Central Nervous System
Cell Pathology  |
Edema /Herniation/Hydrocephalus |
Vascular Disease |
| Trauma |
Congenital Defects |
Infection |
| Neoplasm |
Diseases of Myelin |
Nutritional Disease |
| Metabolic Disease |
Degenerative Disease |
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Neurons
Reaction to Injury:
Liquefactive Necrosis
Pyknosis - Nuclear Contraction
Karyorrhexis - Nuclear Fragmentation
Karyolysis - Loss of staining
Chromatolysis - Nissl Dispersion
Inclusion Bodies
Astrocytes
Structural Framework
Scar Tissue Formation - Astrocytosis (Gliosis)
GFAP - Glial Fibrillary Acidic Protein
Corpora Amylacea - Age Related Glycoproteins
Oligodendrocytes
Myelin production in CNS
Site of demyelinative disorders
i.e. Multiple Sclerosis
Ependymal Cells
Line cerebral ventricles
Prevent CSF entering parenchyma
Microglia
Derived from monocytes
Phagocytic system of CNS
Cerebral Edema
Vasogenic Edema
Leakage of vascular fluid into Brain parenchyma
extracellular fluid accumulation
Ex. Trauma, Stroke, Cancer, Abscesses
Cytotoxic Edema
Hypoxic damage of cell membrane
intracellular fluid accumulation
Ex. Stroke
Herniation
Movement and injury to brain as a result of an increase in ICP (intracranial
pressure).
Subfalcine Herniation
Displacement of cingulate gyrus under falx cerebri.
Ant. cerebral artery compression
Clin. hemiparesis
Transtentorial Herniation
Displacement of medial portion of temporal lobe (uncus) through
tentorium cerebelli.
Post. cerebral artery compression
Clin. hemiparesis, pupillary fixation & dilatation, blindness, Duret's
hemorrhage.
Tonsillar Herniation
Displacement of the cerebellar tonsils through the foramen magnum.
Basilar artery compression
Clin. Respiratory arrest
Hydrocephalus
Accumulation of excessive CSF within the ventricles of the brain.
Causes: Overproduction, impaired reabsorption, obstruction.
Noncommunicating:
Obstruction of flow within ventricular system.
Communicating:
Obstruction of flow outside ventricular system, subarachnoid space.
Ex vacuo:
Expansion of the ventricular system secondary to brain atrophy.
Ex: Alzheimer's, chronic alcoholism
Normal Pressure:
Chronic ventricular dilatation in elderly with no known cause.
Clin. dementia, ataxia, incontinence
Vascular Diseases
Interruption of normal blood flow to brain parenchyma.
Types of vascular disease:
1. Global ischemia/hypoxia
Reduction of blood flow or oxygen to entire CNS.
Ex: Cardiac arrest, carbon monoxide poisoning.
2. Infarcts
Localized vascular obstruction.
Ex: thrombosis in situ, embolization
3. Intracranial hemorrhage
Spontaneous non-traumatic bleeding within parenchyma or
subarachnoid space
Global Ischemia/Hypoxia
Characteristics
hippocampus pyramidal cell necrosis
cerebellar purkinjie cell necrosis
laminar necrosis
watershed infarcts
Clin.: transient neurologic deficits - brain death
Infarcts/CVAs (Cerebrovascular accidents)
Transient Ischemic Attack (TIA)
Neurologic deficit that lasts less than 24hrs followed by complete recovery.
Completed Stroke
Persistent neurologic deficit.
Risk Factors:
Atherosclerosis, hypertension, myocardial infarction, heart valve disease, arteritis, etc.
Major sites for occlusion:
Internal carotid bifurcation, middle cerebral art., basilar art.
Course:
1-3 min. occlusion = infarction
8-12 hrs. = gross brain normal
36-48 hrs = gross edema and liquefaction
1 mo. = gross cavitation
6 mo. = complete cavitation
Thrombosis in situ: Pale/Bland Infarct
Embolism: Red/Hemorrhagic Infarct
Clinical:
TIA's: Carotid -
Contralateral weakness and paresthesia. Leg>arm.
Amaurosis fugax.
Vertebrobasilar -
Vertigo, ataxia, diplopia, dysarthria, paresthesia
Stroke: Anterior Cerebral art. -
Contralateral hemiplegia/paresis
Urinary incontinence
Behavioral and memory changes
Middle Cerebral art. -
Contralateral hemiplegia/paresis
Aphasia
Posterior Cerebral art. -
Contralateral hemiplegia/paresis
Face/upper extrem.> legs
Visual loss
Spontaneous Nontraumatic Hemorrhage
Intraparenchymal:
Major risk factor is hypertension.
Major site is basal ganglia
Charcot-Bouchard microaneurysms
Clinical: Peak age is 60
Acute focal deficits
Intracranial Pressure
Subarachnoid Hemorrhage:
Saccular/Berry aneurysm (1% of pop.)
Major site is Circle of Willis
Clinical: Average age 20-50
50% mortality rate
Sudden severe headache
Vomiting
Loss of consciousness
Nuchal rigidity
Complications: Infarction, hydrocephalus, herniation.
Vascular Malformations (AVM's)
Developmental abnormalities of angiogenesis.
Most commonly associated with middle cerebral artery.
Rupture occurs from age 10-?
Other forms: Cavernous angiomas
Capillary telangiectasias
Venous angiomas
CNS TRAUMA
The most common forms of CNS trauma:
1. Epidural hematoma
2. Subdural hematoma
3. Parenchymal Injury
A. Concussion
B. Diffuse Axonal Injury (DAI)
C. Contusions
Epidural Hematoma:
Middle meningeal artery rupture with temporal bone fracture.
Arterial bleeding leads to medical emergency.
Lucid period may complicate treatment.
Subdural Hematoma:
Disruption of bridging veins connecting dural sinuses and cerebral surface.
Acute subdural hematoma is often seen with history of trauma.
Acceleration/deacceleration injury
Major injury seen in Shaken Baby Syndrome.
Chronic subdural hematoma not always seen in conjunction with trauma
history.
Brain atrophy predisposes to chronic subdural formation.
collagenous granulation tissue derived from fibroblasts of dura.
Parenchymal Injury:
Concussion:
Transient loss of consciousness, retro and/or antegrade
amnesia,seizures,paresis/paralysis. Resolution in hours-days.
Lack of gross brain injury.
DAI:
White matter axonal injury.
Post-traumatic dementia.
Major cause of vegetative state.
Contusions:
Superficial parenchymal hemorrhage and cell injury.
Major sites are anterior portions of frontal and temporal lobes.
Immobile head + blunt force = Coup contusion.
Accelerating head + immobile surface = Contre-coup contusion.
Bar-stool syndrome.
Plaque-jaunes: Hemosiderin deposition.
Congenital Defects
Consequence of genetic abnormalities, toxins, infections, etc. on the CNS during in
utero development.
Neural Tube Defects (Dysraphism):
Most common group of CNS congenital defects.
Anencephaly:
Most common congenital brain defect (1/500).
Absence of calvaria
Absence of cerebral hemisphere development = cerebrovasculosa
Hydramnios
Multiple organ defects
Fatal shortly after birth
Encephaloceles/Cranial Meningoceles
Protrusion of brain and/or meninges through a occipital or anterior cranial
defect.
Spina bifida (spinal dysraphism):
Group of disorders usually involving a vertebral arch defect (most often
lumbosacral) with meningeal and cord involvment.
Myelocele: arch defect + exposed neuroectoderm. Most severe type.
Meningocele: arch defect + protrusion of meninges. No cord herniation.
Meningomyelocele:
arch defect + protrusion of meninges and spinal cord.
Spina bifida occulta:
arch defect without meningeal or cord involvement.
Asymptomatic/ 20% gen. pop.
Posterior Fossa Malformations
Arnold-Chiari malformation:
Shallow post. fossa
Extension of medulla and cerebellum through foramen magnum
Z-kinked cervical cord
Hydrocephalus
Meningomyelocele
Dandy-Walker malformation:
Enlarged post. fossa
Aplasia of cerebellar vermis
Cystic enlargement of 4th. ventricle
Hydrocephalus
Other defects may include cranial encephalocele, etc.
Forebrain Disorders
Megalencephaly: brain wgt.>1800g.
Microencephaly: brain wgt.< 800g.
Polymicrogyria: numerous small gyri
Lissencephaly: Lack of gyri
Patau's Syndrome (Trisomy 13):
Holoprosencephaly:
Defects originating from abnormal division of cerebral hemispheres.
Lack of divisional development leads to single enlarged ventricle.
Facial Abnormalities:
These defects that accompany abnormal CNS development include
facial clefts to the most severe form - cyclopia.
Neurocutaneous Syndromes
Neurofibromatosis type I (von Recklinghausen's disease)
Autosomal dominant
1/3000 Chr. 17
Neurofibromas
Schwannomas
Peripheral nerve malignancies
Meningiomas, gliomas
Cafe-au-lait pigmentation
Lisch nodules of iris
Neurofibromatosis type II
Autosomal dominant
1/40,000 Chr. 22
Bilateral acoustic schwannomas
Meningiomas, gliomas, spinal neurofibromas
Perinatal Injury
Cerebral Palsy
Perinatal hypoxia/anoxia resulting in cerbral cortex injury.
Nonprogressive neurologic deficits
Muscular spasticity
Mental retardation
CNS Infection
Infection of the CNS is a consequence of both host resistance and vector virulence.
Spread of infection can be via hematogenous route, direct implantation, and
contiguous extension of soft tissue/bone infection.
Epidural/Subdural Infection
Epidural (Abscess): Localized
Subdural (Empyema): Diffuse
Major agents: Staph. & Strept.
Cause: Trauma/Contiguous spread from paranasal sinusitis,
mastoiditis.
Leptomeningitis: Infection of arachnoid, pia, and subarachnoid space.
1. Acute purulent meningitis.
2. Lymphocytic meningitis.
3. Chronic meningitis.
Acute Leptomeningitis
Bacterial meningitis that often shows a correlation between patient age and type
of infective agent.
Neonates: E. coli/group B strept.
Children: S. pneumoniae
Adolescents/adults: Neisseria meningitidis
Elderly: S. pneumoniae
In general, patients develop a purulent subarachnoid exudate (fibrin deposition)
and severe meningeal congestion with predominace of neutrophils.
Clinical: Fever, headache, altered mental status, and nuchal rigidity.
CSF: Fluid turbidity, elevated protein, leukocytosis
(neutrophils), decreased glucose, positive culture.
Acute Lymphocytic (aseptic) Meningitis
Patients with this form of infection have a better prognosis than bacterial
forms and course tends to be self-limited.
Types: Mumps, Epstein-Barr, coxsackie, almost any virus has potential.
CSF: Fluid clear to slightly turbid.
Lymphocytosis.
Protein slightly elevated.
Glucose normal.
Culture often negative.
Chronic Meningitis
Rare form of infection typically resulting from exposure to Mycobacterium
tuberculosis, Cryptococcal neoformans, and Treponema pallidium.
CSF: Increased protein, decreased glucose, and lymphocytosis.
Clinical: Variable symptoms, meningeal fibrosis with hydrocephalus.
Encephalitis
Parenchymal infections of the CNS. Bacterial infections tend to be localized
(cerebritis-abscess) and viral infections tend to be more diffuse (encephalitis).
Abscess:
Bacterial infection via hematogenous, contiguous spread, or direct
implantation results in localized lesion.
Cerebritis is initial liquefaction of brain followed by permanent abscess
formation composed of both astrocytic and fibroblastic wall components.
Clinical: Focal deficits, fever, increased ICP.
CSF: Analysis maybe normal with protein elevation, +/- cells.
Viral Encephalitis
Infection of brain parenchyma by viruses can be characterized by some
common findings.
1. Perivascular lymphocytic cuffing
2. Neuronophagia
3. Inclusion body formation
Arbovirus Encephalitides
Common epidemic form.
Types: Eastern, Western, St.Louis
Mosquito vector (rural populations)
Herpes Simplex Encephalitis
Type I: Sporadic adult disease.
Hemorrhagic, necrotizing.
Intranuclear inclusions (Cowdry type A).
Temporal and frontal lobes.
Type II: Rare adult disease.
Severe (often fatal) neonatal encephalitis.
Cytomegalovirus (CMV)
The primary CNS target for this type of herpes virus is the ependymal cell.
Typical patients are those infected in utero and immunocompromised
(AIDS).
Immunocompromised:
Organ transplant recipients.
Allogenic bone marrow. transplants.
AIDS patients.
Multisystem disease (lungs, liver).
Approx. 50-90% of pop. seropositive.
Transmission: Resp., transplacental, breast feeding, transplants,
oral-fecal, venereal.
HIV-1 Encephalitis (AIDS dementia complex)
Direct infection of brain by HIV-1 results in demyelination, atrophy, and
basal ganglia damage.
Clinical: Dementia, incontinence, ataxia.
Progressive Multifocal Leukoencephalopathy (PML)
Viral disease affecting oligodendrocytes of immunocompromised patients.
JC papovavirus.
Clinical: Quadriparesis, dementia, aphasia, ataxia, visual field defects.
Course: 3-6 mos. (Slow Viral Disease)
Subacute Sclerosing Panencephalitis (SSPE)
Altered measles virus replication in children and adolescents.
Clinical: Personality changes, dementia, seizures.
Course: Disease progresses from 1-3 yrs. (Slow viral disease) Approx.
98% fatal.
Spongiform Encephalopathies
Prion based infections of livestock and humans. Infection leads to
microvacuolization of cerebral and cerebellar cortex.
Creutz-feldt (CJ) disease
Human spongiform encephalopathy.
Clinical: Dementia and ataxia with extrapyramidal involuntary limb
movement.
Course: Typically death within 1 yr.
CNS Neoplasms
This category includes tumors derived from brain, cord, meninges, and metastatic
cancer. Most CNS tumors are derived from glial cells. Although many primary
CNS
tumors are highly malignant, spread outside the CNS is extremely rare.
50% primary tumors
50% metastatic tumors
Primary tumors
10-17/100,000 intracranial
1-2/100,000 intraspinal
2% of all cancer deaths
15% of all childhood cancer deaths
Intracranial metastatic cancer is common from lung, breast, and skin.
Intraspinal metastatic cancer is common from lung, prostate, breast,
and kidney.
Most common adult intracranial tumors:
1. metastatic
2. glioblastomas
3. anaplastic astrocytomas
4. meningiomas
Most common child intracranial tumors:
1. astrocytoma fibrillary
2. medulloblastoma
3. ependymoma
Spinal Cord Tumors:
Extradural - metastatic, chordomas
Intradural
Extramedullary - schwannoma, meningioma
Intramedullary - astrocytoma, ependymoma
Tumor Stage: Clinical estimate of size, extent of local invasion, and presence
of reginal/distant metastases. (TNM)
Tumor Grade: Histologic assessment of degree of differentiation.
Gliomas
Astrocytomas
Most common primary CNS tumor. As a group they comprise 80% of
adult primary CNS tumors.
Grading: pilocytic, fibrillary astrocytoma, anaplastic astrocytoma,
glioblastoma multiforme.
Grading dependent on:
1. nuclear pleomorphism
2. mitotic activity
3. vascular proliferation
4. necrosis
Clinical: Non-localizing indications of increased ICP, focal deficits,
seizures, etc.
Tumor 10g. focal signs
Tumor 100g. ICP signs
Prognosis:
Survival rates
Pilocytic > 40 yrs.
Astrocytoma = 5 yrs.
Anaplastic a. = 3 yrs.
Glioblastoma m. = 1 yr.
Oligodendrogliomas
Common adult tumor found in white matter of cerebral hemispheres.
Clinical: Typical patient has long history of poorly defined neurologic
problems including seizures. Detection often resulting of
noting X-ray evident calcification.
Prognosis: Average survival 5-10 yrs.
Tumors may be mixed.
Ependymomas
These tumors are typically found in the 4th ventricle or the central canal of
the spinal cord. Well demarcated and relatively slow growing with
potential for CSF seeding.
Clinical: Primarily affect patients during first two decades.
Choroid plexus papilloma in children.
Major complication is hydrocephalus.
Prognosis: Typical survival is 4 yrs.
Medulloblastoma
The most common tumor classified as primitive neuroectodermal tumors
(PNET).
Primarily a tumor of children it often presents as a undifferentiated mass
developing within the cerebellum.
Clinical: Patients show progressive signs of increased ICP and gait
abnormalities.
Prognosis: Typical survival is 5 yrs.
Meningioma
Primarily an adult benign tumor arising from the arachnoid granulations in
the cranial vault or spinal cord.
Clinical: Manifestations dependent on site plus ICP complications.
Progesterone receptors.
Bone hypertrophy
Prognosis: Variable 10% recurrence rate
Metastatic Neoplasms
These tumors represent about 50% of all intracranial cancer. Metastatic
spread to the CNS in adults is most commonly from breast, lung, skin.
Although malignant, lesions tend to be well demarcated from
surrounding tissue and typically show multiple areas of
tumorgenesis.
Clinical: ICP problems and variable focal deficits.
Prognosis: Variable.
Disease of Myelin
These conditions either affect myelin directly or interfere with oligodendrocytic
function. Two broad categories include acquired myelin dysfunction and the
leukodystrophies.
Acquired demyelination
Multiple Sclerosis
Episodic neurologic deficits separated in time. White matter lesions
separated in space.
Localized lesions (plaques) of demyelination within periventricular white
matter, optic nerve, white matter of spinal cord.
Incidence rate is dependent on number of factors:
1. Average 1/1000
2. Female:male 2:1
3. Target age 20-40
4. Geography
5. Genetic: 1st degree relatives
6. HLA type: A3,B7,DR2,DR3
Disease appears to be autoimmune in origin:
1. Relapsing/remitting course.
2. Presence of CD4 and CD8 cells activated toward myelin basic
protein.
3. Oligoclonal CSF IgG.
4. Cell culture.
Clinical: Muscle weakness/spasticity
Ataxia
Paresthesia/numbness
Optic neuritis/scotoma/diplopia
Fatigue
Spastic/atonic bladder
Sexual dysfunction
Note - Neurologic deficits increase with trauma, surgery, infection,
and pregnancy. Symptoms also increase with elevation of body
temperature.
Course: Benign 20-30%
Relapsing/remitting
Stable progressive 50-60%
Chronic progressive 15-20%
Acute progressive < 5%
Acute Disseminated Encephalomyelitis
Immune mediated demyelination of acute onset following infection
with measles, chickenpox, rubella, and vaccinations.
Clinical: Fever, seizures, spinal cord dysfunction, focal neurologic
deficits, coma.
Prognosis: Variable
Fatal 15-20%
Leukodystrophies
This group of disorders is characterized by inheritable defects of myelin
synthesis leading to progressive severe diffuse demyelination (CNS +/-
PNS) in infancy and childhood.
Metachromatic L. Autosomal rec.
Krabbe's disease Autosomal rec.
Adrenoleukodystophy X-linked/Aut. rec.
Nutritional Diseases
Thiamine (B1) deficiency
This condition is thought to be a major source of CNS/PNS damage in chronic
alcoholics.
Wernicke Encephalopathy
Thiamine dependent cerebral vascular damage leading to hemorrhage and
edema of grey matter. Areas most involved include:
1. mamillary bodies (hypothalamus)
2. thalamus
3. cerebral aqueduct
Clinical: Confusion, ataxia, and extraocular muscle paralysis
Korsakoff's psychosis
Permanent CNS damage leading to loss of short term memory
processing and long term memory retrieval deficits.
Confabulation: fantasy for fact.
Alcoholic Cerebellar Degeneration
Thiamine dependent atrophy of cerebellar vermis leading to:
1. truncal ataxia
2. gait instability
3. dysarthria
Cobalamin (B12) Deficiency
In the nervous system, cobalamin deficiency leads to spinal cord damage termed
Subacute Combined Degeneration of the Cord. Areas most involved include
dorsal and lateral white matter columns.
Metabolic Disease
Wilson's Disease
Autosomal recessive disease seen in adolescents and young adults.
Patients do not produce sufficient ceruloplasmin (copper carrier). Lack
of biliary secretion leads to deposition of copper in the brain and liver
(hepatolenticular degeneration).
Clinical: hepatitis/cirrhosis
psychosis
Kayser-Fleischer rings
Degenerative Disease
This category encompasses a group of disorders characterized by the spontaneous
degeneration of neurons within the brain and/or spinal cord.
Alzheimer's Disease
The most common cause of senile dementia. The disease is sporadic with 10%
showing a familial linkage.
Factors: Many genetic abnormalities have been studied. Chr. 21,19,14
B-amyloid is a breakdown product of amyloid precursor
protein (APP), it is implicated in senile plaques and
vascular angiopathy.
ApoE4 (normal E2) is used as a marker and implicated
with processing APP.
Pathology: Atrophy of frontal, temporal, and parietal lobes.
Hydrocephalus ex vacuo
Acetylcholine depletion
Neurofibrillary tangles
Neuritic (senile) plaques
Amyloid angiopathy
Note: Microscopic lesions appear primarily within the
hippocampus, amygdala, and neocortex.
Clinical: Short term memory and cognitive impairment.
Total disability within 5-15 yrs.
Death usually due to respiratory failure.
Pick's Disease
Condition clinically similar to AD with severe atrophy of frontal and temporal
lobes.
Pick Body: Cytoplasmic inclusion not resistant to proteolysis.
Clinical: Age of onset = 50
Parkinsonism
A degenerative condition (idiopathic/paralysis agitans) primarily resulting from
loss of dopaminergic neurons within the nigrostriatal pathway (substantia
nigra, locus ceruleus). Disease is sporadic with 10% developing profound
dementia.
Clinical: Patient > age 60
Decreased facial expression
Stooped posture
Bradykinesia/akinesia
Festinating gait
Rigidity
Resting tremor
Lewy bodies
Prognosis: Disease is progressive over a course of about 10-15 yrs.. Death
results from infection and/or complications of falls.
Huntington's Disease
A degenerative disease characterized as a hereditary, fatal disease of the
extrapyramidal system. The defect is localized to chr. 4 that codes for a
protein huntingtin. With loss of neurons in the caudate nucleus, putamen, and
globus pallidus, there is reduction of gamma amino butyric acid (GABA)
synthesis.
Clinical: Patient typically age 40-50.
Choreiform movements
Rigidity
Cognitive impairment
Course: Typical progression 15-20 yrs.
Death usually result of infection or suicide.
Amyotrophic Lateral Sclerosis (Lou Gehrig's disease)
Idiopathic progressive motor disease (1-2/100,000). Characterized by
degeneration of the pyramidal system and anterior horn cells of cord thus
patients present with both upper and lower motor lesions. Some patients show
mutations in gene coding for superoxide dismutase.
Clinical: Sporadic onset
Av. age 65
Spacticity/flaccidity
Cognition intact
Fasciculations
Eye movement intact
Course: Median survival 5 yrs.
Death from respiratory failure and/or infection.
Variants: Spinal muscular atrophy (LML)
Progressive bulbar palsy (LML)
Pseudobulbar palsy (UML)
Infantile Muscular Atrophy (Werdnig-Hoffman disease)
Autosomal recessive disorder affecting infants (3-5mos.).
Degeneration of anterior horn cells leads to general hypotonia
followed by respiratory failure and death (1-3 yrs.)
Friedreich's Ataxia
Autosomal recessive disorder resulting in degeneration of posterior columns of
cord and corticospinal tracts.
Clinical: Onset age 10-20
Sensory loss
Staggering gait
Cardiomyopathy
Cognitive decline
Course: Progressive for 10 yrs.
Death due to cardiomyopathy and/or infection.
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