12 patients with bilateral vestibulopathy and normal hearing, but only a few showed any response to immunosuppression treatment and it was unclear whether the response was spon- taneous or due to medication.

About 20% of patients with idiopathic pro- gressive bilateral sensorineural hearing loss who meet the diagnostic criteria for immune- mediated inner ear disease have a combination of ﬂuctuating and progressive sensorineural hearing loss and episodic vertigo that meets the strict diagnostic criteria for Meniere’s syn- drome.29 About a third of patients with typical Meniere’s syndrome have been shown to have the anti–HSP-70 antibodies that are character- istic of immune-mediated inner ear disease.49 This suggests the possibility that a subset of patients in both diagnostic categories have a common pathophysiology.

Diagnosis

AUDIOVESTIBULAR TESTING

Serial audiograms performed every few months are necessary to conﬁrm the presence of, and response to treatment for, bilateral progressive sensorineural hearing loss.50 There is no char- acteristic pattern of hearing loss with immune- mediated inner ear disease in which both up-sloping and down-sloping or even ﬂat pat- terns occur. Occasionally, speech discrimina- tion is affected to a greater extent than hearing thresholds, although, in this case, one should consider a search for retrocochlear disease, such as that associated with multiple sclerosis (MS) or a vestibular schwannoma. Unilateral or bilateral decrease in caloric function will often correlate with the severity of hearing loss. A subset of patients will have severe auditory involvement without any evidence of vestibular dysfunction.

Routine serologic tests are recommended in patients with idiopathic bilateral progressive sensorineural hearing loss to evaluate for ﬁnd- ings suggestive of systemic immune-mediated disease. The typical regimen would include a complete blood count with differential white count, erythrocyte sedimentation rate (ESR),

antinuclear antibody (ANA), rheumatoid fac- tor, and C3 and C4 complement levels. Magnetic resonance imaging (MRI) with con- trast is not likely to be useful in the absence of accompanying brainstem dysfunction, but it may show enhancement of the membranous labyrinth during active stages of the disease.51

A wide range of antigen-speciﬁc laboratory tests have been recommended for the diagno- sis of immune-mediated inner ear disease, but to date, none of these tests are universally avail- able or have been demonstrated to be useful clinically. In his original description in 1979, McCabe15 reported that 6 of 18 patients with immune-mediated inner ear disease had a pos- itive migration inhibition test, using inner ear proteins for the antigenic stimulus. Hughes and colleagues52 at the Cleveland Clinic devel- oped a lymphocyte transformation test, also using inner ear proteins, and found abnormal results in about a quarter of patents with immune-mediated inner ear disease. Berger and colleagues53 used type 2 collagen in a lym- phocyte transformation test and reported a 50% positive rate in patients with immune- mediated inner ear disease versus a 6% posi- tive rate in controls. These cellular immune assays are probably too technically demanding for routine use in the clinical laboratory.54

Between one-third and two-thirds of patients with immune-mediated inner ear disease have anti–HSP-70 antibodies,23,28,29 but these anti- bodies can also be seen in normal subjects.55 The presence of anti-HSP-70 antibodies seems to be correlated with disease activity and with steroid responsiveness.25 Rauch estimated that a positive test indicated as much as a 75% chance of steroid responsiveness, whereas a negative test indicated a chance of response of

<20%.25 However, controlled studies are needed to conﬁrm these observations, and it is unlikely that clinicians would withhold a trial of corticosteroids unless the test could identify patients with a probability of improved recov- ery very close to zero.

Management

The mainstay of treatment of immune- mediated inner ear disease is immune suppres- sion with high-dose corticosteroids.24,29,56 Unfortunately, there have been no prospective

randomized clinical trials of steroid treatment of immune-mediated inner ear disease. Because a short course of corticosteroids is associated with relatively few adverse effects and the medicine is inexpensive and widely available,57,58 most practitioners recommend a therapeutic trial of prednisone in the range of 1 mg/kg/day for 4 weeks, followed by tapering. Some patients will show an immediate response within hours to days of treatment, although many do not show improvement until later in the course of treatment. Shorter courses of treatment might lead to relapse.29 Hearing is typically tested at the initiation of therapy and at the end of the 4 weeks of high-dose steroids. If the threshold has improved by 15 dB at one frequency or 10 dB at two or more frequencies, the diagnosis of immune-mediated inner ear disease is conﬁrmed and the patient is consid- ered a steroid responder. Patients who do not show a response after a month are tapered off the steroid over the next 12 days. Patients who respond to the initial month of therapy con- tinue on the full dosage until their audiogram shows that hearing levels have reached a pla- teau. The steroids are then slowly tapered over about 8 weeks and a smaller maintenance dose is continued for at least 6 months. Relapses are more common in patients who are treated for less than 6 months compared to those treated for 6 months or longer.29 Up to two-thirds of patients who meet the diagnostic criteria for autoimmune inner ear disease respond initially to steroids, but only about 15% continue to respond after 3 years. 16,50,57

Long-term corticosteroid treatment can lead to major side effects, including gastritis and ulcers, labile blood pressures, altered blood sugar metabolism and diabetes, mood changes, sleep disorders, accelerated cataract formation, cushingoid habitus, and ischemic bone necro- sis. All of these side effects tend to be more pronounced with long-term use; the risk dur- ing the initial 30-day high-dose steroids with rapid taper is relatively low.58 Despite these major long-term risks, corticosteroid therapy continues to be the mainstay for empiric treat- ment of immune-mediated inner ear disease.

Methotrexate and cyclophosphamide have been used as an alternative to systemic corti- costeroids, in combination with corticosteroids, or as an alternative to steroids in patients with unacceptable side effects.24,29 Most experience

has been with methotrexate using a low-dose protocol. An initial dosage of 7.5 mg/week (3 doses of 2.5 mg) is given for 2 weeks and, if there is not major toxicity, the dosage is dou- bled to 15 mg/week.29 This dosage is continued for 6 to 8 weeks and then, as with steroids, dis- continued in nonresponders and carried on for about 6 months in responders. The main toxic- ity associated with methotrexate includes myelosuppression, oral ulceration, gastrointes- tinal ulcers, and hepatic ﬁbrosis. This latter severe complication is usually only seen when methotrexate is given for more than a year. In a randomized placebo-controlled trial, metho- trexate did not demonstrate an average beneﬁ- cial effect compared to placebo for maintaining hearing improvement achieved with predni- sone (60 mg/day for 1 month followed by 18-week taper).16 In a pilot placebo-controlled study, the immunomodulatory drug etanercept was no better than placebo for treating autoim- mune inner ear disease.59‌‌

PARANEOPLASTIC IMMUNE DISORDERS

Background

Remote effects of cancer on the brain were ﬁrst described at the end of the nineteenth century, but case reports were largely anec- dotal and, because similar syndromes occur without cancer, many investigators questioned the cause-and-effect relationship. Cancer can have remote effects on the nervous system, from the cortex to cranial and peripheral nerves, including the audiovestibular nerves. Whether there is a selective cochleovestibular paraneoplastic syndrome is unclear, but involvement of audiovestibular structures is common with paraneoplastic encephalomyeli- tis. Many cancers have been associated with paraneoplastic effects, but small-cell carcinoma of the lung is most common. In the majority of cases the underlying cancer is undetectable at the time the neurological symptoms present, so the diagnosis can be difﬁcult.60 The discovery of antineuronal antibodies not only provides a diagnosis for the neurotologic symptoms but also may direct the search for a speciﬁc cancer type.

Pathophysiology

Paraneoplastic syndromes result from an immune-based attack on the nervous system, usually against neurons.61 Presumably, the tumor expresses antigens that are also expressed by neurons. The immune system recognizes the proteins expressed by the tumor as foreign and mounts an immune attack to control tumor growth. In many cases, the immune response is so effective that the tumor remains small and may not be detectable. The immune response consists of both an antibody and cytotoxic T cell response. In paraneoplastic syndromes affecting the brain, inﬂammatory inﬁltrates of T cells and plasma cells occur in both the ner- vous system and in the tumor. The same anti- bodies are found in the brain and the tumor. Different antibodies occur with different tumors and clinical syndromes (Table 13–2).61 These antibodies are directed against a num- ber of onconeural antigens, all important in neuronal function. In many cases the antibod- ies associated with paraneoplastic syndromes have been used as probes to immunohis- tochemically localize the antigen in the nervous system and to clone the gene from complimen- tary DNA expression libraries of genes that code for the onconeural antigens.61 Many of the genes associated with these antigens appear to be important in early neuronal development and in the regulation of gene expression.

The characteristic pathologic ﬁndings with paraneoplastic syndromes are perivascular cufﬁng by lymphocytes, activation of microglia with the formation of microglial nodules, and selective loss of neurons. The process is pre- dominantly, although not exclusively, conﬁned to gray matter. Immunoglobulin G (IgG), nor- mally absent from the brain, can be found not only within the neuropil but also within neu- rons. These antibodies found in the brain are directed against speciﬁc onconeural antigens that are expressed within the tumor in the same patient.

Clinical Features

CEREBELLAR DEGENERATION

The clinical symptoms and signs of patients with paraneoplastic cerebellar degeneration are similar to those of patients with other diffuse

Table 13–2 Antineuronal Antibody Paraneoplastic Disorders

Antibody	Associated Cancer	Syndrome	Brain Antigen	Onconeuronal Antigen
Anti-Hu	SCLC and	Encephalomyelitis,	All neuronal nuclei,	HuD, HuC,
	neuroblastoma	sensory neuropathy	35–40 kDa	Hel-Nl
Anti-Yo	Gynecologic and	Cerebellar ataxia	Cytoplasm Purkinje	CDR34, CDR62-1,
	breast		cells, 34 and 62 kDa	CDR62-2
Anti-Ri	Breast,	Cerebellar ataxia,	Neuronal nuclei CNS,	NOVA1, NOVA2
	gynecologic,	opsoclonus	55 and 80 kDa
	and SCLC
Antiamphiphysin	Breast	Stiff-person,	Synaptic vesicles,	Amphiphysin
		encephalomyelitis	128 kDa
Anti-Ma	Multiple	Cerebellar ataxia,	Neuronal nuclei and	Mai, Ma2
		brain stem	cytoplasm, 37 and

dysfunction

Anti-Ta Testicular Limbic encephalitis,

brain stem dysfunction

40 kDa

Neuronal nuclei and cytoplasm, 40 kDa

Ma2

Anti-Tr Hodgkin’s lymphoma

Cerebellar ataxia Cytoplasm neurons,

Purkinje cells, spiny dendrites

Unknown

Anti-CV2 SCLC and others Encephalomyelitis,

cerebellar ataxia

Glia (subset), 66 kDa POP66

Anti-GAD Multiple Stiff-person, Cerebellar ataxia

Glutamic acid decarboxylase

Unknown

Anti-VGKC Multiple Encephalomyelitis Voltage gated potassium

channels

Unknown

CNS, central nervous system; SCLC, small cell lung cancer.

Source: Data modiﬁed from Dalmau and Posner.61

cerebellar lesions. The trunk and extremities are ataxic and the speech is usually slurred. The course is subacute but can be fulminant. Often intractable nausea and vomiting occur early. Most patients are nonambulatory within 2-4 months from the onset of symptoms.62 Less commonly patients can remain ambulatory throughout the course.62 After about 6 months the symptoms generally stabilize. 63 All types of spontaneous nystagmus are seen, but downbeat nystagmus is most speciﬁc for cerebeller involve- ment.64,65 Gaze-evoked and rebound nystagmus are also common. Eye movement recordings document impairment of smooth pursuit, opto- kinetic nystagmus, and ﬁxation-suppression of vestibular nystagmus. Saccades may be dysmet- ric, but peak velocity remains normal. Vestibular responses are normal or hyperactive.

Patients with anti-Ri antibodies may have a less severe course (less likely to have nystag- mus and more likely to be ambulatory) and also a better outcome when compared to patients with paraneoplastic cerebellar degeneration

associated with anti-Yo, anti-Hu, and anti-Tr antibodies. 63

OPSOCLONUS

A dramatic neurophthalmologic paraneoplastic syndrome is the opsoclonus-myoclonus syn- drome.66 This disorder is characterized by cha- otic conjugate eye movements in all directions, along with myoclonus of the trunk and limbs. It is usually seen in children with neuroblastoma, although it also occurs in adults with occult malignancies in the lung, ovaries, uterus, and breast. With opsoclonus, conjugate saccades occur continuously in all directions, often with torsional components.65 Eye movement record- ings document that the saccades have normal peak velocity for their amplitude.

ENCEPHALOMYELITIS

Paraneoplastic encephalomyelitis can present with a wide range of central and peripheral

nervous system symptoms and signs.67 Involvement of the limbic system in the medial temporal lobes results in a combination of per- sonality change and memory deﬁcits. Brain stem involvement can lead to prominent ver- tigo, nausea, and vomiting, with involvement of oculomotor pathways causing strabismus and nystagmus. Cranial and peripheral nerves are also commonly involved, leading to a combina- tion of central and peripheral signs. Often peripheral sensory nerves are involved to a much greater extent than motor nerves. Cases have been reported with a combination of encephalomyelitis and inner ear involvement, also possibly secondary to a paraneoplastic immune-based mechanism, but so far no anti- bodies directed at the speciﬁc inner ear anti- gens have been identiﬁed.68,69

Diagnosis

Although the role of the antibodies listed in Table 13–2 in the pathogenesis of the different paraneoplastic syndromes is still unclear, iden- tiﬁcation of these speciﬁc antibodies in the clinical laboratory can help lead to a diagno- sis.61 Any patient with subacute cerebellar degeneration should be examined carefully for an occult malignancy. Antineuronal antibodies are identiﬁed in about 50% of patients with paraneoplastic cerebellar degeneration. The most speciﬁc antibody is the anti–Purkinje cell antibody found in women with gynecological tumors (the anti-Yo antibody).70 With immuno- histochemical staining, this antibody binds to the Purkinje cell cytoplasm, producing a char- acteristic “ring of pearls” on microscopic exam- ination of the cerebellum. It is so speciﬁc for gynecological tumors that surgical exploration of the pelvis is indicated in any woman with the antibody, even without an obvious malignancy, regardless of the outcome of other diagnostic studies. A subgroup of adults with opsoclonus and cerebellar ataxia (primarily truncal) has an antineuronal antibody called anti-Ri. Nearly all of these patients have cancer of the breast. The antineuronal nuclear antibody (anti-Hu) is most commonly associated with small-cell lung cancer and either a sensory neuropathy and/or encephalomyelitis.

If an antibody is detected, then the next step is to search for the primary malignancy.

The optimal method to search for a primary malignancy is not clearly deﬁned and can vary from patient to patient depending on the clini- cal scenario and available resources. In addi- tion, the ultimate value of the tests used to search for a malignancy (i.e., how having the tests impacts meaningful patient outcomes) has not been deﬁned. In most cases, the initial imaging test is a whole-body computed tomog- raphy (CT) scan. If no mass is identiﬁed or if uncertainty about the etiology of an identiﬁed mass exists (e.g., benign pulmonary nodule ver- sus lung cancer), then ﬂuoro-2-deoxy-glucose (FDG) positron emission tomography (PET) scan is typically the next step. In some cases, it may be reasonable to order a CT scan and PET scan simultaneously.71 The studies of body imaging to search for cancers in paraneoplastic presentations are all small cases series (10–80 patients) and have demonstrated concerning false-positive rates (typically infection or inﬂammation on PET scans, benign nodules on CT scans) and also false-negative rates (partic- ularly for small gynecologic cancers on CT scans, and slow-growing or very small tumors on PET scans).71 False-positive and false-nega- tive results may stem from suboptimal validity of the tests for malignancy in these presenta- tions or from suboptimal reliability (e.g., inter- observer agreement) of the interpretation of test results.

Even if an antibody is not detected in the serum, imaging studies of the body may still identify an occult neoplasm in patients with the symptom complex suggestive of a paraneoplas- tic disorder.72 However, the false-positive rate of imaging studies is likely to be higher in the absence of a positive antibody test.

Neuroimaging studies in patients with paraneoplastic cerebellar degeneration are usually normal early in the course, although occasionally there can be mild cerebellar atro- phy. Cerebrospinal ﬂuid (CSF) examination may show a mild pleocytosis and elevated gamma globulin synthesis or may be completely normal.60

Management

The ﬁrst goal is to identify and remove the under- lying cancer. Although infrequent, there are case reports of dramatic clinical improvement after

resection of the tumor. Regardless, the best chance to stabilize symptoms is when the cancer can be effectively treated.63,73 Most patients reach a “burnt-out” or plateau stage within 6 months where they remain with a moderate to severe neurologic deﬁcit.63 We have followed a woman with paraneoplastic cerebellar degeneration for more than 25 years after a fallopian tube cancer was removed. Exploratory surgery was initiated after anti-Purkinje antibodies (anti-Yo) were iden- tiﬁed in her serum. Despite complete removal of the tumor and tumor markers returning to nor- mal, her clinical examinations remain relatively unchanged. She continues to have severe ataxia of the trunk and extremities, although her nausea and vomiting have markedly diminished.

Plasmapheresis and immunosuppression are frequently tried but only rarely associated with an improvement.62,63 In occasional cases, par- ticularly in patients with opsoclonus, dramatic improvement has been reported.65 However, unlike the cerebellar symptoms and signs associated with paraneoplastic cerebellar degeneration, spontaneous remissions are more common with paraneoplastic opsoclonus. Exacerbations can occur months after remis- sion. Clonazepam has been reported to improve opsoclonus in some adults,74 but many do not respond to this medication.‌

Rituximab has increased interest as a poten- tial treatment for the paraneoplastic neurologic symptoms because beneﬁcial effects have been presumed in individual patients.75 However, any effect has generally been small. Furthermore, one must also consider that the natural history of paraneoplastic disorders is a symptomatic plateau which could easily be misinterpreted as a treatment effect. There are ongoing early-phase trials of medication treat- ments in paraneoplastic syndromes, including tacrolimus (Clinicaltrials.gov identiﬁer NCT00378326) and rituximab in pediatric patients with opsoclonus-myoclonus syndrome (Clinicaltrials.gov identiﬁer NCT00244361).

MULTIPLE SCLEROSIS

Background

Multiple sclerosis (MS) is a demyelinating dis- ease of the central nervous system (CNS) with

onset usually in the third and fourth decades of life.76 The key to the diagnosis is ﬁnding dis- seminated signs of CNS dysfunction mani- fested in an alternating remitting and exacer- bating course. Although the cause is still not deﬁnitely known, the characteristic ﬁndings at pathology, the similarity with known autoim- mune animal models, and the response to immunomodulatory and immunosuppressive therapies all suggest that the disorder is auto- immune in nature. Auditory and vestibular symptoms are common in patients with MS and not infrequently they are the presenting symptoms.77–79

Pathophysiology

The demyelination in MS is conﬁned to CNS myelin—the myelin produced by oligodendro- gliocytes. Peripheral nerve myelin produced by Schwann cells is minimally affected. Because both peripheral and cranial nerves contain CNS myelin at their root entry zones, a demy- elinated plaque involving the root entry zone may produce signs of peripheral nerve dysfunc- tion. Next to the ﬁrst and second cranial nerves, the eighth cranial nerve has the largest propor- tion of CNS myelin, perhaps making it particu- larly susceptible to the effects of MS.80 Plaques involving the vestibular and auditory root entry zones can explain the frequent ﬁnding of uni- lateral caloric hypoexcitability and hearing loss in patients with MS.79,81,82 In typical demyeli- nated plaques, most of the myelin sheaths are destroyed and those that remain become swol- len and fragmented. The axis cylinders and neurons are relatively spared so that conduc- tion of nerve impulses still occurs but at a decreased frequency and rate. Whether the remissions and exacerbations of symptoms and signs are related to repair of demyelinated regions or changes in the physiology of nerve conduction unrelated to demyelination is cur- rently debated. It has been repeatedly shown, however, that there is a poor correlation between the clinical symptoms experienced during life and the pathologic ﬁndings at necropsy.

The initial areas of demyelination seem to be dependent on T cell inﬁltration into the CNS.83 However, as the lesions expand, other mecha- nisms may come into play, including activation

of CNS glial and microglial cells. In the animal model for MS, autoimmune allergic encephalo- myelitis sensitization to myelin proteins such as myelin basic protein (MBP) leads to an inﬁltra- tion of the CNS by activated T cells that start the demyelinating process. There is a clear genetic component to developing MS that may be related both to factors in the immune system and in target CNS antigens.84 In vitro, oligoden- drogliocytes express major histocompatibility complex (MHC) class 1 molecules and are sus- ceptible to CD8 (positive plus) T cell–mediated cytotoxicity. Oligodendrogliocyte-speciﬁc anti- bodies can be identiﬁed in MS lesions and could induce injury by a complement-dependent mechanism. Oligodendrogliocytes are also sus- ceptible to injury mediated by nonspeciﬁc immune cell mechanisms, such as through the cytokines.

Clinical Features

Although many symptoms occur with MS, cer- tain ones deserve emphasis because of their consistent appearance. Blurring or loss of vision caused by demyelination of the optic nerve (retrobulbar or optic neuritis) is an initial symptom of MS in about 20% of patients. Diplopia, weakness, numbness, and ataxia also occur early in the disease process. Vertigo is the initial symptom in about 5% of patients and is reported some time during the disease in as many as 50%.76 Hearing loss occurs in about 10% of patients. No apparent relation- ship exists between the severity or duration of MS and the hearing loss; auditory impairment may be part of the initial episode or may occur more than 10 years after the onset.79,85,86 The hearing loss can be acute (hours to a few days), subacute (over months), or insidious in onset. Partial or complete remission after onset of hearing loss is common. A typical bout of ver- tigo associated with MS lasts from hours to days, although positional vertigo lasting seconds is also common. Multiple sclerosis can mimic vestibular neuritis, benign positional vertigo, and sudden deafness.82,86,87 Benign positional vertigo is common even in patients with MS, so this treatable cause of positional vertigo should always be considered even in patients with a clear central disorder such as MS.88

Diagnosis

The ﬁndings on examination in a patient with MS are as diverse as the symptoms. In most long-standing cases, there are signs of involve- ment of the pyramidal tracts (hyperreﬂexia, extensor plantar responses), cerebellum (inten- tion tremor, ataxia, slurred speech), sensory tracts (impaired vibratory and position sense), and visual pathways (decreased visual acuity and pallor of the optic disc). The ﬁnding of dis- sociated nystagmus on lateral gaze or acquired spontaneous pendular nystagmus is particularly helpful in the diagnosis of MS because these are common with MS and are relatively unusual in other disease processes.89,90 All varieties of positional nystagmus can be seen with MS and caloric examination is abnormal in about a quarter of patients.91 Pure-tone hearing levels, when abnormal, have no characteristic pattern with MS. Special audiometric studies (speech discrimination, tone decay, acoustic reﬂex) indicate a neural site for the lesion. Brainstem auditory-evoked responses (BAER) can be used to detect subclinical lesions in MS, even when hearing is normal (see Chapter 8).92 Vestibular evoked myogenic potentials (VEMPs) are abnormal in about a third of patients with MS.93,94 This is the only vestibular test able to detect dysfunction within central vestibular pathways (see Chapter 7).

No speciﬁc laboratory test for MS exists, but abnormalities in the CSF can be identiﬁed in about 80% to 90% of patients at some time in the disease course. These ﬁndings include elevated gamma globulin, increased gamma globulin synthesis, oligoclonal banding of gamma globulin, and elevated MBP. Unfortunately, none of these ﬁndings are spe- ciﬁc for MS. Magnetic resonance imaging is currently the gold standard for identifying demyelinating lesions with MS (Fig. 13–2). T2-

weighted and FLAIR images will show charac-

teristic white matter plaques in about 95% of patients with MS, although similar lesions are sometimes seen in patients without the clinical criteria for the diagnosis of MS.95,96

Management

Steroids and adrenocorticotropic hormone may hasten the remission of symptoms and signs

Figure 13–2. Magnetic resonance image demonstrates typical multiple sclerosis white matter lesions including ovoid peri-ventricular and juxta-cortical lesions.

after an acute exacerbation with MS, but no evidence indicates that these drugs alter the natural history.97,98 Immune modulation with interferon-beta (IFN-) and glatiramer acetate have been shown to decrease the frequency and severity of exacerbations with MS, although it is still unclear which of these drugs is best.99,100 Side effects tend to be more prominent with IFN- and include ﬂu-like syndromes, tachy- cardia, headache, myalgias, and gastrointestinal disorders. Neurological toxicity includes gen- eral fatigue along with behavioral and cognitive changes. These latter symptoms may impair quality of life and result in treatment discon- tinuation. Autoantibodies often develop in patients on chronic IFN- treatment and these antibodies may not only interfere with treat- ment but may also be associated with systemic autoimmune symptoms in rare cases.101

OTHER IMMUNE-MEDIATED DISORDERS

If a patient presents with subacute or fulminate progressive cerebellar ataxia, then an immune- mediated disorder should be considered even

if the presentation does not suggest a paraneo- plastic disorder or MS. The case for an immune- based attack can be supported by serum autoantibodies that have been associated with subacute ataxia presentations or by CSF stud- ies indicating an immune-based response.

Serum autoantibodies not associated with a cancer have been found in patients with subacute cerebellar ataxia presentations. In these situa- tions, it is presumed that the antibodies developed spontaneously or in response to a noncancerous antigen and are attacking the cer- ebellum. Though the causal relationship is tenu- ous, the case that these antibodies are involved in the immune-based attack is typically supported by CSF pleocytosis, oligoclonal bands, increased IgG index, and at times even immunohistochem- istry. The main problem with the argument that the speciﬁc autoantibodies are causing the ataxia is that most of the identiﬁed antibodies also occur in the general population. This is different than the paraneoplastic autoantibodies, which are extremely rare to ﬁnd outside of the speciﬁc neu- rologic presentations.

Probably the most widely reported, biologi- cally plausible, and thus convincing evidence of a

speciﬁc antibody association with a nonparaneo- plastic cerebellar ataxia syndrome is with anti- bodies directed at glutamic acid decarboxylase (anti-GAD). Purkinje cells contain high levels of GAD, and immunohistochemistry has found positive immunostaining of axons of Purkinje cells.102–104 Anti-GAD antibodies also have a strong association with other presumed immune- mediated disorders, including Stiffman syn- drome and insulin-dependent diabetes mellitus. Antigliadin antibodies have an association with cerebellar ataxia, but these antibodies are very common in the general population. Furthermore, these antibodies were elevated at higher rates in patients with a known genetic mutation causing the cerebellar ataxia com-

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Chapter 14 ‌‌‌‌

Vascular Disorders

VERTEBROBASILAR ISCHEMIA

Pathophysiology

Transient Ischemic Attacks (TIAs) Stroke Syndromes

Diagnosis Treatment

INTRALABYRINTHINE HEMORRHAGE

Diagnosis and Management

HEMORRHAGE INTO THE BRAIN STEM AND CEREBELLUM

Diagnosis and Management

VASCULAR COMPRESSION SYNDROMES

Vertebrobasilar Dolichoectasia

Vascular Compression by Normal Vessels (Vestibular Paroxysmia)

Rotational Vertebral Artery Syndrome

VERTEBROBASILAR ISCHEMIA

Pathophysiology

As discussed in Chapter 2, the vascular supply to the labyrinth, eighth nerve, brain stem, and cer- ebellum arises from a common source: the verte- brobasilar circulation. The vestibular system is subject to two general categories of vascular isch- emia: (1) hypoperfusion in the vertebrobasilar system, in which case multiple areas (both periph- eral and central) become simultaneously isch- emic, or (2) hypoperfusion in the distribution of a single smaller feeding vessel, in which case there is a circumscribed area of ischemia. In the former case the site of origin of hypoperfusion can be anywhere from the heart and major vessels in the chest and neck to the basilar artery, whereas in the latter case an occlusion is usually situated near the origin or, less frequently, in the smaller feed- ing vessel itself. These two categories of ischemia are not mutually exclusive, however; a patient with small-vessel disease may be as asymptomatic because of collateral circulation, but an added hypoperfusion in the vertebrobasilar system can lead to focal ischemia and or infarction.

The most common causes of vertebrobasilar ischemia (VBI) are large-artery atherosclerosis,

emboli, and penetrating small-vessel disease.1 Other less common causes include dissection, ﬁbromuscular displasia, arteritis, polycythemia, thromboangiitis obliterans, and hypercoagula- tion syndromes. In rare cases, occlusion or stenosis of the subclavian or innominate arter- ies just proximal to the origin of the vertebral artery results in the so-called subclavian steal syndrome. In this syndrome, VBI results from siphoning of blood down the vertebral artery from the basilar system to supply the upper extremity. Occasionally, episodes of VBI are precipitated by postural hypotension, Stokes- Adams attacks, or mechanical compression from cervical spondylosis. Cervical spondylosis is extremely common in the elderly, but docu- mented cases of mechanical compression of the vertebral arteries by neck turning or exten- sion are rare (see later discussion).

Vertigo is the most common symptom of VBI, but it is not always clear which structure or combination of structures is ischemic.2 When vertigo is accompanied by other symp- toms of brainstem ischemia (e.g., slurred speech or a brainstem pattern of motor/sensory symptoms), one can reasonably assume that the vertigo is the result of ischemia of the vestibular nuclei in the lateral medulla or the

319

complex system of vestibular pathways in the brain stem. Similarly, if the vertigo is accompa- nied by typical symptoms of cerebellar dysfunction, it likely results from ischemia to the cerebellum. Isolated episodes of vertigo are more difﬁcult to explain on this basis, however. The anatomy of the vasculature to the brain stem does not explain selective ischemia to the vestibular nucleus with sparing of surrounding structures. Even if the vestibu- lar nuclear neurons are more sensitive to isch- emia than surrounding structures, one would expect only a relative difference in sensitivity, not a complete sparing of surrounding struc- tures. On the other hand, ischemia to the cer- ebellum, particularly to the vestibulocerebel- lum, could result in selective vertigo and imbalance and might mimic a peripheral ves- tibular disorder.3

Isolated episodes of vertigo can also result from transient ischemia to the vestibular laby- rinth.4 Because the labyrinthine circulation is an end circulation with minimal collaterals from the otic capsule, the labyrinth is especially vulnerable to ischemia. Possibly, because of the small caliber of the anterior vestibular artery (see Fig. 2–9 in Chapter 2) and the gen- eral lack of collateralization, the superior part of the vestibular labyrinth is selectively vulner- able to ischemia.5 One would expect ischemia to the labyrinth to be accompanied by hearing loss, but patients may simply be unaware of a transient, mild, unilateral hearing loss when it is accompanied by a severe attack of vertigo.7

Infarction in the distribution of the posterior inferior cerebellar artery (PICA) or the ante- rior inferior cerebellar artery (AICA) is invari- ably associated with severe vertigo, nausea, and vomiting. The full-blown syndromes are easily recognized on the basis of the highly localized neurologic signs,3,6 but there might be more difﬁculty localizing the lesion to these distribu- tions in the case of a partial syndrome. Infarction in the lateral medullary region in the distribu- tion of PICA is usually associated with throm- bosis of the ipsilateral vertebral artery proximal to the take-off of PICA.1,8 Traumatic dissection of the distal vertebral artery is a common cause of lateral medullary infarction in younger patients.9–11 Infarction in the lateral pontomed- ullary distribution of the AICA is usually associated with occlusive disease of the distal vertebral artery and proximal basilar artery.7,12

Often these brainstem syndromes occur with- out associated cerebellar infarction because of the anastomotic channels between the cerebel- lar arteries. Isolated cerebellar infarction in the distribution of the superior, anterior inferior, or posterior inferior cerebellar arteries usually indicates an embolic source.13,14 Emboli typi- cally migrate to the most distal arterial branch— in this case, the cerebellar branches. Patchy areas of infarction in the cerebellum occurring at the junctions of the three major arteries may indicate hypoperfusion within the entire poste- rior circulation, resulting in “watershed infarc- tions.”15,16 These types of infarctions can also be seen with diffuse vasospasm associated with basilar migraine.

Transient Ischemic Attacks (TIAs)

Transient ischemia within the vertebrobasilar system is a common cause of episodic vertigo in older patients. It is typically abrupt in onset, usually lasting several minutes, and is fre- quently associated with nausea and vomiting. In their classical description of TIAs within the vertebrobasilar circulation, Williams and Wilson17 reported that vertigo was the initial symptom in 48% of patients. Invariably, the vertigo is associated with symptoms resulting from ischemia in the remaining territory sup- plied by the posterior circulation (those listed in Table 14–1). Next to vertigo, visual symp- toms are most common. Associated symptoms occur in episodes, either in combination with the vertigo or in isolation.

Fisher’s classic paper on this topic18 is remembered for emphasizing that episodes of vertigo without other neurologic symptoms is strongly suggestive of a disorder other than VBI. However, among his cases of VBI, he described several patients who manifested isolated episodes of vertigo at some time during their course. Fields and Weibel19 also described several patients with isolated episodes of vertigo and VBI. We reviewed the clinical ﬁndings of 42 patients who pre- sented to our neurotology clinic with vertigo due to VBI in 1989.4 The diagnosis was based on their having at least some episodes with a characteristic combination of symptoms (those listed in Table 14–1). There was a surprisingly

Table 14–1 Frequency of Symptoms Associated with Vertigo in 42 Patients with Vertebrobasilar Insufﬁciency

Symptom Patients

Visual (diplopia, visual illusions and 29

hallucinations, ﬁeld defects, etc.)

Stroke Syndromes

LABYRINTHINE INFARCTION

Occlusion of the internal auditory artery leads to a sudden profound loss of both auditory and vestibular function. Hearing loss is usually permanent, and a vestibular imbalance

Drop attacks 14

Unsteadiness, incoordination 9

Extremity weakness 9

Confusion 7

Headache 6

Hearing loss 6

Loss of consciousness 4

Extremity numbness 4

Dysarthria 4

Tinnitus 4

Perioral numbness 2

Source: Data from Grad and Baloh.4

high incidence of isolated episodes of vertigo in these patients; 62% had at least one isolated episode of vertigo and, in 19%, their TIAs began with an isolated episode of vertigo. These patients with isolated episodes of vertigo also reported the same vertiginous sensation in combination with other symptoms at other times, which suggests that the vertigo was indeed due to transient ischemia with the posterior circulation. Subsequently, there have been many other reports emphasizing that isolated attacks of vertigo can be the only manifestation of a TIA within the verte- brobasilar system.20–22 As suggested earlier, it is still unclear whether these isolated episodes of vertigo originate from the brain or inner ear. As a general rule, vertigo may be an isolated initial symptom of VBI or may occur in isolation intermixed with more typical episodes, but VBI becomes extremely unlikely whenever recurrent episodes date back more than 3 months and are unaccompa- nied by other focal neurologic symptoms.1 However exceptions even to this more gener- ous rule do occur. In fact, we reported a patient having hundreds of attacks of vertigo and uni- lateral tinnitus over a 2-year period who was found to have a severe stenosis of the basilar artery just proximal to AICA.23 A stent was placed to open the stenosis and resulted in resolution of the attacks.

remains, although symptoms of dizziness and imbalance gradually improve with central compensation. Pathological studies in such patients show widespread necrosis of the inner ear tissues with subsequent proliferation of ﬁbrous tissue and new bone formation.24 Most documented cases have been associated with ischemia in the distribution of the AICA, accompanied by infarction of the brain stem and/or cerebellum.25 Not infrequently, infarction of the labyrinth is preceded by epi- sodes of transient ischemia within the verte- brobasilar system, in some cases, manifested by isolated episodes of vertigo.7 The diagnosis should be considered in patients with impor- tant risk factors for stroke who present with sudden onset of unilateral deafness and vertigo, particularly if there is a history of TIA, stroke, or known atherosclerotic vascular disease.

The role of vascular occlusion in producing sudden one-sided deafness without associated vertigo is unclear. There is little reason to sus- pect that unilateral deafness in a young, healthy patient is caused by vascular disease. As noted in Chapter 9, most of these cases are probably due to isolated viral infections. However, the sudden onset of deafness without associated vertigo or brainstem signs in a patient with known vascular disease or a hypercoagulation syndrome should raise the suspicion for ischemia within the distribution of the com- mon cochlear artery or one of its branches (see Fig. 2–9 in Chapter 2).25 Sudden deafness (reversible or permanent) has been reported in patients with fat emboli,26 thromboangiitis obliterans,27 and macroglobulinemia.29 Athero- sclerotic disease is also associated with sudden deafness, but pathological conﬁrmation of the site of vascular occlusion is often lacking.28 Examination of the cochlea at necropsy in such patients reveals a loss of the organ of Corti and degeneration of the stria vascularis, spiral ligament, and distal cochlear nerve ﬁbers (ﬁndings similar to those seen in

animals that have had their labyrinthine artery occluded).24

Ischemia that is conﬁned to the anterior ves- tibular artery distribution (see Fig. 2–9 in Chapter 2) can result in transient episodes of vertigo (lasting minutes) or a prolonged attack (lasting days) due to infarction of the vestibular labyrinth.5,22 The former may be associated with hyperviscosity syndromes such as hyperlipidemia, polycythemia, macroglobu- linemia, and sickle cell anemia.30,31 The clinical picture of infarction in the distribution of the anterior vestibular artery is that of the acute vestibular syndrome (i.e., sudden, severe vertigo without hearing loss or brainstem symptoms),2 and as such cannot be distin- guished from vestibular neuritis. After recover- ing from the acute manifestations, patients may develop episodes of typical benign positional vertigo months or years later. The positional vertigo presumably results from ischemic necrosis of the utricular macule, causing a release of otoconia that make their way into the long arm of the posterior semicir- cular canal. Since the posterior semicircular canal is supplied by a branch of the common

cochlear artery, it may be spared even though the superior part of the vestibular labyrinth is completely infarcted.5,32

LATERAL MEDULLARY INFARCTION

The zone of infarction producing the lateral medullary syndrome (Wallenberg’s syndrome) consists of a wedge of the dorsal lateral medulla just lateral to the olive (Fig. 14–1). Although the syndrome is commonly known as that of the PICA, as noted earlier, it usually results from occlusion of the ipsilateral vertebral artery, and only rarely from occlusion of the PICA. In young patients, dissection of the ver- tebral artery is a common cause, particularly if there is a history of trauma or neck manipula- tion.11,33–36 Symptoms may come on right at the time of the trauma or neck manipulation or they may be delayed for several days. Major symptoms include vertigo, nausea, vomiting, intractable hiccups, severe imbalance, ipsilat- eral facial numbness and weakness, diplopia, dysphagia, and dysphonia. A dissection is typi- cally accompanied by occipital headache or neck pain.36 Lesions involving the mid-level of

Dorsal efferent tract of nerve X Nucleus solitarius

Med. vestibular nucleus Inf. vestibular nucleus

Lat. cuneate nucleus

Restiform body

Nucleus of nerve XII

Nucleus ambiguus

Medial longitudinal fasciculus

Pyramid Medial lemniscus

Nucleus and root of nerve V

Vent. spinocerebellar tract

Root of nerve X

Lat. spinothalamic tract

Second ascending tract of nerve V

Inferior olive

Figure 14–1. Cross-section of the medulla illustrating the zone of infarction with Wallenberg’s syndrome (blue area).

Table 14–2 Mechanism of Symptoms and Signs Commonly Seen with Infarction in the Distribution of Posterior Inferior and Anterior Inferior Cerebellar Arteries

Symptoms and Signs Structures Involved with PICA Infarct

Vertigo, nystagmus Vestibular nuclei, posterior inferior

cerebellum

Structures Involved with AICA Infarct

Labyrinth, vestibular nerve, ﬂocculus

Tinnitus, hearing loss None Cochlea, auditory nerve, cochlear nucleus

Gait and limb ataxia Ventral spinocerebellar tract, posterior

inferior cerebellum

Middle cerebellar peduncle, anterior inferior cerebellum

Dysphagia, decreased gag Vagal nuclei and nerve None

Facial hemianesthesia Fifth nerve and nucleus Fifth nerve and nucleus Facial paralysis Seventh nerve Seventh nerve

Crossed hemisensory loss Spinothalamic tract Spinothalamic tract

Horner’s syndrome Descending sympathetic ﬁbers Descending sympathetic ﬁbers

AICA, anterior inferior cerebellar artery; PICA, posterior inferior cerebellar artery.

the lateral medulla produce a characteristic combination of symptoms, including vertigo, nausea, vomiting, hiccups, and dysphagia.37

Neurological examination identiﬁes multiple signs localizing to the lateral medulla (Table 14–2). The spontaneous nystagmus is typically horizontal-torsional with an increase in the horizontal component on gaze toward the side of the lesion and often a change in the direc- tion of the horizontal component with gaze away from the side of the lesion. Patients also may exhibit a transient ocular tilt reaction (ipsi- lateral head tilt, skew deviation, and ocular tor- sion, upper pole of the eye rotated toward the side of the lesion) that is associated with a devi- ation of the subjective visual-vertical in the direction of the head tilt.38 Even with their heads ﬁxed in the true vertical, they perceive it as tilted opposite the direction of the tilt reac- tion. This phenomenon results from involve- ment of the otolith-ocular pathways at the level of the vestibular nucleus.39 Two distinct pat- terns of otolith dysfunction are seen depending on whether the cerebellar nodulus is involved. If the nodulus is infarcted, there is ocular tor- sion and skew deviation with falling and tilt of the subjective visual vertical to the contrale- sional side. If the nodulus is spared, falling and tilt of the subjective visual vertical is ipsilateral without ocular torsion and skew deviation.40

Patients with Wallenberg’s syndrome often suffer a prominent motor disturbance that causes them to deviate toward the side of the lesion as if being pulled by a strong external force.41,42 This so-called lateropulsion also

affects the oculomotor system, causing exces- sively large voluntary and involuntary saccades directed toward the side of the lesion, whereas saccades away from the lesion side are abnor- mally small.43,44

LATERAL PONTOMEDULLARY INFARCTION

Ischemia in the distribution of the AICA usually results in infarction of the dorsolateral pontomedullary region and the middle cerebellar peduncle (Fig. 14–2).6,7 As noted earlier, because the labyrinthine artery arises from the AICA in most cases, infarction of the membranous labyrinth is a common accompa- niment. Severe vertigo, nausea, and vomiting may be the initial and most prominent symp- toms. The key difference between the lateral medullary syndrome and the lateral pontomed- ullary syndrome is that the latter is typically associated with a profound unilateral or bilat- eral hearing loss that can be the result of infarc- tion of the labyrinth, eighth nerve, or even the eighth nerve root entry zone into the brain stem. Sudden unilateral or bilateral hearing loss and vertigo can be the initial or sole mani- festation of AICA infarction.45,46 Neurological examination typically reveals a profound unilateral hearing loss, unilateral facial paraly- sis, cerebellar ataxia, and ipsilateral loss of pain and temperature sensation on the face due to involvement of the trigeminal nucleus and tract, and a contralateral decrease in pain and

A PCA B

IAA

AICA

SCA

4th ventricle

VIII

MCP

1 3 1A

PICA

PICA-AICA

anastamosis

VIII

Flocculus

IAA CCA

AICA

AVA

ASC

Flocculus

Saccule

HSC

PSC

Cochlea

Paraflocculus Nodulus

Figure 14–2. A Classical anterior inferior cerebellar artery (AICA) anatomy with AICA and posterior inferior cerebellar artery (PICA) of equal dominance. Numbers refer to the three zones of AICA supply shown in B, C, and D. Zone 1 is sup- plied by the recurrent penetrating arteries (RPA) off AICA, zone 2 by the internal auditory artery (IAA), and zone 3 by the terminal cerebellar branches of AICA. B Zones 1A and 1B represent the arterial supply to the rostral pons supplied by a premeatal and postmeatal RPA. The cross-hatched area represents the root entry zone of the facial and vestibuloco- chlear nerves. C Zone 2 represents the arterial supply to the inner ear. D Zone 3 is the part of the cerebellum supplied by AICA. ASC, anterior semicircular canal; AVA, anterior vestibular artery; CCA, common cochlear artery; HSC, horizontal semicircular canal; MCP, middle cerebellar peduncle; PCA, posterior cerebral artery; PSC, posterior semicircular canal; SCA, superior cerebellar artery; VA, vertebral artery; V, spinal trigeminal tract and nucleus; VI, abducens nucleus; VII, facial nerve; VIII, vestibulocochlear nerve.

temperature sensation on the body due to involvement of the crossed spinothalamic tract (Table 14–2).

Branches of the AICA supplying the ventro- lateral pons have few anastomoses with adja- cent vessels. By contrast, the root entry zones of the seventh and eighth cranial nerves have a rich network of anastomotic vessels arising from the lateral medullary artery, AICA, and the inferior lateral pontine artery. Thus, occlu- sion of the AICA reliably causes infarction of the lateral pons and middle cerebellar pedun- cle, but because of collateral vessels, the root entry zone of the seventh and eighth nerves is often spared.7

CEREBELLAR INFARCTION

Acute cerebellar infarction may present with prominent vertigo, vomiting, and ataxia; because typical lateral brainstem signs are not present, a mistaken diagnosis of an acute peripheral labyrinthine disorder might be made.3,47,48 We do not know the true proportion of patients with isolated vertigo who harbor an ischemic stroke because there is no large series of such patients who all receive magnetic reso- nance imaging (MRI) with diffusion weight sequences. One of the ﬁrst studies to attempt to address this issue found that 25% (6 out of 24) of patients with risk factors for stroke

who present to an emergency medical setting with isolated severe vertigo, nystagmus, and postural instability had an infarction of the inferior cerebellum, but diffusion-weighted images were not available at the time so the acuity of the infarction could not be deter- mined.49 A more recent study using MRI with diffusion-weighted imaging found that 75% (25/33) of patients with the acute vestibular syndrome had a causative stroke, most involv- ing the cerebellum.50 However, this study only included patients with at least one stroke risk factor and also excluded patients with a recent viral illness, so that the population was at higher risk of stroke etiology than the general popula- tion of patients with acute vertigo.50 The key features suggesting a cerebellar infarction include prominent cerebellar signs, particu- larly severe truncal ataxia (i.e., inability to sit or stand without assistance), and direction-chang- ing gaze-evoked nystagmus (See Video 6–9). Patients with peripheral vestibular disorders will have imbalance, even to the point of falling when trying to walk during the acute phase, but they can sit unassisted and can typically stand unassisted.38,50 Nystagmus, in patients with an acute peripheral vestibular disorder, does not change direction with changes in gaze (See Video 6–4, Video 6–5, and Video 6–6). Spontaneous down-beating nystagmus localizes the lesion to the caudal midline cerebellum (See Video 6–7).

There are three major cerebellar arteries: posterior inferior, anterior inferior, and supe- rior (Figs. 14–2A and 14–3A). After supplying branches to the brain stem, each of these arter- ies supplies the part of the cerebellum indicated by its name. Typically, there are prominent anastomoses between these three cerebellar arteries on the cerebellar surface, so that occlusion near the take-off results only in brainstem infarction with sparing of the cere- bellum. There are also common anatomical variants, the most common being anterior infe- rior cerebellar dominance on one side and pos- terior inferior cerebellar dominance on the opposite side. The PICA typically has two major cerebellar branches—a medial branch and a lateral branch—with the former supply- ing midline structures, including the vermis. Infarction in the territory of the medial branch of PICA can mimic an acute peripheral vestibulopathy probably by interrupting nodulouvular inhibitory projections to the

vestibular nuclei.51 In addition to supplying the anterior inferior surface of the cerebellum, the AICA also supplies the ﬂocculus and para- ﬂocculus, structures known to be critical for visual–vestibular interaction (see Fig. 14–2D). Patients with infarction in the distribution of the superior cerebellar artery typically do not present with vertigo or nystagmus but rather severe ataxia and dysarthria.50,52 There are reports though of rather mild imbalance (able to stand and walk unassisted, but not able to walk in tandem) from a superior cerebellar stroke.50

Diagnosis

CLINICAL EXAMINATION

Vertebrobasilar ischemia can usually be diag- nosed with a careful history and examination. As discussed earlier, TIAs within the posterior circulation typically present with the character- istic symptoms, even though occasionally, diz- ziness or vertigo occurs in isolation. Transient ischemic attacks typically come on abruptly, without an apparent precipitating factor, last for a few minutes, and then end abruptly, usu- ally with minimal or no residual symptoms. The abrupt spontaneous (nonpositional) onset and minutes’ duration are not typical of any of the common inner ear disorders. The acute stroke syndromes within the posterior circulation are usually easily identiﬁed on the basis of their characteristic combination of neurological symptoms and signs (Table 14–3). Although cerebellar infarcts can masquerade as a more benign inner ear disorder, through a careful examination one should be able to identify pro- found truncal ataxia and a direction-changing gaze-evoked nystagmus, which do not occur with inner ear lesions. The suspicion for a cerebellar infarction also increases if uni- directional nystagmus is found but the head- thrust sign is negative.38,50,58 The history can provide risk factors for atherosclerosis, includ- ing a history of coronary artery disease, hyper- tension, diabetes mellitus or hyperlipidemia, and a family history of early-onset atheroscle- rosis. In young patients without obvious vascu- lar risk factors, the history should focus on the possibility of trauma (including neck manipula- tion) and other systemic illnesses that might predispose to hypercoagulation.

Superior cerebellar (SCA)

Lateral branch of SCA

Medial branch of SCA

Basilar (BA) 5

Anterior inferior

cerebellar (AICA) 6

Vertical (VA)

Posterior inferior cerebellar (PICA)

Medial branch of PICA

Lateral branch of PICA

1 2 3

AICA

MSCA

LSCA

MSCA

LSCA MSCA

MPICA

LSCA

4 5 6

AICA AICA

LSCA

LPICA

MSCA

MPICA

LSCA

MPICA MPICA

Figure 14–3. A Branches of the three main cerebellar arteries. B Magnetic resonance imaging horizontal axial sections from rostral to caudal (1 to 6) showing territory supplied by each branch. L, lateral; M, medial.

BRAIN IMAGING

Magnetic resonance imaging is the procedure of choice for viewing brain structures supplied by the vertebrobasilar system.1,59,61 An MRI is usually normal in patients with TIAs within the posterior circulation, although occasionally such patients show evidence of old, silent infarcts, particularly in the occipital poles or

the cerebellar hemispheres. Speciﬁc stroke syndromes, such as the lateral medullary and lateral pontomedullary syndromes, are all eas- ily identiﬁed with MRI (Figs. 14–4 and 14–5).

The typical appearance is a T2 and FLAIR intense lesion within the brain stem in the

distribution of either the posterior inferior or the anterior inferior cerebellar arteries.

Table 14–3 Differentiating among Common Acute Vertigo Syndromes

Syndrome Spontaneous Nystagmus

Gait Other Possible Signs

Acute peripheral vestibulopathy

Unidirectional, beats toward intact side

Falls toward lesion side but can walk

Unilateral hearing loss

Cerebellar infarction Usually changes

direction with gaze

Severe ataxia, may not be able to sit or stand

Scanning speech, extremity incoordination

Lateral medullary infarction

ipsi, ipsilateral.

Usually changes direction with gaze

Falls toward lesion side, may not be able to walk

Decreased gag reﬂex, ipsifacial numbness, ipsi-incoordination, ipsi-Horner’s syndrome, hypophonia

Diffusion-weighted images (DWIs) may show abnormalities in the ﬁrst few hours after the acute stroke syndrome that will not show up on T2-weighted MRI scans for several hours.60

However, even DWIs can give false-negative

images in the ﬁrst 24–48 hours after infarc- tion.38,50,61–63 Typically, areas of infarction do

not enhance with contrast. The territories sup- plied by the different cerebellar artery branches are shown in Figure 14–3B. The sensitivity of computed tomography (CT) scan for acute infarction is extremely low, meaning that a neg- ative result does not alter the probability of infarction in a meaningful way.61 CT scans can

Figure 14–4. Magnetic resonance images showing infarction in the lateral medulla (PICA territory) (A) and in the pontine cerebellar peduncle (AICA territory) (B). T2-weighted axial sections.

Figure 14–5. Posterior inferior cerebellar artery (PICA) acute strokes. A variety of PICA infarctions are seen from four different patients. Arrows point to the region of infarction. A, shows a small discrete acute stroke on a diffusion weighted image (DWI) sequence; B, shows a large PICA stroke on a DWI sequence; C, show a midline PICA infarction on a ﬂuid- attenuated inversion-recovery sequence; and D, shows a very small acute stroke on DWI.

be useful in monitoring for swelling in the posterior fossa once the diagnosis of infarction has been made.

Deciding which patients with acute pro- longed vertigo should be considered for an MRI can be difﬁcult. However the probability of an infarction is extremely low when there is unidirectional horizontal nystagmus, a corre- sponding positive head-thrust test, and no other neurologic signs or symptoms. Red ﬂags for a stroke include any pattern of nystagmus other than unidirectional horizontal nystagmus, normal head-thrust test (indicating the periph- eral vestibular system is intact), inability to sit unassisted, and substantial risk factors for stroke. Red ﬂags for transient ischemic attacks include new onset spontaneous episodes last- ing minutes and a crescendo pattern.

ULTRASOUND

Ultrasound studies of the heart and great ves- sels are used to search for an embolic source in patients with TIAs or stroke of presumed embolic origin.1 Echocardiography is used to search for mural thrombi and can also detect cardiac septal defects that allow direct commu- nication between the left and right heart chambers. Transesophageal echocardiography (TEE) is useful for identifying embolic sources

in the aortic arch. Amarenco and colleagues64 identiﬁed echogenic masses in the aortic arch on TEE in 6 of 12 patients with posterior circu- lation infarcts of unknown cause. Ultrasound studies of the neck (duplex scanning and Doppler) can identify an occlusion of the ver- tebral arteries within their bony canal that may be a source of artery-to-artery emboli within the posterior circulation.65 Through transcra- nial doppler (TCD) imaging, one can assess the intracranial vertebral arteries, but TCD is less accurate for identifying lesions in the basilar artery. TCD is not useful for assessing small branches of the vertebrobasilar system. More than any of the other ultrasound studies, TCD reliability is highly dependent on the skill of the performing technician.

ANGIOGRAPHY

Magnetic resonance angiography (MRA) is the procedure of choice for assessing the verte- brobasilar circulation.1,59 Overall, there is a good correlation between MRA and conven- tional angiography, although MRA is relatively limited for evaluating smaller branches within the vertebrobasilar system. Depending on ana- tomical variations and the positioning of the subject, the distal vertebral artery–basilar artery junction may be difﬁcult to visualize

adequately. The neuroradiologist should be alerted in advance when it is important to visu- alize these structures so that the technician can properly position the patient. High-quality CT angiography (CTA) is also a method for imag- ing the posterior circulation and can be used in place of MRA, particularly if MR is contraindi- cated (e.g., patient with pacemaker).1 CTA is particularly useful for evaluating patients with suspected basilar artery occlusion because CTA takes substantially less time than MRA. Conventional contrast angiography is reserved for patients in whom the pathophysiology remains unclear after MRA or CT angiography (Figs. 14–6 and 14–7).

The main risk of conventional angiography is a TIA or infarction within the distribution of the injected vessel. The mechanism is usually vasospasm, although pieces of atherosclerotic plaque may be dislodged, resulting in a shower of emboli. Less common complications include an allergic reaction, a localized hemorrhage, or, rarely, infection at the site where the cath- eter enters the artery. Patients with a history of

migraine headaches are at greater risk for developing vasospasm.

Treatment

TRANSIENT ISCHEMIC ATTACKS

The urgency regarding any TIA is that 10%–15% of patients diagnosed with this transient event will suffer a completed stroke within 3 months, and half of these occur within the ﬁrst 48 hours.66,67 It is not clear whether the risk of stroke is higher or lower for posterior circula- tion TIAs compared with anterior circulation TIAs.69 As a way to estimate the risk of future stroke in individual TIA patients, the ABCD2 score was developed and validated.67 To deter- mine the ABCD2 score, patients presenting with TIA are assigned points for the following ﬁve factors: age 60 years; blood pressure

140/90 mmHg; clinical features of unilateral weakness or speech impairment; duration 60 minutes or 10–59 minutes; and diabetes.

Figure 14–6. (A) Conventional cerebral angiogram in a patient with recurrent episodes of vertigo due to vertebrobasi- lar insufﬁciency. Magnetic resonance angiography showed an absent left vertebral artery but it was unclear whether this represented a normal variant or occlusion. Right vertebral artery injection (anterior posterior view). Arrowheads show nar- rowing of the right vertebral artery and the left vertebral stump (the left vertebral artery is blocked). Hollow arrows show basilar artery narrowing. The long thin arrows point to the anterior inferior cerebellar arteries. (B) Schematic diagram of the anterior posterior view of the vertebrobasilar system shown in the angiogram. AICA, anterior inferior cerebellar artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery. (From Fife TD, Baloh RW, Duckwiler GR. Isolated dizziness in vertebrobasilar insufﬁciency: clinical features, angiography, and follow up.

Stroke Cerebrovasc Dis 4:4, 1994, with permission.)

Figure 14–7. Conventional angiogram of a patient with recurrent vertigo attacks and basilar stenosis. (A) Pre-stent angio- gram (lateral view), demonstrating basilar artery stenosis proximal to the anterior inferior cerebellar arteries (arrow head) and right vertebral artery occlusion (arrow). (B) Corresponding post-stent angiogram showing the treated vessel after angioplasty and stenting. (Kerber KA, et al. Neurology. 2005;65:962).

Based on the number of points, the risk of stroke at 90 days can be determined. However, the validity of this risk assessment tool in poste- rior circulation TIA is not clear. As with all diz- ziness, vertigo, and imbalance presentations, there are likely to be problems with the reli- ability of the diagnostic classiﬁcation particu- larly in TIA populations from claims databases or large cohort studies such as those used to derive and validate the ABCD2 score.67

Consensus guidelines for the evaluation and management of TIA have been published.66,68 The ﬁrst step includes initiating an antiplatelet agent and other steps to control risk factors for stroke.68 Noninvasive imaging of the head and neck vessels is recommended to search for a critical stenosis. However, this is less relevant in posterior circulation stroke because there are no good trials to support use of surgical approaches to vessel stenosis in the posterior circulation, whereas there is high-level evi- dence to support the use of surgical procedures for patients with symptomatic carotid stenosis. Echocardiography is used to search for a car- diac embolic source, which is particularly com- mon in posterior circulation events.

Anticoagulation is recommended over anti- platelet agents in patients with atrial ﬁbrillation or a prosthetic heart valve.68 Anticoagulation can also be considered when a cardioembolic

source is suspected based on ﬁnding an intracardiac clot or severe dilated cardiomyo- pathy.68 There is uncertainty about the use of anticoagulants versus antiplatelet agents in the management of patients having recurrent ver- tebrobasilar artery ischemic events. Retrospective studies have suggested warfarin may have efﬁcacy in patients with vertebrobasi- lar disease.70–72 However, in the Warfarin ver- sus Aspirin in Symptomatic Intracranial Disease (WASID) trial, warfarin therapy did not reduce the risk of stroke even in the subgroup with stenosis of the posterior circulation.73 Furthermore, the WASID trial was stopped prematurely because warfarin was associated with signiﬁcantly higher rates of adverse events (i.e., increased death, major hemorrhage, and myocardial infarction or sudden death). A sub- group analysis of the Ticlopidine Aspirin Stroke Study (TASS) found that patients classiﬁed as having vertebrobasilar symptom TIAs had a lower risk of stroke on ticlopidine compared to aspirin,74 but this ﬁnding has not been repli- cated and ticlopidine is rarely used because of the potential for adverse effects.

Transient vertigo episodes can be a warning sign of impending basilar artery occlusion— particularly when new in onset, increasing frequency and in patients with signiﬁcant stroke risk factors, or when other neurologic

features (particularly motor weakness or speech disturbance) are reported.78–80 If a severe pos- terior circulation stenosis (50%) is identiﬁed, endovascular therapies become a management option (Fig. 14–7). But randomized trials are lacking for the use of endovascular therapies in treating patients with vertebrobasilar stenosis. Nonetheless, these procedures hold promise in the management of patients with recurrent posterior circulation TIAs or stroke. The Phase I trials of stenting suggest a high technical suc- cess rate (>95%) with a low periprocedural rate of complications (about 6%).75–77 Re-stenosis rates have varied from 7.5% to 35% at 6 months. Hopefully some of the important questions about the use of endovascular treatments will be answered by a large 60-site randomized controlled trial of stenting in intracranial steno- sis, the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial (ClinicalTrials.gov Identiﬁer: NCT00576693).

INFARCTION

Randomized controlled studies and consensus guideline statements support the use of intra- venous thrombolytic therapy for acute ischemic stroke patients when used less than 3 hours from stroke onset.82,83 More recent ﬁndings from a large randomized trial indicate the ben- eﬁts of IV thrombolytics outweigh the risks for up to 4.5 hours from symptom onset.84 Patients with posterior circulation stroke, however, were less likely to be enrolled in these acute stroke trials, with about 5% of the patients in the original thrombolytic trial having a poste- rior circulation stroke.85 In subsequent trials, patients with posterior circulation stroke have either been excluded or were likely to be underrepresented.85 The reasons for this are largely because posterior circulation stroke is less common than anterior circulation stroke and also because it can be more difﬁcult to dis- criminate between patients with posterior cir- culation stroke and patients with stroke-mimics such as peripheral vestibular disorders or even nonspeciﬁc symptom presentations.

The time window for the thrombolytic treat- ment of stroke is generally extended when basilar artery occlusion is identiﬁed, though this remains a controversial topic because of the lack of large randomized controlled data. The main reason that the window is extended

to even up to 24 hours is because the prognosis of basilar occlusion is so poor. One recent small randomized trial found that patients receiving intra-arterial thrombolysis had a good outcome in 4 of 8 patients receiving thrombolysis com- pared with only 1 of 8 patients in the control group.86 A systematic review of published case series of basilar artery occlusion treated with thrombolysis (either intravenous or intra- arterial) found that an outcome of death or dependency was more than 75% among 420 patients, and it did not differ on the adminis- tration route.87 Recanalization was achieved more frequently with intra-arterial thromboly- sis (225 of 344; 65%) than with intravenous

thrombolysis (40 of 76; 53%), but death and dependency rates did not differ. Only 24% of patients with intra-artertial thrombolysis and 22% with intravenous thrombolysis had a good outcome (e.g., modiﬁed Rankin score  2, meaning slight disability but able to walk unas- sisted and able to care for self without assis- tance). Without recanalization the likelihood of a good outcome was only 2%. A similar rate (68%) of a poor outcome (death or depen- dency) was also found in a large international registry study of basilar artery occlusion, and no statistically signiﬁcant superiority was found for any treatment strategy.88 Factors associated with a better outcome include recanalization, treatment within 8 hours of symptom onset, and a Glasgow Coma Scale score 9 at presen- tation (generally meaning not comatose).85,87,88 Importantly, patients with radiographic evi- dence of brainstem infarction have been excluded from many of the studies reporting on the effects of thrombolytic treatment in basilar occlusion.87

After a latent interval of several days, some patients with cerebellar infarction may develop progressive brainstem dysfunction due to com- pression by the swollen cerebellum or due to the production of hydrocephalus.53,54 A large infarction in the cerebellar distribution of the PICA poses the greatest risk for brainstem compression. Surgical management should be a consideration in these cases because relent- less progression to quadriplegia, coma, and death can ensue.55–57 However, uncertainty exists about the timing and selection of patients for surgical management.56,57

Management of labyrinthine infarction is pri- marily symptomatic. Antivertiginous medica- tions can help relieve the acute vertigo and

nausea. Vestibular rehabilitation exercises should be started as soon as the patient is able to cooperate. The clinical course for patients sur- viving a brainstem or cerebellar infarction is typically that of gradual but incomplete recov- ery. Vertigo may persist for months because of damage to central structures important for com- pensation. Many patients complain of disabling oscillopsia due to spontaneous nystagmus and damaged central vestibular and cerebellar path- ways. Antivertiginous medications are less effec- tive for controlling vertigo than with peripheral vestibular lesions and vestibular rehabilitation exercises are often of minimal beneﬁt. One exception to this overall generally poor progno- sis is the recovery seen in young patients with lateral medullary infarction due to vertebral artery dissection. Many of these patients have a complete return to normal and the great major- ity have only minimal residual dysfunction.‌‌‌‌

INTRALABYRINTHINE HEMORRHAGE

Intralabyrinthine hemorrhage can be associ- ated with multiple systemic disorders, includ- ing leukemia, vasculitis, and cocaine abuse.24,91–93 Sudden deafness due to intrlabyrinthine hemorrhage is common in patients with endo- lymphatic sac tumors associated with von Hippel-Lindau disease.94 A small percentage of patients with idiopathic sudden deafness show MRI features of intralabyrinthine hemor- rhage.95 Pathologic examination of the inner ear reveals hemorrhage into the perilymphatic space with smaller focal hemorrhages in the endolymphatic space.24 The vestibular and cochlear end organs, although morphologically intact, are rendered nonfunctional, apparently from altered ﬂuid chemistry. A similar condi- tion may follow from a blow to the head with- out the occurrence of a bony fracture (so-called labyrinthine concussion).

Diagnosis and Management

Diagnosis of intralabyrinthine hemorrhage is based on ﬁnding a sudden auditory and vestibular loss in a patient with an underlying predisposing condition (see earlier discussion). Hearing loss and vestibular loss (documented

with audiometric and electronystagmography tests) are profound and usually permanent. MRI may reveal ﬁndings suggestive of intral- abyrinthine hemorrhage, including increased signal on precontrast T1 sequences and also increased signal on T2 or ﬂuid-attenuated inversion recovery (FLAIR) sequences. However, these imaging ﬁndings could also indicate increased protein concentration rather than hemorrhage. A more advanced FLAIR sequence, three-dimensional (3D) FLAIR, might be a more sensitive test for identifying hemorrhage or increased protein content in the inner ear but requires more detailed study to determine the reliability and validity of the test.95,96 Management consists of symptomatic treatment of the vertigo (see Chapter 19) and correcting an underlying bleeding diathesis when possible.

HEMORRHAGE INTO THE BRAIN STEM AND CEREBELLUM

Spontaneous intraparenchymal hemorrhage into the brain stem or cerebellum produces a dramatic clinical syndrome frequently pro- gressing to loss of consciousness and death.97,98 The cause of hemorrhage is hypertensive vas- cular disease in approximately two-thirds of patients. Anticoagulation therapy, cryptic arte- riovenous malformations, and bleeding diathe- sis are also important etiologic factors, whether alone or in combination with hypertension. Cerebellar hemorrhage can be a remote effect of spinal or supratentorial surgery associated with drainage of large volumes of CSF.99

Vertigo may be an initial symptom with brain stem hemorrhage, but it is never an isolated symptom and is usually only ﬂeeting as the patient rapidly plunges into coma. Hemorrhage into the pons typically results in a rapid onset of coma, ﬂaccid quadriplegia, loss of horizontal eye movements, pinpoint reactive pupils, and ocular bobbing.48 Hemorrhage into the medulla is associated with rapid cardiorespiratory failure and death.

Because of its potential reversibility, cere- bellar hemorrhage deserves particular empha- sis.98 The initial symptoms of acute cerebellar hemorrhage are vertigo, nausea, vomiting, headache, and inability to stand or walk. As with cerebellar infarction, these symptoms

might be confused with an acute peripheral vestibular lesion. Unlike the latter, however, examination in the initial period usually reveals nuchal rigidity, prominent cerebellar signs, ipsilateral facial paralysis, and ipsilateral gaze paralysis. Pupils are often small bilaterally but reactive. Approximately 50% of patients lose consciousness within 24 hr of the initial symp- toms, and 75% become comatose within 1 week of onset.101 The condition is often fatal unless surgical decompression is performed.102 Midline cerebellar hemorrhage is particularly difﬁcult to diagnose because it produces bilat- eral signs and generally runs a more fulminant course than a lateralized hemorrhage. Such patients have profound ataxia, usually being unable to stand—a ﬁnding not associated with benign peripheral vestibular lesions.

Diagnosis and Management

The diagnosis of hemorrhage into the brain stem and cerebellum has been revolutionized with the introduction of CT and MR scanning. Computed tomography is usually superior to MR for identifying intraparenchymal blood (Fig. 14–8). An imaging study is recommended in any patient presenting with the acute onset of vertigo not meeting criteria for a peripheral vestibular disorder and who also exhibits prominent ataxia, either of the trunk and or extremities.

As indicated earlier, hemorrhage into the cere- bellum is often fatal unless surgical decompression is performed.103 The earlier the syndrome is recog- nized, the more likely the surgery will be success- ful. Once the patient is comatose, almost none

Figure 14–8. Computed tomography scan showing hydrocephalus (A) secondary to a cerebellar hemorrhage (arrows) (B).

survive. Small hemorrhages into the brain stem and cerebellum may spontaneously resolve.‌‌

VASCULAR COMPRESSION SYNDROMES

Vertebrobasilar Dolichoectasia

Dolichoectasia refers to an enlargement and elongation of the basilar artery (Fig. 14–9). It is a common ﬁnding on MR images of the brain and on cerebral angiography, typically unasso- ciated with any clinical symptoms. However, there are reports suggesting that vertebrobasi- lar dolichoectasia can be implicated in neuro- logic symptoms, both by compression of the brain stem and cranial nerves or by producing TIAs.104–106 In some cases, both compression and ischemia coexist in the same patient. Patients with vertebrobasilar dolichoectasia can have evidence of both peripheral and cen- tral vestibular dysfunction, most commonly due to compression of the vestibular nerves.107 The pathophysiology for cerebral ischemia is uncertain, but obstruction by atheromata, intraluminal thrombi, or artery-to-artery emboli have been proposed.108 Distortion of small branches of the basilar artery due to elongation and tortuosity and hemodynamic factors related to reduction in ﬂow velocity in the enlarged basilar artery may also contribute to the isch- emia. There is still debate as to whether verte- brobasilar dolichoectasia represents a congeni- tal anomaly or is the result of atherosclerotic

degeneration of the vascular wall. Probably both factors can lead to the production of ver- tebrobasilar dolichoectasia, but often there is a more generalized vascular ectasia of cerebral vessels, suggesting a more diffuse arterial defect. Transient ischemic attacks associated with vertebrobasilar dolichoectasia are treated like other causes of TIAs. The role of percuta- neous transluminal angioplasty and stenting in symptomatic dolichoectasia is not clear.81

Vascular Compression by Normal Vessels (Vestibular Paroxysmia)

There is controversy as to whether audioves- tibular symptoms can result from compression of the eighth cranial nerves by normal arteries. Jannetta et al.109 reported improvement in patients with “disabling positional vertigo” after surgically removing vascular loops that were compressing the eighth cranial nerve near the root entry zone. However, the clinical syn- drome was ill deﬁned and there were no speciﬁc diagnostic tests prior to surgical explo- ration of the posterior fossa. Furthermore, vascular loops, particularly loops of the AICA, are common in the cerebellopontine angle in normal subjects without symptoms. Brandt and Dieterich111 described a syndrome characterized by brief episodes of vertigo— vestibular paroxysmia—which they attributed to neurovascular compression of the eighth cranial nerve. Some patients had associated auditory symptoms and signs, whereas others did not. Episodes could occur spontaneously

Figure 14–9. Vertebro-basilar dolichoectasia. Magnetic resonance images show an ectatic vertebrobasilar artery. Arrows point to the artery. The large and tortuous artery can be seen lateral to the medulla (A), and then compressing the cerebellar peduncle and pons (B and C), before coursing back to the midline (D).

or after head turns or position change. A more recent follow-up study of 32 patients with vestibular paroxysmia found that most responded to either carbamazepine (mean dose 568 mg/day) or oxcarbazepine (mean dose 870 mg/day).112 Patients with vestibular paroxysmia may also respond to low-dose gabapentin.110

Rotational Vertebral Artery Syndrome

Although rare, vertebrobasilar ischemia can be caused by vertebral artery occlusion during neck rotation.113 Nearly always one vertebral artery is hypoplastic or occluded and the other becomes compressed by an osteophyte, usually at the C level, when the head is turned to the

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5-6
opposite
the intact vertebral artery.
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Kikuchi S, Yamasoba T. Neuro-otological ﬁndings

When rotational vertebral artery syndrome is identiﬁed there is still uncertainty about the best management. No long-term studies in a large enough sample of patients has been per- formed so that we can understand the natural history of the disorder. In theory, patients could learn to prevent these attacks by avoiding the movements that trigger them. Surgical decompression of the vertebral artery may be an option for alleviating refractory symptoms and could be important for reducing the risk of stroke.

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Nicoucar K, Sakbani K, Vukanovic S, Guyot JP. Intralabyrinthine haemorrhage following cocaine con- sumption. Acta Otolaryngol. 2005;125(8):899.
Butman JA, Kim HJ, Baggenstos M, et al. Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease. JAMA. 2007;298(1):41.
Sugiura M, Naganawa S, Teranishi M, Nakashima T. Three-dimensional ﬂuid-attenuated inversion recov- ery magnetic resonance imaging ﬁndings in patients with sudden sensorineural hearing loss. Laryngoscope. 2006;116(8):1451.
Yoshida T, Sugiura M, Naganawa S, Teranishi M, Nakata S, Nakashima T. Three-dimensional ﬂuid- attenuated inversion recovery magnetic resonance imaging ﬁndings and prognosis in sudden sensorineu- ral hearing loss. Laryngoscope. 2008;118:1433.
Dinsdale HB. Spontaneous hemorrhage in the poste- rior fossa: a study of primary cerebellar and pontine hemorrhage with observations on the pathogenesis. Arch Neurol. 1964;10:200.
Elijovich L, Patel PV, Hemphill JC, III. Intracerebral hemorrhage. Semin Neurol. 2008;28(5):657.
Brockmann MA, Groden C. Remote cerebellar hem- orrhage: a review. Cerebellum. 2006;5(1):64.
Kushner MJ, Bressman SB. The clinical manifes- tations of pontine hemorrhage. Neurology. 1985; 35:637.
Brennen RW, Bergland RM. Acute cerebellar hem- orrhage. Analysis of clinical ﬁndings and outcome in 12 cases. Neurology. 1977;27:527.
Pollak L, Rabey JM, Gur R, Schiffer J. Indication to surgical management of cerebellar hemorrhage. Clin Neurol Neurosurg. 1998;100:99.
Mayer SA, Rincon F. Treatment of intracerebral hae- morrhage. Lancet Neurol. 2005;4(10):662.
Passero S, Nuti D. Auditory and vestibular ﬁndings in patients with vertebrobasilar dolichoectasia. Acta Neurol Scand. 1996;93:50.
Passero S, Filosomi G. Posterior circulation infarcts in patients with vertebrobasilar dolichoectasia. Stroke. 1998;29:653.
Ubogu EE, Zaidat OO. Vertebrobasilar dolichoecta- sia diagnosed by magnetic resonance angiography and risk of stroke and death: a cohort study. J Neurol Neurosurg Psychiatry. 2004;75(1):22.
Nuti D, Passero S, Di Girolaamo S. Bilateral vestibu- lar loss in vertebrobasilar dolichoectasia. J Vestib Res. 1996;6:85.
Besson G, Bogousslavsky J, Moulin T, Hommel M. Vertebrobasilar infarcts in patients with dolichoec- tatic basilar artery. Acta Neurol Scand. 1995;91:37.
Jannetta PJ, Moller MB, Moller ARC. Disabling posi- tional vertigo. N Engl J Med. 1984;310:1700.
Russell D, Baloh RW. Gabapentin responsive audiovestibular paroxysmia. J Neurol Sci. 2009;281 (1-2):99.
Brandt Th, Dieterich M, Danek A. Vestibular parox- ysmia. Bailliere’s Clin Neurol. 1994;3:565.
Hüfner K, Barresi D, Glaser M, et al. Vestibular par- oxysmia: diagnostic features and medical treatment. Neurology. 2008;71(13):1006.
Brandt T, Baloh RW. Rotational vertebral artery occlusion: a clinical entity or various syndromes? Neurology. 2005;65(8):1156.
Kuether TA, Nesbit GM, Clark WM, Barnwell SL. Rotational vertebral artery occlusion: a mechanism of vertebrobasilar insufﬁciency. Neurosurgery. 1997;41:427.
Choi KD, Shin HY, Kim JS, et al. Rotational vertebral artery syndrome: oculographic analysis of nystagmus. Neurology. 2005;65(8):1287.
Bulsara KR, Velez DA, Villavicencio A. Rotational vertebral artery insufﬁciency resulting from cervical spondylosis: case report and review of the literature. Surg Neurol. 2006;65(6):625.
Petridis AK, Barth H, Buhl R, Mehdorn HM. Vertebral artery decompression in a patient with rotational occlusion. Acta Neurochir (Wien). 2008;150(4):391.

Chapter 15 ‌‌

Tumors

TUMORS OF THE MIDDLE EAR AND TEMPORAL BONE

Malignant Tumors ‌

Glomus Body Tumors (Paragangliomas) Diagnosis

Management

TUMORS OF THE INTERNAL AUDITORY CANAL AND CEREBELLOPONTINE ANGLE

Schwannomas Meningiomas

Epidermoid Cysts (Primary Cholesteatomas) Cholesterol Granulomas

Metastatic Tumors Diagnosis Management BRAIN TUMORS

Brain Stem Fourth Ventricle Cerebellum

Diagnosis and Management

TUMORS OF THE MIDDLE EAR AND TEMPORAL BONE

A wide variety of benign and malignant tumors involve the middle ear and temporal bone.1 Tumors involving the middle ear produce symptoms of fullness or conductive hearing loss early, whereas tumors in the temporal bone outside the middle ear can become quite large without producing symptoms. The tumor may not become apparent until it erodes into the external auditory canal (producing a conductive hearing loss) or through the mastoid cortex into the skin. Anterior extension into the cavernous sinus produces ophthalmoplegia from involve- ment of the third, fourth, and sixth nerves. Malignant tumors in this region tend to spread locally to the regional lymph nodes; distant metastasis is unusual. Ultimately, the tumor can be seen in the nasopharynx, middle ear, or neck.

Malignant Tumors

Squamous cell carcinoma is the most frequent histologic type of malignant tumor involving the middle ear and mastoid.2,3 It typically arises from epidermal cells of the auricle, external auditory canal, or the middle ear and mastoid. The prognosis is good for tumors conﬁned to the auricle and external canal but not for those invading the middle ear and mastoid. The latter are frequently associated with prominent ear symptoms that include vertigo, hearing loss, pain, otorrhea, mastoid swelling, and facial paralysis. Squamous cell carcinomas often begin in an ear with previous otologic disease, partic- ularly chronic suppurative otitis media with a mastoid cavity. Other, less common, tumors originating in the external auditory canal and middle ear include adenoid cystic carcinoma, basal cell carcinoma, mucoepidermoid carci- noma, and ceruminoma. In general, these tumors are less malignant but occasionally will

339

be locally invasive. Adenoid cystic carcinoma arises from glandular tissue of the external canal and middle ear; it typically has severe pain as an early symptom and may be associated with dis- tant metastasis.

Generally, carcinomas occur in an elderly age group, whereas sarcomas occur in the young. Both osteogenic sarcoma and chondrosarcoma occur as primary tumors of the temporal bone, running fulminant courses in older children and young adults. Rhabdomyosarcoma is the most common middle ear malignant tumor in the young, typically occurring in children under the age of 5.4 The initial symptom is often facial paralysis, which may be misdiagnosed as idio- pathic Bell’s palsy. In later stages, the tumor extends beyond the middle ear to involve the petrous apex and may invade the posterior or middle cranial fossi. Rhabdomyosarcoma should be considered in any infant presenting with idiopathic facial paralysis.

Metastatic involvement of the temporal bone is common with several different tumor types but, because of the enchondral layers’ resis- tance, neoplasms rarely invade the bony laby- rinth.5 The most common sites of origin for metastatic tumors in order of frequency are breast, kidney, lung, stomach, larynx, prostate, and thyroid gland.6 Metastatic tumors from the breast and prostate commonly incite new bone formation.

Glomus Body Tumors (Paragangliomas)

Glomus tumors are the most common tumor of the middle ear, and next to schwannomas they are the most common tumor of the temporal bone.7 Glomus tumors arise in the glomera of the chemoreceptor system, which may be found along the vagus nerve, glossopharyngeal nerve, Jacobson’s nerve (tympanic branch of the ninth nerve), and the nerve of Arnold (postauricular branch of the tenth nerve). Most are hamartomas with tissue components found in the normal glomus body.8 Genetic factors are likely important in pathogenesis, and in some families glomus tumors are inherited in an autosomal dominant fashion with genomic imprinting (the gene only results in tumors if inherited from the father).9 The most common tumor sites are the glomus jugulare (jugular bulb), glomus tympanicum (middle ear), and

glomus vagale (along the course of the vagus nerve). Glomus vagale and jugulare tumors often involve the labyrinth and cranial nerves, whereas glomus tympanicum tumors usually produce only local symptoms such as conductive hearing loss, pulsatile tinnitus, and rhinorrhea because of the tumor bulk in the middle ear. Invasion of the labyrinth is an uncommon but serious prognostic sign and is often associated with extension to the petrous apex and into the middle and posterior cranial fossae. The jugu- lar foramen syndrome consisting of ninth, tenth, and eleventh nerve involvement occurs with glomus jugulare and vagale tumors. Involvement of the twelfth nerve is an ominous sign, indicating destruction of the jugular fora- men with tumor extension into the hypoglossal canal and usually into the posterior fossa.

Diagnosis

Tumors of the middle ear space and temporal bone can often be identiﬁed on careful physical examination. A malignant tumor may be visible after it has eroded into the external auditory canal or through the mastoid cortex into the skin. Nearby lymph nodes are often enlarged. A biopsy of these lesions should lead to the cor- rect histologic diagnosis. Glomus body tumors are often visible through the tympanic mem- brane (see Fig. 6–1C). If not all the borders are visible, the tumor may be either a large glomus tympanicum tumor or a much larger glomus jugulare tumor that has extended from the jug- ular bulb into the middle ear. If cranial nerve deﬁcits are present, the tumor is most likely a glomus jugulare type.

Although the presence of a tumor involving the middle ear or temporal bone can often be identiﬁed on physical examination, computer- ized tomography (CT) and magnetic resonance (MR) scanning are used to assess the extent of the tumor. Computed tomography is the diag- nostic procedure of choice for determining bony involvement, and MR is most useful for determining the soft tissue extent. Contrast should be used with either procedure to visual- ize vascular elements.10 Magnetic resonance angiography (MRA) is particularly useful for deﬁning the features of a glomus body tumor.11,12 Individuals in families with glomus tumors should be screened after age 16 to detect early asymptomatic tumors.9

Management

Malignant tumors conﬁned to the ear and external auditory canal can often be surgically resected with minimal cosmetic and functional disability.13 Much more extensive surgical procedures with greater cosmetic and func- tional disabilities are required for tumors invading the middle ear and mastoid, and often only subtotal resection is possible. Most patients are treated with postsurgical radiation, but the long-term prognosis in these patients is poor.

Although some small glomus tympanicum tumors, when the borders are clearly demar- cated, can be removed via the external auditory canal, more extensive procedures are usually required for these tumors. Glomus jugulare and vagale tumors are much more difﬁcult to remove because they are highly vascular and closely interrelated with key neural and vascu- lar structures.7,14 A “wait-and-see” policy has been recommended for most of these tumors.12,15 Radiation therapy may be useful for management of tumor recurrences and for unresectable lesions.16‌

TUMORS OF THE INTERNAL AUDITORY CANAL AND CEREBELLOPONTINE ANGLE

Tumors arising in the narrow conﬁnes of the internal auditory canal typically produce a gradual compression of the seventh and eighth cranial nerves. Sensorineural hearing loss, tin- nitus, and facial paresis insidiously evolve usually over months to years. Vertigo is uncom- mon with such lesions because the nervous system is able to adapt to the gradual loss of vestibular function. Lesions within the cerebel- lopontine (CP) angle produce a similar, slowly progressive compression of the seventh and eighth cranial nerves, although if the tumor arises in the angle, it can grow to a much larger size before critical compression occurs. Most often, tumors begin in the internal auditory canal and grow outward into the CP angle, inasmuch as it is the path of least resistance. Next to the seventh and eighth nerves, the ﬁfth nerve is most commonly involved with CP-angle tumors, causing ipsilateral facial numbness.

In later stages of progression, involvement of the sixth, ninth, and tenth nerves may give rise to diplopia, dysphonia, and dysphagia. Compression of the brain and cerebellum results in ipsilateral gaze dysfunction and dys- metria of the extremities.

In a series of over 2000 tumors of the CP angle, 92% were vestibular schwannomas (acoustic neuromas); 3%, meningiomas; 2.5%, epidermoid cysts; and 1%, facial nerve schwannomas.17

Schwannomas

Tumors arising from the sheaths of the cranial and peripheral nerves have been called neuro- mas, neurilemmomas, and neuroﬁbromas, but convincing evidence that most represent pro- liferation of the sheath-producing schwann cells makes schwannoma a more appropriate term.6 These tumors comprise about 5% of intracranial neoplasms and are by far the most common tumor found in the temporal bone. They arise from the vestibular nerve in more than 90% of cases, and much less frequently from the facial, acoustic, or trigeminal nerves. The general term acoustic neuroma, therefore, is inappropriate on two accounts. Mostly, schwannomas are circumscribed and encapsu- lated, encroaching on and displacing neural structures as they grow, without direct invasion of tissue. Vascularity is variable, but they are usually less vascular than meningiomas. Vestibular schwannomas typically arise at the myelin–glial junction near the porous acousti- cus, producing symptoms by exerting pressure on surrounding neurovascular structures. Infrequently, the tumor arises from the vestib- ular nerve terminals near or in the end organ, in which case end-organ destruction occurs, or it may arise from the nerve after it leaves the canal in the angle, in which case it can be rela- tively large before producing symptoms and signs. Intralabyrinthine schwannomas typically begin in the cochlea and later spread to the vestibular labyrinth.18 Schwannomas usually grow very slowly but occasionally hemorrhage into the tumor; cyst formation or associated edema produces clinical evidence of more rapid growth. Malignant schwannomas are rare; approximately half of them occur with neuroﬁbromatosis type II.

Schwannomas are usually encapsulated and grow at a very slow rate. On histological exami- nation, they are typically composed of two different tissues—Antoni type A and Antoni type B. Antoni type A is compact and cellular with elongated spindle cells forming palisades. By contrast, Antoni type B is loose and much less cellular. Most schwannomas are predomi- nantly Antoni type A with some focal areas of type B tissue. Larger tumors often become cys- tic because of necrosis and degeneration within the tumor.

VESTIBULAR SCHWANNOMAS (ACOUSTIC NEUROMA)

The incidence of vestibular schwannomas has been estimated at about 1 per 100,000 person/ years.19,20 Although several studies identiﬁed an increasing incidence over the past 25 years, this increase can probably be attributed to easier access to magnetic resonance imaging (MRI) particularly in elderly patients, in whom small intracanalicular tumors predominate.21 To date, there is no conclusive evidence that cel- lular phone use leads to an increased incidence of vestibular schwannomas.22 By far the most common symptom associated with a vestibular schwannoma is a slowly progressive unilateral hearing loss.23 Occasionally, patients will expe- rience ﬂuctuating or sudden hearing loss, apparently from compression of the labyrin- thine vasculature. Often patients will complain of an inability to understand speech when using the telephone even before they are aware of a loss of hearing. Unilateral tinnitus is the next most common symptom. True vertigo occurs in

<20% of patients, although about half will com- plain of some mild impairment of balance.24 When vertigo is reported in acoustic neuroma patients, it can sometimes be difﬁcult to deter- mine whether the tumor is the cause of the symptom because bothersome dizziness symp- toms, including vertigo, are common symptoms in the general population.25 At the bedside a positive head-thrust test can be seen if the tumor is causing sufﬁcient dysfunction. Next to the auditory nerve, the most commonly involved cranial nerves (by compression) are the seventh and ﬁfth, producing facial weakness and numb- ness, respectively. Involvement of the sixth, ninth, tenth, eleventh, and twelfth nerves occurs only in the late stages of disease with massive tumors. Large vestibular schwannomas

may also produce increased intracranial pres- sure from obstruction of cerebrospinal ﬂuid (CSF) outﬂow, resulting in severe headaches and vomiting.

FACIAL NERVE SCHWANNOMAS

Facial nerve schwannomas typically present with a slowly progressive facial paralysis devel- oping over months to years—although rare cases with sudden onset of paralysis, ﬂuctuat- ing paresis, and facial tic have been reported. Hearing loss from compression of the cochlear nerve in the internal auditory canal is the sec- ond most common presenting symptom. When the tumor is conﬁned to the internal auditory canal, differentiating vestibular from facial nerve schwannomas is impossible prior to surgery.26 Conductive hearing loss can occur when the tumor arises in the middle ear, where it can disrupt the ossicular chain. In these cases, the tumor mass may be visible behind the pos- terior superior tympanic membrane.

BILATERAL VESTIBULAR SCHWANNOMAS AND NEUROFIBROMATOSIS TYPE 2

Neuroﬁbromatosis type 2 (NF2) is an auto- somal dominantly inherited syndrome charac- terized by the development of bilateral vestibular schwannomas; schwannomas of other cranial, spinal, and cutaneous nerves; and men- ingiomas involving cranial and spinal nerves.27 It occurs in about one in 25,000 live births and is nearly 100% penetrant by age 60. About half are due to de novo mutations. Since about 10% to 20% of patients with NF2 present with a unilateral vestibular schwannoma, treatment of these patients should be based on the knowl- edge that they will eventually develop a ves- tibular schwannoma on the opposite side (Table 15–1). The key features that suggest the diag- nosis of NF2 in a patient with a unilateral ves- tibular schwannoma are a family history of NF2 or at least two other neural tumors, particularly meningiomas.28

The NF2 gene is a tumor-suppressor gene located on chromosome 22q.29 It codes for the protein schwannomin/merlin (S/M) that inter- acts with the extracellular matrix to regulate cell cycle processes.30,31 A wide range of muta- tions in the NF2 gene have been described, from small and large deletions to missense and

Table 15–1 Average Risk per Decade of Patients Presenting with Vestibular Schwannoma Having Neuroﬁbromatosis Type 2

Age (years)	NF2 (%)	NF2 UVS at Diagnosis (%)	NF2 with no FH and no Other NF2 Features (%)
10–19	33 (22–50)	6 (2.6–9)	1 (0.3–1.4)
20–29	15 (8–22)	2.7 (0.9–4)	0.45 (0.1–0.6)
30–39	5 (3–8)	0.9 (0.3–1.4)	0.15 (0.03–2.2)
40–49	2 (1–3)	0.36 (0.1–0.54)	0.06 (0.01–0.08)
50–59	1 (0.5–1.5)	0.18 (0.06–0.27)	0.03 (0.007–0.05)

FH, family history; NF2, neuroﬁbromatosis type 2; UVS, unilateral vestibular schwannoma.

(From Evans DGR, et al. Probability of bilateral disease in people presenting with unilateral vestibular schwannoma.

J Neurol Neurosurg Psychiatry. 1999;66:764–767, with permission.)

nonsense mutations. Only about half of the patients who meet the diagnostic criteria for NF2 have identiﬁable mutations in the NF2 gene in peripheral blood, probably because of somatic mosaicism with the NF2 mutation being present in only a proportion of somatic cells. A mutation that is present in an insufﬁ- cient proportion of cells to detect in lympho- cyte DNA may still be found as an identical mutation in all tumors from that patient. Sporadic schwannomas lack normal S/M protein either due to a spontaneous mutation in the NF2 gene or activation of a protease cascade that leads to ineffective S/M.31

Of patients with a vestibular schwannoma, about 5% have NF2 and of patients with NF2, about 15% are likely to present initially with a unilateral tumor.28 Therefore, <1% of patients who present with a unilateral vestibular schwan- noma will go on to develop a tumor on the other side. The likelihood of developing the second bilateral tumor in a patient presenting with a unilateral vestibular schwannoma decreases with age so that a patient presenting with a uni- lateral vestibular schwannoma between the ages of 10 and 20 without a family history or other features of NF2 has about a 1% chance of developing bilateral tumors. In contrast, a patient presenting with a unilateral vestibular schwannoma after the age of 30 without a fam- ily history or other features of NF2 has less than a 0.1% chance of developing bilateral tumors.28

Meningiomas

Meningiomas comprise about 14% of intracra- nial tumors and after schwannomas are the most common primary tumor of the CP

angle.32,33 Meningiomas arise from arachnoid ﬁbroblasts, usually in the posterior aspect of the petrous pyramid near the sigmoid and pet- rosal sinuses. They displace cranial nerves and compress the brain stem and cerebellum but do not invade brain tissue. In the posterior fossa, the lobulated variety is more common than the ﬂat (enplaque) type. Meningiomas in the CP angle are frequently calciﬁed and induce osteoblastic reaction in adjacent bone. Because these tumors usually arise outside of the internal auditory canal, they often become very large before producing symptoms and signs. As with schwannomas, the most common symptoms are auditory—hearing loss and tin- nitus. Large tumors compress the brain stem and cerebellum and stretch the ﬁfth and sev- enth cranial nerves, producing facial numbness and weakness. In the rare cases that originate in the internal auditory canal, symptoms and signs are identical to schwannomas.34

Epidermoid Cysts (Primary Cholesteatomas)

Epidermoid cysts arise from congenital epithe- lial inclusion rests in the area of the petrous apex.35,36 They slowly enlarge to ﬁll the CP angle, stretching nearby cranial nerves and eventually compressing the brain stem and cerebellum. Because these cysts are slow grow- ing, the symptoms do not become manifest until the second to fourth decade of life. As with other CP-angle tumors, involvement of the eighth nerve is a common early feature, but unlike other tumors in this area, hemifacial spasm is a frequent early distinguishing feature.

Cholesterol Granulomas

Cholesterol granulomas arise in the pneuma- tized spaces of the temporal bone when a small hemorrhage into the air cells causes a foreign body reaction and progressive granuloma for- mation.36,37 The lesion within the temporal bone expands and can produce compression of the structures in the CP angle. As with other CP-angle lesions, eighth nerve involvement is most common, with hearing loss being the most frequent presenting symptom. This is an impor- tant lesion to recognize because the surgical management is quite different from that of other CP-angle tumors (see later discussion).

Metastatic Tumors

The internal auditory canal is a frequent site of metastatic tumor growth.5 From this site, tumor cells destroy the seventh and eighth nerves and extend into the inner ear or into the CP angle. The rapid onset of hearing loss and vertigo, fol- lowed by other signs of cranial nerve compres- sion and brainstem dysfunction, suggests the likelihood of a malignant tumor rather than the more common benign CP-angle tumors. The lung and breast are the most common sites for the primary neoplasm.6

Diagnosis

By far the most common presentation of a CP-angle tumor is a slowly progressive unilat- eral sensorineural hearing loss (Fig. 15–1). Unilateral tinnitus is the next most common symptom, with vertigo being an infrequent symptom. The neurologic examination should focus on the involved and nearby cranial nerves—including the vestibular component of cranial nerve eight (nystagmus and the head thrust test) and the ﬁfth and seventh nerves. If there are ﬁndings localizing to the internal auditory canal or CP angle, one would proceed directly to neuroimaging, beginning with an MRI. The sudden onset of vertigo and unilat- eral hearing loss can occasionally be seen with benign tumors, but a malignant tumor should also be considered whenever a mass is identi- ﬁed and the symptoms are abrupt in onset or rapidly progressive.5,38

In those cases in which the neurologic exam- ination is nonlocalizing (other than audioves- tibular deﬁcits), the ﬁrst diagnostic test should be an audiogram. If a progressing unilateral sensorineural hearing loss is documented, then one would proceed directly to an MRI with contrast because there is an important likeli- hood of an expanding lesion. If the audiogram is normal or if there is a unilateral sensorineu- ral hearing loss of unknown duration, then one can consider a brainstem auditory-evoked response (BAER). For some time, BAER was a widely used test in the workup for acoustic neuroma. Early small studies in patients with known vestibular schwannomas reported BAER to be abnormal in 85% to 95% of the patients (see Fig. 8–8 in Chapter 8).39,40 However, currently the role and the value of BAER is uncertain because more recent stud- ies (including systematic reviews of studies) show that when BAER results are compared with MRI, the sensitivity and speciﬁcity of BAER ranges widely with values, indicating it can be very accurate to values indicating a high risk for false-positive and false-negative results.42 BAER is most sensitive when tumors are 1 cm, though false-positive rates remain a concern.42 If the BAER is used and the results are normal, then the patient should be followed with at least one repeat audiogram in 6 months. Whether further repeat studies are necessary, should the second audiogram be normal, depends on whether the patient notes a subjec- tive progression of either the hearing loss or tinnitus. If the BAER is abnormal, then one would proceed directly to an MRI with con- trast with emphasis on the internal auditory canal and CP angles.

Magnetic resonance imaging with contrast is the imaging procedure of choice for identifying a vestibular schwannoma (Fig. 15–2).42 It can identify small tumors a few millimeters in diameter that would be missed without con- trast.41,42 MRI can also result in false-positive and false-negative results as well.42 The dilemma is often deciding which patients with audio-vestibular symptoms or signs should have an MRI to evaluate for a tumor. Studies on symptoms with acoustic neuroma demon- strate the wide variability in symptoms and that these tumors are even incidental ﬁndings on an imaging study done for other purposes in a patient with no audiovestibular symptoms.42 One study used the prevalence of symptoms in

History

Unilateral hearing loss or tinnitus

Neurologic examination

Focal findings

Normal

Repeat in 6 months

Normal

Audiogram

Unilateral sensorineural, unknown duration

Unilateral sensorineural, progressing

Unilateral sensorineural, unknown duration

Unilateral sensorineural, progressing

MRI

Normal

Abnormal

Normal

Abnormal

Typical schwannoma

Atypical tumor

Meningioma, epidermoid cyst, cholesterol granuloma

Figure 15–1. Algorithm for diagnosis of tumors of the cerebellopontine angle. CT, computerized tomography; MRI, magnetic resonance imaging.

the general population and the prevalence of vestibular schwannomas (or any CP angle mass) to estimate that approximately 2500 MRI stud- ies would need to be performed to detect one vestibular schwannoma in patients with non- speciﬁc dizziness.43 Among patients with dizzi- ness and subjectively normal hearing, 9307 MRI scans would be need to be performed to identify one vestibular schwannoma. Using more stringent criteria of patients with dizzi- ness and asymmetric hearing loss (deﬁned as asymmetry of 15dB at two or more pure-tone frequencies), it would take 638 MRI scans to diagnose one vestibular schwannoma.

Computed tomography scanning is most useful for identifying bony erosion and/or

calciﬁcation within tumors. Meningiomas are usually more dense than vestibular schwanno- mas on CT. With contrast infusion they appear very dense and homogeneous, a feature that differentiates them from schwannomas.32 There may be calciﬁcation within the tumor, and the nearby temporal bone may be thick- ened. Epidermoid cysts also have a characteris- tic proﬁle on CT; they are less dense than brain and do not enhance after intravenous contrast material. They have an irregular scalloped surface contour and are usually eccentric to the opening of the internal auditory canal. Cholesterol granulomas appear as a punched- out lesion in the temporal bone with a central density the same as that of brain and with a rim

Figure 15–2. Vestibular schwannoma (acoustic neuroma). Pre-contrast (A) and postcontrast (B) magnetic resonance images show that no lesion is seen on the precontrast image (A), but the small schwannoma is clearly seen on the postcon- trast image.

of enhancement after contrast infusion.36 The lesions are smooth walled and the contralateral petrous bone is always well pneumatized. On MRI they give a high-intensity signal in both T1-and T2-weighted images.36,44

Management

Vestibular schwannomas are generally very slow-growing tumors. Over time, there is the chance that if left untreated the hearing loss would become severe, which is important because substantial unilateral hearing loss is associated with disability, including difﬁculty hearing on the affected side, in noisy environ- ments, sounds at a distance, and difﬁculty judg- ing the direction of sound.45,46 But there is also a very reasonable chance that the tumor will not grow or may even regress over time. In fact, systematic reviews have found that about 50% of tumors do not demonstrate growth and about 6% show regression.42 There is the pos- sibility that surgical treatment could protect one against future hearing loss and also reduce the chance for other deﬁcits from the tumor, but the surgery itself could lead to hearing loss, facial paralysis, or the many other complica- tions that can arise from surgery in general. No one would want to subject a patient whose tumor will not grow to the surgical risk. But we

also should not wait too long to intervene in a growing tumor since the chance of surgical complications increases with increasing size of the tumor. There are no large randomized con- trolled trials of surgical versus conservative management of vestibular schwannoma, and there are also no validated predictive models to assess the likelihood of future problems from an untreated vestibular schwannoma in an individual patient.

There is a recent trend toward more conser- vative management of patients with vestibular schwannomas since clinical outcomes appear no different in patients who fail conservative management versus those who receive primary treatment without conservative manage- ment.47–49 Patients with an intracanalicular or small (2 cm) CP angle vestibular schwannoma can be followed with serial MRIs without treat- ment. This approach is particularly recom- mended for older patients, asymptomatic patients with “incidental” tumors,50 and patients with underlying medical problems at increased risk for surgery. Large tumors (generally con- sidered >2 cm) are more likely to grow than small tumors, but there are no reliable clinical indicators to predict growth. Surgical or radiation treatment may lead to total unilateral hearing loss, whereas patients treated conservatively often show no change in hearing even after years of follow-up.47 If the tumor

demonstrates initial growth (>2 mm/year), then there is increased risk that it will continue to grow; however, about 40% of tumors with ini- tial growth will not demonstrate future growth. In patients managed conservatively, an initial follow-up MRI is recommended at 6 months, then annually for 2 years, then 2 years later and then every 5 years.49‌‌

There are three general surgical approaches to the CP angle: (1) translabyrinthine, (2) sub- occipital, and (3) middle fossa.23,51 The trans- labyrinthine approach destroys the labyrinth but often allows complete removal of the tumor without endangering other nearby neural struc- tures, particularly the facial nerve. This would be the procedure of choice for a patient with severe hearing loss and a tumor under 3 cm in size. With the suboccipital and middle fossa approaches, residual hearing can be saved, as the labyrinth is not destroyed during the surgi- cal procedure. With the introduction of the modern operating microscope, preservation of hearing is now a distinct possibility with either of these procedures.52 Traditionally, the suboc- cipital approach has been performed by neuro- surgeons, whereas the middle fossa approach was developed by otologic surgeons. The mid- dle fossa approach is more likely to save hear- ing and avoid damage to the facial nerve when the tumor is <3 cm in size. For tumors >3 cm in diameter, a combined translabyrinthine sub- occipital approach is commonly used. This procedure allows the surgeon to reduce the size of the tumor from behind by working between the tumor capsule and the brain stem. Furthermore, large tumors are often adjacent to or attached to the basilar artery; with the combined approach the surgeon can dissect the artery from the tumor capsule under direct vision. As many as 10% of patients with vestib- ular schwannomas will have tumor recurrence after surgery mainly due to regrowth of microf- ragments left in the operative ﬁeld along the course of the facial nerve or at the surface of the pons.53

Stereotaxic radiosurgery using ionizing radi- ation provides another alternative for manag- ing vestibular schwannomas, particularly smaller tumors conﬁned to the internal audi- tory canal.54,55 Radiosurgery provides a better chance of preserving hearing, is more cost effective, and has less impact on patient’s activ- ities of daily living than traditional surgery.56 Although radiosurgery reliably stops the growth

of most tumors, long-term follow-up is still lacking. Stereotaxic radiosurgery is ideal for managing vestibular schwannomas associated with NF2, since eventually the tumors will be bilateral. Subach et al.57 were able to preserve hearing in about half of the patients with vestibular schwannomas and NF2 treated with radiosurgery. In addition, normal facial nerve function was preserved in most patients.

Cholesterol granulomas involving the petrous apex can often be managed without surgery, particularly when the symptoms are stable or improving.58 When symptoms are progressive, however, a transmastoid extra- dural approach with simple drainage into the mastoid sinus or middle ear can be accom- plished with low morbidity. Cholesterol granu- lomas do not need to be resected. Solid tumors involving the petrous apex, however, do require surgery for removal, usually via a middle fossa or infratemporal fossa approach.59

BRAIN TUMORS

Brain Stem

Gliomas of the brain stem usually grow slowly and inﬁltrate the brainstem nuclei and ﬁber tracts, producing multiple symptoms and signs. Although brainstem gliomas are ﬁve to ten times more common in children than in adults, they still make up approximately 1% of adult intracranial tumors.60,61 The neurologic symp- toms and signs of childhood brainstem gliomas do not differ in essence from those of adults. The typical history is that of relentless progres- sive involvement of one brainstem center after another, often ending with destruction of the vital cardiorespiratory centers of the medulla. Vestibular and cochlear symptoms and signs are common (occurring in approximately 50% of cases), the brainstem origin of which is usu- ally obvious because of the multiple associated ﬁndings. Tumors originating in the pons or midbrain usually cause long tract signs, cranial nerve deﬁcits, and ataxia. Spontaneous, gaze-evoked, and central paroxysmal positional nystagmus all occur, and impairment of sac- cade and pursuit eye movements further sug- gests an intrinsic brainstem disorder. Although less common, gliomas originating in the

medulla may present with recurrent vertigo and vomiting.

Cerebral cavernous malformations (CCM; cavernomas) are common vascular malforma- tions of the brain that occur as a sporadic or as a familial autosomal dominant disorder. So far, mutations in three genes have been identiﬁed in families with cavernomas: CCA1/KRIT1, CCA2/MGC4607, and CCA3/PDCD10.62 A

small percentage will bleed and can produce dramatic symptoms and signs, particularly when the cavernoma is located in the brain stem. Bleeding into a cavernoma near the ves- tibular nuclei or outﬂow tracts to the oculomo- tor nuclei can produce episodes of vertigo and nystagmus. Patients are often thought to have either an infarct or primary hemorrhage prior to identifying the characteristic vascular mal- formation on MRI.63 Patients can have primary position upbeat nystagmus, downbeat nystag- mus, and central types of positional nystagmus associated with cavernomas of the brain stem. Brainstem metastasis also commonly leads to a dramatic clinical syndrome that may mimic a stroke or a primary hemorrhage. Hemorrhage into the metastatic tumor may account for the sudden symptoms and signs. As with other metastatic brain tumors, the most common pri- mary sites are lung and breast.

Fourth Ventricle

Many tumors arising in the fourth ventricular region compress the vestibular nuclei and pro- duce vestibular symptoms. Medulloblastomas, occurring primarily in children and adoles- cents, are rapidly growing, highly cellular tumors that arise in the posterior midline or vermis of the cerebellum and invade the fourth ventricle and adjacent cerebellar hemi- spheres.64,65 Vertigo and disequilibrium are common initial complaints. Headaches and vomiting also occur early from an obstructive hydrocephalus and associated increased intrac- ranial pressure. An attack of headache, vertigo, vomiting, and visual loss may result from a change in head position, producing transient CSF obstruction (Bruns’ symptom). In Nylen’s classic study66 of patients with subtentorial tumors, 17 of 27 patients with medulloblastoma demonstrated positional nystagmus, and in two cases it was the only focal neurologic sign.

Grand67 reported two cases of medulloblastoma in which paroxysmal positional nystagmus was the initial abnormal neurologic sign. Other fourth ventricular tumors that produce similar clinical pictures include ependymomas, papil- lomas, teratomas, epidermoid cysts, and, in endemic areas, cysticercosis.

Cerebellum

The most common cerebellar tumor in adults is metastasis, whereas in children the most common tumor is an astrocytoma. A metastatic cerebellar tumor can be the initial sign of a distant tumor, or it can occur many years after treatment of a primary cancer.68 The location of the tumor in the cerebellum is the key to determining the nature and severity of symptoms and signs. A tumor in the cerebel- lar hemisphere can grow large with relatively few symptoms, whereas a tumor near the midline will usually lead to early symptoms and signs due to either brainstem compression or CSF obstruction. In children, gliomas can inﬁltrate a large part of the cerebellum, being relatively silent until they become large enough to obstruct CSF circulation or compress the brain stem.69 The characteristic symptoms include new-onset severe headache, position-provoked vertigo and vomiting, and gait imbalance. Most patients will develop papilledema from increased intracranial pres- sure. As with medulloblastoma, occasionally positional vertigo can be the initial symptom of a cerebellar tumor.70 Other tumors of the cer- ebellum that can produce identical symptoms and signs include teratomas, hemangiomas, and hemangioblastomas.

Diagnosis and Management

Magnetic resonance imaging is the diagnostic procedure of choice for identifying brainstem and cerebellar tumors71 (Fig. 15–3). Gliomas of the posterior fossa are particularly difﬁcult to identify with non-contrast CT because they are often isodense; the only evidence for a lesion is enlargement of the brain stem or compression of the fourth ventricle (the tumor shown in Fig. 15–3 was not seen on CT scanning). Magnetic resonance imaging, however, can reliably identify

Figure 15–3. Magnetic resonance scans (T2 weighted) showing a brain stem glioma (arrows) involving the root entry zone of the right eighth nerve. (A) Transverse section. (B) Coronal section.

both brainstem and cerebellar gliomas as well as the other tumor types mentioned earlier. In some cases, CT scanning can complement MRI by identifying calciﬁcation and helping differentiate between tumor and associated edema. If an MRI scan is not possible, then a CT scan with contrast is also an accurate test for identifying a tumor in the posterior fossa.

When possible, biopsy and surgical resection of the tumor is the treatment of choice. Microsurgical resection of superﬁcial caverno- mas may be possible.72 For metastatic tumors, the primary tumor can be biopsied if it can be found. Occasionally, a solitary metastatic lesion can be resected. For nonresectable tumors, radiation therapy may be an option. Prolonged survival (>5 years) is not uncommon with low- grade astrocytomas. Medulloblastomas are also very sensitive to radiation therapy.73

major concern for radiation therapy of cerebellar and brainstem tumors is delayed neurological damage from the radiation. This can be a particularly difﬁcult problem in a
young patient who presents with minimal deﬁ- cits at the time of diagnosis. Radiation to the brain stem or cerebellum can produce late radiation damage that is slowly progressive and unresponsive to treatment.71,73

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42. Fortnum H, O’Neill C, Taylor R, et al. The role of magnetic resonance imaging in the identiﬁcation of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness and natural history. Health Technol Assess. 2009;13(18):iii, ix, 1.
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48. Hajioff D, Raut VV, Walsh RM, et al. Conservative management of vestibular schwannomas: third review of a 10-year prospective study. Clin Otolaryngol. 2008;33(3):255.
49. Martin TP, Senthil L, Chavda SV, Walsh R, Irving RM. A protocol for the conservative management of vestibular schwannomas. Otol Neurotol. 2009;30(3): 381.
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52. Snyder WE, Pritz MB, Smith RR. Suboccipital resection of a medial acoustic neuroma with hearing preservation. Surg Neurol. 1999;51:548.
53. Roche PH, Ribeiro T, Khalil M, Soumare O, Thomassin JM, Pellet W. Recurrence of vestibular schwannomas after surgery. Prog Neurol Surg. 2008; 21:89.
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  Chapter 16 ‌‌
  
  Trauma
  
  TRAUMA TO THE TEMPORAL BONE
  Fracture
  Labyrinthine Concussion Posttraumatic Positional Vertigo Diagnosis ‌
  Management
  PERILYMPH FISTULA
  Pathophysiology Diagnosis Management
  SEMICIRCULAR CANAL DEHISCENCE SYNDROME
  
  Pathophysiology Diagnosis Management BRAIN TRAUMA
  Intracranial Complications Associated with Temporal Bone Fractures
  Dizziness Due to Brainstem Trauma Postconcussion Syndrome Whiplash Injuries
  Diagnosis Management
  
  TRAUMA TO THE TEMPORAL BONE
  Fracture
  Fractures of the temporal bone most com- monly result from direct lateral blunt trauma to the skull in the parietal region of the head.1,2 Trafﬁc accidents are by far the most common cause.3 Because the otic capsule surrounding the inner ear is very dense bone, the fracture usually courses around it to involve the major foramina in the skull base, the most common being that of the carotid artery and the jugular bulb. Fractures commonly occur near the root of the external auditory canal and run parallel along the petrous apex, extending anteriorly to the foramen lacerum and the carotid artery. They may also extend into the temporal man- dibular joint region. Ecchymosis in the mastoid region (Battle’s sign) occurs when the fracture line extends into the mastoid.
  Although temporal bone fractures have been classiﬁed as longitudinal and transverse, mod- ern high-resolution computed tomography (CT) scanning shows that most fractures are actually oblique.4,5 The fracture line typically extends anteriomedially to the skull base, mak- ing its way through the weakest places in the skull base but avoiding the compact bone of the otic capsule surrounding the labyrinth. Transient or persistent facial paralysis occurs in about two-thirds of patients.3 Conductive hear- ing loss due to ossicular chain dislocation occurs in more than half, but sensorineural hearing loss occurs in less than 20%. Overall, the audi- tory system is more vulnerable to temporal bone fracture than the vestibular system.
  
  Labyrinthine Concussion
  Auditory and vestibular symptoms (either isolated or in combination) can follow blows to the head that do not result in temporal
  
  353
  bone fracture. The absence of associated brain- stem symptoms and signs and the usual rapid improvement in symptoms following injury support a peripheral localization for the lesion. The pathology is presumably microscopic hem- orrhages in the membranous labyrinth.6 Although protected by a bony capsule, the del- icate labyrinthine membranes are susceptible to blunt trauma. Of 57 cases of labyrinthine damage due to blunt head trauma reported by Davey,7 51% resulted from blows to the occipi- tal region; 26%, to the frontal region; and 23%, to other areas.
  Sudden deafness following a blow to the head without associated vestibular symptoms is often partially or completely reversible.8 It is probably caused by intense acoustic stimula- tion from pressure waves created by the blow, which are transmitted through the bone to the cochlea just as pressure waves are transmitted from air through the conduction mechanism.9 Supporting this suggestion is the observation that the pathologic changes in the cochlea pro- duced by experimental head blows in animals are similar to those produced by intense air- borne sound stimuli.10 These changes consist of degeneration of hair cells and cochlear neurons in the middle turns of the cochlea. Pure-tone hearing loss is usually most pronounced at 4000 and 8000 Hz.
  
  Posttraumatic Positional Vertigo
  Benign positional vertigo is a common sequela after any kind of head injury. The most com- mon cause of head trauma is motor vehicle accidents followed by common falls.11 Otoconia are dislodged from the otolithic membrane and typically enter the posterior semicircular canal, where they move under the inﬂuence of gravity and trigger episodes of vertigo. Animal studies have shown that otoconia are easily dislodged from the otolithic membrane with high accel- erations. Karl Wittmaack performed a series of experiments on guinea pigs in Germany in the 1930s, showing that the otolithic membrane could be denuded of otoconia with centrifugal accelerations.12 He also noted that these ani- mals with free-ﬂoating otoconia in their laby- rinth developed positional nystagmus, which he attributed to loading of the posterior semi- circular canal cupula. As described in Chapter 10, we now know that the otoconial debris
  usually enters the long arm of the posterior semicircular canal, where it moves under the inﬂuence of gravity to trigger bouts of vertigo and nystagmus. Benign positional vertigo after head trauma can be delayed since not only does the otoconial debris have to be free ﬂoating, but patients must get their head in a critical position so that the debris can enter the long arm of the posterior semicircular canal (back and to the side). Patients may be unconscious or be heavily medicated for multiple injuries, so they may only recognize the positional ver- tigo once they begin to recover and are able to make the critical positional changes that will trigger vertigo. Benign positional vertigo occurs after nearly half of head injuries associated with temporal bone fractures.13 Bilateral involve- ment and multiple recurrences are more com- mon in posttraumatic positional vertigo than from other causes of positional vertigo.11,14
  
  Diagnosis
  Signs of a temporal bone fracture can often be identiﬁed on physical examination.2 If the fracture line transverses the tympanic annulus, the tympanic membrane is lacerated, produc- ing a step-like deformity in the external auditory canal (see Fig. 6–1D in Chapter 6). Cerebrospinal and hemorrhagic otorrhea are common, and the combination of laceration of the tympanic membrane, ossicular damage, and hemotympanum produces a conductive hearing loss. If the fracture line passes through the vestibule of the inner ear, the membranous labyrinth may be torn and the vestibular and cochlear nerves lacerated, producing complete loss of vestibular and cochlear function. Vertigo, nausea, and vomiting are prominent for several days after the fracture, typical of any acute peripheral vestibular lesion. The facial nerve may also be lacerated and loss of function may be permanent unless surgical repair is insti- tuted. Examination of the ear can reveal hemo- tympanum, but bleeding from the ear occurs infrequently because the tympanic membrane remains intact. Cerebrospinal ﬂuid (CSF) may ﬁll the middle ear and drain through the eusta- chian tube into the nasopharynx. Meningitis is a late complication of all types of temporal bone fractures.
  The diagnosis of labyrinthine concussion rests on the ﬁnding of acute vertigo and/or
  hearing loss after a blow to the head that did not produce a fracture. In most cases, the blow to the head is associated with a loss of consciousness (brain concussion). The diagno- sis of posttraumatic benign positional vertigo rests on ﬁnding the characteristic torsional vertical nystagmus after performing the Dix-Hallpike positioning test (see Fig. 6–6 in Chapter 6).
  High-resolution CT scanning with bone windows is the radiologic procedure of choice for evaluating trauma to the temporal bone and skull base.2 With CT scanning, one is able to identify fracture lines throughout the base of the skull (Fig. 16–1). Magnetic resonance (MR) scanning can be of some use for identifying soft tissue lesions but is of little use for identifying fractures. Once the patient stabilizes, a systematic evaluation of the audi- tory, vestibular, and facial nerves should be undertaken.
  Management
  There is no treatment for sensorineural hear- ing loss secondary to temporary bone trauma unless there is evidence for a perilymphatic ﬁs- tula (discussed later). If on the basis of audio- metric testing and tympanometric studies a conductive hearing loss is identiﬁed, surgical intervention may lead to restoration of normal hearing. Separation of the incudostapedial joint with or without dislocation of the body of the incus from the articulation with the malleus head is the most common type of ossicular dis- location seen with temporal bone injury.15 The surgeon can usually deal with these problems through a transcanal route under local anesthe- sia using a tympanomeatal ﬂap.
  Damage to the vestibular apparatus results in acute symptoms, with gradual improvement as central compensation occurs. Symptomatic treatment of vertigo is helpful initially, and the
  
  Figure 16–1. Computed tomography scan of the temporal bone showing longitudinal and transverse fractures in the same patient. The longitudinal fracture (arrowheads) crosses the middle ear, disrupting the ossicular chain, and the transverse fracture (white arrow) enters the vestibule, damaging the membranous labyrinth. C, cochlea; ER, epitympanic recess; IAC, internal auditory canal; IMJ, incudomalleal joint; V, vestibule.
  patient is encouraged to begin vestibular exer- cises as soon as possible to accelerate the compensation process (see Chapter 20). Posttraumatic positional vertigo responds to the particle-repositioning maneuver in a man- ner similar to that of other varieties of benign positional vertigo (see Figs. 10–3 and 10–4 in Chapter 10). Persistent ﬂuctuating audioves- tibular symptoms may indicate the presence of a perilymphatic ﬁstula and necessitate explora- tion of the middle ear (see later discussion). The decision regarding surgical intervention in patients with facial nerve injury secondary to temporal bone trauma is often difﬁcult.2,16
  As suggested earlier, most fractures do not interrupt the continuity of the facial nerve. In these cases, it is appropriate to observe the facial weakness closely with regular follow-up from the time of the accident. If function does not return within 4 to 6 months, surgical inter- vention is probably indicated.17 As a general rule, regeneration of a damaged but uninter- rupted nerve occurs at a rate of about 1 mm a day. There is marked variability in this rate, however; some patients show evidence of con- tinued improvement for a year or longer after injury. In cases of transverse fracture of the temporal bone with associated severe auditory and vestibular loss, the likelihood of mechani- cal disruption of the facial nerve is great, so the decision regarding surgical intervention is eas- ier. In these cases, translabyrinthine decom- pression and repair of the facial nerve may be achieved because there is already a total loss of auditory and vestibular function. Some cases of severe blunt head injury may result in a tear of the facial nerve at the root entry zone into the brain stem. These patients invariably have a prolonged period of unconsciousness at the time of the accident, and there are nearly always associated symptoms and signs of brain- stem injury. Obviously, there is little prospect for recovery of facial nerve function with this type of lesion.‌
  
  PERILYMPH FISTULA
  A perilymph ﬁstula results when there is a break in the bony labyrinth or the oval or round win- dows, allowing perilymph to leak out.18 The most common symptoms associated with a perilymph ﬁstula are vertigo, tinnitus, and hearing loss,
  typically associated with a change in pressure such as occurs with coughing, sneezing, or straining.19 The symptoms and signs are remark- ably variable; a perilymph ﬁstula should be con- sidered in the differential diagnosis of sudden hearing loss, recurrent vestibulopathy (particu- larly with associated hearing loss), Meniere’s syndrome, congenital sensorineural hearing loss, posttraumatic hearing loss and vertigo, and sta- pedectomy failure (Fig. 16–2).20
  
  History
  
  Sudden onset hearing loss, tinnitus, vertigo associate with:
  - Head trauma
  - Barotrauma
  - Cough, sneeze, straining, exercise
  - Cholesteatoma
  - Post-stapedectomy
  - Congenital malformation
  Examination
  - Hearing loss – conductive or sensorineural
  - Positive fistula test
  - ENG – Spontaneous nystagmus, caloric hypoexcitability
Management

Bed rest, elevate head, antivertiginous medication, avoid straining

Recurrent symptoms

Explore middle ear

Figure 16–2. Algorithm for diagnosis and management of a perilymph ﬁstula. ENG, electronystagmography.
The cause of a ﬁstula is obvious when there is a disruption of the otic capsule or a tear in the bony labyrinth associated with trauma, sur- gery, or infection; spontaneous ﬁstulae are more difﬁcult to explain.19 A sudden negative or positive pressure change in the middle ear from violent nose blowing, sneezing, or barotraumas could lead to rupture of the round window. Flying with a common cold and poor middle ear equalization should be avoided.21 A sudden increase in cerebrospinal ﬂuid (CSF) pressure associated with lifting, straining, coughing, or vigorous activity leads to a change in CSF pressure that is transmitted to the inner ear via the cochlear aqueduct and/or internal auditory canal (see Chapter 2). A direct force through the auditory canal that damages the ossicular chain may rupture the oval window, producing a large perilymph ﬁstula.22,23 Perilymph ﬁstulae may also be associated with developmental abnormalities of the middle or inner ear (e.g., Mondini malformation, defects in the stapes footplate, malformations of the stapedial arch). Recurrent meningitis can result from a congenital perilymph ﬁstula.24

Pathophysiology
How leakage of perilymph leads to ﬂuctuating vestibular and auditory symptoms is unclear. Removal of the round window in animals has little effect on cochlear electrical potentials,25 and the perilymphatic space is routinely entered during stapedectomy surgery, usually without sequelae. The cochleosacculotomy operation for Meniere’s syndrome produces a round-window membrane puncture, yet the incidence of postoperative sensorineural hearing loss is less than 25%.26 Although the sensorineural hearing loss associated with peri- lymph ﬁstulae is usually not reversible, patients have occasionally been reported with dramatic recovery of hearing as long as 10 years after the onset of hearing loss.27 Obviously, such patients could not have had irreversible damage of their sensory epithelium. Presumably, the perilymph ﬁstula leads to aberrant or inefﬁcient transmis- sion of mechanical energy within the cochlea.
Vestibular symptoms are even more difﬁcult to explain on the basis of perilymph ﬁstulae. How would such a leakage lead to stimulation of the vestibular receptors? Pressure changes presumably displace ﬂuid toward the site of the
leak, which may either deﬂect the cupula of one of the semicircular canals or create a shear force on one of the maculae.18 More persistent dizziness may be the result of permanent damage to the vestibular sensory receptors.

Diagnosis
The classical presentation of an acute peri- lymph ﬁstula is a sudden audible pop in the ear immediately followed by hearing loss, vertigo, and tinnitus, which occur in the setting of trauma or substantial pressure change (e.g., decent on airplane, sneeze, etc.). The key to the diagnosis is to identify the characteristic precipitating factors listed in Figure 16–2.
Nonspeciﬁc imbalance and disequilibrium aggravated by quick head movements or sud- den turning may result from chronic perilymph ﬁstulae. Patients report aggravation of these symptoms in certain head positions, preferring to sleep on one side rather than on the other to avoid an ill-deﬁned uncomfortable “dizzy” sen- sation. The latter feature might suggest benign positional vertigo, but such patients do not show the characteristic torsional vertical parox- ysmal positional nystagmus. Occasionally, peri- lymph ﬁstulae are discovered during middle ear exploration for other reasons in a patient with auditory or vestibular symptoms.
Unfortunately, there is no pathognomonic test for a perilymphatic ﬁstula. A positive ﬁstula test (see Chapter 6) is suggestive but not spe- ciﬁc. False negatives are common, and false positives occur with Meniere’s syndrome and after stapedectomy. Furthermore, dizziness and imbalance are occasionally reported by normal subjects when the air pressure is changed in the external auditory canal during routine pneuma- toscopy. Auditory examination may identify either a conductive or sensorineural hearing loss, and a unilateral caloric hypoexcitability may appear on electronystagmography (ENG); these ﬁndings are not unique to a perilymph ﬁs- tula. Even when the middle ear is explored at the time of surgery, serum or local anesthetic introduced into the middle ear may be mistak- enly identiﬁed as leaking perilymph. Mini- endoscopes allow the surgeon to explore the middle ear under more natural conditions, but this technique has not proved to be sensitive or speciﬁc for perilymph ﬁstula.28 Fluid identiﬁed in the middle ear can be analyzed for substances
found in CSF and perilymph but not in serum (e.g., beta 2 transferrin, prostaglandin D syn- thase).29,30 It is hoped that these newer diagnos- tic studies will enable the surgeon to identify perilymph ﬁstula before surgery. Computed tomography scanning of the temporal bone can identify erosion of the otic capsule by infection or tumor (see Fig. 9–2 in Chapter 9).

Management
The great majority of perilymph ﬁstulae heal spontaneously without intervention. For this reason, most authors advocate conservative management with an initial period of bed rest, sedation, head elevation, and measures to decrease straining. The one exception to this conservative approach might be acute barotrau- mas in which immediate exploration has been advocated,31 but randomized controlled trials are lacking. Persistent auditory and vestibular symptoms after the classical presentation of a perilymph ﬁstula are indications for explora- tion of the middle ear after an initial trial of conservative management. The rate of occur- rence of spontaneous ﬁstulae continues to be a controversial issue. Endoscopic studies indi- cate a much lower incidence than has been generally reported in the literature.32 The peri- lymph leak may become apparent only when the patient is placed in the Trendelenburg position, after performing a Valsalva maneuver, after jugular vein compression, or with manip- ulation of the ossicular chain.‌
The goal of surgery is to stabilize the hearing loss and relieve vestibular symptoms. The middle ear is typically entered through a posterior tym- panotomy.20 Most often the ﬁstula is in the area of the oval window. Most surgeons will patch the oval window region with perichondrium or fascia and cover the graft with gelatin sponge (Gelfoam). Recurrence of symptoms after repair occurs in at least 10% of cases; rarely, intractable symptoms will necessitate destructive surgery with laby- rinthectomy or nerve section.

SEMICIRCULAR CANAL DEHISCENCE SYNDROME
Normally there is a bony capsule completely surrounding the semicircular canals. Dehiscence of this bony capsule can cause a wide range of vestibular and auditory symptoms. Unlike a
perilymph ﬁstula, where perilymph leaks from the inner ear, dehiscence of the bony capsule sur- rounding the semicircular canals results in inap- propriate activation of the affected canal when pressure waves enter the inner ear. Episodes of vertigo can be triggered by sound (Tullio phe- nomenen) or positive or negative pressure changes in the ear or CSF.33 Eye movement recordings during the episodes of vertigo show bursts of nystagmus in the plane of the affected semicircular canal. The anterior (superior) canal is most frequently involved since normally there is only a thin plate of bone separating the apex of the canal from the middle fossa. In some patients the bone is so thin it cannot be seen on CT (on either side). Presumably this thin bony plate can be fractured by minor trauma. Typically infec- tiom or cholesteotoma are associated with poste- rior or horizontal canal involvement.34,35
Vertigo attacks may occur after loud noise, exertion, straining, coughing, or sneezing. Exposure to continuous loud noise can cause prolonged nonspeciﬁc dizziness.33,36 Sudden drop attacks can occur even without vertigo.37 The most common auditory symptoms are auto- phony of voice and sensation of blocking in the ear.36 Bone conduction is increased and air con- duction decreased, leading to the characteristic air/bone gap on audiometry. Vibration any- where in the body can often be heard in the affected ear. Patients may hear their pulse or even their eye movements. This clinical presen- tation can mimic middle ear disease and patients may undergo inappropriate middle ear surgery.

Pathophysiology
The symptoms and signs of semicircular canal dehiscence can be explained by the presence of a pathological “third window.”33,34 The inner ear ﬂuid compartments are normally completely sur- rounded by the bone of the otic capsule. Since the inner ear ﬂuids are incompressible, an inward dis- placement of the stapes at the oval window is accompanied by an outward displacement of the round window. This ﬂuid ﬂow produces a pres- sure gradient along the length of the basilar mem- brane. The presence of a third window allows a portion of the sound energy to be shunted away from the cochlea, activating the affected semicir- cular canal and resulting in loss of hearing sensitiv- ity to air-conducted sound. Any positive or negative pressure change in the external ear canal or CSF can activate the affected canal (Fig. 16–3).38

A
Endolymphatic sac

Dura mater
Superior canal

Posterior
canal
CSF

Cochlear aqueduct
Endolymphatic duct
Scala vestibuli Perilymph

Horizontal
canal

Endolymph

Utricle

Oval window

Cochlear duct Scala tympani
Saccule
Rounded window
C D

Figure 16–3. Mechanism of symptoms and signs with superior semicircular canal dehiscence syndrome. (A) Schematic drawing of inner ear. There are normally two windows in the bony capsule—the oval window (ﬁlled by the stapes foot plate) and the round window. A third window in the bony wall of the superior semicircular canal leads to vertigo and nystagmus with loud sounds or pressure changes in the middle ear or CSF (B and C). If the window is large enough, the superior semi- circular canal can be blocked (D). See text for details. (From Baloh RW. Superior semicircular canal dehiscence syndrome: Leaks and squeaks can make you dizzy. Neurology. 2004;62:684 with permission).

Bone-conducted hearing normally results because of higher impedance at the round win- dow compared to the oval window.34 A patho- logical third window on the vestibular (oval window) side of the cochlear partition lowers the impedance on the vestibular side (round window), increasing the cochlear response to bone conduction. Thus, the air/bone gap typi- cally seen with semicircular canal dehiscence is due to a combination of decreased air conduc- tion and increased bone conduction.

Diagnosis

The diagnosis of semicircular canal dehiscence rests on ﬁnding the characteristic symptoms and signs (Table 16–1) in a patient with dehis- cence of a semicircular canal on CT of the tem- poral bone. Loud noise or pressure changes in the ear or CSF may trigger brief bursts of nystagmus in the plane of the affected canal. For the most common superior canal syn- drome, positive pressure in the external ear canal or a Valsalva maneuver against pinched nostrils (forcing air into the middle ear through the eustachian tube) causes inward displace- ment of the stapes and excitatory ampullofugal displacement of the cupula of the superior semicircular canal, producing an upbeating torsional vertical nystagmus in the plane of the canal (see Fig. 16–3A). Conversely, negative ‌

Table 16–1 Symptoms and signs of dehiscence of the superior semicircular canal

Symptoms Signs

pressure in the external ear canal or a Valsalva maneuver against a closed glottis (taking a deep breath and bearing down) results in an inhibi- tory ampullopetal displacement of the cupula of the superior canal, producing torsional downbeat nystagmus (see Fig. 16–3B).38 Vibration applied to the suboccipital cranium may also trigger nystagmus.39 Nine out of ten patients have an air/bone gap (conductive hear- ing loss) on audiometric testing (Fig. 16–4A,B). Many of these show bone-conduction thresh- olds less than 0 dB at 250 and 500 Hz. Key ﬁndings that separate canal dehiscence from middle ear causes of conductive hearing loss are a normal acoustic reﬂex and a hyperactive VEMP (decreased threshold). These reﬂexes are usually absent with middle ear causes of conductive hearing loss.36,40,41 High-resolution CT with thin cuts reformatted in the planes of the semicircular canals identiﬁes areas of dehis- cence (Fig. 16–4C,D).33,42,43 False positives are not uncommon, however, so the report of dehiscence alone without clear clinical symp- toms and signs does not make the diagnosis.44

Management

Conservative management is a valid option and one that many patients select, since patients can learn to avoid symptom triggers and the most common symptoms are brief and transient. Several different surgical procedures have been used to treat semicircular canal dehiscence, but randomized controlled trials and studies with long-term follow-up are lacking. For the supe- rior semicircular canal syndrome, initially a middle fossa approach was used to resurface

Sound-induced vertigo—“Tullio phenomenon”

Pressure-induced vertigo—coughing, blowing nose, straining

Hyperacusis to bone- conducted sound— hear pulse, eye movements

Sound-induced nystagmus, eye movement, head tilt

Pressure-induced nystagmus, eye movement, head tilt

Conductive hearing loss

the canal but delayed hearing loss occurred in several patients.33,45 Subsequently plugging or capping the canal produced overall better results.46,47 More recently a transmastoid approach was reported to be as effective as the middle fossa approach without the need for a prolonged hospital admission.48 Vestibular nerve section and occlusion of the round win- dow are other options for refractory cases.49

Chronic disequilibrium Increased vestibular-

evoked myogenic potentials

Oscillopsia Decreased VOR gain in plane of superior canal

BRAIN TRAUMA

The most common mechanism of brain injury with blunt head trauma is movement and

250

Right ear Left ear

500 1k 2k 4k 8k 250 500 1k 2k 4k 8k

Hearing level in dB

100

B 250

500 1k 2k

4k 8k 250 500 1k 2k 4k 8k

100

Frequency in Hz

Figure 16–4. Audiograms from 2 patients with superior semicircular canal dehiscence syndrome (A) and (B) show a low-frequency air-bone gap on the affected side. High-resolution CT images of the temporal bones (C) and (D) show dehiscence of the superior semicircular canal on the affected side. Arrows point to where there is normally a thin bony roof to the superior canal. (From Brantberg K, Ishiyama A, Baloh RW. Drop attacks secondary to superior canal dehiscence syndrome. Neurology. 2005;64:2126 with permission).

deformation of the brain within the skull. When the rapidly moving head is suddenly stopped, the viscoelastic brain continues to move and may rotate in the skull around the axis of the brain stem. The internal shearing and stress forces traumatize neurons and disrupt axons and blood vessels. The latter may cause multi- focal petechial hemorrhages or even massive intracerebral hemorrhage. The term concus- sion refers to a brief loss of consciousness after head trauma unassociated with focal neuro- logic signs or radiologic evidence of structural

brain damage. Usually the loss of conscious- ness lasts for only a few minutes, although residual symptoms may last for months to years (see later discussion). The mechanism for such a brief loss of consciousness and rapid recovery is unknown. Often the terms concussion and mild traumatic brain injury are used inter- changeably.50

Most patients who suffer concussion proba- bly have some injury to brain cells, but nearly all rapidly regain function within minutes of the injury. They can usually remember the

events up to a few moments before the injury and have little or no retrograde amnesia. The blow itself is rarely recalled, and there is invari- ably a brief period of memory loss following the injury (posttraumatic amnesia). The dura- tion of postconcussion symptoms and signs var- ies with the intensity of the blow and the degree of brain deformity.51

Intracranial Complications Associated with Temporal Bone Fractures

In most cases of temporal bone fracture, brain injuries overshadow injuries to the labyrinth or eighth nerve. In a series of 43 patients treated for temporal bone fractures at Temple University in Philadelphia over 3 years, 19 patients (44%) required an open neurosurgical procedure.52 Subarachnoid hemorrhage, sub- dural hemorrhage, and cerebral edema were the most common brain ﬁndings. Four patients died (all due to neurological causes) and seven required institutional care after discharge. Most patients had a prior history of signiﬁcant alcohol or drug use.

Dizziness Due to Brainstem Trauma

Brainstem injury from blunt head trauma is not a common cause of isolated auditory and ves- tibular symptoms. Severe head blows may pro- duce hemorrhage or infarction in the brain stem, but these pathologic changes are invari- ably associated with alteration in the level of consciousness and multiple neurologic signs. In their classic study, Mitchell and Adams53 sectioned the brain stem in 100 cases of fatal blunt head injury. Only 18 patients showed no evidence of increased intracranial pressure, and of these, only 7 had abnormalities in the brain stem attributable to the primary impact. In these seven patients, other areas of the brain were damaged, suggesting to the authors that so-called primary brainstem injury does not exist but, rather, is one aspect of diffuse brain damage. As a general rule, isolated episodes of vertigo occurring after brain trauma should not be attributed to brainstem injury.

Caloric examination can be particularly help- ful in evaluating the brainstem status in patients who are comatose from blunt head injuries.

These patients do not produce saccades, so a “normal” response is a conjugate tonic devia- tion of the eyes toward the side of a cold stimu- lus or away from the side of a warm stimulus. Absence of this tonic deviation afﬁrms that the brainstem vestibulo-ocular reﬂex pathways have been damaged, assuming that the eighth nerve and end organs are intact. Unilateral loss of tonic deviation or nonconjugate deviation indicates focal involvement of the reﬂex path- ways. The absence of caloric responses after an acute head injury is a poor prognostic sign.54

Postconcussion Syndrome

The postconcussion syndrome has long been the center of medical–legal controversy.55–57 Symptoms include dizziness, headache (usually diffuse), increased irritability, insomnia, forget- fulness, mental obtuseness, and loss of initia- tive—all of which occur after a concussion. Because of the ill-deﬁned nature of these symp- toms, it is difﬁcult to localize the site of lesion and the patient is frequently diagnosed as being psychoneurotic (compensation neurosis). The dizziness associated with the postconcussion syndrome is nearly always nonspeciﬁc; patients use terms such as swimming, light-headed, ﬂoat- ing, rocking, and disoriented to describe the sensations they feel. If vertigo is present, an addi- tional labyrinthine lesion should be suspected.

Rutherford and colleagues58 followed 145 patients with concussion from minor head inju- ries to assess the type and frequency of symp- toms and to evaluate whether the symptoms correlated with the severity of injury, associ- ated neurologic signs, or other circumstances related to the injury. Concussion was deﬁned as a period of amnesia—no matter how brief— caused by a blow to the head. All of the patients were released from the hospital after a brief observation. Table 16–2 lists the symptoms and their frequency of occurrence reported by the

145 patients 6 weeks after the concussion. Approximately one-half were symptom-free, but the other half complained of one or more symptoms. In those patients with multiple symptoms, no consistent pattern was found to support the concept of a postconcussion syndrome. A signiﬁcant correlation existed between the presence of multiple symptoms at 6 weeks and the occurrence of positive neurologic signs and symptoms within 24 hr of

Table 16–2 Symptoms Reported 6 Weeks after Concussion in 145 Patients58

Symptom n (%)

Headache	36	24.8
Anxiety	28	19.3
Insomnia	22	15.2
Dizziness	21	14.5
Irritability	13	9.0
Fatigue	13	9.0
Loss of concentration	12	8.3
Loss of memory	12	8.3
Hearing defect	10	6.9
Sensitivity to alcohol	9	6.2
Depression	8	5.5
Visual defect	7	4.8
Anosmia	4	2.8
Epilepsy	3	2.1
Diplopia	2	1.4
Other	16	11.0
No symptoms	71	49.0

the concussion. Postconcussion symptoms were more frequent in women and in patients who blamed their employers or large impersonal organizations for their accidents. The authors concluded that both organic and psychosomatic factors were involved in the pathogenesis of postconcussion symptoms. Although modern neuropsychiatric and electrophysiologic stud- ies can identify subtle brain abnormalities in most patients with postconcussion syndrome, the type and degree of abnormality do not cor- relate with the severity of symptoms, and psy- chosocial factors continue to be important in long-term prognosis.57,59

Whiplash Injuries

A perplexing problem because of the frequency of occurrence and the medical–legal ramiﬁca- tions is the role of soft-tissue injuries of the neck in producing dizziness and disequilib- rium.60,61 Patients often describe the dizziness in nonspeciﬁc terms such as lightheaded, swim- ming, off-balance, ﬂoating, and rocking; as with psychophysiologic dizziness, they may describe a sensation of spinning inside the head unas- sociated with an illusion of movement or with spontaneous nystagmus. The dizziness may last for months or years after the injury, although it

usually disappears as the swelling and pain sub- side. The occasional ﬁnding of unilateral caloric hypoexcitability is likely due to associated laby- rinthine trauma.

From the known anatomic substrate for neck–vestibular interaction (see Chapter 3), it is unlikely that lesions involving only soft tis- sues of the neck could produce vertigo and dis- equilibrium. The major neck afferent input to the vestibular nuclei arises from the paraverte- bral joints and capsules, with relatively minor input from the paravertebral muscles. The skin and superﬁcial muscles do not appear to provide any input to the vestibular system. In addition, the relative contribution of neck affer- ent input to the vestibular nuclei is small com- pared with the direct labyrinthine and indirect visual signals transmitted via other brainstem nuclei and the cerebellum. Lesions involving the neck afferents in primates are rapidly com- pensated, and therefore prolonged dizziness after neck injuries of any type would be difﬁ- cult to explain on the basis of damage to the neck afferent input to the vestibular nuclei.

Diagnosis

Persistent dizziness after a blunt head injury often poses a difﬁcult diagnostic dilemma (Table 16–3). The diagnosis of postconcussion syndrome rests on ﬁnding the characteristic symptoms in the absence of focal neurologic ﬁndings. A careful neurotologic examination should identify most speciﬁc syndromes that require individualized treatment. Examination of the ear may reveal evidence of a temporal bone fracture or perilymph ﬁstula, positional testing may reveal benign paroxysmal posi- tional nystagmus, and neurologic examination may identify signs of brainstem damage. Standard audiometric, brainstem auditory- evoked response (BAER), and ENG testing methods are useful to assess the functional sta- tus of the auditory and vestibular systems and thus can be used to document intact physiolog- ical and quantiﬁable laboratory measures of the audio-vestibular system, though false- positive and false-negative results are not uncommon. Neuroimaging is usually helpful only when there are focal ﬁndings on the neu- rologic examination.

Computed tomography scanning is most useful for evaluating the base of the skull and

Table 16–3 Differential Diagnosis of Persistent Dizziness after Head Trauma

Diagnosis Dizziness Exam Laboratory

Benign positional vertigo

Labyrinthine concussion

Brief episodes, position induced

Severe initially, gradual improvement

Fatigable positional nystagmus

Peripheral spontaneous nystagmus

Normal

Caloric vestibular paresis, unilateral hearing loss

Perilymph ﬁstula Fluctuating, induced by

coughing, sneezing, straining

Positive ﬁstula test Caloric vestibular paresis,

unilateral hearing loss

Brain stem contusion

Postconcussion syndrome

Severe, associated brain stem symptoms

Continuous, associated headaches, irritability, etc.

Focal neurologic signs MR scan shows focal lesions Normal Normal

for identifying blood in the subarachnoid or subdural space and within the brain paren- chyma in the acute setting. Magnetic resonance scanning is best for identifying brain contusion and edema.

Management

Management of traumatic brain injuries has become increasingly sophisticated with the development of electronic and chemical moni- toring devices and advances in critical care medicine. So far, however, clinical trials of neuroprotective drugs have been largely unsuc- cessful.62 Acute surgical intervention is usually aimed at relieving intracranial pressure most commonly associated with hemorrhage. The degree of recovery after a closed head injury typically depends on the severity of the injury. As a general rule, the major part of the recov- ery occurs within the ﬁrst 6 months. Physical rehabilitation should begin as soon as practical after the acute effects of the head injury have subsided. It is important that the patients and their families are counseled regarding the expected rate of recovery and whether perma- nent deﬁcits are expected.

Treatment of the postconcussion syndrome begins by providing the patient with reassurance that there is no evidence of structural damage, that the symptoms are not unusual after head injury, and that they nearly always resolve over time. The patient should be encouraged to return to a normal exercise level gradually, even though initially the dizziness and other symp- toms may be aggravated.63 Tranquilizers such as diazepam and alprazolam can be useful for a

transient period, but prolonged use should be avoided as dependency is common. Endogenous depression is a common sequela after brain injury, and antidepressant medications (e.g., tri- cyclic amines, selective serotonin reuptake inhibitors [SSRIs]) may be helpful in severe cases. Although recovery is the rule, some patients will have persistent symptoms for years after a concussion. Although there is a positive correlation between the severity of head injury and the length of postconcussion symptoms, one cannot reliably judge the prognosis for recovery based on the nature of the head injury.

Soft-tissue injuries of the neck are usually associated with focal muscle tenderness and spasm. Initial management consists of rest and immobilization with a soft collar to allow the muscle contusions to heal. Once serious prob- lems have been ruled out, the patient should be reassured that there is no evidence of neu- rologic damage and that the symptoms nearly always spontaneously disappear. As in patients with postconcussion syndrome, it is important to begin a gradual exercise program as the acute soft-tissue injuries heal. Heat and mas- sage along with judicious use of pharmacologic muscle relaxation provide relief of the muscle spasm, which may come and go for weeks to months. Active range-of-motion exercises per- formed on a regular basis provide the best long-term relief of muscle spasm. Patients should be encouraged to sleep with a single ﬂat pillow and avoid long periods of hyperﬂexion of the neck. In our experience, the nonspeciﬁc dizziness associated with whiplash injuries improves as the local symptoms of muscle spasm and stiffness subside (assuming the medicolegal aspects can be resolved).

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Goto F, Ogawa K, Kunihiro T, Kurashima K, Kobayashi H, Kanzaki J. Perilymph ﬁstula—45 case analysis. Auris Nasus Larynx. 2001;28(1):29.
Shott SR, Pensak ML. Perilymphatic ﬁstula. Ear Nose Throat J. 1992;71:568.
Klokker M, Vesterhauge S. Perilymphatic ﬁstula in cabin attendants: an incapacitating consequence of ﬂying with common cold. Aviat Space Environ Med. 2005;76(1):66.
Suzuki M, Shigemi H, Mogi G. The leaking laby- rinthine lesion resulting from direct force through the auditory canal: report of ﬁve cases. Auris Nasus Larynx. 1999;26:29.
Hatano A, Rikitake M, Komori M, Irie T, Moriyama
1. Traumatic perilymphatic ﬁstula with the luxation of the stapes into the vestibule. Auris Nasus Larynx. 2009;36(4):474.
Rupa V, Rajshekhar V, Weider DJ. Syndrome of recur- rent meninigitis due to congenital perilymph ﬁstula with two different clinical presentations. Int J Pediatr Otorhinolaryngol. 2000;54(2-3):173.
Weisskopf A, Murphy JT, Merzenich MM. Genesis of the round window rupture syndrome: some experimental observations. Laryngoscope. 1978; 88:389.
Schuknecht HF. Cochleosacculotomy for Meniere’s disease: theory, technique and results. Laryngoscope. 1982;92:853.
Shannon DA, Blum SL. Surgical treatment of long term sensorineural hearing loss due to labyrinthine ﬁstula. J Am Audiol Soc. 1979;5:1.
Selmani Z, Pyykkö I, Ishizaki H, Marttila TI. Role of transtympanic endoscopy of the middle ear in the diagnosis of perilymphatic ﬁstula in patients with sensorineural hearing loss or vertigo. ORL J Otorhinolaryngol Relat Spec. 2002;64(5):301.
Bassiouny M, Hirsch BE, Kelly RH, Kamerer DB, Cass SP. Beta 2 transferrin application in otology. Am J Otol. 1992;13:552.
Michel O, Petereit H, Klemm E, Walther LE, Bachmann-Harildstad G. First clinical experience with beta-trace protein (prostaglandin D synthase) as a marker for perilymphatic ﬁstula. J Laryngol Otol. 2005;119(10):765.
Pullen FW, Rosenberg GH, Cabeza CH. Sudden hearing loss in divers and ﬂiers. Laryngoscope. 1979;84:1373.
Friedland DR, Wackym PA. A critical appraisal of spontaneous perilymphatic ﬁstulas of the inner ear. Am J Otol. 1999;20:261.
Minor LB, Solomon D, Zinreich JS, Zee DS. Sound- and/or pressure-induced vertigo due to bone dehis- cence of the superior semicircular canal. Arch Otolaryngol Head Neck Surg. 1998;124:249.
Merchant SN, Rosowski JJ. Conductive hearing loss caused by third-window lesions of the inner ear. Otol Neurotol. 2008;29(3):282.
Brantberg K, Bagger-Sjöbäck D, Mathiesen T, Witt H, Pansell T. Posterior canal dehiscence syndrome caused by an apex cholesteatoma. Otol Neurotol. 2006;27(4):531.
Zhou G, Gopen Q, Poe DS. Clinical and diagnos- tic characterization of canal dehiscence syndrome: a great otologic mimicker. Am J Otol. 2007;28(7): 920.
Brantberg K, Ishiyama A, Baloh RW. Drop attacks secondary to superior canal dehiscence syndrome. Neurology. 2005;64(12):2126.
Baloh RW. Superior semicircular canal dehiscence syndrome: leaks and squeaks can make you dizzy. Neurology. 2004;62(5):684.
White JA, Hughes GB, Ruggieri PN. Vibration- induced nystagmus as an ofﬁce procedure for the diag- nosis of superior semicircular canal dehiscence. Am J Otol. 2007;28(7):911.
Welgampola MS, Myrie OA, Minor LB, Carey JP. Vestibular-evoked myogenic potential thresholds normalize on plugging superior canal dehiscence. Neurology. 2008;70(6):464.
Roditi RE, Eppsteiner RW, Sauter TB, Lee DJ. Cervical vestibular evoked myogenic potentials (cVEMPs) in patients with superior canal dehiscence syndrome (SCDS). Otolaryngol Head Neck Surg. 2009;141(1):24.
Crane BT, Minor LB, Carey JP. Three-dimensional computed tomography of superior canal dehiscence syndrome. Am J Otol. 2008;29(5):699.
Krombach GA, DiMartino E, Schmitz-Rode T, et al. Posterior semicircular canal dehiscence: a morpho- logic cause of vertigo similar to superior semicircular canal dehiscence. Eur Radiol. 2003;13(6):1444.
Cloutier JF, Bélair M, Saliba I. Superior semicircular canal dehiscence: positive predictive value of high- resolution CT scanning. Eur Arch Otorhinolaryngol. 2008;265(12):1455.
Peterson EC, Lazar DA, Nemecek AN, Duckert L, Rostomily R. Superior semicircular canal dehiscence syndrome: successful treatment with repair of the mid- dle fossa ﬂoor: technical case report. Neurosurgery. 2008;63(6):E1207.
Crane BT, Minor LB, Carey JP. Superior canal dehiscence plugging reduces dizziness handicap. Laryngoscope. 2008;118(10):1809.
Vlastarakos PV, Proikas K, Tavoulari E, Kikidis D, Maragoudakis P, Nikolopoulos TP. Efﬁcacy assess- ment and complications of surgical management for superior semicircular canal dehiscence: a meta- analysis of published interventional studies. Eur Arch Otorhinolaryngol. 2009;266(2):177.
Deschenes GR, Hsu DP, Megerian CA. Outpatient repair of superior semicircular canal dehiscence via the transmastoid approach. Laryngoscope. ePub ahead of print, June 24, 2009.
Silverstein H, Van Ess MJ. Complete round window niche occlusion for superior semicircular canal dehis- cence syndrome: a minimally invasive approach. Ear Nose Throat J. 2009;88(8):1042.
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Chapter 17 ‌‌

Toxic/Metabolic Disorders

DIZZINESS AND SYSTEMIC METABOLIC DISORDERS

Diabetes Mellitus Uremia Hypothyroidism ‌

Alcohol and Thiamine Deﬁciency Management

METABOLIC DISORDERS OF THE TEMPORAL BONE

Otosclerosis Paget’s Disease Other Disorders Diagnosis

Management

OTOTOXINS

Aminoglycosides “Loop” Diuretics

Anti-inﬂammatory Drugs Platinum Compounds Diagnosis

Management

NEUROTOXINS

Heavy Metals Organic Solvents Diagnosis Management

DIZZINESS AND SYSTEMIC METABOLIC DISORDERS

Diabetes Mellitus

Auditory and vestibular symptoms and signs are common in patients with diabetes mellitus, but convincing evidence does not exist for a speciﬁc type of diabetic lesion of the inner ear or eighth nerve.1–5 In those diabetic patients with audiove- stibular dysfunction whose temporal bones and nervous systems have been studied at necropsy, pathologic changes can be explained on the basis of associated vascular disease.6–8 Three types of vascular changes occur with diabetes mellitus:

microangiopathy with thickening of the base- ment membrane of small vessels, (2) arterioscle- rotic narrowing of small arteries and arterioles, and (3) atherosclerotic narrowing of the large arteries. These vascular changes may damage the auditory and vestibular system from the peripheral end organs and eighth nerve to their

diffuse central nervous system (CNS) connec- tions. The most common ﬁnding in the labyrinth at necropsy in patients with diabetes mellitus is a thickening of the capillary walls, which is most prominent in the vascular stria of the cochlea, where it may account for the progressive, bilat- eral high-frequency hearing loss characteristic of the disease.7 Similar changes are found in the vestibular end organs; these, along with degen- eration of vestibular nerve and ganglion, could explain complaints of chronic disequilibrium and dizziness in diabetic patients.8

Sudden onset of hearing loss and/or vertigo in patients with diabetes mellitus can result from occlusion of the vessels to the labyrinth or the eighth nerve. The prevalence of diabetes mellitus was signiﬁcantly higher in patients with idiopathic sudden sensorineural hearing loss compared with age- and sex-matched con- trols.9 Cranial nerve mononeuropathies are a well-known clinical phenomenon associated with diabetes mellitus; they are most likely due

367

to arteriosclerotic occlusion of arterioles sup- plying the cranial nerve. Atherosclerosis of larger vessels predisposes the patient to tran- sient vertebrobasilar insufﬁciency and to spe- ciﬁc occlusive syndromes, such as the anterior vestibular artery syndrome and the lateral med- ullary syndrome (see Chapter 14). Postural hypotension is a common cause of presyncopal light-headedness in patients with diabetic mellitus.10

Uremia

Multiple causes of auditory and vestibular symptoms can be identiﬁed in patients with chronic renal disease. The same pathologic process can affect both the kidneys and the labyrinths, as seen in Alport’s syndrome (hered- itary nephritis and deafness; see Chapter 18), diabetes mellitus, and Fabry’s disease. Immu- nosuppressive treatment either of the primary renal disorder or to avoid transplant rejection predisposes the patient to otologic infections, often with exotic or saprophytic organisms.11 Patients with renal disease are particularly vul- nerable to the ototoxic effects of aminoglyco- side antibiotics and loop diuretics because of their inability to clear these substances from the blood; ototoxicity is probably the most com- mon cause of auditory and vestibular symptoms in uremic patients (see “Ototoxins”).

Hyponatremia causes reversible hearing loss and tinnitus in patients undergoing chronic hemodialysis. There is a high degree of correla- tion between the hearing loss and serum sodium levels, irrespective of the blood urea level.12 The hearing loss can be corrected in most patients by returning the serum sodium level to normal. Patients undergoing chronic hemodi- alysis and those receiving kidney transplants often experience ill-deﬁned ﬂuctuating auditory and vestibular symptoms. Oda and colleagues13 performed necropsy studies on temporal bones of eight patients with chronic uremia who had undergone long-term hemodi- alysis therapy (24 to 546 treatments). At least one kidney transplant was performed in seven of the eight patients. Vestibular symptoms occurred in ﬁve patients and audi- tory symptoms in three—all symptoms began after the start of hemodialysis. Abnormal con- cretions were found in the vascular stria of the cochlea and in the subepithelial connective

tissue of the maculae and cristae in seven of the eight patients. The source of these abnor- mal deposits is unknown. Chronic dialysis is also associated with several neurological syn- dromes, including the disequilibrium syn- drome, subdural hematoma, and Wernicke’s encephalopathy.14

Hypothyroidism

A symmetrical, mild to moderate sensorineural hearing loss is commonly associated with spo- radic, nonendemic hypothyroidism.15,16 Vertigo may also occur in hypothyroid patients, although there is no vertiginous syndrome that is characteristic of this disorder. Some investi- gators have found a high incidence of hypothy- roidism in patients with idiopathic Meniere’s syndrome but others have not.17,18 Thyroid hor- mone is critical for the normal development of both the auditory and vestibular systems. Congenital hypothyroidism in rats leads to loss of auditory and vestibular function, and replace- ment hormone in the early stages of postnatal development prevents the loss of function.19 Similarly, there appears to be a critical thera- peutic window for preventing hearing loss in children with congenital hypothyroidism.20 Auditory and vestibular abnormalities have also been documented in animals who have been made hypothyroid.21 However, these abnor- malities typically do not recover after hormone replacement.

Alcohol and Thiamine Deﬁciency

ACUTE TOXIC EFFECTS OF ALCOHOL

Acute alcohol intoxication is regularly associ- ated with unsteadiness of gait, slurring of speech, and, occasionally, vertigo. The gait ataxia and slurring of speech suggest cerebellar dysfunction, but an additional vestibular com- ponent may be involved. In animal studies, alcohol selectively interferes with synaptic transmission within the vestibular nuclei.22 Vestibular function testing with rotational stimulation in patients with alcohol intoxication has shown normal vestibulo-ocular reﬂex gain in the dark, but impaired ﬁxation suppres- sion of vestibular nystagmus consistent with cerebellar dysfunction.23,24 Slowing of saccades

Slow phase velocity (deg/sec)

10 Right lateral position

800

0.1

Left lateral position

Right-beating nystagmus Left-beating nystagmus

Blood alcohol (percent)

0.05

0 400 800

Time (minutes)

Figure 17–1. Direction-changing positional nystagmus after a normal subject ingested 150 ml of whiskey. Nystagmus initially beat toward the ground (undermost ear) in both lateral positions, but as the blood alcohol level decreased, the nystagmus beat away from the ground in both lateral positions.

and smooth pursuit is consistently found in subjects after only moderate alcohol ingestion.25–27 Gaze-evoked nystagmus is a reli- able sign of intoxication, the magnitude of which is highly correlated with the blood alcohol concentration.28

Positional vertigo is another well-documented effect of alcohol on the vestibular system (Fig. 17–1).29 Within 30 min after ingesting a moderate amount of alcohol (e.g., 150 ml of whiskey), the subject develops a direction- changing static positional nystagmus often associated with vertigo. The positional nystag- mus beats to the right in the right lateral posi- tion, to the left in the left lateral position, and is inhibited by ﬁxation. The primary phase of the positional nystagmus reaches its peak in about 2 hr, at approximately the time of peak blood alcohol level (near 0.1% for the earlier exam- ple). Four to 5 hr after alcohol ingestion, when the blood alcohol level is below 0.01%, posi- tional nystagmus is still present, but now it is right-beating in the left lateral position and left-beating in the right lateral position (sec- ondary phase). The positional nystagmus can last up to 12 hr, at which time alcohol cannot be detected in the blood.

Direction-changing positional nystagmus in the reverse direction of primary alcohol posi- tional nystagmus can be produced by giving subjects heavy water—H3O.30 When subjects

with alcohol direction-changing positional

nystagmus (primary phase) are given H3O, the nystagmus disappears. Alcohol and heavy-

water direction-changing positional nystagmus are likely due to a different rate of diffusion of alcohol and heavy water into the cupula and the surrounding endolymph.30 In the primary phase of alcohol positional nystagmus, alcohol rapidly diffuses into the base of the cupula because of the latter’s proximity to blood capil- laries while it slowly diffuses into the endo- lymph. The cupula then has a lower speciﬁc gravity than that of the endolymph and acts as a gravity-sensing organ, maintaining a slight deﬂection as long as the position is held. After approximately 3 hr, the endolymph and cupula have approximately the same alcohol concen- tration, and the positional nystagmus disap- pears. As the blood alcohol level falls, the reverse situation occurs, with the cupula being heavier than the surrounding endolymph, and the secondary phase of positional nystagmus occurs.

Three-dimensional recordings of alcohol positional nystagmus showed that the buoyancy mechanism accounts for only part of the observed nystagmus.31 After consuming alco- hol, subjects were positioned so that the hori- zontal canals were earth-vertical and then rotated in the plane of the horizontal canals about an earth-horizontal axis to either 45 degrees or 90 degrees, right or left ear down. Spatial analysis of the recorded eye movements

showed that in addition to the positional nys- tagmus attributed to the buoyancy of all six cupulae, there was a vertical offset (slow phase down in all subjects) independent of the sub- ject’s orientation in space. This offset was thought to be due to toxic effects of the alcohol on central vestibulo-ocular reﬂex pathways.

WERNICKE’S ENCEPHALOPATHY

This is a common clinical syndrome caused by thiamine deﬁciency. In the past it was almost exclusively associated with alcoholism but now is commonly recognized with other causes of mal- nutrition, including cancer, and its treatments and bariatric surgery.32–34 It is characterized by the subacute onset of confusion, ophthalmople- gia, and ataxia of stance and gait. Dizziness and vertigo are not common complaints. Hearing loss is a rare presenting symptom.35 The truncal ataxia is often dramatic, with the patient being unable to take even a few steps without sup- port, and yet standard cerebellar function test- ing with ﬁnger-to-nose and heel-knee-shin is often normal or minimally impaired. The ataxia is increased with eye closure or darkness. These ﬁndings suggest a combination of midline cer- ebellar and either proprioceptive or vestibular impairment. Caloric responses can be dimin- ished or absent.36,37 Magnetic resonance imaging (MRI) of the brain typically shows symmetrical ﬂuid-attenuated inversion recov- ery imaging (FLAIR) hyperintensities in the thalami, mamillary bodies, tectal plate, and periaquaductal area.38

Experimental studies in thiamine-deﬁcient rats39 and monkeys40 showed that the earliest pathologic changes originate in the vestibular nuclei, particularly in the lateral nucleus. The nerve terminals and axons degenerate without evidence of damage to the neuronal parikaria. Neurologic signs appear even before these early pathologic changes. Loss of transketolase activity (a thiamine-dependent enzyme) in the lateral pontine tegmentum, including the lat- eral vestibular nuclei, correlates better with the onset of clinical signs. Injection of thiamine promptly restores transketolase activity and improves clinical signs.

Pathologic changes are seen in the vestibular nuclei of patients with thiamine deﬁciency studied at necropsy. Vascular changes include endothelial swelling in small arteries and veins and ﬁbrinoid degeneration and hemorrhage

involving arterioles and capillaries on the arte- rial side.41 The medial vestibular nucleus is most commonly involved, but the other nuclei are also involved in between 30% and 50% of cases.32 The changes in the vestibular nuclei are relatively mild, however, compared with the frank necrosis and demyelination occurring in other areas. In the cerebellum, Purkinje cell loss is most prominent.42 Apparently, most of the clinical ﬁndings (including impaired ves- tibular function) are secondary to thiamine- dependent enzyme loss in the brain stem and cerebellum, and only after prolonged and/or repeated episodes of deﬁciency do irreversible structural changes occur.

CEREBELLAR DEGENERATION

In 1959, Victor and associates43 reported a dra- matic clinical syndrome in 50 alcoholics that was manifested by severe truncal ataxia with relative sparing of the upper extremities. On clinical examination, all patients exhibited severe ataxia of stance and gait, with instability of the trunk while standing and severe incoor- dination on the heel-knee-shin test. On neuro- pathologic examination, atrophy was remark- ably localized to the superior cerebellar vermis, paramedian superior cerebellar hemispheres, and the ﬂocculi. Subsequent pathological stud- ies have conﬁrmed these ﬁndings,44 and neu- roimaging studies have documented shrinkage of the cerebellum, particularly the superior vermis in chronic alcoholics (Fig. 17–2).45,46 The cerebellar damage is most likely due to malnutrition rather than direct alcohol toxicity, as similar cellular changes have been seen in malnourished nonalcoholics47 and some of the symptoms and signs seen with acute cerebellar degeneration can be reversed with massive doses of thiamine.48 Still, ethanol may have direct toxic effects on the cerebellum or pro- mote the toxic effects of thiamine deﬁciency.49

Management

There is no speciﬁc treatment for the neuroto- logic manifestations of diabetes mellitus. Presumably the likelihood of vascular occlu- sion (small and large vessel) decreases with good control of blood glucose levels.49 Although it has been suggested that auditory and vestib- ular dysfunctions occur in the prediabetic state,

Figure 17–2. Magnetic resonance image of the brain in a patient with alcoholic cerebellar degeneration showing atrophy of the superior vermis (arrow). T1-weighted sagittal section.‌‌

as with the retinal and renal changes, there have been no controlled studies to support this supposition. The single most important aspect in preventing auditory and vestibular dysfunc- tions in patients with uremia is to avoid the use of potential ototoxic drugs. Careful manage- ment of electrolytes in patients undergoing chronic renal dialysis will prevent ﬂuctuating auditory and vestibular symptoms. The bilat- eral sensorineural hearing loss associated with acquired hypothyroidism improves in a small percentage of patients after thyroid hormone replacement.15

With Wernicke’s encephalopathy the oph- thalmoplegia, confusion, and ataxia usually respond rapidly to thiamine replacement.32,40 Some patients are left with a chronic memory disorder (Korsakoff’s syndrome) as well as mild ataxia due to midline cerebellar degeneration. In patients receiving thiamine replacement, vestibular function as measured by serial caloric testing slowly returns toward normal over sev- eral weeks, although in some cases recovery is asymmetric and incomplete. As suggested ear- lier, alcoholic cerebellar degeneration may also respond to thiamine replacement. Some patients with alcoholic cerebellar degeneration who stop drinking exhibit a signiﬁcant and sometimes dramatic decrease in body sway as measured with posturography, compared with patients who continued drinking.51 This improvement after abstinence from alcohol may result from central plastic changes or from recovery of function where structural damage was not complete. The cortical shrinkage and

ventricular dilation seen on imaging of the cer- ebellum are partially reversible with abstinence from alcohol.52 Proton magnetic resonance spectography showed increases in the concen- tration of choline-containing compounds within the superior cerebellar vermis in chronic alco- holics after 3 to 4 weeks of abstinence, followed by a reduction in these compounds with relapse.53

METABOLIC DISORDERS OF THE TEMPORAL BONE

Otosclerosis

Otosclerosis is a metabolic disease of the bony labyrinth that usually manifests itself by immo- bilizing the stapes and thereby producing a conductive hearing loss.54,55 The disease, how- ever, can less commonly involve the entire otic capsule and be associated with sensorineural hearing loss and vestibular symptoms. Seventy percent of patients with clinical otosclerosis note hearing loss between the ages of 11 and

30. The disorder is most common in whites (prevalence about 0.2%–1%), is infrequent in blacks, and is almost nonexistent in Asians and American Indians.56 A positive family history for otosclerosis is reported in between 50% and 70% of cases. Otosclerosis is genetically hetero- geneous with rare autosomal dominant forms, but the majority are due to an interaction between genetic and environmental factors.57

So far in families with autosomal dominant transmission at least seven monogenic chromo- somal loci have been reported but no genetic mutations identiﬁed. Three susceptibility alleles have been identiﬁed and replicated in case control association studies: TGFB1, BMP2, and BMP4. All three are part of the transform- ing growth factor-beta pathway.57

Although otosclerosis is primarily a disorder of the auditory system, vestibular symptoms and signs are more common than generally appreciated. In one study,58 46% of 500 patients with nonsurgically treated otosclerosis com- plained of vestibular symptoms. The most common symptoms were recurrent attacks of vertigo (26%) and postural imbalance (22%). Those patients with more severe sensorineural hearing loss were more likely to have vestibular complaints. Abnormalities on vestibular func- tion testing have been found in as many as 50% of patients tested, with the most common abnormality being unilateral hypoexcitability to caloric stimulation.59,60 The vestibular abnor- malities are more common in patients with greater sensorineural hearing loss, but they are not necessarily seen in the poorer hearing ear.

The basic pathologic process of otosclerosis is a resorption of normal bone, particularly

around blood vessels, and its replacement by cellular ﬁbrous connective tissue.55,61,62 With time, immature basophilic bone is produced in the resorption space; after several cycles of resorption and new bone formation a mature acidophilic bone with a laminated matrix is produced. Bilateral involvement is usual, but about a fourth of cases are unilateral. Areas of predilection for otosclerotic foci include the oval window region, the round window niche, the anterior wall of the internal auditory canal, and within the stapedial footplate (Fig. 17–3). Although conductive hearing loss is the hall- mark of otosclerosis, a combined conductive– sensorineural hearing loss pattern is frequent. The sensorineural component is perhaps caused by foci of otosclerosis next to the spiral ligament of the cochlea, producing atrophy of the spiral ligament. About 10% of patients with otosclerosis eventually develop a profound sen- sorineural hearing loss across all frequencies.63 The mechanism for the production of dizzi- ness in patients with otosclerosis is poorly under- stood. Direct mechanical deformation of the labyrinth or biochemical abnormalities of inner ear ﬂuids are likely possibilities. Endolymphatic hydrops has been identiﬁed in a few temporal bones with multiple foci of otosclerosis.64

Figure 17–3. Histopathological section showing an otosclerotic lesion involving the bony labyrinth at the anterior margin of the oval window (small arrow) and the entire footplate of the stapes (larger arrow). The patient exhibited a combined conductive–sensorineural hearing loss. (Courtesy Harold Schuknecht, Boston, MA.)

Sando and colleagues65 studied four temporal bones of two patients with otosclerosis who complained of prominent vestibular symptoms and found otosclerotic foci in opposition to the superior vestibular nerve in each patient. Vestibular nerve degeneration distal to these foci was also present, and three of the four temporal bones exhibited a marked degenera- tion of the sensory epithelium of the cristae of the lateral semicircular canals.

Paget’s Disease

Paget’s disease is a metabolic disorder of bone marked by pronounced osteoclastic resorption of old, fully calciﬁed bone and deposition of new osteoid layers that calcify normally.66–68 It usually becomes clinically manifest in the sixth decade, affecting men four times more commonly than women. The clinical picture varies from the classic one of an enlarged skull, progressive kyphosis, and short stature to the more common restricted forms conﬁned to the skull, spine, pel- vis, and femur. Hearing loss is a common symp- tom, initially described by Paget in his early reports and subsequently studied in detail by numerous investigators.69,70 A progressive com- bined sensorineural and conducting hearing loss is usually found. The vestibular labyrinth may also be progressively destroyed, resulting in unsteadiness of gait and, in rare cases, episodic vertigo. In the late stages, complete destruction of the bony labyrinth may occur with invasion of the inner ears, fractures, and degeneration of the membranous labyrinth.

Genetic factors play an important role in the pathogenesis of Paget’s disease, and so far mutations have been identiﬁed in four differ- ent genes.71,72 By far the most common is SQSTM1, a gene that codes for a scaffold pro- tein in the nuclear factor KappaB signaling pathway. There is a mutation hot spot at the UBA domain of SQSTM1 with P392L being by far the most common mutation. Environmental factors must explain the varied clinical expres- sion within families with the mutation.

Other Disorders

Other less common metabolic disorders of the temporal bone that are associated with hearing loss and dizziness include osteogenesis

imperfecta,73 ﬁbrous dysplasia,74 and osteopet- rosis.75 The clinical presentation of these disorders is often indistinguishable from that of otosclerosis and of Paget’s disease.

Diagnosis

The diagnosis of otosclerosis is based on ﬁnd- ing a conductive hearing loss in a patient with the clinical picture outlined earlier. A ﬂat tym- panogram with maximum compliance near zero pressure is characteristic (see Fig. 8–4C in Chapter 8). As the disease progresses, a mixed conductive, sensorineural hearing loss is com- mon. About 10% of patients exhibit hyperemia of the promontory mucosa of the middle ear, visible through the tympanic membrane (Schwartze’s sign). Computed tomography (CT) may show changes in the otic capsule (ranging from a small dehiscence in the nor- mal, crisp outline of the capsule to entire loss of anatomic details), but these changes are not speciﬁc for otosclerosis, as they are also found in osteogenesis imperfecta, ﬁbrous dysplasia, and even some normal subjects. CT bone den- sity measurements at the ﬁssula antefenestram may be useful for the diagnosis and as an indi- cator of disease progression.76

The diagnosis of Paget’s disease rests on ﬁnding the characteristic roentgenographic ﬁndings of increased density of bone with loss of the normal architecture, mingled with areas of decreased bone density.66 The skull is enlarged, with indistinct margins giving a “cotton wool” appearance. High-resolution CT scans of the temporal bone typically reveal poor deﬁnition of the cortical margins of the inner ear and internal auditory canals.

Management

In small observational studies, sodium ﬂuoride has been associated with reduced progression of otosclerosis.77,78 A single controlled study from Denmark and France documented both biochemical and audiometric changes in a treated group of patients with otosclerosis com- pared with a control group.79 At 6 months, 7% (3/43) of treated patients had progressive hear- ing loss (>10 dB increase from baseline in pure- tone average) whereas 25% (13/52) of the control patients had progressive hearing loss.

This study has some methodological limitations (nearly a 10% dropout rate) and the results have not been replicated. The usual dosage is 40 to 50 mg sodium ﬂuoride per day, given most con- veniently as Florical (8.5 mg sodium ﬂuoride and 364 mg calcium carbonate per capsule) plus 500 mg of vitamin D daily. The calcium and vitamin D prevent secondary hyperpara- thyroidism from developing. Side effects occur in as many as 20% of patients, with the most common being gastrointestinal upset and mus- culoskeletal pain. Whether sodium ﬂuoride can reverse the vestibular abnormalities associated with otosclerosis is not known.

Surgical treatment of otosclerosis is directed at improving the conductive hearing loss. Many different operations have been developed, and most have a high success rate. Although data on the results of surgical therapy in patients with vestibular symptoms are not available, there is little reason to expect improvement in such patients. In fact, surgical therapy may aggravate the vestibular symptoms. Smyth80 detected decreased caloric responses 3 months postoperatively in 30% of 26 ears with normal values preoperatively.‌

Bisphosphonate reduces bone turnover, and it has been shown to clear radiological lesions and restore normal histology in patients with Paget’s disease.71 Long-term follow-up on disease progression is lacking.

OTOTOXINS

Patients who receive ototoxic drugs are often bedridden and suffer from multiple symptoms of systemic illness, so additional symptoms of audi- tory and vestibular dysfunction may be easily overlooked. Vestibular symptoms are particularly difﬁcult to identify in this setting. Only after the patient begins to recover do the devastating effects of vestibular loss become apparent. By this time, the damage is irreversible. The examin- ing physician must be keenly aware of the poten- tial auditory and vestibular toxicity of any drug that is used, if ototoxicity is to be prevented.

Aminoglycosides

The commonly used aminoglycosides are listed in Table 17–1. Although each of these drugs can

Table 17–1 Relative Vestibular and Auditory Ototoxicities of Commonly Used Aminoglycosides

	Vestibular	Auditory
Streptomycin	+ + +	+
Gentamicin	+ + +	+
Tobramycin	+ +	+ +
Kanamycin	+	+ + +
Amikacin	+	+ + +
Dibekacin	+	+
Netilmicin	+	+
Sisomicin	+	+

produce both auditory and vestibular damage, streptomycin and gentamicin are relatively spe- ciﬁc for the vestibular system, whereas kanamy- cin, tobramycin, and amikacin produce more damage to the auditory system.81,82 The newer aminoglycosides sisomicin, dibekacin, and netilmicin are overall less ototoxic than the older aminoglycosides.83 Although high blood levels and long durations of treatment are most likely to produce ototoxicity, some susceptible patients may develop ototoxicity after a brief low-dose course (see later discussion). The majority of patients with gentamicin vestibulotoxicity receive a total dose within the generally accepted safe range,84 and serum peak-and-trough gen- tamicin levels do not correlate with develop- ment of vestibulotoxicity.85 Also, both vestibular and cochlear toxicity have been observed with ototopic aminoglycoside ear drops.86

The pharmacologic and biochemical charac- teristics are similar for all of the aminoglyco- side antibiotics.87,88 They are excreted almost exclusively by glomerular ﬁltration; they are not metabolized. Patients with renal impair- ment cannot excrete the drugs, so the amino- glycosides accumulate in the blood and inner ear tissues. The ototoxicity of the aminoglyco- sides has been shown convincingly to be due to hair cell damage in the inner ear. Unlike peni- cillin and other common antibiotics, aminogly- cosides are concentrated in the perilymph and endolymph. The earliest effect of the vestibu- lotoxic compounds, such as streptomycin and gentamicin, is a selective destruction of type I hair cells in the crista. Later, type II hair cells are destroyed, but the supporting cells remain unaffected. With the cochleotoxic agents, such as kanamycin and amikacin, there is ﬁrst a selective destruction of the outer hair cells in

the basal turn of the cochlea, followed by total hair cell loss throughout the cochlea as the dos- age and duration of treatment are increased. Consistent with these pathologic changes, the sensorineural hearing loss caused by the amin- oglycosides usually begins in the high frequen- cies and progresses to a ﬂat 60 to 70 dB loss across all frequencies. Degeneration of neu- rons may occur years after the loss of inner and outer hair cells that is caused by the aminogly- cosides. Even after treatment is terminated, some of the aminoglycosides (dihydrostrepto- mycin, gentamicin, and tobramycin in particu- lar) have been shown to produce continued damage to the sensory structures of the organ of Corti.

The mechanism by which aminoglycosides damage hair cells is only partially under- stood.82,83,88 Several studies suggest that amino- glycosides may interfere with mitochondrial energy metabolism by binding to the mitochon- drial membrane and increasing membrane permeability. Aminoglycosides have also been shown to reversibly block calcium-sensitive potassium channels, increase free-radical forma- tion, and have an excitotoxic effect on cochlear N-methyl-d-aspartate (NMDA) receptors.89,90 With the discovery of increased sensitivity to ototoxicity in families with mutations in the mitochondrial gene for the 12S ribosomal ribo- nucleic acid (rRNA), the possibility was raised that even normal human mitochondrial rRNA may be affected by the aminoglycosides.91,92 Interestingly, the region on the 12S rRNA that is mutated in families with ototoxin susceptibil- ity is morphologically similar to the area of bac- terial rRNA to which aminoglycosides bind in the course of their bacterial cytoaction. This mechanism could not explain the vestibular loss associated with gentamicin and streptomy- cin, however, since families with the predispos- ing mutations in the 12S rRNA gene have hearing loss but normal vestibular function.93 Furthermore, no mutations with conﬁrmed pathogenicity were identiﬁed in the 12S rRNA gene in 66 patients with aminoglycoside ves- tibulotoxicity or in 15 patients with idiopathic bilateral vestibulopathy.92

As noted earlier, vestibular symptoms and signs due to aminoglycoside toxicity are often subtle. Although some patients complain of vertigo (presumably due to asymmetric involve- ment of the vestibular system), most complain of an unsteady gait, particularly at night or in a

darkened room. Head movement–induced oscillopsia is also common. The head-thrust test can be used at the bedside to identify ves- tibular impairment. Serial caloric and rotational examinations document a progressive bilateral loss of vestibular responsiveness. Because of their highly selective effect on the vestibular endorgan, streptomycin and gentamicin are used to produce a chemical vestibulectomy in patients with episodic vertigo from Meniere’s syndrome (see Chapter 11).

“Loop” Diuretics

The two main ototoxic diuretics, furosemide and ethacrynic acid, act by inhibiting active resorption of chloride in the loop of Henle, thereby preventing the renal resorption of sodium that passively follows chloride. The mechanism of their ototoxic effect is not com- pletely known, although these drugs clearly inﬂuence ion channels in the kidney and in the cochlear duct.94 They inhibit the Na-K-2Cl- cotransporter in the marginal and dark cells of the stria vascularis, resulting in a reduction in the endolymphatic potential and endolym- phatic K+ concentration. The ototoxic effects of the loop diuretics appear to be primarily conﬁned to the cochlea, although vertigo has been rarely reported. About 6% of patients receiving furosemide develop a temporary hearing loss that is nearly always reversible. The newer loop-inhibiting diuretics, bume- tanide and piretanide, appear to have a much lower rate of cochleotoxic effects in both ani- mal and human studies.95,96 Loop diuretics may enhance aminoglycoside ototoxicity.97

Anti-inﬂammatory Drugs

Anti-inﬂammatory drugs known to be associ- ated with ototoxicity include salicylates, non- steroidal anti-inﬂammatory drugs (NSAIDs), and quinine.98 Salicylates and NSAIDs are among the most commonly used drugs for inﬂammation, fever, and pain. Quinine, origi- nally an antimalarial drug with properties simi- lar to those of the salicylates, is commonly used for treating nocturnal leg cramps. The main ototoxic effect of these drugs is a reversible, mild to moderate ﬂat or high-frequency hearing loss along with a high-pitched tinnitus.

The salicylates have been studied most exten- sively and reliably produce hearing loss and tin- nitus when the plasma salicylate level approaches

mg/ml.99 There is almost a linear relation- ship between serum unbound salicylate con- centration and ototoxic symptoms, although the threshold level for symptoms varies from patient to patient. These ototoxins cause a transient dysfunction of outer hair cells documented by both ultrastructural and electrophysiological studies. There is no evidence that the vestibular system is affected. All symptoms and signs are typically rapidly reversible after cessation of the drug ingestion (usually within 24 hr).

Platinum Compounds
Cis-platinum and carboplatin are the two most commonly used ototoxic chemotherapeutic agents. Both are associated with auditory toxicity, although carboplatin is less toxic than cis-platinum.88,100 By way of comparison, the incidence of aminoglycoside ototoxicity is about 10%, whereas the incidence of cis-platinum ototoxicity is in the range of 50%. Tinnitus and hearing loss are extremely common. Typically, the tinnitus is transient, lasting from a few hours to up to a week after therapy. The hear- ing loss is usually bilateral, beginning in the high frequencies and progressing to involve all frequencies; it may not appear until several days after treatment. The hearing loss usually has some degree of reversibility, although when it is severe and involves all frequencies it is often permanent. The critical cumulative oto- toxic dose of cis-platinum has been reported to be in the range of 3 to 4 mg/kg of body weight.101 The ototoxic effects can be decreased by using slow infusions and dividing the doses over sev- eral months.102 The vestibular system is relatively spared by these chemotherapeutic ototoxins.103 Morphologic studies in animals that have been given cis-platinum show hair cell damage similar to that seen with the amin- oglycosides. Free radical formation in the kidney and ear have been implicated in the pathogen- esis of toxicity with both compounds.94

Diagnosis
The clinician must be constantly on the alert for the early symptoms of ototoxic drugs.
This is particularly important in a patient who is seriously ill and conﬁned to bed or in any patient who has renal impairment, particularly renal failure. Bedside audiometric assessment is available in most hospitals; bedridden patients can be tested with reproducible audi- tory stimuli. Although less satisfactory than conventional testing in a soundproof room, earphones help exclude ambient noise. Because the hearing loss due to ototoxic drugs usually begins in the high-frequency range, a screen of the high frequencies can be used to predict future low-frequency loss. By contrast, quanti- tative bedside vestibular testing (i.e., caloric and rotational testing) is not available in most hospitals so that the clinical examination is crit- ical for identifying early vestibular loss (see tests of vestibulo-ocular reﬂexes, Chapter 6). The head-thrust test can be performed even in critically ill patients and has consistently been shown to be a sensitive test for vestibulo- toxicity.104,105 Whenever possible the Romberg and tandem walking tests should be used to assess balance function. Ambulatory patients can undergo quantitative caloric and rotational testing. Rotational testing is ideally suited for identifying early vestibular ototoxic effects, because the normal response variability is much less than that seen with caloric testing (see Chapter 7). The earliest changes are short- ening of the dominant time constant and decreased gain at the lowest and highest frequencies.104

Management
The key to the management of the ototoxicity is prevention. Kidney function should be mea- sured prior to beginning any potentially oto- toxic drug. Patients in high-risk groups (Table 17–2) should be monitored with periodic audi- tory and vestibular testing. All patients should be questioned on a regular basis to identify early symptoms of auditory or vestibular loss. When the earliest effects of ototoxicity are identiﬁed, the drug should be stopped. Usually other drugs can be used that have less ototoxic potential.
Based on the hypothesis that aminoglycoside ototoxicity results from iron chelation and free- radical formation, use of iron chelators and radical scavengers was shown to prevent ototox- icity in guinea pigs.106 At the same time, these
Table 17–2 Major Risk Factors for Drug Ototoxicity‌‌
Impaired renal function High serum levels
Prior use of ototoxic drugs Course > 14 days
Preexisting sensorineural hearing loss Age > 65 years

drugs have no effect on serum levels of the aminoglycosides nor on its antibacterial efﬁ- cacy. Assuming that the ototoxic effects of the aminoglycosides are at least in part due to exci- totoxic activation of cochlear NMDA receptors, Segal et al.90 showed that NMDA antagonists protected animals from aminoglycoside ototox- icity. Antioxidants may prevent both the free- radical formation and the excitotoxic effects on the NMDA receptors.107 A double-blind pla- cebo-controlled study in China found that aspi- rin (an antioxidant) given in combination with gentamicin was signiﬁcantly more effective than placebo with gentamicin in preventing hearing loss.108,109 At 5–7 weeks after being treated with intravenous gentamicin for an acute infection, 3% (3/89) of patients treated with 3 g of aspirin per day had ototoxicity (deﬁned as hearing loss of >15 dB from baseline at both 6 and 8 kHz) compared to 13% (14/106) of the control group. In another controlled study the antioxidant N-acetylcysteine (NAC) signiﬁcantly decreased the incidence of hearing loss in hemodialysis patients receiving gentamicin for dialysis cathe- ter-related bacteremia.110 In this study at 6 weeks after gentamicin, 25% (5/20) patients treated with NAC had ototoxicity (deﬁned as
>20 dB loss at any frequency or >10 dB loss at any two adjacent frequencies) compared to 60% (12/20) of the control group. Neither of these studies assessed vestibular or balance function as an outcome, despite the fact that gentamicin is more toxic to the vestibular sys- tem than to the auditory system.
As with other vestibular disorders, manage- ment of patients with permanent bilateral ves- tibular loss due to ototoxins should be directed at retraining the nervous system to use other sensory signals to replace the lost vestibular signals. Practical suggestions on how to avoid head movement–induced oscillopsia (stopping and holding the head still when attempting to
read a sign) and gait unsteadiness (always have a light on throughout the night) are useful, along with an active exercise program to force central compensation (see Chapter 20). Younger patients often will return to nearly normal activity over a period of years, but elderly patients are rarely able to compensate fully for the vestibular loss.

NEUROTOXINS
Heavy Metals
Both lead and mercury intoxication are known to produce auditory and vestibular symptoms, but the pathophysiologic mechanisms of these symptoms is poorly understood. In adults, acute lead poisoning typically leads to a motor neuropathy, whereas in children encephalopa- thy is more prominent. Chronic lead absorp- tion can lead to more subtle symptoms and signs, including nonspeciﬁc dizziness, imbal- ance, and cognitive deﬁcits. Rats exposed to chronic low concentrations of lead acetate in their drinking water showed abnormalities in postrotatory nystagmus in the absence of clinical signs of lead intoxication.111 Segmental demyelination and axonal degeneration of the eighth nerve were identiﬁed in guinea pigs given weekly intraperitoneal injections of 1% lead acetate solution for 7 weeks.112 The end organs and ganglion cells showed no visible morphologic changes. By contrast, adult squirrel monkeys that were chronically poi- soned with lead showed minimal changes in the auditory and vestibular systems, both on clinical and histologic examination.113 The dif- ference in ﬁndings may be due to the well- known decreased susceptibility of the adult nervous system to lead toxicity. Hearing loss and vertigo have occasionally been reported in isolated cases of childhood and adult lead poisoning, but no detailed study has been undertaken of auditory and vestibular function in a large population of lead-poisoned patients.
Two large patient populations with organic mercury poisoning have undergone detailed neurotologic examination in Japan. Mizukoshi and colleagues114 studied 144 patients with organic mercury poisoning acquired from eat- ing contaminated ﬁsh caught in the Aganagawa
River in Niigata. Impaired hearing was found in 50% of patients and 67% complained of dizziness and unsteadiness of gait. Episodes of vertigo were reported in 10%. Audiological examination revealed sensorineural hearing loss usually consistent with a cochlear origin in the early stages and with a retrocochlear origin in later stages. Spontaneous vestibular nystag- mus was present in 27%, 17% had gaze paretic nystagmus, and 65% had positional nystagmus. Results of caloric testing were reported to be abnormal in 46% of cases, with a directional preponderance being the most consistent ﬁnd- ing. Unfortunately, normative data were not included for comparison and, therefore, the frequent occurrence of abnormalities on nys- tagmography must be interpreted with caution. Similar ﬁndings on neurotologic examination were reported in patients who acquired mercury poisoning from seafood caught in Minamata Bay.115
The site of vestibular and auditory dysfunction in mercury-poisoned patients is unclear. Oral administration of methyl mercury to rats rapidly leads to accumulation of mercury in the brain stem, particularly in the ventral cochlear nucleus and the superior vestibular nucleus.116 Mercury intoxication in guinea pigs resulted in changes in the labyrinth and cerebellum.117,118 Necropsy studies have not been performed on the tempo- ral bones and eighth nerves from patients dying of mercury intoxication. Examination of the brain in such patients reveals a selective sensitiv- ity of the granule cell layer of the neocerebellum, but cases of demyelination of the subcortical and brainstem white matter and peripheral nerves have also been reported.119,120

Organic Solvents
Acute intoxication with organic solvents leads to a well-described toxic encephalopathy mani- fested by symptoms of confusion, dizziness and imbalance, nausea, and generalized weakness. Whether a chronic toxic encephalopathy devel- ops from chronic low-level exposure to organic solvents is a more controversial issue.121,122 Some workers with long-term occupational exposure to organic solvents may become intol- erant even to low air concentrations so that they are no longer able to work in the industry.123 Studies in animals show direct effects of organic solvents on both vestibulo-ocular reﬂex gain
and the ability to suppress the vestibular-ocular reﬂex with ﬁxation.124 Auditory and vestibular function testing in workers exposed to organic solvents identiﬁed a variety of nonspeciﬁc abnormalities, compared to controls, most being consistent with dysfunction within cen- tral auditory and vestibular pathways.125,126 However, these auditory–vestibular deﬁcits found in workers with organic solvent exposure do not correlate with the degree of exposure or with the severity of symptoms. The effects of organic solvents on hearing may be synergistic with exposure to noise and other chemicals in the work environment.

Diagnosis
Auditory and vestibular symptoms and signs due to neurotoxins are typically part of a more generalized encephalopathic syndrome, with some unique features being associated with each of the different neurotoxins. Heavy metal intoxication leads to multisystem involvement with clear neurologic ﬁndings. With acute exposure, blood levels typically correlate with the severity of exposure and the severity of symptoms and signs. However, with chronic exposure, heavy metals are bound to bone and other hard tissues so that blood levels do not reﬂect the level of the body burden. Past expo- sure may be identiﬁed in hair and nail samples or by mobilizing bone stores with chelating agents. A 24-hr urine collection after exposure to a chelating agent provides a good means of assessment of body heavy-metal burden. There is no good way of assessing past exposure to organic solvents other than taking a careful history regarding types of exposure.

Management
The ﬁrst step in managing exposure to neuro- toxins is to remove the exposure. With acute intoxication to heavy metals, residual symp- toms and signs are common, even with aggres- sive treatment. Chelating agents can be used to decrease the body burden of heavy metals, but neurologic damage is often irreversible. The chelating agents must be used with caution since they pull heavy metals from hard tissue into the blood, which can lead to further neurologic damage.
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78. Naumann IC, Porcellini B, Fisch U. Otosclerosis: incidence of positive ﬁndings on high-resolution com- puted tomography and their correlation to audiologi- cal test data. Ann Otol Rhinol Laryngol. 2005;114(9): 709.
79. Bretlau P, Causse J, Causse JB, et al. Otospongiosis and sodium ﬂuoride. Ann Otol Rhinol Laryngol. 1985;94:103.
80. Smyth GDL. Recent and future trends in the man- agement of otosclerotic conductive hearing loss. Clin Otolaryngol. 1982;7:153.
81. Smith CR, Lipsky JJ, Laskin OL, et al. Double blind comparison of the nephrotoxicity and auditory tox- icity of gentamicin and tobramycin. N Engl J Med. 1980;302:1106.
82. Selimoglu E. Aminoglycoside-induced ototoxicity.
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83. Roland JT, Jr, Cohen NL. Vestibular and auditory oto- toxicity. In: Cummings CW, Fredrickson JM, Harker LA, Krause CJ, Schuller DE, eds. Otolaryngology Head and Neck Surgery. 3rd ed. St. Louis, MO: CV Mosby; 1998.
84. Halmagyi GM, Fattore CM, Curthoys IS, Wade S. Gentamicin vestibulotoxicity. Otolaryngol Head Neck Surg. 1994;111:571.
85. Black FO, Pesznecker S, Stallings V. Permanent gentamicin vestibulotoxicity. Otol Neurotol. 2004;25(4):559.
86. Matz G, Rybak L, Roland PS, et al. Ototoxicity of oto- topical antibiotic drops in humans. Otolaryngol Head Neck Surg. 2004;130(suppl 3):S79.
87. Lerner SA, Matz GJ. Aminoglycoside ototoxicity. Am J Otolaryngol. 1980;1:169.
88. Rybak LP, Ramkumar V. Ototoxicity. Kidney Int. 2007;72(8):931.
89. Schacht J. Aminoglycoside ototoxicity: prevention in sight? Otolaryngol Head Neck Surg. 1998;118:674.
90. Segal JA, Harris BD, Kustova Y, Basile A, Skolnick
  P. Aminoglycoside neurotoxicity involves NMDA receptor activation. Brain Res. 1999;815:270.
91. Casano RA, Johnson DF, Bykhovskaya Y, et al. Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications. Am J Otolaryngol. 1999;20:151.
92. Elstner M, Schmidt C, Zingler VC, et al. Mitochondrial 12S rRNA susceptibility mutations in aminoglycoside-associated and idiopathic bilat- eral vestibulopathy. Biochem Biophys Res Commun. 2008;377(2):379.
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94. Humes HD. Insights into ototoxicity. Analogies to nephrotoxicity. Ann NY Acad Sci. 1999;884:15.
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96. Tnzel IJ.Comparison of adverse reactions of bumetanide and furosemide. J Clin Pharmacol. 1981;21:615.
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98. Jung TT, Rhee CK, Lee CS, et al. Ototoxicity of sali- cylate, nonsteroidal anti-inﬂammatory drugs and qui- nine. Otolaryngol Clin North Am. 1993;26:791.
99. Myers E, Bernstein J, Fostiropolous G. Salicylate ototoxicity: a clinical study. N Engl J Med. 1965; 273:587.
100. MacDonald MR, Harrison RV, Wake M, et al. Ototoxicity of carboplatin: comparing animal and clinical models at the Hospital for Sick Children. J Otolaryngol. 1994;23:151.
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102. Schaefer SD, Post JD, Close LG, Wright CG. Ototoxicity of low- and moderate-dose cisplatinum. Cancer. 1985;56:1934.
103. Myers SE, Blakely BW, Schwan S. Is cis-platinum vestibulotoxic? Otolaryngol Head Neck Surg. 1993;108:322.
104. Ishiyama G, Ishiyama A, Kerber K, Baloh RW. Gentamicin ototoxicity: clinical features and the effect on the human vestibulo-ocular reﬂex. Acta Otolaryngol. 2006;126(10):1057.
105. Weber KP, Aw ST, Todd MJ, McGarvie LA, Curthoys IS, Halmagyi GM. Horizontal head impulse test detects gentamicin vestibulotoxicity. Neurology. 2009;72(16):1417.
106. Conlon BJ, Aran JM, Erre JP, Smith SW. Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid. Hear Res. 1999;128:40.
107. Sha SH, Schacht J. Are aminoglycoside antibiotics excitotoxic? Neuroreport. 1998;9:3893.
108. Chen Y, Huang W-G, Zha D-J, et al. Aspirin attenu- ates gentamicin ototoxicity: from laboratory to the clinic. Hearing Res. 2007;226:178.
109. Sha SH, Qiu JH, Schacht J. Aspirin to prevent gentamicin-induced hearing loss. N Engl J Med. 2006;354:1856.
110. Feldman L, Efrati S, Eviatar E, et al. Gentamicin- induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int. 2007;72(3):359.
111. Mameli O, Caria MA, Melis F, et al. Neurotoxic effect of lead at low concentrations. Brain Res Bull. 2001;55(2):269.
112. Gozdzik-Zolnierkiewicz T, Moszynki B. VIIIth nerve in experimental lead poisoning. Acta Otolaryngol. 1969;68:85.
113. Wilpizeski D. Effects of lead on the vestibular system: preliminary ﬁndings. Laryngoscope. 1974;84:1585.
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115. Nosaka Y, Setoguti A, Suko H. Auditory and vestibu- lar disturbances in Minamata disease (in Japanese). Kumamoto Med J. 1958;32:1465.
116. Moller-Madsen B. Localization of mercury in CNS of the rat. III. Oral administration of methylmer- curic chloride (CH3HgCl). Fundam Appl Toxicol. 1991;16:172.
117. Anniko M, Sarkady L. Morphological changes of labyrinthine blood vessels following metal poisoning. Acta Otolaryngol Suppl (Stockh). 1977;330:15.
118. Young YH, Chuu JJ, Liu SH, Lin-Shiau SY. Neurotoxic mechanism of cinnabar and mercuric sulﬁde on the vestibulo-ocular reﬂex system of guinea pigs. Toxicol Sci. 2002;67(2):256.
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120. Takeuchi T, Eto K, Kinjo Y, Tokunaga H. Human brain disturbance by methyhnercury poisoning, focusing on the long-term effect on brain weight. Neurotoxicology. 1996;17:187.
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122. Herpin G, Gargouri I, Gauchard GC, et al. Effect of chronic and subchronic organic solvents exposure on balance control of workers in plant manufactur- ing adhesive materials. Neurotox Res. 2009;15(2): 179.
123. Gyntelberg F, Vesterhauge S, Fog P, Isager H, Zillstorff K. Acquired tolerance to organic solvents and results of vestibular testing. Am J Ind Med. 1986;9:363.
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125. MorataTC, Nylen P, Johnson AC, Dunn DE. Auditory and vestibular functions after a single or combined exposure to toluene: a review. Arch Toxicol. 1995;69:431.
126. Niklasson M, Arlinger S, Ledin T, et al. Audio- logical disturbances caused by long-term exposure to industrial solvents. Relation to the diagnosis of toxic encephalopathy. Scand Audiol. 1998;27:131.

Chapter 18 ‌‌

Developmental and Genetic Disorders

THE INNER EAR ‌

Acquired Disorders Hereditary Disorders Pathology

Diagnosis Management

DISORDERS OF THE CRANIAL VERTEBRAL JUNCTION

Basilar Impression Bony Fusions

Atlantoaxial Dislocation Chiari Malformation

Syringobulbia Diagnosis Management

INHERITED SPINOCEREBELLAR ATAXIA SYNDROMES

Autosomal Dominant Spinocerebellar Ataxia Syndromes

Autosomal Recessive Spinocerebellar Ataxia Syndromes

Episodic Ataxia and Vertigo Syndromes Diagnosis

Management

THE INNER EAR

Permanent hearing loss occurs in about 1 to 3 out of every 1000 live births.1–3 In high-risk neonates, the prevalence is much higher, in the range of 1 in 50 live births. Although <10% of infants are treated in neonatal intensive care units, these newborns account for more than half of all cases of early-onset sensorineural hearing loss.1,4

Congenital deafness is usually recognized during infancy, but a congenital vestibular impairment is not, because the manifestations are more subtle. Children with a vestibular impairment typically learn to use other sensory information to compensate for vestibular loss and thus appear to be asymptomatic and often testnormalonstandardassessments. Congenital deafness has therefore received extensive study, whereas congenital vestibular loss has been relatively neglected. Given the large

number of children with congenital hearing loss, it seems likely that a large number of children also have congenital vestibular loss.

A consequence of congenital vestibular loss is that babies have difﬁculty learning to crawl and walk. Walking is often delayed to 15 to 18 months or later and the children are often con- sidered clumsy. They typically will participate in all children’s games and activities, although they will not perform well in tasks that require quick turns or excellent balance (for example, gymnastics). As they get older and develop good muscle control, their walking and running appear normal as long as they have good vision. However, if they begin to lose vision, the bal- ance problems become more and more notice- able, even becoming profound if a visual loss becomes severe.

Congenital disorders of the inner ear can be divided into two major categories: acquired and hereditary. Acquired disorders result from

383

development of a normal fertilized egg, and hereditary disorders result from abnormal genes or epigenetic factors.5 A large number of studies have looked at the relative frequency of hereditary and acquired hearing loss and most have found that each category accounts for about 30% to 40% of cases, with the remaining 20% to 40% of cases being due to unknown cause. It must be kept in mind, however, that these studies were all conducted before the recent rapid advances in the identiﬁcation of genetic causes of hearing loss, so no doubt future studies will ﬁnd a higher frequency of hereditary hearing loss.

Acquired Disorders

Currently, most cases of acquired severe hearing loss are associated with the perinatal complex of premature delivery, anoxia, and hyperbilirubinemia.1,4,6 A gestation <32 weeks, birth weight <1500 g, prolonged mechanical ventilation for >10 days, and an Apgar score after 5 or 10 min  6 are all signiﬁcant risk fac- tors for developing permanent hearing loss. Hyperbilirubinemia at a level exceeding the indication for exchange transfusion is another major risk factor. Also, premature infants often receive potential ototoxic medications includ- ing but not limited to aminoglycosides.6

Pre-, peri-, or postnatal infections with toxo- plasmosis, herpes, cytomegalovirus, and rubella can all lead to permanent inner ear damage with hearing loss and vestibular loss. The inci- dence of congenital rubella and associated inner ear damage has markedly decreased since vaccines have been widely used.7–9 Infants born to mothers who acquire rubella in the ﬁrst trimester of pregnancy may have multiple con- genital defects, including cataracts, patent duc- tus arteriosus, microcephaly, dental defects, and generally impaired growth and develop- ment. Hearing loss is more common than ves- tibular loss (apparently because of the longer critical developmental period). Although less common, the infant’s fully developed inner ear can be damaged by a maternal rubella infec- tion in the last two trimesters. Congenital cyto- megalovirus (CMV) infections are the leading cause of acquired hearing loss in developed countries. In the United States at least 1000 infants/year have hearing loss at birth due to CMV and another 3000–4000 have hearing loss

in childhood.10,11 Most infants with CMV- related hearing loss have no other symptoms or signs of CMV infection. Meningitis is another common cause of unilateral or bilateral auditory and vestibular loss in the postnatal period.4,6

The fetal alcohol syndrome is commonly associated with developmental abnormalities of the inner ear and other craniofacial struc- tures.12,13 Hearing loss, which can be traced to conductive, sensorineural, and central patholo- gies, contributes to delayed speech and language development. Postural imbalance results form both vestibular and cerebellar dysfunction.

Hereditary Disorders

INHERITED SYNDROMES

Although it is beyond the scope of this mono- graph to review all of the hereditary syndromes that may produce sensorineural deafness and vestibular loss, a few common disorders deserve mention (Table 18–1). About 3% to 6% of con- genitally deaf children have Usher’s syndrome, which is the leading cause of the combination of deafness and blindness.14,15 Usher’s syndrome was initially divided into three types on the basis of clinical features, with type 1 showing the most severe early-onset auditory and vestibular loss. Patients with type 2 Usher’s syndrome are born hard of hearing with a sloping sensorineural hearing loss, but vestibular function is normal. Type 3 is characterized by later-onset progres- sive hearing loss with some moderate loss of vestibular function. Visual loss due to retinitis pigmentosa begins in infancy or early childhood with type 1 but can be delayed until the teenage years with types 2 and 3. To date, seven differ- ent genetic loci have been linked to families with the clinical syndrome of Usher’s type 1 while only a single genetic locus has been linked to types 2 and 3 (for review see reference 16).

The protein products of the genes associated with all three Usher types are critical for devel- opment and maintenance of the inner ear ste- reocilia and kinocilia.16 Usher type I proteins cadherin 23 and protocadherin 15 are struc- tural components of the tip links (see Fig. 2-12 in Chapter 2), while Usher type II proteins are key components of the ankle link molecular complex. The actin-based motor protein myo- sin VIIA (Usher syndrome type 1B) is probably

Table 18–1 Genetic Syndromes with Audiovestibular Loss

Syndrome Mode of Inheritance

Unique Clinical Features Gene(s)

(Chromosome)

Gene Product

Usher 1B Recessive Retinitis pigmentosa MYO7A (11q) Myosin VIIa

Waardenberg type 1

Dominant White forelock, high nasal

root, hyperplastic eye brows, lateral displacement of medial canthi, heterochromia iridis

PAX3 (2q) Developmental protein

Jervell-Lange- Nielson (Long Q-T syndrome)

Pendred (enlarged vestibular aqueduct)

Dominant Cardiac arrhythmias KCNE1 (21q) K+ channel

Recessive Thyroid goiter PDS (7q) Pendrin

Alport’s X-linked Interstitial nephritis COL4A5 (Xq) Collagen Dominant COL4A4 (2q)

Dominant COL4A3 (2q)

the general transporter of the Usher proteins to their intended destination in the stereocilia. In the retina, Usher proteins have been local- ized to the cilia that connect the metabolically active inner segment to the photosensitive outer segment of the photoreceptor cell.17

The Dutch ophthalmologist Waardenberg described a syndrome characterized by con- genital hearing loss, white forelock (i.e., white hair that falls on the forehead), unusual eye color, and dystopia canthorum.18,19 The syn- drome has subsequently been expanded to include four subtypes, with type 1 representing Waardenburg’s initial families. With this syn- drome, vestibular function is usually impaired bilaterally and computed tomography (CT) studies of the temporal bone may reveal bony abnormalities of the inner ear. The gene for Waardenburg’s syndrome type 1 and type 3 is PAX-3, one of several genes that are important for controlling development of the face and inner ear. Other Waardenberg genes include MITF and SNA12 (type 2); and EDNRB, EDN, and SOX10 (type 4).19

The Jervell and Lange-Nielsen syndrome (also known as the long Q-T syndrome) is characterized by recessive congenital audiove- stibular loss and cardiac defects. The genes for this syndrome (KCNQ1 and KCNE1) code for potassium channels that allow potassium accumulating in the marginal cells to ﬂow back into the endolymph, maintaining the high

potassium concentration in the endolymph required for endocochlear potentials (see Chapter 2).20–22 This is an important syndrome to recognize since children are at risk for sud- den infant death syndrome (from arrhythmias). Pendred syndrome is an autosomal recessive disorder characterized by the combination of congenital deafness and goiter (usually devel- oping in early puberty).23 It constitutes about 5% of all cases of childhood deafness. The inner ear is often malformed with a “Mondini- like” malformation, including an abnormal cochlea and an enlarged internal auditory canal and vestibular aqueduct. The degree of thyroid dysfunction is variable. The gene for Pendred’s syndrome, SLC26A4, codes for a chloride- iodide transporter (pendrin) critical for both inner ear and thyroid function.24 Mutations in SLC26A4 can also lead to a nonsyndromic autosomal recessive hearing loss associated with an enlarged vestibular aqueduct (see later

discussion).25,26

Alport’s syndrome has a combination of kid- ney and inner ear involvement.19,27 Hereditary nephritis (previously known as Bright’s disease) can have onset from childhood into adulthood and is the reason for about 2% of kidney trans- plants in this country. A bilateral progressive sensorineural hearing loss developing after the ﬁrst decade is usually mild to moderate, although in rare patients the loss can be profound. Decreased vestibular responses have

also been identiﬁed in some patients.27 Mutations responsible for Alport’s syndrome have been found in three different collagen genes, the most common being inherited in an X-linked fashion (see Table 18–1).19,28

NONSYNDROMIC AUDIOVESTIBULAR LOSS

Most childhood deafness occurs in isolation without any other organ involvement and, as noted earlier, most of these cases are thought to be inherited.19,29 Of those with inherited hearing loss, the great majority are inherited in an autosomal recessive fashion. The number of genes associated with nonsyndromic inherited hearing loss is expanding at a rapid rate (Table 18–2). To date, there are more than 60 genetic loci linked to inherited hearing loss in different families. Many of the affected genes have already been identiﬁed and the rest will no doubt be identiﬁed within the next few years.30 Interestingly, different mutations in the same gene can lead to well-described syndromes or to nonsyndromic hearing loss with either a recessive or dominant pattern of inheritance (compare Tables 18–1 and 18–2). Correlation between the type of mutation and clinical

expression is just beginning to be investigated. As a general rule recessively inherited deafness is prelingual (e.g., present prior to language development) while dominantly inherited deaf- ness is postlingual (e.g, develops after language development). Vestibular loss occurs with many mutations, but most have not been ade- quately evaluated. A better understanding of how mutations in these genes cause audioves- tibular loss will lead not only to improved diag- nostic tests but also to improved understanding of pathophysiology and ultimately to the devel- opment of more effective treatments.

Recessively Inherited Hearing Loss

DFNB1 accounts for about two-thirds of Caucasians with recessively inherited hearing loss.31 It was initially linked to the long arm of chromosome 13 in several large families. The causative gene GJB2 codes for con- nexin-26, a component of a large family of pro- teins involved in gap junctions that are critical for transport of ions between cells in the inner ear.32,33 A frame-shift mutation in GJB2 (35delG) was found in most patients with DFNB1. This mutation has a carrier frequency of approximately 1 in 25 people in the

Table 18–2 Genes Associated with Nonsyndromic Hearing Loss

Disorder	Gene (Chromosome)	Protein	Location	Vestibular Lossa
Dominant
DFNA1	Diaphanous (5q)	Diaphanous protein	Hair cells	No
DFNA2	KCNQ4 (5q)	K+ channel	Hair cells	No
DFNA3	GJB2 (13q)	Connexin 26	Gap junctions	No
DFNA8/12	TECTA (11q)	Tectorin	Tectorial membrane	No
DFNA9	COCH (14q)	Secreted protein	Extracellular matrix	Yes
DFNA11	MYO7A (11q)	Myosin VIIa	Hair cells	Yes
DFNA15	POU4F3 (5q)	Transcription factor	Inner ear	Yes
Recessive
DFNB1	GJB2 (13q)	Connexin 26	Gap junctions	No
DFNB2	MYO7A (11q)	Myosin VIIa	Hair cells	Yes
DFNB3	MYO15 (17p)	Myosin XV	Hair cells	No
DFNB4	PDS (7q)	Pendrin	Inner ear	Yes
DFNB21	TECTA (11q)	Tectorin	Tectorial membrane	No
X-linked
DFN3	POV3F4 (Xq)	Transcription factor	Inner ear	Yes

aBased on human or animal studies.

Source: Data from www.boystown.org/hhirr.

Mediterranean area and causes deafness in at least 1 in 2500 newborns in that area.34 Of 52 sequential probands with congenital sen- sorineural hearing loss referred for genetic analysis in the Midwest of the United States,

22 (42%) were found to have mutations in GJB2. The 35delG mutation was found in 29 of the 41 mutant alleles.37 Analysis of 560 controls for the carrier rate was determined to be 3%.

A wide range of auditory phenotypes has been associated with recessively inherited mutations in GJB2. In most, the deafness is congenital and nonprogressive. The typical audiogram is ﬂat with a 50 to 60 dB loss. However, the hearing loss can be progressive and asymmetric with a sloping downward pat- tern.33 So far, only a few patients with the 35delG mutation in GJB2 have been tested for vestibular function and no abnormalities have been found.

Another recessively inherited hearing loss syndrome deserves comment because its com- bination of auditory and vestibular symptoms can mimic acquired disorders such as Meniere’s syndrome and perilymph ﬁstula. As noted ear- lier, mutations in the SLC26A4 can result in Pendred’s syndrome, characterized by a com- bination of thyroid and inner ear dysfunction. Other mutations in the same gene can result in just audiovestibular symptoms associated with an enlarged vestibular aqueduct on imaging.25,35 The clinical picture is that of a childhood-onset bilateral sensorineural hearing loss that ﬂuctu- ates in severity, with episodic worsening being triggered by head trauma or by coughing and sneezing. Vertigo spells can also be triggered by the same factors and there can be a gradual progressive deterioration in both auditory and vestibular function. The vertigo and vestibular dysfunction can be delayed into adulthood, even though the hearing loss was present since childhood. Most of the mutations causing this syndrome have been missense mutations, although deletions and insertions with frame shifts have also been found.

Dominantly Inherited Hearing Loss

Although less common than recessively inherited hearing loss, dominantly inherited hearing loss is more easy to recognize because multiple generations are typically involved.19,29

Depending on the type of mutation, several genes can produce either a recessive or domi- nant disorder (for example, GJB2, MYO7A, and tectorin) (Table 18–2). As a rule, the domi- nantly inherited sensorineural hearing loss dis- orders have a later onset (e.g., postlingual) and are less severe than the recessively inherited disorders. Some of them may even present later in life and be part of what is generally con- sidered presbycusis.

DFNA9 is of particular clinical interest because of the late onset of progressive bilat- eral auditory and vestibular loss.38 Hearing loss is typically noted in the ﬁfth decade with an annual progression of about 3 dB eventually leading to profound bilateral hearing loss. There is a similar progression in vestibular loss, with a complete loss occurring in most patients by the sixth decade. Some patients will show ﬂuctuating hearing loss and episodic vertigo suggestive of Meniere’s syndrome.39 A low- frequency hearing loss pattern can also be rem- iniscent of Meniere’s syndrome. Vestibular involvement is common although often clini- cally silent.36

The gene for DFNA9, COCH, located on 14q codes for a protein that is secreted into the extracellular matrix of the inner ear.40 The mechanism by which mutations in this gene lead to the delayed onset of progressive audio- vestibular loss is still unknown. Postmortem studies of temporal bones from patients with DFNA9 showed an acidophilic mucopolysac- charide-containing ground substance in the cochleas, macules, and cristae as well as some degeneration of vestibular and cochlear sensorineural elements.37,41 These deposits occurred in sites similar to those where COCH gene expression was seen in the normal inner ear.

Maternally Inherited Mitochondrial Disorders

Each mitochondrion contains 2 to 10 mito- chondrial chromosomes, so each cell contains thousands of mitochondrial chromosomes. Each of these mitochondrial DNA molecules is double stranded and forms a closed circle, and replication and transcription occur within the mitochondrion. Mitochondrial DNA encodes 13 messenger RNA genes, 2 ribosomal

RNA genes, and 22 organ-speciﬁc transfer RNA genes. The 13 messenger RNAs are translated on mitochondrion-speciﬁc ribo- somes with a mitochondrion-speciﬁc genetic code into 13 proteins. These mitochondrial- generated proteins interact with about 60 nuclear encoded proteins to form the ﬁve enzyme complexes required for oxidative phosphorylation. Mutations in mitochondrial DNA lead to both syndromic and nonsyndro- mic deafness.19,42 Hearing loss with mitochon- drial DNA mutations is typically delayed into adulthood, and there is often a great deal of variability in the degree of hearing loss among different family members. The charac- teristic maternal transmission suggests the pos- sibility of a mitochondrial DNA mutation. An A-to-G transition mutation at nucleotide 3243 in the mitochondrial gene for the leucine transfer RNA can produce a range of clinical syndromes, including mitochondrial encepha- lomyelopathy with lactic acidosis and stroke- like episodes (MELAS) and a combination of diabetes mellitus and hearing loss.43,44 This mutation was found in 2% to 6% of diabetic patients in Japan and in 3 out of 5 patients with diabetes and deafness.45 Twenty-seven of 44 patients with diabetes and the nucleotide 3243 mutation also had hearing loss. None of these cases had the other typical neurologic features of MELAS. In 37 adult patients identiﬁed with 3243A>G in Finland, ﬁrst clini- cal manifestations appearing in childhood included sensorineural hearing loss, delayed maturation, migraine, learning difﬁculties, and exercise intolerance.46 A homoplasmic mutation at nucleotide 1555 in the mitochon- drial 12S RNA gene can produce a nonsyndro- mic deafness and an increased susceptibility to aminoglycoside-induced deafness in different families.47 Investigation of these families showed that mitochondrial mutations might lead to disease only in the presence of a speciﬁc nuclear genotype or some environ- mental factor. Mitochondrial DNA mutations presumably lead to hearing loss by interfering with the high energy requirements of the inner ear. Interestingly, although the 12S RNA gene mutations result in increased susceptibility to aminoglycoside-induce hear- ing loss, vestibular loss does not occur (see Chapter 17).

Inherited Vestibular Loss with Normal Hearing

Some patients presenting with a bilateral vestib- ular loss do not have hearing loss, and the clinical picture does not indicate a structural lesion, immune mediated disorder, or other etiology. In these presentations the most likely cause is an inherited vestibulopathy. In contrast to the many genetic causes of hearing loss, only a few familial bilateral vestibulopathy families have been described.48–50 As mentioned earlier, this dispar- ity is likely explained by difﬁculty in recognizing the symptoms and signs of a bilateral vestibul- opathy and because quantitative rotational ves- tibular function testing is not widely available. In addition, many patients with a bilateral vestibul- opathy may not present to a physician if they have achieved an acceptable level of compensa- tion or substitution. Patients with inherited bilat- eral vestibulopathy typically have recurrent attacks of isolated vertigo and a high prevalence of migraine headaches.48 Age of onset ranges from the ﬁrst to sixth decade. Vertigo attacks are often brief in duration (seconds to minutes). Progression of peripheral vestibular function loss will eventually cause imbalance and oscillopsia, typically by the ﬁfth decade. The bedside head- thrust test may show bilateral corrective saccades when vestibulopathy is severe enough; otherwise the rotational chair test is used to identify these patients. As the vestibulopathy becomes more severe, attacks of vertigo become less frequent and eventually cease. Linkage analysis performed in four families with familial bilateral vestibulop- athy maps to a chromosomal locus on 6q.49 This region does not overlap any known autosomal- dominant deafness or migraine syndromes. One additional familial bilateral vestibulopathy family did not link to the region on chromosome 6, thus supporting genetic heterogeneity. A candidate gene, OPRM1, in the region of interest on chro- mosome 6 was sequenced in probands, but no mutations were found.49 A survey of gene expres- sion within the vestibular labyrinth would enhance the ability to identify genetic causes of familial bilateral vestibulopathy.

Pathology

The ﬁrst pathologic study of an inner ear con- genital malformation was described by Mondini

Figure 18–1. Computed tomography scan of the temporal bones showing a Mondini malformation on the right side. Only the basal turn of the cochlea is fully developed (arrow). Cochlea on the left is normal.

in 1791. The Mondini malformation consists of subtotal development of the osseous and membranous labyrinth with only the basal turn of the cochlea being completely formed (Fig. 18–1).51,52 The endolymphatic duct sys- tem is dilated and the vestibular labyrinth is underdeveloped. This deformity occurs with many different syndromes, both hereditary and acquired, and is invariably associated with some (and often complete) loss of auditory and ves- tibular function. Cochleosaccular dysgenesis initially described by Scheibe consists of dys- plasia of the pars inferior (cochlea and saccule) with a fully developed bony labyrinth and normal pars superior (semicircular canals and utricle).53 The Scheibe deformity has classically been associated with congenital rubella, accounting for the relative sparing of vestibular function in many of these children. A rare deformity characterized by complete failure of development of the inner ear (Michel’s defor- mity) is associated total loss of auditory and vestibular function. This deformity has been found in several patients with thalidomide anomalies of the ear.54

Diagnosis

As noted earlier, although inherited loss of auditory and/or vestibular function may be part of a well-described multiorgan syndrome, most cases occur in isolation with an autosomal

recessive mode of inheritance. Even with the well-deﬁned syndromes, variability in gene penetrance can complicate the clinical picture. For example, with Waardenburg’s syndrome, penetrance for deafness is only 20%. Thus, although this dominant disorder is passed to 50%, only 20% of the 50% will be deaf. For nonsyndromic audiovestibular loss, allelism and modiﬁer genes are important for pheno- type expression.55 In the initial assessment of any patient with early-onset hearing loss, one should obtain a detailed family history and search for other family members with possible hearing loss, vestibular loss, or other features characteristic of the syndrome.56

LABORATORY TESTS

Identiﬁcation of hearing loss or vestibular loss in an infant requires objective measurements, as behavioral testing is usually impractical. Brainstem auditory-evoked responses (BAERs) reﬂect the electrical activity of the auditory pathways in the brain stem and therefore pro- vide an objective measure of whether the end organ and peripheral nerve generate signals to transmit through the brainstem pathways.57 One must keep in mind, however, that the presence of BAER does not mean that the infant is able to discriminate sounds. Measurement of otoacoustic emissions pro- vides an objective measurement of outer hair cell function. Vestibular evoked myogenic

potentials (VEMPs) provide a rapid objective measure of vestibular function in infants.58 Rotational testing can be performed on infants by rotating the child on the mother’s lap while eye movements are recorded with electro- or videonystagmography. Caloric testing is more difﬁcult to perform but also can be obtained in most infants.58‌‌

Most genetic disorders of the inner ear do not affect the otic capsule and therefore the inner ear appears normal both on high-resolu- tion CT scans and on magnetic resonance imag- ing (MRI). Malformations are readily identiﬁed both with CT and MR scans of the temporal bone.59 An enlarged vestibular aqueduct in a patient with auditory and vestibular symptoms suggests the likelihood of a mutation in SLC26A3. In patients with fetal alcohol syn- drome, MRI will often show abnormal develop- ment of the cerebellar vermis (lobules I–V).60

GENETIC TESTING

At the present time, the only genetic test for congenital hearing loss that is widely available is for the 35delG mutation in GJB2. Since the carrier rate for this recessive deafness-causing mutation is approximately 3%, screening for the mutation could lead to an early diagnosis in a large percentage of patients with recessively inherited deafness. None of the other muta- tions in GJB2 or in any of the other genes associated with either recessively or dominantly inherited deafness occur with a frequency rate high enough to warrant routine screening. However, speciﬁc genes can be selected for based on the following: (1) a characteristic clinical syndrome (e.g., Usher syndrome type IB, MYO7A), (2) recognizable imaging features (e.g., enlarged vestibular aquaduct, SLC26A3); (3) recognizable audioproﬁle (e.g., DFNA6, WFS1); or (4) prominent vestibular symptoms (e.g., DFNA9, COCH).30 In the future, with rapidly developing technology, “gene chips” will be available to screen a large number of mutations in several genes at the same time.

Management

Congenital hearing loss is obviously important to identify as early as possible because of the rami- ﬁcations regarding early language development

and learning abilities. Congenital vestibular loss might explain delayed developmental milestones and early problems with coordination. It is also critical to identify such patients since they need to be counseled about the dangers of drowning when diving into deep water. Infants with sib- lings or parents with known hereditary deafness should be screened for hearing loss. Genetic counseling is an important part of management in these families. Many but not all are candidates for cochlear implants.61

DISORDERS OF THE CRANIAL VERTEBRAL JUNCTION

Cranial vertebral junction disorders are often congenital disorders and many have familial patterns of inheritance. Patients with disorders of the cranial vertebral junction present with a range of brainstem and lower cranial nerve symptoms, including tinnitus, vertigo, hearing loss, pharyngeal dysfunction, hoarseness, or even airway obstruction. The basic pathophysi- ologic mechanism for these symptoms is com- pression of the nervous system at the upper spinal cord and medulla. The rostrocaudal extent of the compression is variable, and the impingement can be ventral, dorsal, or (rarely) both. A second, less common, cause of symp- toms is vascular insufﬁciency due to angulation, stretching, or extrinsic compression of the anterior spinal or vertebral arteries.

Basilar Impression

Basilar impression is an upward indentation or invagination of the ridged cervical spine into the normally convex skull base.62 The odontoid projects intracranially to compress the ventral aspect of the medulla: the cerebellum is compressed posteriorly by the ﬁrst and second cervical vertebrae. Disorders known to cause basilar impression include Paget’s disease, rheumatoid arthritis, osteomalacia, osteogenesis imperfecta, cretin- ism, and rickets.63 The term platybasia has been used synonymously with basilar impres- sion by some authors. Technically, it is not a measure of basilar impression and although the two often coexist, platybasia by itself causes no symptoms.

Bony Fusions

Assimilation of the atlas (also called occipital- ization of the atlas) is a bony union between the ﬁrst cervical vertebra and the skull.64 The amount of union varies, but motion between the two structures does not occur. As a result, the odontoid impinges on the effective anterior-posterior diameter of the foramen. Frequently, there is associated fusion of the axis to the third cervical vertebra. Many differ- ent varieties of cervicovertebral fusion have been reported. Klippel and Feil initially described a patient with only four cervical ver- tebrae that were fused into a single column of bone. These anatomic features were associated with a clinical triad of short neck, low hair line, and limitation of neck movements. Although partial coalescence of two or more cervical ver- tebrae occurs in many patients, few develop the syndrome originally described by Klippel and Feil. Probably fusion of cervical vertebrae should be called congenital cervical synostosis and the term Klippel-Feil should be used to describe only typical clinical syndromes associ- ated with either complete fusion of the cervical spine or reduction in the number of cervical vertebrae.65 Most cases of Klippel-Feil syn- drome are sporadic, but both dominant and recessive inheritance has been described. Recently mutations in bone morphogenetic protein 13 (BMP13) have been associated with numerous skeletal and developmental defects, including spinal fusion.66 Associated develop- mental anomalies such as split cervical spinal cord and cleft palate are common.67 Hearing loss is common.68 The temporal bone of one such patient showed a vestigial inner ear hav- ing a rudimentary cystic cavity for a cochlea and only one semicircular canal incompletely formed.69 The inner ear abnormalities with Klippel-Feil syndrome may be unilateral or bilateral and may be evident on high-resolution CT scans of the temporal bone.

Atlantoaxial Dislocation

During ﬂexion and extension of the neck, con- genital fusion of the occiput to the atlas increases the strain on the structures that nor- mally restrict the motion of the atlas on the axis, especially if there is fusion of other cervi- cal vertebrae as well.70 The transverse ligament

that normally secures the odontoid against the anterior aspect of the arch of the atlas may weaken because of this repeated strain, and the resultant laxity allows the odontoid to move posterior into the lumen of the foramen mag- num. Flexion or extension of the neck may then produce symptoms, depending on whether the predominant neural compression is anterior from the odontoid or posterior from the poste- rior arch of C1. When the atlas or congenital cervical fusion has been assimilated, the transverse odontoid ligament is sometimes hypoplastic, which makes laxity and atlantoaxial dislocation even more likely. Atlantoaxial insta- bility is also known to be associated with a number of congenital and acquired disease processes. It occurs in 18% to 30% of individu- als with Down’s syndrome and is frequently seen with spondyloepiphyseal dysplasia, Hurler’s syndrome, Morquio’s syndrome, and in achondroplastic dwarfs.70,71 Of patients with rheumatoid arthritis, 25% have atlantoaxial instability secondary to destruction of normal stabilizing mechanisms by inﬂammatory rheu- matoid tissue in the synovial membrane.72 Similarly, ligamentous laxity can result from inﬂammatory conditions affecting retropharyn- geal soft tissue or cervical bony structures, such as tuberculosis (or other bacterial) osteitis, retropharyngeal abscess, or lymphadenitis.

Chiari Malformation

In 1895, Chiari described a congenital malfor- mation of the hindbrain in which the brain stem and cerebellum were elongated downward into the cervical canal. Most frequently, the defor- mity manifests itself in the ﬁrst few months of life and is associated with hydrocephalus and other nervous system malformations (Chiari type II malformation). Less frequent but more important to the neurotologist are those cases in which the onset of symptoms and signs is delayed until adult life (Chiari type I malforma- tion). These cases often present with subtle neurotologic symptoms and signs and are usu- ally not associated with other developmental defects.73–75 The most common neurologic symptom is slowly progressive unsteadiness of gait, which the patient frequently describes as dizziness. Vertigo (particularly positional vertigo), tinnitus, hearing loss, and recurrent facial paresis occur in a small percentage

of patients.75,76 Some patients have ﬂuctuating hearing loss and vertigo suggestive of Meniere’s syndrome.74 Abnormalities on the neurologic exam are generally required before considering low-lying cerebellar tonsils to be a pathological ﬁnding. On neurologic examination the patient is ataxic, suggesting midline cerebellar involve- ment. Pathologic nystagmus is nearly always present. Spontaneous and positional downbeat nystagmus are particularly common, but other forms of central spontaneous nystagmus and rebound nystagmus also occur. Oscillopsia is nearly always associated with the spontaneous nystagmus. Dysphagia, hoarseness, and dysar- thria result from stretching of the lower cranial nerves, and obstructive hydrocephalus results from occlusion of the basilar cisterns. Some patients experience episodes of dizziness or even syncope triggered by coughing or sneez- ing. The Chiari type 1 malformation is a devel- opmental disorder of para-axial mesoderm leading to underdevelopment of the posterior cranial fossa and overcrowding of the normally developed hindbrain.73 Although usually spo- radic, both autosomal dominant and recessive families have been described.

Syringobulbia

Syrinx formation in the medulla (syringobul- bia) damages any of the lower cranial nerve nuclei but most often involves the twelfth nuclei and the descending tract and nucleus of the ﬁfth nerve, producing atrophy and fascicu- lations of the tongue and loss of pain and tem- perature sensation on one or both sides of the face. Dysphonia and dysphagia are also preva- lent because of the damage to the ninth and tenth nuclei. As with Chiari malformation, pathologic nystagmus is a common ﬁnding in nearly all reported series, and occasionally it is the only abnormal neurologic sign.77 A pure torsional nystagmus either in the primary posi- tion or on lateral gaze is particularly character- istic of syringobulbia. Any adult presenting with oscillopsia and central spontaneous nys- tagmus should be suspected of having either syringobulbia or a Chiari type I malformation.

Diagnosis

Patients with congenital abnormalities of the craniovertebral junction often exhibit

associated morphologic abnormalities of the neck, such as low hairline, short neck, abnor- mal head position, limitation of motion, and painful torticollis. Accentuation of symptoms by coughing, straining, or change in neck posi- tion is common. Clinical manifestations of cervi- comedullary compression are usually relentless and severe, progressing over months to years. Occipital pain with radiation toward the vertex is a common presenting symptom. Other symp- toms can be related to brainstem and cranial nerve dysfunction from compression.

The diagnosis of basilar impression is con- ﬁrmed when lateral radiographs of the skull demonstrate that the tip of the odontoid either extends above Chamberlain’s line (a line drawn from the posterior edge of the hard palate to the posterior lip of the foramen magnum) or projects posterior to Wackenheim’s clivus– canal line.70 With assimilation of the atlas or atlantoaxial dislocation, the critical assessment is whether the abnormality is reducible and the direction of encroachment on the cervical medullary junction. High-resolution CT scan- ning is performed in the frontal and lateral pro- jections with the patient’s head in both neutral and extended positions (with the attending neurosurgeon supervising the procedure).78 Magnetic resonance imaging is the procedure of choice for assessing the degree of soft tissue compression and for identifying Chiari malfor- mations and syrinx formation.73,57 Midline saggital sections are ideal for identifying the level of the cerebellar tonsils (Fig. 18–2) and syrinx formation in the medulla and high cervical cord. Vertical descent of the brain due to a cerebrospinal (CSF) leak can mimic a Chiari malformation, but usually there is an associated dural enhancement on MRI after contrast.80

Management

A series of operations have been developed to correct bony deformities at the craniovertebral junction, to eliminate the cervical medullary compression, and to prevent its recurrence. They are designed to reduce the odontoid from its cranial position, to remove any bony liga- mentous or inﬂammatory soft tissue compres- sion of the cervicomedullary junction, and to ﬁx the skull to the cervicovertebral column in the reduced position when necessary. In patients with Chiari type I malformations,

Figure 18–2. Chiari type I malformation. Magnetic resonance image shows a Chiari type I malformation. Arrow points to the tip of the cerebellar tonsils.

suboccipital decompression of the foramen magnum region can stop the progression and occasionally lead to improvement in neurologic symptoms and signs.73,81,83 Special emphasis should be given to patients with rheumatoid arthritis because up to 25% of them have sig- niﬁcant cranial vertebral abnormalities. In a series of 45 patients surgically treated for cervi- cal medullary compression secondary to rheu- matoid arthritis and cranial settling, there were no operative deaths and no infections.83 All the patients improved to a functional class two grades above the preoperative level, and some improvement in cranial nerve function occurred in patients who had preoperative deﬁcits.‌

INHERITED SPINOCEREBELLAR ATAXIA SYNDROMES

Early classiﬁcations of the inherited spinocer- ebellar ataxias (SCAs) were based on a confus- ing array of eponyms and clinical–pathological terms (e.g., Marie ataxia, Holmes ataxia, olivo- pontocerebellar ataxia, parenchymal cerebellar ataxia, etc.). With the rapid advances in genetic analysis at the turn of the century, classiﬁca- tions based on phenotypic descriptions have been replaced with a classiﬁcation based on the genotype.84 The prevalence of inherited SCA in the general population has not been well studied, although it is probably no more than 1 to 5 per 100,000 in unselected populations. In some isolated populations, however, the preva- lence can be as high as 20 to 25 per 100,000.85

Auditory and vestibular symptoms and signs occur with several of the hereditary SCA syn- dromes. In addition, isolated families with

atypical ataxia syndromes associated with hear- ing loss and abnormal vestibular function have been reported.86–88 Clinically, however, cere- bellar ﬁndings usually overshadow the loss of vestibular function; patients present with ataxia and incoordination. In most, the symptoms are slowly progressive, although in some they are episodic. Head movement–induced oscillopsia and dizziness are common, usually because of the patient’s inability to suppress the vestibulo- ocular reﬂex with ﬁxation, but in some cases, also because of bilateral vestibular loss. Often, only after performing caloric or rotational test- ing is the loss of vestibular function identiﬁed. Vertigo is usually not present because the vestibular loss occurs gradually in a bilateral symmetrical fashion, but vertigo is a common feature of several of the episodic ataxia syn- dromes. Many types of pathological nystagmus are encountered, including gaze-evoked, cen- tral spontaneous (particularly upbeat and downbeat), rebound, and central paroxysmal positional. Bedside and laboratory assessment of eye movements can be helpful in identifying the phenotype prior to genetic testing (see later discussion).

Autosomal Dominant Spinocerebellar Ataxia Syndromes

About a third of the inherited SCA syndromes are inherited in an autosomal dominant fashion. Classiﬁcation of the autosomal domi- nant SCA syndromes has long been a source of confusion and controversy. Harding89 sepa- rated these disorders into types 1 through 3. The most common, type 1, manifested ataxia, pyramidal and extrapyramidal signs, and

Table 18–3 Mutations associated with some common Spinocerebellar Ataxias

Classiﬁcation Chromosomal Mutational Mechanisms Characteristic Features Location

SCA-1 6q CAG: nl 16–37,a abnl 39–81 Dysphagia, pyramidal signs,

vibratory loss

SCA-2 12q CAG: nl 15–32, abnl 34–64 Slow saccades, loss of reﬂexes,

dementia

SCA-3/MJD 14q CAG: nl 12–40, abnl 66–84 Pyramidal and extrapyramidal

signs, peripheral motorsensory neuropathy

SCA-5 11cent Coding mutations in beta-III

spectrin

Relatively benign course, pyramidal signs in early onset

SCA-6 19p CAG: nl 4–19, abnl 21–29 Predominant cerebellar signs SCA-7 3p CAG: nl 7–17, abnl 38–130 Retinal degeneration

SCA-8 13q CTG: nl < 50, abnl 80–250 Predominant cerebellar syndrome SCA-10 22q ATTCT: nl<280, abnl 850–4,500 Predominant cerebellar syndrome

with epilepsy

aThere are longer normal SCA-1 alleles, but they carry a CAT interruption. Number of repeats, nl-normal, abnl-abnormal

ophthalmoplegia. Type 2 was similar to type 1 but also included retinal degeneration, while type 3 was a relatively pure cerebellar syn- drome. This classiﬁcation has been shown to be genetically heterogeneous, composed of a vari- ety of distinct SCA subtypes (Table 18–3).67 To date, 28 autosomal dominant SCA syn- dromes have been linked to chromosomal loci, and 17 causative genes have been identiﬁed.90 Spinocerebellar ataxia types 1, 2, 3, and 6 are by far the most common of the SCA syndromes, accounting for more than half of all cases.91 Each of these disorders is caused by an expanded CAG triplet repeat in the open read- ing frame of the gene, leading to an expanded polyglutamine tract in the predicted protein.92,93 The size range of the repeat expansion for each is roughly similar, with less than about 30 repeats being asymptomatic and more than about 40 being symptomatic. The size of the repeat correlates with disease severity and age of onset. Repeat expansion constitutes the molecular basis of anticipation, which typically occurs with paternal transmission. With each generation, the disease tends to come on ear- lier and be more severe. Spinocerebellar ataxia type 6 is the lone exception to this rule, having a smaller stable repeat expansion, although disease severity is correlated with the length of the expansion.94

All of the SCA syndromes share the main clinical features of gait ataxia, dysarthria, dysphagia, dysmetria, and intention tremor due to involvement of the afferent and efferent cerebellar pathways.95 Involvement of other structures, including brain stem and spinal cord, basal ganglia, peripheral nerves, optic nerve and retina, and cerebrum, occurs in indi- vidual syndromes. Disorders of oculomotor control are common with all of the SCA syn- dromes, and the particular pattern can help deﬁne the phenotype (Table 18–4).96 The ves- tibular-ocular reﬂex gain is typically decreased in SCA-3, presumably because of involvement of brainstem vestibulo-ocular reﬂex pathways. Slowing of both voluntary and involuntary sac- cades is prominent with SCA-1, SCA-2, and SCA-7, so that even though the vestibulo- ocular reﬂex remains intact, vestibular nystag- mus may not be generated and vestibular test- ing results in a slow deviation of the eyes and pinning in an extreme lateral position because of the absence of fast components.

Autosomal Recessive Spinocerebellar Ataxia Syndromes

Friedreich’s ataxia (FA) is by far the most com- mon of the hereditary ataxias, accounting for

Table 18–4 Summary of Type and Degree of Horizontal Eye Movement Abnormalities with Different Spinocerebellar Ataxia Syndromes

	Saccade Velocity	Pursuit/OKN Gain	VOR Gain	VOR-Fix Gain
SCA-1	Moderate	Moderate	Normal	Moderate
SCA-2	Severe	Mild	Normal	Mild
SCA-3	Mild	Moderate	Moderate	Mild
SCA-6	Normal	Severe	Normal	Severe
SCA-7	Severe	Severe	Mild	Severe

OKN, optokinetic nystagmus; VOR, vestibular-ocular reﬂex; VOR-Fix, ﬁxation suppression of VOR.

Source: Adapted from Buttner et al.96

the majority of the recessively inherited ataxias.97–99 Its prevalence of about 2 per 100,000 equals nearly that of all of the domi- nant ataxia syndromes combined. It was ﬁrst described by Nicholas Friedreich in 1863.100 He emphasized the progressive ataxia, sensory loss, and muscle weakness often associated with scoliosis, foot deformity, and heart dis- ease. The currently accepted clinical criteria include (1) autosomal recessive inheritance,

onset before age 25 years, (3) progressive limb and gait ataxia, (4) distal loss of position and vibration sense, and (5) absent tendon reﬂexes in the legs. Cardiomyopathy, kyphosco- liosis, pes cavus, optic atrophy, hearing and vestibular loss, and diabetes mellitus occur in some patients. With the discovery of the gene for FA, it has become clear that the disease can show remarkable clinical variability, sometimes even within the same family.99,101 Age of onset, presence or absence of deep tendon reﬂexes, and presence or absence of associated features can all be variable according to the type of genetic defect.

Friedreich’s ataxia results from a large expan- sion of a GAA repeat in intron 1 of the gene frataxin.102,103 This gene has 5 exons spread over 40,000 base pairs encoding a 210 amino acid protein designated frataxin. Most patients have the expanded GAA repeat in both alleles, but some have an expanded GAA repeat in one allele and a point mutation in the other, and rare patients have point mutations in both alleles. Frataxin is a mitochondrial protein that is important in iron metabolism.104 Yeast organ- isms deﬁcient in the frataxin homologue accu- mulate iron in mitochondria and have increased sensitivity to oxidative stress. From this observation, it has been suggested that the

neurological degeneration seen with FA results from free-radical toxicity due to mitochondrial damage. Selective cell vulnerability may be due to the levels of respiratory activity (which is high in the brain and heart) and to levels of iron metabolism.

Both auditory and vestibular loss commonly occur with FA, particularly in the later stages of the disease.105,106 Two sisters with FA showed extensive degeneration of the neurons of the eighth nerve (both auditory and vestibular), with preservation of the peripheral receptor organs.107 These changes correlated with the clinical ﬁndings of progressive bilateral deaf- ness and caloric hypoexcitability for several years prior to death. Oculomotor testing typi- cally shows prominent saccade dysmetria and ocular ﬂutter superimposed on voluntary and involuntary eye movements.105,108

As with the other trinucleide repeat syn- dromes, larger expansions are correlated with earlier disease onset and more rapid progres- sion.103 The best correlation is seen with the size of the smaller allele, indicating that smaller expansions are consistent with some residual function. The frequencies of cardiomyopathy, ﬂexor plantar responses, and skeletal deformi- ties all increase with increasing GAA repeat number.103

Several FA-like syndromes can result from metabolic disorders that lead to vitamin E deﬁ- ciency. Mutations in the alpha-tocopherol transfer protein (-TTP) on chromosome 8q and mutations in the microsomal triglyceride transfer protein (MTP) on chromosome 4q result in vitamin E deﬁciency and a clinical syndrome similar to FA.99,109 These syndromes are important to recognize because they can be treated with vitamin E replacement.

Refsum’s syndrome is characterized by a combination of retinitis pigmentosa, bilateral sensorineural hearing loss, cerebellar ataxia, and peripheral neuropathy. Patients with Refsum’s disease have an elevated serum phy- tanic acid, the result of a defect in lipid alpha oxidase.110 The disorder typically begins in the ﬁrst decade, is slowly progressive, and like FA can be associated with cardiac conduction defects and cardiomyopathy. Refsum’s syn- drome results from missense mutations in the phytanoyl-CoA hydroxylase (PAHX) gene located on chromosome 10.111

Several recessively inherited ataxia syn- dromes are associated with oculomotor apraxia: ataxia telangectasia, ATM gene; ataxia with oculomotor apraxia I, APTX gene; ataxia with oculomotor apraxia II, SETX gene.112–114 Children with these disorders have impaired voluntary and reﬂexive saccades so that vestib- ular stimulation causes a slow deviation of the eyes without corrective fast components. Reﬁxations are made with head thrusts rather than saccades. How these genes that are pri- marily involved in DNA repair lead to ataxia and oculomotor apraxia is poorly understood.

Episodic Ataxia and Vertigo Syndromes

The episodic ataxias are a group of rare disor- ders characterized by attacks of generalized ataxia with normal or near-normal neurologic function in between.115,116 The attacks typically begin in early childhood or early adulthood. Although a large number of recessive and X-linked causes of episodic ataxia are known, most cases are autosomal dominant. The genes for several dominant forms of episodic ataxia have recently been discovered; this may pro- vide insight into the pathophysiology of other episodic vertigo and ataxia syndromes.116

EPISODIC ATAXIA TYPE 1

Episodic ataxia type 1 (EA-1) is characterized by brief episodes of ataxia (minutes) and interictal myokymia.117 The myokymia (muscle rippling) is typically most evident in the eyelids and ﬁngers. In some cases it can only be identi- ﬁed with electromyography. The gene for EA-1 is a voltage-gated potassium channel gene (KCNA1) located on chromosome 12q.118

A large variety of missense mutations in KCNA1 have been found in families with EA-1 with no mutation being predominant.

EPISODIC ATAXIA TYPE 2

Episodic ataxia type 2 (EA-2) is characterized by more prolonged episodes of ataxia (lasting hours) and interictal nystagmus.119 Often the episodes of ataxia are associated with vertigo and nausea and vomiting. The ataxia can be conﬁned to just the trunk or may involve the upper extremities as well. The interictal nys- tagmus can be gaze-evoked, rebound, or spon- taneous vertical (particularly downbeat). Some patients develop a slowly progressive ataxia later in life. The gene for EA-2 is a calcium channel gene, CACNA1A, located on chromo- some 19p.120 Missense mutations in CACNA1A typically lead to a variety of familial hemiplegic migraine, whereas nonsense mutations result in EA-2.

EPISODIC ATAXIA TYPES 3–7

At least ﬁve other autosomal dominant EA syn- dromes have been described in one or two families.116 Genetic analysis ruled out linkage to the EA1 and EA2 loci, and two additional genes have been identiﬁed: EA-5, CACNB4, another calcium channel gene and EA-6, SLC1A3, a glutamate transporter gene.121,122 All of the genes identiﬁed so far with autosomal dominant episodic ataxia code for ion channels or transporters. Similar genes are good candi- dates for other EA syndromes and for the more common episodic vertigo syndromes, including migrainous vertigo.

Diagnosis

The ﬁrst step in the diagnosis of one of the inherited SCA syndromes is to recognize the phenotype. This will deﬁne the diagnostic workup and the type of DNA testing.95,99 The clinical examination will indicate whether the phenotype is a pure cerebellar syndrome or whether there are combined brainstem, cerebellar, and spinal cord ﬁndings. Most patients with an inherited disorder will have a positive family history. It must be kept in mind, however, that a negative family history based on the patient’s report can be deceptive.

Often families are too small to be informative or critical members cannot be evaluated or have died early.

Neuroimaging studies, particularly MRI of the brain and upper cervical cord, can help conﬁrm which anatomical structures are involved. Of the common dominant SCA syndromes, SCA-1, -2, -3, and -7 show com- bined cerebellar and brainstem atrophy at least by the mid to late stages, whereas SCA-6 shows a selective cerebellar atrophy, which is most prominent in the vermis.123 With FA, the cerebellum is typically spared, but the spinal cord is atrophic. Cerebellar vermian atrophy is also seen with EA-2 (Fig. 18–3)124 but not with EA-1.

Speciﬁc DNA tests are now available for all of the trinucleotide repeat syndromes. The battery of tests can be ordered on any patient with a dominantly inherited SCA syndrome. The GAA expansion with FA should be consid- ered in just about any patient with a recessively inherited ataxia syndrome. Unfortunately at the present time, none of the missense muta- tions, either in the frataxin gene or in the epi- sodic ataxia genes, can be routinely ordered since no single dominant missense mutation has been identiﬁed. However, as in the case with the many missense mutations causing nonsyndromic hearing loss, “gene chips” should be available in the near future to screen for the large number of mutations that have been

identiﬁed. The genes can be sequenced, but this is expensive especially for a large gene such as CACNA1A.

Management

With a few exceptions, management of patients with inherited ataxia is symptomatic. Patients are encouraged to use a cane or walker to improve sensory input and to avoid falls. Regular physical therapy to maintain range of motion for all joints is critical to avoid painful contractures. A special diet low in long-chain fatty acids can be effective in controlling the progression of symptoms and signs in patients with Refsum’s syndrome.110 Acetazolamide (Diamox) is remarkably effective for relieving the episodic symptoms in patients with EA-2 and, to a lesser degree, in patients with EA-1.115 Acetazolamide is not very effective in patients with other EA syndromes. Acetazolamide pre- sumably works by altering the pH within the cerebellum, thus stabilizing the mutated ion channels. One typically begins with a low dos- age (125 mg/day) and then works up to an aver- age effective dosage of between 500 and 750 mg/day. Most patients will experience par- esthesias of the extremities after taking the drug, but these symptoms typically decrease over time. The main long-term side effect is the development of kidney stones, which may

Figure 18–3. Magnetic resonance image of brain in a patient with episodic ataxia type II (EA-2) showing atrophy of the cerebellar vermis. T1-weighted sagittal section.

markedly decrease if the patient regularly drinks citrus juices. Patients with SCA-6 who have episodic features may also respond to acetazolamide.125 It is unknown whether the long-term slowly progressive ataxia is affected by the regular use of acetazolamide. A thera- peutic trial of acetazolamide should be consid- ered in any patient with early-onset episodic

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PART 4 ‌

Symptomatic Treatment of Vertigo

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Chapter 19 ‌‌

Antiemetic and Antivertigo

Drugs

VESTIBULAR SUPPRESSANTS

How Do They Work? How to Use Them Indications Precautions

What to Tell the Patient

ANTIEMETIC DRUGS

How Do They Work? How to Use Them Precautions

What to Tell the Patient

SPECIFIC DRUGS

Scopolamine (Transderm Scop) Buclizine Hydrochloride (Bucladin-S)

Diphenhydramine Hydrochloride (Benadryl) Meclizine (Antivert, Bonine) Dimenhydrinate (Dramamine) Promethazine Hydrochloride (Phenergan) Betahistine (Serc)

Metoclopramide (Reglan)

Benzquinamide Hydrochloride (Emete-con) Trimethobenzamide Hydrochloride (Tigan) Diazepam (Valium)

Droperidol (Inapsine) Diphenidol (Vontrol) Prochlorperazine (Compazine) Dronabinol (Marinol)

Vertigo is an unpleasant sensation that is frequently accompanied by nausea and vomiting. These symptoms can result from a variety of diseases affecting the vestibular system (see Chapters 9–18). The best therapy is to elimi- nate vertigo with speciﬁc treatment of the underlying disease. However, in cases in which the disease is not readily treatable, when treat- ment must be continued for a long period before improvement occurs or when vertigo is prolonged and severe, there is a need for symp- tomatic therapy.

The ideal symptomatic medication should suppress the sensation of vertigo, help restore normal balance, and prevent vomiting. There should be minimal side effects, and the treat- ment should not impede the normal process of recovery from the vestibular lesion. At the present time, there is no medication available that would meet these objectives. In the absence of the ideal drug, the choice of thera- pies should take into account the patient’s

underlying disease, the expected course of the disease, and the patient’s need for mobility during recovery.

Two general classes of drugs are used to treat vertigo, nausea, and vomiting: vestibular suppressants and antiemetics.1 Vestibular sup- pressants treat a variety of symptoms associ- ated with vestibular illness, usually reducing the sensation of vertigo and associated nausea and vomiting. Antiemetics are more selective in action; they are used primarily to reduce nausea and vomiting associated with many illnesses and can also be used in combination with vestibular suppressants for treating vertigo.

The main types of vestibular suppressants include antihistamines, anticholinergics, and benzodiazepines, although a variety of other drugs have also been used (Table 19–1). Abundant empirical evidence demonstrates the efﬁcacy of these medications in the treat- ment of vertigo. Although the exact mechanism

405

406

Clinical Neurophysiology of the Vestibular System

Table 19–1 Main Actions of Commonly Used Antivertiginous and Antiemetic Drugs

Class	Drug	Histamine Antagonist	Acetylcholine Antagonist	Dopamine Antagonist	Serotonin GABA Agonist Opiate Agonist Antagonist
Antihistamine	Diphenhydramine	+	+
	Meclizine	+	+
	Cyclizine	+	+
	Buclizine	+	+
	Promethazine	+	+	+
Anticholinergic	Scopolamine		+
Benzamide derivative	Trimethobenzamide	+	+
	Benzquinamide	+	+
	Metoclopramide		+	+	+
Phenothiazine	Chlorpromazine		+	+
	Perphenazine		+	+
	Prochlorperazine		+	+
Butyrophenone	Droperidol		+	+
Antiserotonergic	Ondansetron				+
Benzodiazepine	Diazepam					+
	Lorazepam					+
Cannabinoid	Dronabinol					+
Other	Diphenidol		+	+
	Domperidone		+	+

Cortex

(Cannabinoids) (Benzodiazepines)

Chemoreceptor trigger zone

(Antidopaminergics)

G.I. tract

Emetic center

Vestibular nuclei

(Antiseritonergics) (Antihistamines) (Anticholinergics)

(Antihistamines) (Anticholinergics) (Benzodiazepines) (Antidopaminergics?)

Figure 19–1. Schematic drawing of the major inputs to the emetic center and probable site of action of different classes of drugs. G.I., gastrointestinal.

of action of many of these drugs is unclear, most appear to act at the level of the neu- rotransmitters involved in propagation of impulses from primary to secondary vestibular neurons and in maintenance of tone in the ves- tibular nuclei. Antiemetic drugs are directed against the areas of the nervous system control- ling vomiting (Fig. 19–1).2 This system of neu- rons contains central components (loosely described as the emetic center) and peripheral components in the gastrointestinal tract.3 Although the exact pathways mediating vestib- ular-induced vomiting are not completely known, patients who have a baseline sensitivity to motion (i.e., low threshold for developing nausea and vomiting) are often more affected by nausea and vomiting in the setting of a ves- tibular disorder.4 Many of the vestibular suppressants also have antiemetic action and vice versa, and many of the antiemetic drugs produce vestibular suppression.‌

VESTIBULAR SUPPRESSANTS

The study and understanding of neurotrans- mitters within the vestibular nuclei is in its infancy (see Chapter 3). New information on the neurotransmitters will lead to new and bet- ter vestibular suppressants and a better under- standing of how vestibular suppressants work. For example, substantial evidence shows that the main neurotransmitter between primary and secondary vestibular neurons is an excit- atory amino acid, either glutamate or aspartate, acting on kainate receptors.5,6 Despite this information, the therapeutic potential of drugs

that block or otherwise modulate excitatory amino acid receptors has been limited. Possibly because of the widespread distribution of excit- atory amino acid receptors in the central ner- vous system (CNS), therapeutic beneﬁts that could be derived from systemic administration of antagonists of the excitatory amino acid receptor are offset by generalized side effects.

How Do They Work?

As noted earlier, vestibular suppressants are thought to work by depressing transmission of vestibular signals through the vestibular nuclei to the emetic center and other brainstem auto- nomic centers. As shown in Table 19–1, these drugs typically have multiple actions. The transmitters that they affect are not speciﬁc to the vestibular system but are present through- out the CNS. This may account for the many associated side effects. Acetylcholine is an excitatory neurotransmitter in the vestibular system; muscarinic receptors in the vestibular nuclei are the presumed site of action for anti- cholinergic vestibular suppressants.6,7 A major histaminergic system projects to the vestibular nuclei and brainstem autonomic centers.8,9 All three histamine receptors are expressed in the vestibular nuclei and in the vestibular periphery.10,11,12 H1and H2 receptors are post-

synaptic, while H3 receptors are presynaptic. Most antihistamines used in the treatment of

vertigo are H1 blockers, but they also have anti- cholinergic actions. The benzodiazepines are agonists of -aminobutyric acid (GABA), which

is the primary inhibitory neurotransmitter for vestibular neurons.13 Furthermore, H3 receptors

modulate GABAergic transmission in the ves- tibular nuclei.14 Dopamine receptors have also been identiﬁed within the vestibular nucleus complex,15 but it is unclear whether antidop- aminergic drugs have a direct effect on the vestibular nuclei or affect other centers that inﬂuence the vestibular nuclei. Finally, sero- tonergic neurons in the dorsal raphe nucleus project directly to the vestibular nuclei.16

How to Use Them

Vestibular suppressants can be used acutely to treat a discrete attack or chronically as prophy- laxis against future attacks. To decrease the risks of unacceptable side effects, the choice of drug and administration must be determined by the underlying vestibular problem. Acute severe attacks of vertigo accompanied by severe nausea and vomiting are the most distressing form of vestibular illness. Vestibular suppres- sants are useful only for attacks that last long enough for the drug to reach an effective blood level before the attack ends. This limits acute therapy to attacks lasting at least an hour. Because maximum vestibular suppression may not be reached for 2 or more hours after dos- ing, treatment is most useful for attacks that last several hours. In general, the stronger sup- pressants are more sedating and should be reserved for acute treatment. Brief vertigo spells, such as those associated with benign positional vertigo or vertebrobasilar insufﬁ- ciency, cannot be controlled by ingestion of a suppressant at the time of the attack.

Chronic prophylactic treatment with vestib- ular suppressants should be avoided because of potential problems with tolerance and depen- dency. Withdraw symptoms such as motion sensitivity and nausea commonly occur and may be misinterpreted as due to the underly- ing disorder. The need to control vertigo must be weighed against the need for the patient to maintain full mobility and function. Patients who complain of almost continuous weeks to months of dizziness should not be managed with vestibular suppressants. Such a complaint suggests a diagnosis other than a speciﬁc ves- tibular disorder. Vestibular suppressants are not useful in treating chronic dizziness of non- vestibular origin.

A sudden loss of peripheral vestibular func- tion on one side is a common disorder with

many different causes, but regardless of the cause, central compensation will occur and the patient will recover. Vestibular suppressants can impair the process of central compensation.17,18 Patients are often extremely vertiginous with severe nausea and vomiting for the ﬁrst few days after the vestibular lesion, and it is appropriate to use strong vestibular suppressants in that time frame. However, as soon as the vomiting ceases, vestibular suppressants should be with- drawn gradually to allow compensation.

The commonly used antihistamine vestibular suppressants require 20 to 30 min to initiate action, reach a peak plasma level in 1 to 2 hr, and have a half-life of about 8 hr. Therefore, dosing can be as infrequent as twice a day. Transdermal scopolamine is programmed to deliver through the systemic circulation 0.5 mg of scopolamine at a constant rate each day over the 3-day life- time of the system. When used as a prophylaxis for motion sickness, the patch should be in place several hours before exposure to motion.

Indications

The less sedating drugs are milder vestibular suppressants than the more sedating drugs (Table 19–2). The less sedating medications, such as scopolamine and meclizine, are partic- ularly useful for treating chronic recurrent attacks of vertigo during which the patient is attempting to carry on normal activities, includ- ing work. The more sedating medications, such as promethazine, the benzodiazepines, and droperidol, are particularly effective for an acute severe attack of vertigo, nausea, and vomiting when the patient desires sedation and rest. For similar reasons, the less sedating medications are used in the prophylaxis of motion sickness.

Precautions

Because drowsiness and disorientation can occur with all of these drugs, patients should be warned about engaging in tasks requiring mental alertness. All medications with anticho- linergic properties should be used with caution in patients with glaucoma, pyloric obstruction, or urinary bladder neck obstruction and who are suspected of having intestinal obstruction. These drugs should be used with caution in

Table 19–2 Indications for Use of Common Vestibular Suppressants

19 Antiemetic and Antivertigo Drugs

LESS SEDATING MORE SEDATING

Type of Vertigo

Acute periph- eral vertigo

Chronic recurrent peripheral vertigo

Central

vertigo Prevent

409

motion sickness

Scopolamine Meclizine Cyclizine Buclizine Diphenhydramine Promethazine Diazepam Lorazepam Droperidol

+ + + +

+ + + + + +

+ + +

+ + + + + +

patients using CNS depressant drugs or con- suming alcohol because the additive effects on the CNS may cause adverse reactions. As noted earlier, withdrawal symptoms can occur after discontinuing any of these medications but are particularly prominent with the benzodiaz- epines and scopolamine.19 These symptoms include dizziness, nausea and vomiting, headaches, and disturbances of equilibrium, all of which may be similar to the symptoms that initially triggered the use of the drug. Withdrawal symptoms, of course, are most likely to occur in patients who have been on the medication for many days. Abrupt with- drawal of the benzodiazepines can lead to gen- eralized seizures. Addiction-prone individuals should be under careful surveillance while receiving benzodiazepines because of the pre- disposition of such patients to habituation and dependence.‌‌

Because of the multiple effects of each of these drugs, possible drug interactions should always be considered before use. The drugs with anticholinergic properties and the benzo- diazepines are contraindicated in patients with glaucoma unless they are receiving appropriate therapy. The antihistamines should not be used in patients with asthma, emphysema, chronic pulmonary disease, or difﬁculty in urinating because of an enlarged prostate. The benzodi- azepines are generally not recommended for children younger than 6 months. Transdermal scopolamine should not be used in children because it is unknown whether the amount of scopolamine released will produce serious adverse effects in children. Extra caution should be taken when treating elderly patients because of a higher risk of drug-related prob- lems or toxic effects.20 Medicines with no or fewer anticholinergic properties (e.g., prochlo- rperazine) are favored over medicines with more anticholinergic properties (e.g, promet- hazine). Short-acting sedating medicines (e.g., lorazepam) at low doses are favored over long- acting sedating medicines (e.g., diazepam). Because of its potential for producing memory loss, hallucinations, and alterations in mental status, scopolamine should be used with extreme caution in older people.

All of these drugs should be used with cau- tion in patients with renal or hepatic impair- ment because of their multiple actions, particularly their anticholinergic properties. Meclizine and dimenhydrinate are considered

safe to use during pregnancy.21 An increased risk of congenital malformations associated with diazepam during the ﬁrst trimester of pregnancy has been suggested in several stud- ies. Small doses of benzodiazepines may be safe later in pregnancy.21 Diazepam is excreted in breast milk and, because neonates metabo- lize diazepam more slowly than adults, accu- mulation of the drug and its metabolites to toxic levels is possible.

What to Tell the Patient

These medications are used to suppress vertigo and the commonly associated nausea and vom- iting. They treat the symptoms but do not address the underlying cause of the vertigo. It is not a good idea to use vestibular suppressants on a chronic basis because they can interfere with the brain’s ability to compensate for the underlying problem. These medications typi- cally are sedating, so at least initially they should not be used when performing activities that require a high level of alertness, such as driving, operating machinery, or performing athletic activities. Patients should not take other drugs without discussing it with the doctor. Avoid excessive alcohol consumption since the effects could be additive.

ANTIEMETIC DRUGS

The antiemetic drugs are used to suppress nau- sea and vomiting regardless of the cause. They can be used with vestibular suppressants when treating vertigo, nausea, and vomiting due to vestibular lesions or they can be used in isola- tion when treating nausea and vomiting due to other causes. These drugs are directed at the areas of the nervous system controlling vomiting (Fig. 19–1). Dopamine, histamine, acetylcholine, and serotonin are all neurotrans- mitters believed to act on these sites to produce vomiting.22 The emetic center is not a discrete localized area in the brain. The ﬁnal process involved in emesis is coordinated in the reticu- lar formation of the brain stem, but input is received from numerous areas of the brain stem and cortex.23 The chemoreceptor trigger zone, located in the area postrema, is a major relay in triggering emesis.

How Do They Work?

Many antiemetics act by suppressing activity in the reticular formation or area postrema. Others suppress major centers feeding into the chemoreceptor trigger zone or the emesis cen- ter. Still others suppress activity in visceral afferents running from the gastrointestinal to the emetic center. Each of the antiemetic drugs probably have multiple sites of action within the CNS (Fig. 19–1). The cannabinoids and benzodiazepines are thought to work at the level of the cerebral cortex, controlling input to the brainstem vomiting center.24 The antidop- aminergics block input to the emetic center from the chemoreceptor trigger zone located in the area postrema.25 Serotonin antagonists, particularly antagonists to the 5-HT3 receptors,

block the activity of visceral afferents that run

from the gut to the emetic center and the area postrema.26 Newer 5-HT3 receptor antagonists

and Neurkinin-1 (NK-1) antagonists work

centrally although the exact mechanism of action is unclear. Finally, antihistamines and anticholinergics appear to work directly on the emetic center.

How to Use Them

The indications for using any of the common antiemetic drugs are summarized in Table 19–3. The antihistamines, anticholinergics, and benzodiazepines are most effective when treat- ing nausea and vomiting associated with vestib- ular lesions; the cannabinoids, antidopaminer- gics, and antiserotonergics are most useful in treating nausea and vomiting associated with surgery, chemotherapy, and radiation treat- ment. Through its antidopaminergic and antise- rotonergic actions, metoclopramide suppresses the central chemoreceptor trigger zone and diminishes the activities of visceral afférents in the gut;28 it is particularly effective for treating postoperative nausea and vomiting and in com- bination with other agents for treatment of postirradiation and chemotherapy-induced nausea and vomiting.29 Ondansetron is a well-tolerated selective blocker of 5-HT3 that has been effec-

tive for treating chemotherapy-induced nausea

and vomiting.30 Palonosetron is a newer 5HT

drugs in the NK-1 receptor agonist class.27 The benzodiazepines, as a single agent, are of limited use for treating nausea and vomiting, but they can be used in combination with other antiemetic drugs because of their action on the central emetic centers and their ability to reduce akathisia and anxiety.31 Of the vestibular suppressants, promethazine and droperidol are the most effective antiemetic drugs.32

Domperidone is chemically unrelated to the butrophenones, phenothiazines, or metoclopr- amide; however, it shares pharmacologic prop- erties with these agents. In the medulla, the drug produces a direct blocking effect of dopamine receptors in the chemoreceptor trig- ger zone. Like metoclopramide and haloperi- dol, domperidone is a peripheral dopamine antagonist; however, it does not cross the blood–brain barrier and produce CNS effects.

Precautions

Extrapyramidal symptoms and signs occur with use of phenothiazines and butyrophenones, and they may be confused with CNS signs of undiagnosed primary disease responsible for the vomiting.33 Tardive dyskinesia, a syndrome consisting of potentially irreversible involun- tary dyskinetic movements, also commonly occurs with using these drugs. The risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as duration of treatment and total cumulative dose administered to the patient increase. Potentially fatal symptoms often referred to as neuroleptic malignant syndrome have been associated with phenothiazines and butyrophenones.34 Alcohol should be avoided with all of these drugs because of possible addi- tive side effects. Because of the multiple effects of each of these drugs, possible drug interac- tions should always be considered before use.

The antidopaminergic antiemetic drugs should be used with great caution in children because there is a high incidence of extrapyra- midal side effects in children. Although the incidence of extrapyramidal side effects is less than 1%–2% in adults, it can be as high as 25% in children.35,36 These reactions frequently

receptor antagonist with a higher

binding

develop during the ﬁrst few days of treatment.

afﬁnity and longer half-life than ondansetron.27 Aprepitant and casopitant are new antinausea

Sometimes the drugs can be restarted at a lower dose once the acute reaction subsides.

412 ClinicalNeurophysiologyoftheVestibularSystem

Domperidone

Dephenidol

Dronabinol

Ondansetron

Droperidol

Prochlorperazine

Perphenazine

IndicationsforUseofCommonAntiemeticDrugs

Chlorpromazine

Metoclopramide

Benzoquinamide

Trimethobenzamide

Promethazine

Table19–3

TypeofNausea andVomiting

Vestibular induced Postoperative

Radiation induced Chemotherapy induced

Vestibular induced Postoperative

Radiation induced Chemotherapy induced

Scopolamine

Older patients are particularly prone to the sedating and extrapyramidal side effects of the antidopaminergic antiemetic drugs.

Chlorpromazine should be administered cautiously to persons with hepatic disease because patients with a history of hepatic encephalopathy from cirrhosis may have an increased sensitivity to the CNS effects of chlorpromazine. Most of the antidopaminergic drugs are excreted at least in part by the kidneys and therefore should be used with cau- tion in patients with renal failure. Most of these drugs have not been assessed adequately regarding their safety during pregnancy, and therefore use during pregnancy must be weighed against possible hazards to mother and child.

What to Tell the Patient ‌

These drugs are used to suppress nausea and vomiting but do not treat the underlying cause. Patients should understand the symptoms of extrapyramidal side effects and with tardive dyskinesia so that they can report them to the physician immediately if any become evident. If a child shows any type of unusual behavior or excessive excitement, the drug should be with- held and the symptoms should be immediately reported to the physician. As with all of these medications, adults should not drive or operate machinery until the full effects of drug are real- ized. Sedation may range from mild drowsiness to severe sleepiness.

SPECIFIC DRUGS

Scopolamine (Transderm Sco¯ p)

Scopolamine transdermal system is an anticho- linergic agent classiﬁed as a belladonna alka- loid that is most useful for prevention of nausea and vomiting associated with motion sickness. Because of its short half-life in plasma and dose-dependent side affects, oral or parenteral administration is of limited use. The transder- mal system of scopolamine is programmed to deliver 0.5 mg at a constant rate (5 µg/hour) to the systemic circulation over a 3-day lifetime of the system.37 To be most effective in

preventing motion sickness, the system should be applied about 8 to 12 hr before exposure to motion. The scopolamine transdermal system should be used with great caution in older people because they are particularly susceptible to the CNS side effects, such as memory loss, delusions, and hallucinations. Drug withdrawal symptoms, including dizziness, nausea, vomiting, headaches, and disturbances of equilibrium, can occur after discontinuation of the transdermal sys- tem, particularly if it has been used for several weeks.19 Sometimes these withdrawal symp- toms are confused with the symptoms that ini- tiated the use of the transdermal scopolamine system.

Buclizine Hydrochloride (Bucladin-S)

Buclizine hydrochloride is a vestibular sup- pressant and antiemetic agent that is useful for treating vertigo due to vestibular lesions and for preventing motion sickness. It is a piperazine-type antihistamine with anticho- linergic properties. Like the other antihista- mine anticholinergic drugs, sedation and dry- ness of the mucous membranes are the most common side effects. The tablets can be taken without swallowing water by placing the tablet under the tongue and allowing it to dissolve. This route of administration can be useful when the patient is having severe nausea and vomiting.

Diphenhydramine Hydrochloride (Benadryl)

Diphenhydramine hydrochloride is a vestibu- lar suppressant and antiemetic agent with mod- erate sedating properties. It is an ethanolamine antihistamine that is also an anticholinergic agent. It is most useful for treating mild to moderate episodes of vertigo and for preven- tion of motion sickness. The most common side effects are dryness of the nose, throat, and mouth and moderate sedation. Diphen- hydramine is often effective for treating the extrapyramidal side effects that occur with the antidopaminergic drugs.38

Meclizine (Antivert, Bonine)

Meclizine is a vestibular suppressant and anti- emetic agent that is less sedating than most of the other vestibular suppressant drugs.39 It is a piperazine-type antihistamine that also has anticholinergic properties. Peak effect is not reached until 7 to 9 hr after ingestion. It is par- ticularly useful for treating mild to moderate episodes of vertigo and for suppressing motion sickness. It should be taken several hours before exposure to motion to be effective in preventing motion sickness. Because it has a very low risk of teratogenicity, it can be useful for treating nausea and vomiting during pregnancy. As with the other antihistaminic anticholinergic agents, the main side effects are dryness of the mucous membranes and mild sedation.

Dimenhydrinate (Dramamine)

Dimenhydrinate is a vestibular suppressant and antiemetic agent that is primarily used for

particularly useful for treating severe vertigo with recurrent nausea and vomiting. It is an antidopaminergic agent and also has antihista- minic and anticholinergic properties. As an antihistamine, it acts by competitive antago- nism but does not block release of histamine; it antagonizes in varying degrees most pharmaco- logic effects of histamine.41 Although infre- quent, extrapyramidal symptoms can occur secondary to promethazine, and occasionally such symptoms can be confused for CNS signs of an undiagnosed primary disease. Pro- methazine can be very sedating, particularly in older people, and it should not be used in patients with a history of sleep apnea. It can be more effective with less sedation by combining it with 25 mg of ephedrine.42 Because of its excellent antiemetic action, it can be combined with other vestibular suppressants that have fewer antiemetic properties, such as scopol- amine and the benzodiazepines.

Betahistine (Serc)

Betahistine is an H receptor antagonist that

preventing motion sickness. Like other drugs

in this class, it has antihistaminic and anticho-

has long been used larly vertigo

for

treating vertigo particu- with Meniere’s syn-

linergic activity and the main side effects are

dryness of mucous membranes and mild to

associated

drome.43–45 Betahistine was brieﬂy approved by

the Food (FDA) for

moderate sedation. The sedation associated

and Drug Administration

use in the

ago, but

with dimenhydrinate and other H blockers

United States about 40 years

can be reduced or avoided by release formulations.40 Patients

using

slow-

subsequently approval was withdrawn due to lack of evidence for efﬁcacy. It is still avail-

over age

may have a stronger reaction and require

smaller doses. Dimenhydrinate

able in Europe and Canada and can be

obtained through compounding pharmacies

should be used

with caution in patients with

in the United States. Curiously, by blocking

cardiovascular or respiratory disease and in patients with convul-

presynaptic H3

increased

receptors, betahistine causes an of histamine and activation of

sive disorders. For prevention of motion sick-

ness, the ﬁrst dose should be given 30 min

release

H1 receptors (the opposite effect of antihista-

before exposure to motion. Since dimenhydri- nate may cause drowsiness or impair judgment and coordination, patients should be warned not to operate any machinery or drive a vehicle because of the sedative effect. They should avoid alcohol and drink plenty of ﬂuids for dry mouth and to prevent constipation.

Promethazine Hydrochloride (Phenergan)

Promethazine hydrochloride is a potent ves- tibular suppressant and antiemetic drug that is

minic vestibular suppressants). However, by blocking H3 receptors in the vestibular periph-

ery, betahistine may decrease spontaneous

afferent activity.10,46

Metoclopramide (Reglan)

Metoclopramide is an antiemetic medication that appears to work both centrally on the chemoreceptor trigger zone and peripherally on the gastrointestinal tract.47 It has antidop- aminergic and anticholinergic properties and thus has the potential side effects of extrapyramidal symptoms and dryness of the

mucous membranes. Its gastrointestinal effects are mediated through blockage of serotonin receptors; blocking activity originates in vis- ceral afferents running from the gastrointesti- nal tract to the emetic center. Metoclopramide is an antiemetic agent useful for treating many causes of nausea and vomiting. It also can be used in combination with vestibular suppres- sants and other antiemetic drugs.19 It can be administered orally or by injection with onset of action within the ﬁrst hour (the half-life is 5 to 8 hr).

Benzquinamide Hydrochloride (Emete-con)

Benzquinamide hydrochloride is a short-acting non–amine-depleting benzamide derivative, chemically unrelated to the phenothiazines and other antiemetic drugs. It has antihistaminic and anticholinergic properties, but the mecha- nism of action of its antiemetic properties is unknown. It is most useful for treating mild, persistent nausea but has sedating properties like all of the other antiemetic drugs. A sudden increase in blood pressure and transient arrhythmia has been reported following intra- venous administration of benzquinamide.

Trimethobenzamide Hydrochloride (Tigan)

Trimethobenzamide hydrochloride is a benz- amide derivative that has antihistaminic and anticholinergic properties. This drug is an anti- emetic agent that is suitable for mild to moder- ate nausea and vomiting. It can produce drowsiness and may be additive with other sedating medications. Extrapyramidal side effects can also occur.

Diazepam (Valium)

Diazepam is a benzodiazepine agent that is a vestibular suppressant and has antianxiety and sedative effects.48 It may also help control nau- sea associated with vertigo and motion sick- ness.49 Diazepam is a GABA agonist that decreases transmission of signals through the vestibular nucleus. It can be given intravenously

to rapidly suppress acute severe vertigo, but the intravenous route must be used with extreme caution particularly in patients with limited pul- monary reserve, because of the possibility of producing apnea or cardiac arrest. Abrupt with- drawal of diazepam may be associated with prominent withdrawal symptoms, including sei- zures. Patients should be warned about the simultaneous use of alcohol or other CNS depressant drugs because of the additive effect.

Droperidol (Inapsine)

Droperidol is a butyrophenone derivative that has prominent antiemetic effects. The onset of action is within 30 min after injection; thera- peutic levels persist 2 to 4 hr and vestibular suppression can be demonstrated for as long as 24 hr.50 Like the phenothiazines, its mode of action is blockage of dopaminergic transmis- sion in the chemoreceptor trigger zone.35 It can produce marked tranquilization and sedation and therefore should be used with great cau- tion in older people. The drug also produces a mild -adrenergic blockade. Hypotension, pos- sibly associated with hypovolemia, and extrapy- ramidal effects should be watched for. The FDA placed a black box warning on the use of droperidol because of the possibility of induc- ing fatal cardiac arrhythmias due to prolonga- tion of the QT interval.32

Diphenidol (Vontrol)

Diphenidol is a piperidinebutanol compound that has antiemetic properties but is chemically unrelated to the other antiemetic drugs. Diphenidol does have weak peripheral antich- olinergic effects and therefore can have the usual side effects associated with these agents. Because of its potential for producing halluci- nations, confusion, and disorientation, it should be used with caution in older patients, particu- larly those who are hospitalized. The mode of action of its antiemetic effect is unknown.

Prochlorperazine (Compazine)

Prochlorperazine is an antidopaminergic agent that is a piperazine-type phenothiazine. Like the other phenothiazines, it works directly on

the chemoreceptor trigger zone by blocking dopaminergic transmission. Antihistaminic effects have been shown during chronic treat- ment, and it is an -adrenergic blocker.36 Antiemetic effects are maximal 2 to 4 hr after the peak blood level is reached, and the half- life exceeds 8 hr. It has a high incidence of extrapyramidal effects, moderate sedative effects, and a low incidence of anticholinergic effects and orthostatic hypotension. In some patients, the sedation may impair driving performance.51

Dronabinol (Marinol)

Dronabinol is an antiemetic cannabinoid extracted from Cannabis sativa (marijuana) that, like other cannabinoids, has complex effects on the CNS; dronabinol is classiﬁed as an antinau- seant with antianorectic activities. It seems to work by diminishing activity from the cortex to the chemoreceptor trigger zone. It has been used mostly for treating nausea and vomiting associated with chemotherapy and radiation.

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South Med J. 1983;76:1271.
Shupak A, Gordon CR. Motion sickness: advances in pathogenesis, prediction, prevention, and treatment. Aviat Space Environ Med. 2006;77(12):1213.

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Chapter 20 ‌‌

Vestibular Rehabilitation

ADAPTIVE CONTROL OF NORMAL VESTIBULAR REFLEXES

MECHANISMS FOR COMPENSATION AFTER VESTIBULAR LOSS

SPECIAL CIRCUMSTANCES

Vestibular Loss in Children Vestibular Loss in the Elderly Failure of Compensation

CONTROLLED TRIALS OF VESTIBULAR EXERCISES

STRATEGY FOR DESIGNING VESTIBULAR EXERCISES

Unilateral Vestibular Lesions Bilateral Vestibular Lesions Central Vestibular Lesions VESTIBULAR EXERCISES FUTURE DIRECTIONS APPENDIX 20–1

SAMPLE HOME EXERCISE PROGRAM

Head-Turning Practice Walking Practice Other Exercises Dizziness Exercises

When the vestibular system has been perma- nently damaged, the initial state of imbalance at the level of the brainstem nuclei results in acute vertigo (see Pathophysiology of vestibu- lar symptoms in Chapter 1). Gradually, the patient adapts to this imbalance through a pro- cess of compensation that requires intact vision and depth perception, normal proprioception in the neck and limbs, and intact sensation in the lower extremities. Central pathways are also integral to compensation, and damage to these areas results in less effective recovery.

Clinicians have long been aware that vestib- ular compensation occurs more rapidly and is more complete if the patient begins exercising as soon as possible after a vestibular lesion.1,2 Controlled studies in primates have supported this general clinical observation. Baboons whose hind limbs were restrained by plaster casts after a unilateral vestibular lesion showed markedly delayed recovery of balance com- pared with lesioned animals that had been allowed normal motor exploration.3 Visual experience is also necessary; lesioned animals

kept in the light compensated faster than those kept in darkness.4,5 Compensation was acceler- ated in cats by stimulant drugs (amphetamine) and slowed by sedating drugs (diazepam, dimenhydrinate), with the authors postulating that the effect of the stimulating drugs was due to increased physical activity levels.6 For these reasons, vestibular exercise programs probably should be instituted as soon as possible after an injury to the vestibular system has been identi- ﬁed, and the use of sedating drugs should be limited to the acute stage.

In addition to producing the subjective sen- sation of vertigo, vestibular lesions interfere with reﬂexes controlling eye movements dur- ing active head motion and with postural right- ing reﬂexes.7,8 This interference can result in oscillopsia caused by head movements and a tendency to veer or fall when walking. These symptoms and the associated dizziness can be improved by active exercises designed to speed compensation. Many of the exercises will result in dizziness. This sensation is a necessary stimulus for compensation; antivertiginous

419

medications should be avoided during this period to allow the compensation process to occur.‌‌

Although there is a consensus that vestibular rehabilitation is helpful for patients with ves- tibular lesions,9,10 few physical therapists receive training in vestibular rehabilitation during their formal education.11 Most learn about vestibular rehabilitation at short continu- ing education courses or from colleagues. Standards need to be established and thera- pists need to be educated about the vestibular system.

ADAPTIVE CONTROL OF NORMAL VESTIBULAR REFLEXES ‌

Adaptive control of vestibular reﬂexes is con- stantly occurring in all of us. A common example is the adjustment in the gain of the vestibulo-ocular reﬂex (VOR) that occurs in normal people when they wear magnifying lenses in glasses. In order to maintain clear vision during head movements, the gain of the VOR must be rapidly adjusted up and down as they take the glasses on and off. In the labora- tory, subjects show even more dramatic changes in the VOR gain when they wear more powerful magnifying or minifying lenses.12,13 An extreme example is the reversal in VOR direction that occurs in animals and humans who wear revers- ing prisms for several days.14,15 These gain adjustments occur within central VOR path- ways since there is no change in peripheral sen- sory input. In subjects taking their glasses on and off, the adjustment in gain occurs immedi- ately before there is any sensory conﬂict as though the brain has two separate gain settings that can be turned on and off like a switch. An example of this presetting of gain within the vestibulospinal reﬂex occurs when a normal subject brieﬂy loses balance when stepping onto an escalator that is unexpectedly out of service. The brain has preprogrammed a change in posture to compensate for the impending movement of the escalator, so that a correction for movement is automatically made even though no actual motion is experienced when the subject steps onto the stationary surface. This ability of central pathways to preprogram motor responses plays an important role in compensation after loss of vestibular reﬂexes.

Adaptive changes in vestibular reﬂexes are typically context speciﬁc.12,13 Experimental studies in animals and humans have shown that adaptive changes in the angular VOR induced by head rotation can be gated in and out depending upon the static orientation of the head, even though the pattern of semicircular canal activation is the same. Therefore, physi- cal therapy programs that are attempting to promote adaptation—so-called adaptation exercises—should be used in a natural setting where the compensated vestibular reﬂexes will be used. Cognitive factors also play an impor- tant role in vestibular adaptation, even to the point that mental exercises may be able to sub- stitute for actual movements in the adaptation process. For example, imagined ﬁxed or mov- ing visual targets can have the same effect in modifying VOR gain as real targets. By going through their routines in their minds, such as a professional golfer analyzing his or her swing, professional athletes can adapt a motor behavior without actually performing the motor act. Thus, psychological factors such as motiva- tion, attention, effort, and interest play a part in any therapy program aimed at vestibular rehabilitation.

Vestibular adaptation typically has a charac- teristic time course both for acquisition and loss (see Fig. 3–22 in Chapter 3).16 In order to maintain adaptation, one requires continued exposure to sensory inputs for the continued elaboration of the adapted response. Central pathways are key in maintaining adaptation, so obviously lesions within these pathways can lead to loss of adaptation. Adaptive capabilities seem to decline with normal aging, which may in part explain why vestibular compensation tends to be slower in older people.7,17 In addi- tion, older patients who lose vestibular func- tion may also have an impaired somatosensory or visual system and thus be less able to com- pensate for the loss of vestibular function.

MECHANISMS FOR COMPENSATION AFTER VESTIBULAR LOSS

Common mechanisms used for recovery after loss of labyrinthine function are summarized in Table 20–1. In patients with partial peripheral vestibular lesions, the gain of the vestibulo-ocular

Table 20–1 Mechanisms for Compensation after Loss of Vestibular Function

Adjust gain centrally

Use other sensory inputs Use other motor responses

Anticipate intended motor behavior Change movement strategy

Adjust central perception

and vestibulospinal reﬂexes can be adjusted to help compensate for the peripheral loss. For example, after a unilateral peripheral lesion, the gain asymmetry is gradually adjusted and the dominant time constant is shortened to help maintain the gain in the high-frequency range.18 The input from one normally functioning remain- ing labyrinth is enough to drive most of the vestib- ulo-ocular and vestibulospinal responses over a wide functional range. There are limitations to these central adjustments in gain, however, and there must be enough residual peripheral func- tion to allow the adaptive mechanisms to act. Also, these gain adjustments only work within a certain range of movements, so that compensation is not possible for high acceleration head thrusts (the basis of the bedside head-thrust test).19‌

Substitution with other sensory inputs and alternative motor responses is commonly used in the compensation process after vestibular lesions. Substitution exercises are used to enhance these other inputs. For example, input from cervical muscle proprioceptors can be used to help generate compensatory eye move- ments in patients with labyrinthine damage. Studies in patients with bilateral labyrinthine disease show that the cervical–ocular and opto- kinetic reﬂexes have increased gains compared to normal subjects.20,21 Subjects also can substi- tute alternative motor responses in lieu of the vestibular compensatory responses. For exam- ple, small anticompensatory saccades can be substituted for vestibular slow phases to help stabilize gaze during head rotation.

Patients with labyrinthine lesions develop strategies that use prediction or anticipation of intended motor behavior to substitute for ves- tibular reﬂexes.22 For example, patients who have lost labyrinthine function learn to prevent gaze overshoot during combined eye and head movements by preprogramming compensatory

slow phases and decreasing saccade size in anticipation of head movement.

Patients with vestibular lesions will com- monly alter their behavior to avoid excessive demands on the compromised vestibular reﬂexes.23 They may walk slower, widen their base, and avoid head movements to decrease symptoms of dizziness and imbalance. Although these changes in movement strategies may initially decrease symptoms, they may be counterproductive in the long run since they prevent the brain from receiving sensory sig- nals needed in the compensation process.

The brain has the ability to adjust central perception of movement that occurs in patients after vestibular lesions. For example, the oscil- lopsia that occurs after bilateral vestibular loss becomes less and less many years after the lesion. Patients usually have no problem driv- ing or carrying on other routine activities.24 Patients with central vestibular lesions and long-standing spontaneous nystagmus also report decreasing oscillopsia over time.

In summary, the vestibular compensation process after a vestibular lesion is a fragile and dynamic process. It requires complex senso- rimotor integrations within the brain, involving many different pathways. Intercurrent illness, injury, and excessive medication or alcohol use may lead to temporary reemergence of long- compensated symptoms from a prior vestibular lesion. The compensation process is generally slower and less complete in older patients, par- ticularly if they have comorbidities resulting in additional defects in sensory inputs from other modalities as occurs with peripheral neuropathy or impaired vision.

SPECIAL CIRCUMSTANCES

Vestibular Loss in Children

As a general rule, the vestibular compensation process is more robust in children than in adults. However, this is not to say that children do not show signiﬁcant deﬁcits from early-onset vestibular loss. In children who are born with vestibular loss or who lose vestibular function within the ﬁrst year, motor milestones are seri- ously delayed during the ﬁrst 2 or 3 years of life.25 However, during the preschool age, most children achieve standard landmarks of motor

development such as head control, independent walking, and running. By the time they enter elementary school (about 6 years of age), most have standard motor skills that would not be outside of the normal range. Many can swim even under water and maintain good balance even with eyes closed. These remarkable motor skills in the context of severe vestibular loss pre- sumably depend on compensatory input from visual, somatosensory, and proprioceptive senses and the maturation of motor systems in the cer- ebellum, basal ganglia, and motor cortex.‌‌

Vestibular Loss in the Elderly

Vestibular compensation is more difﬁcult and less complete in older patients than in young adults.26,27 All of the compensatory mechanisms outlined in Table 20–1 may be diminished in older people. Other sensory inputs such as somatosensory and visual sense are typically diminished so they are less able to compensate for the loss of vestibular sense. Their ability to substitute other motor responses for vestibular responses is also limited because of slowing of all motor responses due to aging; both periph- eral and central mechanisms are affected. The severity of age-related white matter abnormali- ties correlates with the severity of gait and motor abnormalities.28,29 Overall cognitive decline that occurs with normal aging may interfere with their ability to anticipate intended motor behavior and adjust central perception. Changing movement strategy may be one of the few remaining options, so they may adopt a sedentary lifestyle that may further interfere with the compensation process.

Failure of Compensation

A small percentage of patients continue to complain of persistent dizziness and imbalance months to years after an acute peripheral ves- tibular lesion. The cause of this lack of com- pensation and whether it could be prevented by a vestibular compensation exercise program are largely unknown. In one study 31% of 210 patients continued to complain of disequilib- rium more than 3 months after the surgical removal of an acoustic neuroma.26 Age >55.5 years, female gender, constant preoperative disequilibrium present for >3.5 months, and

central ﬁndings on electronystagmography were all signiﬁcantly associated with this poor outcome. In another study 29 of 142 patients (20%) continued to have signiﬁcant dizziness after they underwent surgical procedures to section the vestibular nerve for a variety of ves- tibular disorders.30 Possible reasons for the persistent dizziness were incomplete vestibular nerve section, poor central nervous system (CNS) compensation, new vestibular disease in the opposite ear, and the presence of other CNS diseases. A prospective study of 60 patients with vestibular neuritis found that only 34 (57%) reported complete relief from sub- jective symptoms at long-term follow-up.31 A common theme in these and other studies is that older patients with evidence of CNS dis- ease have the highest likelihood for persistent dizziness (failure of compensation) after an acute vestibular lesion.

CONTROLLED TRIALS OF VESTIBULAR EXERCISES

Most early studies of vestibular exercises in the treatment of patients with acute and chronic vestibular lesions were not controlled and focused on improvement in vestibular symp- toms, so it is difﬁcult to separate the beneﬁt of the vestibular exercises from other nonspeciﬁc effects. Several recent randomized controlled studies found that vestibular rehabilitation exercises improve the functional outcome after unilateral vestibular loss.32–36 A systematic review of the literature by The Cochrane Collaboration concluded that there is moder- ate to strong evidence from high-quality ran- domized trials supporting safety and efﬁcacy of vestibular rehabilitation for unilateral periph- eral vestibular dysfunction.9,10

Importantly most of the vestibular rehabilita- tion trials were conducted in the population of patients with surgical lesions or groups of mixed or vaguely stated etiologies. Very few studies have been performed in the population of patients with vestibular neuritis. This difference in the etiology of the peripheral deﬁcit is impor- tant because many patients with vestibular neu- ritis will have spontaneous return of vestibular function as the viral-inﬂammatory process resolves. On the other hand, patients with a ﬁxed and complete surgical lesion will not have

return of function. For this reason, the effects of rehabilitation found in patients with surgical lesions or other ﬁxed deﬁcits may not be gener- alizable to patients with vestibular neuritis.

One study in vestibular neuritis patients

Table 20–2 Unilateral Peripheral Vestibular Lesions

Goal Force compensation, rebalance, adaptation

found that the sway as measured by posturoga-

phy was signiﬁcantly improved in patients treated with an intense vestibular therapy pro- gram compared to controls.32 However, the

Sample

exercises

Fixate targets, track targets; rapid head movements when sitting, then walking; walk in dark, on uneven surface

randomization procedure was violated in this study because 43 of the original 82 randomized patients were excluded because they showed a partial or complete caloric response recovery on day 30. Other outcomes including ocular torsion and subjective visual vertical were not signiﬁcantly different between the groups. The intervention in this study involved physical therapists treating the study group for 5–7 days in the hospital, which is likely to be more intense therapy than is practical in routine care.‌

A second trial in a vestibular neuritis popula- tion did not use a placebo group.37 Instead this trial compared a program of home training (e.g., oral and written vestibular therapy instruction) to the same program of home training but also with additional physical ther- apy sessions (i.e., three 40-minute supervised sessions during the ﬁrst week and then one ses- sion per week for 9 weeks). No differences were seen in any of the subjective outcomes (i.e., rating of vertigo or imbalance) or objec- tive outcomes (i.e., caloric testing, Romberg test, one-leg stance, and tandem walking) at any of the follow-up intervals (1 week, 10 weeks, or 6 months).

Customized vestibular rehabilitation pro- grams appear to be superior to general instruc- tions that simply emphasize the need for exposure to movement in patients after surgery for an acoustic neuroma.35 For patients who are to undergo unilateral ablative surgery, begin- ning vestibular exercises a few weeks before the surgery and continuing after surgery may speed up recovery.38

STRATEGY FOR DESIGNING VESTIBULAR EXERCISES

Unilateral Vestibular Lesions

Persons with unilateral vestibular lesions demon- strate a series of deﬁcits requiring compensation

Expect Complete recovery, minimal subtle

deﬁcits

(Table 20–2). A near-complete recovery of nor- mal abilities can be expected, although speciﬁc deﬁcits will remain.

GAZE STABILITY

Because of the unilateral loss of the VOR in the acute patient, there is spontaneous nystagmus that results in a complete loss of gaze stability. This can be complicated by diplopia as part of the ocular tilt reaction. These acute severe visual symptoms resolve gradually over the ﬁrst several days to a week as the remaining vestib- ular labyrinth restores VOR function or if the function of the lesioned side recovers. As this occurs, gaze stability improves but may not return to normal. Quick movements toward the side of the lesion can result in a sense of oscillopsia and dizziness. In some patients, these symptoms will remain permanent. Treatment involves maintaining full neck mobility to allow increased input from neck proprioceptors during head turns and ocular ﬁxation practice while at rest and at low and high head accelerations in both the vertical and horizontal planes.

BALANCE

Before compensation occurs, otolith input is asymmetric. This results in a perceptual illu- sion that the environment is tilted. There is a tendency to veer toward the side of the lesion when walking. Because of an increased depen- dence on visual input, falls can occur if lighting is poor or if the eyes are closed. This visual dependence is complicated in the acute situa- tion by the presence of spontaneous nystagmus and skew diplopia. After the acute nystagmus and skew deviation disappear within a few days, balance improves but there are still deﬁcits,

particularly when visual and proprioceptive inputs are reduced or conﬂicting—for example, when climbing stairs in darkness. Treatment includes maintaining or improving ankle strength and mobility. One strategy is to use supportive high-top shoes to increase ankle- cutaneous input. Using shoes with ﬁrm soles is recommended over shoes with heavy cushion- ing. As patients continue to improve, they should begin walking and balancing exercises with eyes closed or in the dark.

Bilateral Vestibular Lesions

Very few randomized studies have tested ves- tibular therapy interventions in patients with a bilateral vestibulopathy. Persons with bilateral vestibular loss demonstrate a series of perma- nent deﬁcits that require compensation (Table 20–3). Some compensation involves strength- ening of existing reﬂexes such as the cervical- ocular reﬂex and smooth pursuit, while the remainder requires trained behaviors such as substituting centrally programmed eye move- ments for the lost VOR.39

GAZE STABILITY

Because of the absence of the VOR, head movements that are of sufﬁcient velocity to exceed the smooth pursuit system (>1 Hz) result in retinal slip, which leads to symptom- atic oscillopsia. Treatment strategies center on attempting to substitute other sensory input systems for the vestibular loss. Exercises are used to maintain full neck mobility to allow the

Table 20–3 Bilateral Peripheral Vestibular Lesions

Goal Substitute other sensory information to replace vestibular

cervical-ocular reﬂex to provide help with com- pensatory eye movements. Slow head oscilla- tions can be used to strengthen pursuit abilities during head movements, and saccade exercises (looking back and forth between targets) may help optimize the voluntary use of fast eye movements. Ultimately, some patients learn that to obtain maximum visual acuity, they must hold the head still.

One small randomized trial of vestibular exercises assessed the efﬁcacy of the exercises on improvement of dynamic visual acuity (e.g., visual acuity under movement) and subjective intensity of oscillopsia in patients with bilateral vestibulopathy.39 The exercises used as the intervention in this study were “adaptation” exercises (i.e., focusing on a target during head movements while the target is either stationary or moving) and balance exercises. The investi- gators chose to remove two out of seven con- trol subjects after randomization because one subject was moving her head during the pla- cebo exercises and the other had better- than-expected improvement in dynamic visual acuity. The study found that the intervention group did improve dynamic visual acuity per- formance, while the placebo group did not. Although one would think improvement in dynamic visual acuity would lead to less symptomatic oscillopsia, this study found that the change in dynamic visual acuity did not correlate with change in subjective ratings of oscillopsia.

BALANCE

In the absence of peripheral vestibular input, postural control relies upon the ankle and step- ping strategies. Loss of the vestibulospinal reﬂex leads to an increased dependence on ankle proprioception and cutaneous sensation from the feet and ankles to provide balance. These other senses are used to substitute for the vestibular loss. Such patients are also visu- ally dependent, but there are limitations to their compensation because of the associated

Sample

exercises

Track targets with and

without head movement Learn to hold head still to

read

Walk on foam and uneven surfaces with vision

oscillopsia. Deﬁcits become apparent when they are exposed to poor support surfaces (soft or shifting surfaces, narrow support base), par- ticularly if visual inputs are misleading. Treatment strategies for balance include main- taining or improving ankle strength and mobil-

Expect Mild to moderate persistent

limitations

ity, increasing cutaneous input in the lower extremities (e.g., use of supportive high-top

shoes, shoes with ﬁrm soles), gait and balance exercises, and stressing the importance of solid footing and good lighting at all times.‌‌

Central Vestibular Lesions

Recovery from central vestibular lesions is typ- ically much slower than recovery from periph- eral vestibular lesions (Table 20–4). No doubt this can be traced to the fact that structures involved in the recovery process are themselves damaged. The cerebellum is a key structure for compensation and patients with cerebellar lesions improve the least with vestibular rehabilitation.40

GAZE STABILITY

Patients with central vestibular lesions often will have spontaneous nystagmus that persists for months to years. Although the oscillopsia associated with this spontaneous nystagmus may decrease over years, it rarely completely disappears. Often there is a null region where the nystagmus is less, or maybe even absent, so patients can learn to hold their eyes near the null region when best visual acuity is critical (for example, when reading). If a null point is present, then the use of an eyeglass prism or ocular surgery may be beneﬁcial. There are no data to suggest that either head or eye exercises will decrease the magnitude of the eye move- ment or the subjective oscillopsia. In some cases, such exercises seem to aggravate the problem by causing nausea and even vomiting.

BALANCE

Central balance disorders tend to be much more severe than those associated with peripheral

Table 20–4 Central Vestibular Lesions

Goal Suppress nausea, dizziness, diminish oscillopsia, diplopia, help compensation

vestibular lesions; thus, patients are at a much higher risk of falling. Physical therapy should be aimed at maintaining strength, particularly in the lower extremities, and instructing the patient on using proper support such as a cane or a walker. Regular walking (with support) is encouraged because it maintains strength and mobility, but there are no adequate randomized studies to indicate the beneﬁt of a vestibular rehabilitation program in central disorders.

VESTIBULAR EXERCISES

Vestibular exercises should begin as soon as the acute stage of nausea and vomiting has ended and the underlying disease process is subsid- ing. Many of the exercises will result in dizzi- ness. This sensation is a necessary stimulus for compensation; antivertiginous medications should be avoided as much as possible during this period to maximize the beneﬁcial effect. Exercises should be done at least twice daily for several minutes but may be done as often as the patient can tolerate (see Appendix 20–1 for sample exercises that can be given to the patient).

While nystagmus is present, adaptation exer- cises should begin with the patient attempting to focus the eyes and to move and hold them in the direction that provokes the most dizziness. Once the nystagmus diminishes to the point that a target can be “held” visually in all direc- tions, the patient should begin eye and head coordination exercises. A useful exercise involves staring at a visual target while oscillat- ing the head from side to side or up and down. The speed of the head movements can be grad- ually increased, as long as the target can be kept in good focus. Target changes using com- bined eye and head movements to jump quickly back and forth between widely separated visual targets are also useful. Blinking during these fast head turns can help reduce symptoms of dizziness or blurring of vision.

Gait and balance exercises should begin by having the patient try to stand and walk while

Sample

exercises

Expect

Fixate near and far, different gaze positions

Walk touching wall, up and down slopes

Moderate to severe limitations, particularly in older people

nystagmus is still present. It may be necessary to walk in contact with a wall or to use an assistant in the early stages. Slow, supported turns should be made initially. As improvement occurs, head movements should be added while standing and walking—at ﬁrst slow

side-to-side or up-and-down movements, then fast head turns in all directions. Learning to combine fast head turns with brief eye closure or blinks during walking turns can increase sta- bility and decrease dizziness.‌‌

Compensation can require as long as 2 to 6 months. Dizziness that persists beyond this time indicates either the presence of an ongo- ing, recurrent vestibular illness or poor com- pensation. The patient’s history should be reviewed, and any vestibular suppressants should be discontinued. Evidence of central involvement or impairment of vision, proprio- ception, or sensation should be evaluated. If all areas are normal, no evidence of active disease is present, and no medications are in use, a pro- gram of habituation to dizziness is generally the next step. All movements that provoke dizziness should be identiﬁed, and they should then be repeated as often as possible to maximize the symptoms. This type of therapy can gradually result in habituation to the provoking stimulus.

FUTURE DIRECTIONS

With the recent rapid advances in virtual tech- nology, virtual environments could theoreti- cally be useful for training patients to adapt to complex, multimodel environments.41 Individ- ualized programs could be developed and ther- apists could more easily assess the patient’s progress and need for further therapy. Improved understanding of the cellular and molecular mechanisms involved in hair cell and nerve ﬁber regeneration after injury may make it possible to replace damaged hair cells and nerve ﬁbers by injecting growth factors or other factors that enhance the regeneration process.42 As described in Chapter 2, BDNF induces hair cell regeneration after ototoxic damage in chin-

acceleration in the planes of the semicircular canals and provides a pulse-frequency modula- tion of the ampullary nerve from each canal. When such a devise was implanted in chinchil- las whose vestibular system was ablated with gentimicin, partly compensatory vestibulo- ocular responses were recorded in multiple planes.44 However, current spread beyond the electrode’s targeted nerve branch was a major problem. No doubt progress will be made in the design of the acceleration sensor and elec- trodes and in surgical techniques for implant- ing the devises.

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Venosa AR, Bittar RS. Vestibular rehabilitation exer- cises in acute vertigo. Laryngoscope. 2007;117(8): 1482.
Vereeck L, Wuyts FL, Truijen S, De Valck C, Van de Heyning PH. The effect of early customized vestibu- lar rehabilitation on balance after acoustic neuroma resection. Clin Rehabil. 2008;22(8):698.
Giray M, Kirazli Y, Karapolat H, Celebisoy N, Bilgen C, Kirazli T. Short-term effects of vestibular reha- bilitation in patients with chronic unilateral vestibular dysfunction: a randomized controlled study. Arch Phys Med Rehabil. 2009;90(8):1325.
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39 Herdman SJ, Hall CD, Schubert MC, Das VE, Tusa RJ. Recovery of dynamic visual acuity in bilateral ves- tibular hypofunction. Arch Otolaryngol Head Neck Surg. 2007;133(4):383.

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APPENDIX 20–1. SAMPLE HOME EXERCISE PROGRAM ‌‌

Head-Turning Practice

These exercises can be performed while sitting in a chair. They should be repeated several times at each session, and they can be practiced as many times as you wish during the day. Sessions should be done at least twice daily, as a minimum. Gradually increase how long and how often you perform these exercises.

FIXATION PRACTICE

Select a target directly in front of you. While looking at the target, slowly turn your head from side to side. Try to keep the target from moving or jiggling as you turn. Repeat this, using up-and-down head movements. If you can keep the target perfectly still while you move, practice doing the head turns a bit faster.

Extend your hand out in front of you and use your thumb as a target. Move your arm back and forth, and follow your thumb with your eyes. Next, combine head and target move- ments. For example, while moving your arm to the left, move your head to the right, all the time keeping your eyes on your thumb. Go back and forth.

TARGET CHANGES

Select two targets, one off to your left, the other off to your right, and far enough apart so that you have to turn your head to look from one to the other. Look at one target; then, as fast as you can, close or blink your eyes and turn your head to look at the other. Go back and forth between the two targets as quickly as possible.

Walking Practice

You should try to spend at least 30 min a day practicing your walking. The more time you spend, the quicker you will adjust.

GUIDED WALKING

Stand next to a wall in a long hallway or a length of wall that you can walk along for at least

15 feet. Touch the wall with your hand and keep it in contact with the wall as you walk along it. When you reach the other end, turn around and go back, using the other hand. Once you are able to walk in both directions along the wall without bumping into it or need- ing to use your hand for support, start walking close to the wall with your hands at your side. Your goal is to walk in a straight line down the middle of the hall or room without needing to use your hands or the wall for balance.

WALKING TURNS

Pick a wall several feet in front of you and place a piece of tape or other target in the middle of it at eye level. Walk toward the target. When you reach the wall, keep your head and eyes locked in place on the target as you start to turn with your shoulders and body. When you can no longer turn without moving your head, close your eyes and rapidly turn your head, opening your eyes as soon as the turn is completed. Walk in a straight line away from the wall. Repeat, turning in the other direction.

OUTDOOR WALKS

Go for walks daily, beginning with a 5-min walk and increasing by at least 5 min every day until you are walking for 30 min. Try to walk at a normal pace. Turn your head from side to side to look at the scenery, closing your eyes or blinking to reduce dizziness.

Other Exercises

Spend as much time as you wish doing these exercises. Aim for at least 5 min each day.

READING PRACTICE

Read anything that you like. If needed, you can balance your head on your hand to keep the words steady as you read. Try to keep the letters in focus while you read.

ROCKING CHAIR EXERCISES

Slowly rock in a rocking chair while you watch TV, or pick a target and try to keep focused on it as you rock. As you improve, rock faster. Turn your head to one side and pick something to

focus on as you rock; then practice rocking with your head turned to the other side.

RIDING IN CARS

Whenever you have the opportunity, ride as a passenger in a car. While the car is in motion, slowly turn your head from one side to the other with eyes closed, then with eyes open. Have the driver accelerate or slow down periodically. It is normal to feel unusual sensa- tions of motion at ﬁrst, but these diminish with practice.

Dizziness Exercises

These exercises can be done as often as you wish, to keep dizziness under control.

HEAD MOVEMENT DIZZINESS

If dizziness occurs only when your head is turned, check to see if it goes away when you turn your head with your eyes closed. If it does, try to blink or close your eyes while you turn your head, and turn your head faster

than normal. Use the target practice exercises listed earlier. At least twice a day, do the ﬁxa- tion practice exercise, but turn your head quickly to make yourself feel as dizzy as possi- ble. The more you repeat this, the quicker your dizziness will go away. If dizziness occurs even with the eyes closed, you will need to practice turning your head with eyes closed—slowly at ﬁrst, and gradually increasing the speed until you become used to the dizziness.

EYE MOVEMENT DIZZINESS

Use this exercise if dizziness occurs when you move your eyes, even when your head is held perfectly still. Lie down with your eyes closed. Slowly rotate them around as far to the sides, up, and down as you can. If you feel increased dizziness in one particular direction, try to keep your eyes turned in that direction as you count to 10. Then open your eyes and try to focus on something. As soon as the dizziness decreases (a few seconds), close your eyes and again turn them in the most unpleasant direction. Keep repeating this exercise until the dizziness is decreased.

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Chapter 21 ‌

Future Directions

When the ﬁrst edition of this book was written in the late 1970s, there was great excitement regarding the potential for engineering models to describe vestibular function in normal sub- jects and patients. Steinhausen’s pendulum model of semicircular canal function was shown to reliably predict the ﬂow of action potentials in isolated ampullary nerves in several mam- mals, including primates. A simple ﬁrst-order approximation of this linear model remarkably predicted vestibulo-ocular responses in normal subjects and provided a framework for inter- preting abnormal responses in patients. These models consisted of “black boxes” represented by transfer functions that described the rela- tionship between the input and output. Little was known about what actually went on in these black boxes. David A. Robinson, one of the pioneers in oculomotor modeling, warned that “Block diagrams of oculomotor organiza- tion serve as a compact description of system behavior but seldom have much bearing on the way in which the real system, composed of nerve and muscle, actually operates. The models thus do not contribute much to the neurophys- iology (or neurology) of eye movements and incur the danger of suggesting that there actu- ally are segregated portions of the nervous system which perform differentiation, integra- tion and other operations indicated in the boxes of the diagrams.”1 But progress in understand- ing basic cellular and molecular mechanisms awaited technical advances in cell and molecular biology. As technical advances have occurred, we can now focus on these black boxes. How do the mechanosensory channels and the ribbon synapses in hair cells work? What transmitters are released and what recep- tors are expressed at peripheral and central

vestibular synapses? What ion channels are expressed in the peripheral and central vestib- ular pathways, and how do these ion channels explain the observed physiology? What changes occur at the molecular level after damage to peripheral and central vestibular structures? In this fourth edition, answers to these questions are beginning to be addressed, but we are still in the early stages of understanding. Future scientiﬁc discoveries will no doubt improve our understanding of the vestibular system in health and disease. A better understanding of this intricate system will hopefully lead to the future ability to modulate it or even to substi- tute for it—advances that could enhance the care of patients with vestibular disorders.

Meaningful scientiﬁc progress requires translating basic science discoveries into inter- ventions that improve our well-being—a step that hinges on rigorous clinical studies. A poster child for scientiﬁc progress in the ﬁeld of clini- cal neurophysiology of the vestibular system is benign positional vertigo (BPV). BPV is now a well-deﬁned entity, and we have a solid under- standing of the underlying pathophysiology of the disorder. The diagnostic tests for it are reli- able and valid. A hypothesis introduced in the 1960s led to the development and reﬁnement of a treatment, and an early case series in the 1980s suggested its usefulness. Numerous ran- domized clinical trials followed over the past 20 years, and the efﬁcacy of the treatment was solidly established by several independent systematic reviews of the clinical trials. As a result, clinical practice guidelines have been published within the past year.

As noted previously, some future advances will require new scientiﬁc discovery, but others will require determining ways to optimize the

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432 Clinical Neurophysiology of the Vestibular System

use of services already available. Which of our vestibular patients will meaningfully beneﬁt from the interventions we direct them toward andwhichwillbeharmedbythem? Randomized controlled trials are the gold standard method to study the efﬁcacy of any intervention, yet other than a few examples adequate trials are lacking in many areas important for the man- agement and treatment of our patients. Beyond randomized trials, we also need research that deﬁnes the effectiveness of our interventions in the real world and that helps us better identify the patients most likely to beneﬁt from what we have to offer.

Our clinical tests need later phase diagnostic test research to better deﬁne their value. Many sophisticated tests have been developed to make laboratory measurements of the vestibu- lar system. Most of these tests have been reﬁned for optimal performance. Others are still in the early development phases. These tools play an essential role in research studies. Clinically, some of these tests have proven to be very good discriminators of vestibular pathology, but others have not, particularly when used in certain populations such as the elderly or patients with mild or early-stage dis- orders. Most have not undergone rigorous assessment of the reliability (reproducibility) of the test or the test interpretation outside of expert centers. Furthermore, later phase diag- nostic test research has not been performed with most of these tests. The validity of these tests for important endpoints (imaging ﬁnd- ings, clinician consensus diagnosis, future diag- nosis or outcome) has not been assessed in populations of patients having important levels of clinical uncertainty. Finally, none of the tests has been subjected to the gold standard deter- minant of the clinical value of a diagnostic test. The gold standard is to assess whether the patients who receive the test have better future meaningful outcomes than patients who do not receive the test. In these designs, the test is

considered the intervention and patients are randomized to have it. When considered at the aggregate level of utilization, the routine use of tests prior to these later phase assessments may result in more unintended consequences (e.g., inconvenience to the patient, adverse events, adverse emotional effects of false-positive results, and excess costs) than meaningful beneﬁt to the patient.

More research to deﬁne the clinical value of bedside information (i.e., medical history and examination ﬁndings) may help in deciding which patients are likely to beneﬁt from tests or therapies and which are not. For example, the head-thrust test seems to be an exception- ally effective way to assess the likelihood of stroke in patients with acute vestibular syn- drome presentations, but what is the reliability of the test in these circumstances (particularly among frontline clinicians who do not regularly use it) and would it perform better than a validated scale of stroke risk factors?

Finally, we need to understand why one of the most efﬁcacious and simple interventions in all of clinical medicine—particle reposition- ing for BPV—is substantially underutilized. In fact, patients with BPV are more likely to receive a brain imaging study than to be cured with repositioning. Many disorders are desper- ately in need of the discovery of a cure, but BPV already has one. What good are efforts to discover new treatments if they ultimately go unused or misused? Is the underutilization a matter of “clinical inertia” or could underuti- lization stem from other factors, such as policy disincentives?

REFERENCE

1. Robinson DA. Models of oculomotor neural organiza- tion. In: Bach Y, Rita P, Collins C, Hyde J, eds. The Control of Eye Movements. New York: Academic Press;1971:519.

Video Legends*‌

Video 6-1. The past pointing test

With eyes closed, the patient is instructed to lift his arm off the target and then bring the ﬁnger back down in the same spot. The patient in the video consistently misses the target to the right side, which is the affected side. Note that the patient in this video is the same patient in Video 6-5.

Video 6-2. The head thrust test

The patient’s eye stays ﬁxed on the target after quick, small amplitude movements of the patient’s head to the left, which is consistent with an intact vestibular ocular reﬂex on the left side (i.e., negative head thrust test). However, after head movements to the patient’s right side, the patient’s eyes move off the target and then a re-ﬁxation (corrective) saccade is required to bring the eyes back to the target, which is consis- tent with a positive head thrust test on the right side indicating de-afferentation or a lesion of the right vestibular system. Note that the patient in this video is the same patient in Video 6-5.

Video 6-3. The head thrust test

Note that after quick, small amplitude move- ments of the patient’s head to the right side, the patient needs to make a corrective saccade to bring the eyes back to the target (i.e., a posi- tive head thrust test). But, the eyes stay on tar- get after the head thrust test to left side (i.e., a negative head thrust test). This video is partic- ularly helpful for demonstration purposes because the voluntary corrective saccade to the right side is delayed on the ﬁrst test.

Video 6-4. Spontaneous nystagmus

Patient with high velocity spontaneous left beating nystagmus which increases velocity when the patient looks to the left side and then stops when the patient looks to the right side.

This recording was made on the ﬁrst day of a vestibular neuritis presentation.

Video 6-5. Spontaneous nystagmus

The patient has spontaneous left-beating nystag- mus. The patient was videotaped on the second day of a vestibular neuritis, and thus the velocity of the nystagmus is less than seen in Video 6-4.

Video 6-6. Second degree nystagmus

The nystagmus velocity increased when the patient looks to the left. The nystagmus stops when the patient looks to the on right gaze. Note that the patient in this video is the same patient in Video 6-5.

Video 6-7. Spontaneous down-beating nystagmus

In primary position, the patient has persistent small amplitude down-beating nystagmus.

Video 6-8. Spontaneous up- beating nystagmus

In primary position, the patient has persistent small amplitude up-beating nystagmus.

Video 6-9. Gaze-evoked nystagmus (multi-directional)

In a patient presenting with acute vertigo and imbalance Note the prominent left-beating nystagmus in left gaze. Next, note that the patient clearly also develops right- and down- beating nystagmus on right gaze. Because the nystagmus changes direction, this is a central pattern even though the velocity is greater in one direction.

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434 Video Legends

Video 6-10. Gaze-evoked nystagmus and impaired smooth pursuit

The patient develops right beating nystagmus when the patient looks to the right side and left-beating nystagmus when looking to the left side. Also note the impairment of smooth pursuit (i.e., saccadic pursuit) as the patient follows a target back and forth.

Video 6-11. Gaze-evoked downbeating nystagmus

On gaze to either side, the patient develops down-beating nystagmus.

Video 6-12. Benign positional vertigo, posterior canal

The patient was just placed in the right head- hanging position (i.e., right Dix-Hallpike posi- tion). After a brief delay, a burst of upbeat and torsional nystagmus is seen. The duration of the nystagmus is about 12 seconds.

Video 6-13. Benign positional vertigo, posterior canal, testing using goggles

Video goggles were used in this video. The patient is placed in the left Dix-Hallpike posi- tion and a burst of upbeat torsional nystagmus is seen.

Video 6-14. Convergence retraction nystagmus

The patient has spontaneous convergence nys- tagmus. Also note that the patient has impaired upgaze.

Video 6-15. Ocular ﬂutter

Spontaneous bursts of back and forth horizon- tal saccades consistent with ocular ﬂutter. Note

that there is no pause between the individual saccades.

Video 7-1. Saccade dysmetria

The patient is being instructed to look back and forth from one target to another. With each saccade eye movement, the patient over- shoots the target then has to make another sac- cade back to the target.

Video 10-1. Epley Maneuver for right posterior canal benign positional vertigo

First, the patient’s head is turned to the right side. Next, the patient is rapidly brought down to the right head hanging position (i.e., the right Dix-Hallpike test). The clinician observes for the typical burst of upbeat and torsional nystag- mus (see Video 6-7). Next the patient’s head is turned toward the left and the patient rolls over onto the left side, making certain not to allow the patient to lift the head up. At the end of this position, the patient is lying on the left side with the face turned so the patient is looking at the ground. This position is maintained for about 30 seconds. Then, the patient is rapidly brought back up to the sitting position.

Video 10-2. The Gufoni maneuver for patients with left horizontal canal benign positional vertigo

From the seated position, the patient is quickly placed in the right decubitus position. This position is maintained for approximately 10-20 seconds. Next, the patient’s head is turned so that the patient is looking into the table. This position is maintained for approximately 20-30 seconds, then the patient is quickly brought back up to sitting position.

* Videos can be found at the following website: www.oup.com/us/cns/vestibular