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Infantile Spasms
by Dr. Ted Guarino
Note: (The following article does not contain all treatments
currently available for treatment of Infantile Spasms).
Infantile spasms (herein "IS") are part of an age-related
epilepsy known as West Syndrome. The spasms typically are refractory to
anticonvulsants and are associated with a characteristic pattern on EEG
known as hypsarrhythmia. Prognosis for normal development is poor;
however, early aggressive treatment can maximize the cognitive outcome
in these patients.
Since West wrote to Lencet some 153 years ago describing his son’s
"…bowing and relaxings…from 10 to 20 or more times at each
attack," 1 IS remain one of the most dreaded
pediatric diagnoses. The triad of IS, hypsarrhythmia on EEG, and
developmental delay has come to be known as West Syndrome. Current
anticonvulsant therapy seems to have made little impact on the long-term
prognosis of this poorly understood epilepsy.
Ictal Patterns
Variously referred to as jackknife seizures, massive myoclonic seizures,
salaam attacks, cheerleader spasms, infantile myoclonic seizures,
lightning seizures, or other imaginative descriptions, four ictal
patterns of IS are recognized. 2 The flexor
spasm consists of rapid flexion at the waist that may be so violent it
mimics a jackknife action. If the infant is sitting, this rapid flexion
may resemble the salaam greeting. If the infant is supine, brief flexor
spasms may resemble sit-ups or abdominal "crunches". The
extensor spasm involves a rapid extension of the back and extremities,
typically with arm abduction so that the infant may resemble a
cheerleader waving pom-poms. The mixed spasm contains components
of both flexion and extension. The akinetic spasm is the least
common type and consists of sudden loss of motor activity. Most studies
report that flexor or mixed spasms are the usual presentation, followed
in frequency by extensor and akinetic types. 3-5
The spasms typically present in clusters or flurries of a dozen or more,
interspersed by several seconds or minutes of respite. Respiratory
changes, crying or laughing, and flushing or other autonomic features
may be associated with these seizures. 3
More recently, focal or asymmetric spasms, as well as spasms with focal
seizures, have been studied. 6, 7 An asymmetric
spasm (one with asymmetric contractions) indicates a focal cerebral
lesion or symptomatic origin. The presence of partial seizures
concomitant with IS also implies a symptomatic origin and is highly
correlated with asymmetric hypsarrhythmia on interictal tracing.
EEG Patterns
In 1952, Gibbs and Gibbs derived the term hypsarrhythmia from the Greek hypsi,
meaning high. 8 Hypsarrhythmia describes the
chaotic high-amplitude slow waves and spikes that are seen on the
interictal EEG usually associated with IS. Gibbs and Gibbs described
"random high-voltage slow waves and spikes" as varying from
moment to moment, both in duration and location. At times, they appear
to be focal, and a few seconds later they seem to originate from
multiple foci. Occasionally, the spike discharge becomes generalized,
but it never appears as a rhythmically repetitive and highly organized
pattern. The abnormality is almost continuous, and in most cases it
shows as clearly in the waking as in the sleeping record. It is referred
to as hypsarrhythmia. 8
Hrachovy et al studied 24-hour EEG’s of 67 infants with IS and
identified some hypsarrhythmia variants. 9
Hypsarrhythmia with increased interhemispheric synchronization (modified
hypsarrhythmia) may be a transient feature in a patient’s course not
necessarily correlated with a change in prognosis. Asymmetric
hypsarrhythmia or hemihypsarrhythmia seems to be associated with
porencephaly, agenesis of the corpus calosum, megaloencephaly, or other
identifiable cerebral lesions. Hypsarrhythmia with periods of
generalized or focal voltage attenuation is most evident during nonrapid
eye movement (NREM) sleep and resembles a burst suppression pattern.
Brief NREM sleep may produce a semiperiodic grouping of spike and slow
wave discharges. REM sleep tends to produce a relative normalization of
background activity, with marked reduction of hypsarrhythmia that
persists throughout the stage. Arousal from REM or NREM sleep also
causes a transient, marked reduction of hypsarrhythmia, lasting seconds
to minutes.
The ictal EEG appears to consist of three main patterns, each correlated
to a particular spasm. Fusco and Vigevano recorded 955 spasms in 70
infants and described the characteristic EEG pattern of a spasm to be a
positive vertex slow wave with medium to high amplitude. 6
The two other patterns correlated with spasms are a medium-amplitude
spindle-like activity at 14 to 16 Hz (associated with a clinical stare
or akinetic spell) and diffuse attenuation that seems to immediately
follow the ictus.
Etiology
The International Classification of Epilepsies and Epileptic Syndromes
(1989 Commission) divides West Syndrome into two groups based on
etiology: symptomatic and cryptogenic. Symptomatic cases have a prior
history of brain injury (clinically or radiographically) or known
etiology. Cryptogenic cases have no prior signs of brain injury or known
etiology. A review of the literature shows the proportion of cryptogenic
cases of IS has decreased over time from "50% to approximately
30%," attributable to improved diagnostic techniques.
Causes of IS among symptomatic patients may include virtually any brain
disturbance expressed prenatally, perinatally, or postnatally. In a
retrospective study of 363 infants with IS, Lombroso found 165
symptomatic cases. 3 He identified prenatal
etiologies in 49% (including dysgenetic, chromosomal, and hypoxic-ischemic
injury): perinatal etiologies in 24% (obstetric trauma, acidosis,
fetal-heart deceleration with hypoxic-ischemia): and postnatal
etiologies in 30% (including metabolic, hemorrhagic, and infectious).
More recently, Ohlahara et al reviewed 162 symptomatic cases and found a
similar high percentage of prenatal causes (47%).12
The single most common identifiable etiology in both studies was
tuberous sclerosis (11% in Lombroso, 14% in Ohlahara et al).
In the past year, Vegevano et al proposed a third subgroup of patients
with West Syndrome: those with no known or suspected etiology other than
possible hereditary predisposition, based on family history or EEG
genetic traits. 13 Recent studies indicate that
this "idiopathic" form may represent 10% to 15% of cases of
West Syndrome 12, 13 and often is associated with
a good neurologic outcome.
Neuropathologic findings reflect the diverse etiologies of West
Syndrome. Jellinger reviewed 264 autopsies of infants with IS and
identified 5 morphologically distinct groups in descending order of
occurrence: embryofetal lesions, including agyria, micropolygyria,
agenesis of the corpus callosum, heterotopias, cortical dysplasia,
tuberous sclerosis, and metabolic disorders, such as lipidosas and
leukodystrophies; perinatal and postnatal encephalopathies, including
white-matter scars and lobar and hippocunpal sclerosis; combined
developmental and perinatal and postnatal lesions, such as
interdysplasias with secondary anoxic changes; acute vascular or
inflammatory injuries; and no pathology. 14
Vinters et al found two major identifiable abnormalities among cortical
tissue resected during surgery for IS: cystic-gliotic encephalomalacia
seen in destructive lesions and dysplastic changes, such as bizarre
gemistocytic "balloon" cells, and secondary cytoskeletal
changes, as may be seen in tuberous sclerosis. 15
Genetics
West Syndrome is an age-related epilepsy syndrome that seems to have a
peak incidence at approximately 5 months, with a range from birth to 24
months. 16 A male preponderance of 2:1 has been
reported. 17
Because other epilepsy syndromes have a familial recurrence, and the
male-to-female ratio suggests a sex-linked trait, the risk of recurrence
of West Syndrome has been studied. The incidence of IS is approximately
.24 cases per 1,000 livebirths. 17 Fleiszar and
colleagues studied pedigrees of 77 cases of West Syndrome and estimated
the empiric risk of recurrence among siblings was 15/1,000, and 7/1,000
for first-degree relatives. 18 They cautioned that
West Syndrome is multifactorial, and certain cases may have polygenic
susceptibility or may be completely environmental. Their study failed to
confirm a male preponderance.
More recently, Dulac et al studied familial antecedents of 223 cases of
West Syndrome and found that after excluding those with an identifiable
predisposing factor (i.e., twin gestation with prematurity, tuberous
sclerosis, or recurrent maternal toxemia), the risk of recurrence among
siblings approached that of the general population. 19
Even without excluding the known predisposing factors, the risk of
recurrence for siblings remained less than 2%.
Diagnostic Investigations
Routine blood and spinal fluid evaluations will be normal unless an
underlying infection or metabolic disorder is present. Tests should be
directed to the suspected etiology of the individual patient. In
addition to the EEG, neuroimaging or even functional neuroimaging has
proven useful in determining the etiology or evaluating the patient for
surgical resection.
Computerized tomography (CT) has been shown to detect pathology in 75%
to 90% of cases of West Syndrome 20, with better
results as technology improved. Ludwig studied 51 patients with West
Syndrome via CT before coticotropin (ACTH) therapy and found 21% had
embryofetal lesions (cerebral malformations); 57% had evidence of
perinatal and postnatal injury (encephalomacia, hypoxic-ischemic
necrosis, or inflammatory lesions); 12% had both embryofetal and
perinatal and postnatal lesions; and 10% were normal. 21
Magnetic resonance imaging (MRI) has been demonstrated to be more
sensitive than CT in detecting lesions in patients with partial
seizures. 22 Recently, MRI also has been shown to
be more sensitive than CT in detecting lesions in approximately 5% to
10% of cases of West Syndrome with unknown etiology, especially
regarding abnormal myelination and focal corticosubcortical lesions. 23
Functional neuroimaging is emerging as an important tool in the
preoperative evaluation of patients with West Syndrome. Interictal
singe-photon emission computed tomography (SPECT) has shown that
hypoperfused foci at the onset of IS appear to correlate with EEG foci. 24
Chugani et al described four patients with cryptogenic West Syndrome who
had normal MRI scans but had focal hypometabolism on positron emission
tomography (PET). 25 These infants underwent
successful surgical resection, and the pathology showed microscopic
cortical dysplasia.
Treatment
IS are poorly responsive to most conventional anticonvulsants. The drugs
that do have some activity against IS are a diverse group but appear to
share some agonist properties for gamma-amniobutyric acid (GABA) – an
inhibitory neurotransmitter.
Benzodiazepines often are effective initially in up to 40% to 50% of
patients with West Syndrome26 but may cause
unacceptable sedation and tolerance months later. Dreifuss and
colleagues reported an initial equivalent response between nitrazepam
and ACTH over a four-week period. 27 Our
experience at Stanford also has shown nitrazepam to be superior to the
other benzodiazepines; however, oversedation, secretion aspiration, and
eventual drug tolerance were seen. Benzodiazepines are known to
facilitate GABA-mediated synaptic inhibition. 28
Valproate, at high doses (up to 100 mg/kg/day), has been shown to be
effective in up to two-thirds of cases of IS in short-term trials.
Valproate is known to inhibit GABA metabolism, thus increasing
cerebrospinal fluid GABA levels.
High-dose pyridoxine (vitamin B6), 200 to 400 mg/kg/day, also has been
studied in the treatment of IS. A recent series of 17 patients with West
Syndrome showed 5 responded to pyridoxine, 300 mg/kg/day, within 2
weeks. 30 A pyridoxal phosphate (vitamin B6
metabolite)-dependent enzyme is involved in the synthesis of GABA; when
this enzyme is supplemented, an increase in cerebrospinal fluid levels
of GABA may occur.
Based on anecdotal remissions of refractory seizures after viral
infections and immunoglobulin (Ig) injections, Ig therapy has been
studied in the treatment of IS. Ariizumi et al administered intravenous
Ig (97% IgG and 3% IgA) at 100 to 200 mg/kg every 2 to 3 weeks for 6 to
10 doses. 31 They found complete remission among
all six patients studied with cryptogenic West Syndrome. The mechanism
is unknown.
Vigabatrin (gamma-vinyl-GABA) is a new anticonvulsant agent that
inhibits GABA-transminase, thus increasing cerebrospinal fluid levels of
GABA. 32 Recently, 2 small studies showed a 50% to
80% early response (within 1 to 2 weeks) in patients with West Syndrome
treated with Vigabatrin. 33, 34 Divided doses were
used, from 50 to 200 mg/kg/day. Reported side effects included
agitation, sedation, and hypotonia in up to 40% of patients.
Felbamate (Felbatol), a carbamate derivative recently approved by the
FDA, has been shown to have activity against the refractory mixed
seizures of Lennox-Gastaut Syndrome. A study of felbamate in the
treatment of Lennox-Gastaut Syndrome has shown a 34% reduction in
frequency of atonic seizures.35 Encouraged by
these results, others have begun using felbamate for refractory spasms.
In a small, ongoing series, Shields (personal communication) expects 10%
to 20% of patients with IS to obtain a good response to felbamate,
similar to our experience at Stanford. Divided doses are increased
gradually to approximately 50 to 60 mg/kg/day, or until the appearance
of unacceptable side effects (e.g., agitation, anorexia, and sleep
disturbance).
The most effective therapy for IS was discovered by Sorel and
Dusaucy-Bauloye in 1958. 36 Intramuscular ACTH
remains the standard by which other treatments of IS are judged. Various
dosing schemes have been proposed, but our experience at Stanford seems
to support Snead’s recommendation of high-dose ACTH (up to 150
U/m2/day).37 Studies of ACTH often compare
efficacy to high-dose prednisone (2 mg/kg/day). Steroids also have been
shown to be effective in the early control of IS; Hrachovy et al have
even shown equivalency between low-dose ACTH (20 U/day) and high-dose
prednisone. 38 However, Snead and colleagues have
shown that high-dose ACTH achieved control of spasms in 90% of cases,
versus 40% with high-dose prednisone. 39, 40
Another comparison of high-dose ACTH versus high-dose prednisone showed
ACTH was associated with better developmental outcome and decreased
frequency of other seizure types among 72 patients with cryptogenic West
Syndrome over a six-year period. 3 Furthermore,
infants who received ACTH within one month of spasm onset had better
developmental outcome and seizure control than those in whom treatment
was delayed. 3
Based ont hese data, early high-dose ACTH should be instituted in hope
of earlier spasm control and better cognitive outcome. At our
institution, the patient may be admitted overnight or evaluated in the
day-hospital setting to obtain baseline laboratory tests (e.g., blood
count, urinalysis, glucose, electrolytes, and renal and hepatic function
panels) and to teach intramuscular injection to caretakers. ACTH gel, at
20 U/day intramuscularly, is begun, with a rapid increase to 150
U/m2/day over 2 to 3 weeks if no response is seen. The peak dose is
maintained over 4 to 6 weeks and then tapered off to complete a 10 to
12-week course. Prophylactic trimethoprim-sulfamethoxazole is also given
to minimize opportunistic infection. Weekly follow-up is obtained
initially to monitor blood pressure, glucosuria, and general health.
Should relapse occur during or after the course of ACTH, a second trial
is sometimes effective. Oral prednisone, 2 mg/kg/day in divided doses,
provides a simpler and somewhat safer alternative. The same baseline
laboratory tests are obtained, and the steroid is given over ten weeks
with gradual taper. Reversible side effects are common in both regimens
and include cushingoid features, hypertension, glucose intolerance,
irritability, and cerebral atrophy. Cardimyopathy and sepsis are the
more serious complications and demand clinical vigilance.
The mechanism by which steroid hormones inhibit IS is not known.
However, some neuroactive effects are recognized, 41
including enhanced myelin formation, which may expedite a critical stage
of brain maturation; stabilization of cell membranes, including
hyperpolarization of neurons; increased integrity of the blood-brain
barrier; and enhanced midbrain and striatal GABA-receptor binding.
Corticotropin-releasing hormone (CRH) in an excitatory neuropeptite with
potent convulsant properties in infant rats. 42
This gene expression in rats seems to correlate with the age specificity
of IS 43, and is induced by injury or stress. ACTH
and glucocorticoids provide feedback suppression of CRH synthesis. Baram
proposed that stress-induced increases in CRH activity during a critical
time may be responsible for IS, 44 accounting for
the age specificity of the disease as well as the unique response to
ACTH and prednisone.
Surgery is an emerging therapy for refractory spasms. Chugani et al
described 23 cases of refractory spasms: 23 by EEG and PET localization
and 7 by MRI localization. 45 Following the
cortical resection or hemispherectomy, 15 children were free of
seizures, 4 had a greater than 75% seizure reduction, and 4 had no
seizure improvement (mean follow-up was 28 months).
Natural History
Approximately 75% to 90% of infants with spasms will have
moderate-to-severe developmental delay. 3, 46
Although 90% will be free of spasms by 5 years of age, 50% to 60% will
have developed other seizure types, including tonic-clonic and myoclonic
seizures. 11, 47 Of infants with spasms, 10% to
50% will develop Lennox-Gastaut Syndrome (slow spike-wave EEG pattern,
mixed seizures, and developmental delay). 3, 5
Despite the statistical association between West Syndrome and Lennox-Gastaut
Syndrome, they appear to be distinct entities that usually have in
common sever underlying brain injury.
Attempts have been made to identify West Syndrome populations with
improved outcomes. Most studies have shown the best outcomes in the
cryptogenic group, with normal development seen in 30% to 70% of these
infants. 11, 45 In contrast, the symptomatic group
has a 5% to 25% incidence of normal development, with an increased risk
of subsequent refractory seizures as well. 3, 11
The more apparent pathology seen in symptomatic patients is presumed to
be responsible for this discrepancy.
Riikonen identified five factors associated with improved outcome: later
age of onset (older than 5 months), prior normal development, early
treatment (less than one month after spasm onset), shorter duration of
spasms, and lack of preceding seizures. 48 Plouin
et al recently have shown the presence of concomitant partial seizures,
asymmetric hypsarrhythmia, and focal spasms belies a poor prognosis. 7,
49
Summary
West Syndrome is an age-specific epilepsy with multiple diverse
etiologies. Although the pathogenesis remains unknown, a subgroup can be
identified with improved prognosis. Early, aggressive ACTH therapy is
associated with a better outcome, perhaps by virtue of earlier spasm
control. Promising therapies include emerging anticonvulsants and
surgical resection in carefully selected patients.
-Dr. Guarino is a First-Year Epilepsy Fellow and Clinical Instructor
in the Department of Neurology at Stanford, California. He received his
medical degree in 1986 from Loyola-Stritch School of Medicine in
Chicago, Illinois.
Click here to refer to Dr. Guarino's
endnotes from the above article.
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