Seizure Disorders 0031-3955/89 $0.00 + .

20

Infantile Spasms

Richard A. Hrachovy, MD, * and James D. Frost, Jr, MDt

Infantile spasms, referred to in the literature as massive spasms, flexion

spasms, jackknife seizures, infantile myoclonic seizures, and so forth, have
been recognized as an epileptic phenomenon since they were first described
by West in 1841. 89 A large percentage of patients with infantile spasms
have some degree of mental and developmental retardation. 41- 43 In 1952,
Gibbs and Gibbs23 described a unique EEG pattern, hypsarrhythmia, which
was noted to occur in a large number of infantile spasm patients. The triad
of infantile spasms, retardation, and hypsarrhythmia has become known as
West's syndrome. The disorder is age specific, and developmental factors
are probably important to its genesis. The seizures usually are refractory to
standard anticonvulsants. In 1958, the first therapeutic breakthrough in
treating infantile spasms was reported by Sorel and Dusaucy-Bauloye,85
who noted that patients treated with ACTH had cessation of spasms and
improvement in their EEGs.
During the past three decades, a considerable world literature pertain-
ing to this disorder has accumulated; however, the classifications and
clinical descriptions of the seizures, based largely on routine bedside
observation, have been highly variable, and this lack of uniformity has led
to considerable confusion and controversy concerning many aspects of this
disorder.
The introduction oflong-term polygraphic/video monitoring techniques
in the 1970s19 has improved our understanding of the clinical manifestations
of this disorder and also has provided, for the first time, an objective means
of studying the acute effects of therapy on the EEG and on seizure
frequency.

*Associate Professor, Section of Neurophysiology, Department of Neurology, Baylor College

of Medicine; Associate, Neurophysiology Service, The Methodist Hospital, Houston,
Texas
tProfessor, Section of Neurophysiology, Department of Neurology, Baylor College of Medi-
cine; Attending Physician, Neurophysiology Service, The Methodist Hospital, Houston,
Texas

Pediatric Clinics of North America-Vol. 36, No.2, April 1989 311

312 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

This article characterizes infantile spasms as precisely as possible so

that they can be distinguished from other types of seizures of infancy and
from normal infant behavior. We will also address some of the more
controversial and still unresolved issues concerning this disorder, including
therapy and pathophysiology.

EPIDEMIOLOGY

Infantile spasms usually have their onset within the first 6 to 8 months
of life (Fig. 1). About 90 per cent of the spasms begin before the age of 12
months. 41 The incidence of infantile spasms has been estimated to be 1 per
4000 to 6000 live births. 88 In reality, this number may be somewhat low
because some parents and physicians either fail to recognize the disorder
or diagnose the spasms as some other type of seizure. There is no clear
evidence to suggest a preponderance of one sex over the other, and familial
occurrence of infantile spasms is rare. 50

CLINICAL MANIFESTATIONS

Infantile spasms are generally brief contractions of the muscles of the

neck, trunk, and extremities, usually occurring bilaterally and symmetri-
cally. The character of the seizure depends on whether the flexor or

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Figure 1. Age at onset of infantile spasms for 96 infants studied from 1976 to 1987.
INFANTILE SPASMS 313

extensor muscles are predominantly affected and on the number and

distribution of the muscle groups involved. 19.45 Thus, spasms may vary from
massive contractions of all flexor muscles to contractions of only neck
muscles or abdominal recti.
There are three main types of infantile spasms: flexor, extensor, and
mixed flexor-extensor. Mixed spasms are the most common type (about 42
per cent), followed by flexor spasms (about 34 per cent); extensor spasms
are the least common (about 23 per cent). 19. 45 Most infants with this disorder
have more than one type of spasm, and the type observed at any given
moment may be influenced by body position.
Flexor spasms consist of abrupt flexion of the muscles of the neck,
trunk, and extremities. The contraction of the abdominal muscles may be
so great as to cause the body to jackknife at the waist. Involvement of the
upper extremity muscles may result in either abduction or adduction of the
arms in a self-hugging motion. The intensity of the muscle contraction and
the extent of musculature involved in a given attack may vary from a brief
contraction of the abdominal recti to total involvement of the axial muscles
of the neck and trunk and flexors of the extremities. If the contraction is
limited to the neck flexors, there may be only a head bob, whereas
involvement of the upper limb girdle may result in elevation and adduction
of the shoulders in a shrug-like movement. Extensor spasms occur when
extensor muscles are predominantly involved. These spasms consist of
abrupt extension of the neck and trunk, with extension and abduction or
adduction of the arms or legs.
Mixed flexor-extensor spasms consist of flexion of the neck, trunk, and
arms, with extension of the legs, or, less commonly, flexion of the legs and
extension of the arms.
Asymmetrical infantile spasms are rare «1 per cent). Periods of
attenuated responsiveness (arrest phenomena), which, when seen, usually
follow a motor spasm, also may occur as independent phenomena.
Eye movements, consisting of deviation either alone or followed by
rhythmic nystagmoid movements, occur in approximately 60 per cent of
motor spasms. Alterations in respiration occur in about 60 per cent of
spasms; changes in heart rate are rare «1 per cent). Although a cry may
frequently follow a spasm, crying does not occur as an ictal phenomenon.
Although there is little variation in the number of spasms occurring in
consecutive 24-hour periods, there is a marked variation in the number
recorded at 2-week intervals (Fig. 2).29 The number of spasms recorded
during such 24-hour periods has ranged from 3 to 763.
About 80 per cent of infantile spasms occur in clusters (i. e., the interval
between successive spasms is less than 60 seconds). The number of spasms
per cluster has varied from 2 to 138, with succession rates of up to 15 per
minute. Usually the intensity of the spasms initially will wax and then wane
within a given cluster.
Approximately the same number of spasms occur during the night as
during the day. Although they rarely occur when the infant is actually
asleep «3 per cent), they usually occur immediately on arousal or soon
thereafter. Infantile spasms may rarely be elicited by unexpected loud
 314 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

500

... 400
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Figure 2. Variation in spasm
frequency in a patient monitored
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100

Baseline 2 weeks 4 weeks

Monitoring Sessions

noises or tactile stimulation but are not precipitated by feeding or by photic

stirn ulation.

ELECTROENCEPHALOGRAPHIC FINDINGS

Interictal
A variety of EEG findings may be seen at the time a patient is having
infantile spasms. These findings include normal background activity, diffuse
slowing of the background rhythms, generalized slow-spike and slow-wave
activity, and focal and multifocal spikes and sharp waves. However, the
interictal pattern usually associated with infantile spasms is hypsarrhythmia
(Fig. 3). Gibbs and Gibbs 23 originally defined hypsarrhythmia as
random high voltage slow waves and spikes. These spikes vary 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 that could be confused with a discharge of the petit
mal or petit mal variant type. The abnormality is almost continuous, and in most
cases it shows as clearly in the waking as in the sleeping record.
This prototypic pattern usually is seen only in the early stages of the
disorder and most often in younger infants. Serial studies have shown that
there is a tendency for this pattern to modify with time so that the anarchic
and chaotic characteristics give way to a more organized pattern. Prolonged
monitoring studies of patients with infantile spasms have demonstrated that
INFANTILE SPASMS 315

Figure 3. Hypsarrhythmic EEG pattern in an 8-month-old infant.

hypsarrhythmia is a highly variable and dynamic EEG pattern. 33 The

character of the pattern may change dramatically from minute to minute
and from hour to hour. The specific EEG features seen in a given patient
depend on the length of the EEG recording, the state of the patient, and
the presence of various structural abnormalities of the brain.
Although the patterns described below have certain features that differ
from the original pattern described by Gibbs and Gibbs,23 they are included
under the general category of hypsarrhythmia because they retain some of
the specific characteristics of the original pattern (e.g., high voltage) and
are associated with the same ictal EEG patterns and seizures. These
variations are referred to as modified hypsarrhythmia and include hypsar-
rhythmia with increased interhemispheric synchronization, asymmetrical or
unilateral hypsarrhythmia, hypsarrhythmia with a consistent focus of ab-
normal discharge, hypsarrhythmia with episodes of generalized, regional,
or localized voltage attenuation (suppression-burst variant), and hypsar-
rhythmia composed primarily of high-voltage, bilaterally asynchronous,
slow-wave activity. 33
In addition to these basic variations, transient alterations in hypsar-
rhythmia occur throughout the day. The pattern is most pronounced and
persists to the latest age in slow-wave sleep and is least evident or absent
during rapid eye movement (REM) sleep, when the background EEG
activity may appear normal. 32 Also, there is often a marked reduction or
disappearance of the hypsarrhythmic pattern on arousal from slow-wave or
REM sleep. This "normalization" may last from a few seconds to many
minutes. 33 This latter observation is important because it may account for
some of the dramatic acute changes in the EEG that have been reported
following the injection of various agents, including pyridoxine (see pyridox-
316 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

ine therapy). Finally, there may be a reduction or disappearance of the

hypsarrhythmic EEG during a cluster of spasms, with the pattern returning
immediately thereafter.
Ictal
In a study of infantile spasms by our group,45 eleven different ictal
EEG patterns were observed. Generalized slow-wave transients, sharp-
and slow-wave transients, attenuation episodes, or attenuation episodes
with superimposed faster frequencies occurred singly or in various combi-
nations. The most common EEG event associated with infantile spasms was
a high-voltage, generalized slow-wave transient followed by an abrupt
attenuation of background activity in all regions that lasted from 1 second
to many seconds. There was no close correlation between the character of
the ictal EEG event and the type of spasm. The duration of the ictal EEG
event ranged from 0.5 to 106 seconds, with the longer episodes being
associated with the arrest phenomenon.

ASSOCIATED ETIOLOGIC FACTORS

In about 60 per cent of the patients, etiologic factors can be clearly

identified. Various pre- , peri- , and postnatal factors have been implicated. 50
Prenatal factors include intrauterine infection, prematurity, cerebral dys-
genesis (e.g., lissencephaly), hypoxia-ischemia, and genetic disorders (e.g.,
tuberous sclerosis). Perinatal factors include hypoxia-ischemia and trau-
matic delivery, whereas postnatal factors include head injury, inborn errors
of metabolism (e. g., nonketotic hyperglycinemia), CNS infection, hypoxia-
ischemia, and intracranial hemorrhage.

IMMUNIZATION

During the past several decades, there has been major disagreement
over whether immunization is an etiologic factor associated with infantile
spasms. This issue is important not only from a medical standpoint but also
from a legal one, as evidenced by the increasing number of lawsuits against
manufacturers of vaccines.
Although infantile spasms have been associated with various vaccines,
the one most frequently implicated has been diphtheria-pertussis-tetanus
(DPT). The pertussis agent has generated the most concern. 3. 41, 48, 63, 64, 86, 91
The major problem in determining whether there is a relationship
between infantile spasms and DPT immunization is that the vaccine is
given at a time when infantile spasms usually have their onset «6-8
months of age). Therefore, if a large population were studied, an association
between infantile spasms and DPT immunization would be expected on
the basis of coincidence alone. In fact, such an association also could be
made between infantile spasms and any other event that commonly occurs
during this period of life,
Fukuyama et al. 21 studied the role of immunization (DPT, smallpox,
INFANTILE SPASMS 317

antipolio, and anti-Japanese encephalitis) as an etiologic factor in 110

patients with infantile spasms. Of these 110 patients, 22 had been immu-
nized within 1 month of the onset of the disorder. These 22 patients were
then studied, using strict criteria to establish causal relationships. Only five
patients satisfied these criteria. The authors concluded that this small
number could be explained as occurring by chance.
Melchior62 compared the age at onset of infantile spasms in two patient
populations: one who received the DPT vaccine at 5, 6, and 15 months of
age, and one who received it at 5 weeks, 9 weeks, and 10 months of age.
If there were an association between infantile spasms and DPT vaccination,
it would be expected that the age at onset would be lower in the second
group of patients. However, analysis of the data revealed no statistically
significant differences between the two groups with respect to the age at
onset of infantile spasms.
Cody et al. 11 prospectively studied 15,752 children, aged from birth to
6 years, to determine whether reactions occurred within 48 hours following
their DPT immunizations. None of the children developed infantile spasms.
Bellman et al. 5 reported the results of the British National Childhood
Encephalopathy Study, in which the risk of developing spasms following
DPT and DT immunizations was investigated. In this study, two controls
were selected, matChed for age, sex, and area of residence, for each case
of infantile spasms. The timing of the immunization was compared between
the two groups. This case-controlled analysis showed no significant associ-
ation between infantile spasms and pertussis immunization in the 28 days
before spasm onset.
Thus, the available evidence indicates that the reported association
between infantile spasms and DPT immunization is coincidental and that
the two are not causally related.

ASSOCIATED NEUROLOGIC FINDINGS

Approximately 85 to 90 per cent of patients with infantile spasms show

some degree of mental and developmental retardation. About 50 per cent
have major neurologic defects, and another 40 per cent have minor ones. 44.50

COMPUTED TOMOGRAPHY

In our earlier studies of 54 patients with infantile spasms, computed

tomographic (CT) scans revealed the follOwing: no abnormalities in 17
patients (31 per cent), generalized atrophy in 8 (15 per cent), predominantly
focal atrophy in 19 (35 per cent), and congenital anomalies in 10 (19 per
cent). These findings are comparable to those previously reported. 22, 81

PATIENT CLASSIFICATION

In the past, the classification of patients was somewhat variable and

inconsistent, 50 At present, patients can best be classified on the basis of
318 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

CT-scan findings, past medical history, developmental history, and the

neurologic examination. With this information, patients can be divided into
two groups: cryptogenic and symptomatic. A patient is classified as cryp-
togenic if there is no known associated etiologic factor, development is
normal prior to onset of the spasms, there is no abnormality on neurologic
examination, and the CT scan is normal prior to therapy. With these strict
criteria, approximately lO to 15 per cent of patients can be classified as
cryptogenic. 25, 34-36 The remainder are classified as symptomatic. As will
become evident in the discussion of therapy, the classification of patients
as cryptogenic or symptomatic is crucial when one is considering long-term
outcome.

PATHOPHYSIOLOGY

A large number of pathologic abnormalities have been identified in

infantile spasm patients. 50 However, considerable evidence implicates the
brain stem as the area giving rise to infantile spasms and the hypsarrhythmic
EEG pattern. Kellaway44 reported a case of infantile spasms in which the
only pathologic findings were well-delineated inflammatory changes con-
fined to the brain stem. Morimatsu et al. 67 and Satoh et aP9 reported
several cases in which the common pathologic changes were located within
the pons. Chugani et aI., 10 using positron emission tomography, reported
relative hypermetabolism in the brain stem compared with cortical struc-
tures of patients with infantile spasms. Our recent work, utilizing long-
term monitoring,32 provides supportive evidence that certain regions of the
brain stem implicated in the control of sleep cycling also may be responsible
for the generation of spasms and the associated EEG changes. A patho-
physiologic model based on these data suggests that the sleep alterations,
spasms, and EEG changes seen in infantile spasms can be explained in one
of three ways: (1) partial damage to, or inactivation of, cholinergic brain
stem areas; (2) increased influence of serotonin, norepinephrine, or com-
pounds with similar effects at brain stem cholinergic sites; or (3) increased
activity within the dorsal raphe or locus ceruleus. 30, 32 This hypothesis
currently is being tested using drugs with antiserotonergic or antiadrenergic
activity.31 Others have suggested that dysfunction of monoaminergic neu-
rotransmitter systems may be responsible for the generation of infantile
spasms. 12,46,70,78,80 However, two other major pathophysiologic mechanisms
have been proposed. First, infantile spasms result from a failure, or delay,
of normal developmental processes. 76 This theory is based largely on the
assumption that ACTH and corticosteroids accelerate certain normal devel-
opmental events in immature animals. 1, 14, 75 Another hypothesis is that
infantile spasms are the result of a defect in the immunologic system. 30, 37,
38, 58, 60. 65, 66, 66, 73 These hypotheses are not necessarily mutually exclusive.
For example, an immunologic reaction to brain tissue could alter the
functional activity of neurotransmitter systems to produce the clinical
manifestations observed in this disorder.
INFANTILE SPASMS 319

TREATMENT

No other aspect of this disorder has generated as much controversy

and confusion as the issue of therapy. The opinions concerning the treatment
of infantile spasms expressed in numerous studies published during the
past three decades have been so diverse that no consensus of opinion exists,
nor has a "standard of care" been established. We will not attempt to
provide an extensive review of the literature concerning the treatment of
this disorder; nor is such a review warranted, because of the many
methodologic problems present in most of the published studies (see below).
We have, however, reviewed the prevailing attitudes and opinions and will
make suggestions and recommendations concerning the most appropriate
therapy based on the best available data. We will also point out areas in
which further investigation is needed.

HORMONAL THERAPY

Acute Effects
In 1958, Sorel and Dusaucy-Bauloye85 reported that treatment of
infantile spasms with ACTH resulted in cessation or amelioration of the
seizures and disappearance of the hypsarrhythmic EEG pattern. Since that
time, an extensive literature concerning the treatment of this disorder with
ACTH and corticosteroids has appeared; however, most studies have been
plagued with methodologic problems, making it difficult to interpret the
results. Some of these problems are
1. The natural history of the disorder is not completely under-
stood-particularly the phenomenon of spontaneous remission. As the
duration of a treatment regimen increases, the possibility of a spontaneous
remission occurring during that time also increases, thus making it more
difficult to determine medication effect.
2. Few well-controlled prospective single- or double-blind studies
have been performed, and most studies have been retrospective in char-
acter.
3. There have been marked variations in dosages of medication given
and durations of treatment.
4. Until recently, 19, 34-36 objective means of determining the acute
effects of hormonal treatment had not been used. Instead, previous studies
relied on parental observation to determine seizure frequency, which, as
we learned from our monitoring experience, is totally unreliable. 19, 34-36, 45
Parents often underestimate spasm frequency to such an extent that they
report no seizures in a child who, in fact, is experiencing many spasms per
day.
5. In most studies, response to therapy has been defined in a graded
fashion. Long-term monitoring of patients with infantile spasms treated
with ACTH and prednisone34-36 indicates that the response to therapy is an
all-or-none phenomenon: complete control or no control.
In spite of these methodologic shortcomings, several major opinions
320 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

concerning hormonal therapy for infantile spasms have evolved. Some

individuals consider ACTH and prednisone to be equipotential, whereas
others consider ACTH superior. 49 • 50. 54. 55. 83. 84. 90 Furthermore, two thera-
peutic approaches have evolved for ACTH treatment. Some authors suggest
using larger doses of ACTH (40-160 units per day) and longer durations of
therapy (3->12 months).8. 27, 51, 53, 54, 82, 83 Others utilize low-dose ACTH
therapy (5-40 units per day) for relatively brief periods (1-6 weeks). 40, 75,
87,90 Some proponents of high-dose, long-duration ACTH therapy report
better control of seizures and greater EEG improvement with such treat-
ment compared with low-dose, short-duration therapy. 54, 83
To determine whether the relative efficacies of low-dose ACTH and
prednisone were similar, we performed the first double-blind/crossover
study of the effects of ACTH versus prednisone in treating this disorder, 36
ACTH was administered at a dose of 20 to 30 units per day for 2 to 6
weeks; prednisone, at a dose of 2 mg per kg per day for 2 to 6 weeks,
Serial 24-hour polygraphic/video monitoring studies were performed to
determine the response objectively. The important results and observations
of this study are as follows,
1. Response to hormonal therapy is all or none: complete control or no controL
We did not observe a graded response.
2, A major difference in therapeutic efficacy between ACTH (20-30 units per
day) and prednisone (2 mg per kg per day) in stopping the spasms and improving
the EEG could not be demonstrated,
3. About 60 to 70 per cent of infantile spasm patients respond to either ACTH
or corticosteroid therapy.
4. Only a short course (2 weeks) of hormonal therapy is required for most
patients to obtain a response.
5, Once a response to hormonal therapy is documented, the therapy can be
immediately discontinued and the response maintained.
6, If a patient fails to respond to a course of ACTH, he or she may respond to
prednisone, and vice versa,
7, About one third of the patients will experience a relapse. This figure is
comparable to those previously reported by Lacy and Penry. 50 If a relapse occurs,
a second course of therapy is usually effective,
8. Etiology and treatment lag (the time from the onset of the spasms to the
initiation of treatment) are not useful predictors of response, Symptomatic patients
responded just as well as cryptogenic patients, and patients with long treatment
lags responded as well as those with short treatment lags.
9, Relative normalization of the EEG may occur in patients who continue to
have spasms. This is an important point to remember, because many physicians
rely heavily on the EEG to determine whether a response to therapy has occurred.

Although this study provided valuable information concerning the

acute effects of low-dose ACTH compared with prednisone, it did not
address the controversy of high-dose, long-duration ACTH therapy versus
low-dose, short-duration ACTH therapy. Unfortunately, no comparable
prospective, blinded, objectively controlled studies of high-dose, long-
duration ACTH therapy are available. In the only retrospective analysis of
the results of high-dose versus low-dose ACTH therapy, Riikonen 75 showed
that larger doses of ACTH (120-160 units per day) produced no better
INFANTILE SPASMS 321
results than smaller doses (20-40 units per day) in patients with infantile
spasms.
Long-term Outcome
Unique to hormonal treatment of infantile spasms is the belief that
ACTH or corticosteroids not only improve the EEG and control the spasms
but also improve the outlook for mental and motor development. It is
important to distinguish between the immediate effects of hormonal therapy
on the behavioral state of an infant when the seizures are controlled and
the EEG has improved, and the long-term effects of ACTH or corticoste-
roids in preventing mental and developmental retardation. It has been
known since West's first description that at the time the spasms are
occurring, there is a regression in the patient's behavioral development and
social interaction which usually reverses if the seizures are controlled.
When lower doses and shorter durations of treatment are used, about
9 to 13 per cent of patients with infantile spasms have been reported to
show normal development. 42 • 43, 49, 61, 72, 92. 93 Some investigators have found
similar outcomes in treated and untreated patients. 18, 42, 49 Others have
reported an improved prognosis for long-term mental and motor develop-
ment with the use of high-dose, long-duration ACTH therapy. 54, 82 Also
implicit in many reports is that long-term outcome is affected adversely
when the treatment lag is prolonged. so, 54, 82 Like the studies that evaluated
the acute effects of hormonal therapy in infantile spasm patients, however,
the design of most studies concerned with long-term outcome does not
permit definitive conclusions to be established. Past reports of long-term
prognosis typically have been retrospective or have not used such diagnostic
evaluations as CT scans to aid in classifYing patients as cryptogenic or
symptomatic. Our own study of the long-term outcome in 64 patients
followed prospectively and treated with ACTH (20-30 units per day for 2-
6 weeks) and prednisone (2 mg per kg per day for 2-6 weeks)25 revealed
the following:
1. The overall prognosis is poor, with only 5 per cent of the total population
having normal outcomes.
2. Severe or very severe impairment was observed in 69 per cent of the
patients,
3. There was no significant difference between responders and nonresponders
with respect to long-term outcome.
4. There was no significant difference in outcome between patients treated
within 5 weeks of the diagnosis of infantile spasms and those treated more than 5
weeks after the diagnosis. Early treatment (within 5 weeks), even in the cryptogenic
group, did not ensure a normal long-term outcome.
5. The only factor that appears to affect long-term outcome is whether a patient
is classified as cryptogenic or symptomatic, This has also been noted by others.9, 42,
54,84 In our study, cryptogenic patients had a significantly better long-term outcome

than symptomatic patients; 38 per cent of the cryptogenic patients were normal or
had only a mild impairment, in contrast to 5 per cent of the symptomatic patients.
This finding is not surprising. For the large number of infants who exhibit preexisting
brain damage, as evidenced by the presence of other neurologic deficits, structural
brain abnormalities shown on CT scan, or severe underlying disease processes such
as inborn errors of metabolism, it seems highly unlikely that hormonal therapy
322 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

would greatly influence long-term outcome in terms of mental and motor develop-
ment.
6. There is no way to predict which cryptogenic patients will have normal
outcomes and which will be retarded.
Still, the question remains whether higher doses of hormonal therapy
given for longer periods increase the chance for a normal outcome. The
answer to this question awaits proper evaluation in prospective, controlled
protocols. As noted previously, in a retrospective study, Riikonen 75 observed
no Significant difference in the effects of large doses of ACTH compared
with lower doses in patients with infantile spasms. In fact, patients treated
with lower doses had better outcomes and fewer side effects. 77
Recommended Treatment Regimen
The following treatment regimen is our recommendation for all patients
with infantile spasms, regardless of treatment lag, age, or patient classifi-
cation (cryptogenic versus symptomatic).
A baseline EEG should be obtained on all patients prior to initiation
of therapy. A CT scan also should be performed to aid in classifying patients
as symptomatic or cryptogenic. Either ACTH or prednisone may be given
initially. If ACTH is chosen, the initial dose is 20 units per day. After 2
weeks of ACTH therapy at a dose of 20 units per day, the EEG is repeated.
If the patient has responded (which we define as improvement in the EEG
and cessation of spasms), ACTH is tapered and discontinued. If, after 2
weeks of ACTH, the patient has not responded, the dose is increased to
30 units per day. ACTH is continued at this dose for an additional 4 weeks,
after which it is tapered and discontinued. A repeat EEG is performed at
this point. If the patient has responded to the ACTH, he is followed in a
routine clinical manner. If a relapse occurs, the patient is given a repeat
course of ACTH at the dose at which the initial response occurred. If the
patient does not respond to ACTH and has not been treated with predni-
sone, prednisone is given after the patient has been off ACTH for 1 week.
If prednisone is administered, the dose is 2 mg per kg per day. The
follow-up is similar to that used for ACTH. After 2 weeks of therapy, a
repeat EEG is performed. If the patient demonstrates a response at this
time, prednisone is tapered and discontinued, and the patient is followed
routinely. If the patient has not responded after 2 weeks of prednisone
therapy, the drug is continued at a dose of 2 mg per kg per day for an
additional 4 weeks, after which it is tapered and discontinued. A repeat
EEG is performed at this time. If the patient has responded, he or she is
followed in a routine manner. If a relapse occurs, the patient is given a
repeat course of prednisone. If the patient does not respond to prednisone
and has not been treated with ACTH, ACTH is started after the patient
has been off prednisone for 1 week.
Throughout the entire course of ACTH or prednisone therapy, the
patient's blood pressure should be monitored closely, and serum electrolyte
studies should be performed on a weekly basis.
Side Effects
The side effects of ACTH or corticosteroid therapy, some of which
may preclude treatment or require its termination, are hypertension,
INFANTILE SPASMS 323

electrolyte imbalance, suppression of the immune system, ocular opacities,

gastrointestinal disturbances, and transient brain shrinkage.
Hypertension. The incidence of hypertension in infantile spasm patients
treated with ACTH and corticosteroids varies from 10 to 25 per cent. 34-36, so
We define hypertension as a blood pressure> 140/90 mm Hg. The long-
term effects of sustained hypertension on the developing cardiovascular
system are not known; however, it is possible that sustained elevated blood
pressure for many months could result in the development of vascular
abnormalities of the brain and elsewhere. Another complication of hyper-
tension associated with hormonal therapy is intracranial hemorrhage. 77 A
significant finding in our double-blind/crossover study of ACTH versus
prednisone36 is that not all patients who develop hypertension on ACTH
will do so on prednisone, and vice versa.
Electrolyte Imbalance. Although electrolyte imbalance is one of the
most frequently cited side effects of steroid or ACTH therapy,69 in our
recent studies, in which electrolytes have been closely monitored, no
Significant electrolyte disturbances have been encountered.34-36 A synthetic
corticotropin (Synacthen), used in Europe, has been reported to produce
hypocalcemia. 13
Suppression of the Immune System. The preexistence or development
of significant respiratory or other infections constitutes sufficient reason to
delay or withdraw treatment. The occurrence of intercurrent infection has
been evaluated by various individualsY' 74. 77
Ocular Opacities. Long-term oral steroid therapy has been associated
with the development of posterior capsular cataract. The dose and duration
of therapy appear to be critical factors. In the dosages we employ,34-36 this
complication has not been noted.
Gastrointestinal Disturbances. We have not encountered gastrointes-
tinal disturbances or hemorrhages in our studies,34-36 but these complica-
tions have been observed by others in patients treated with ACTH or
corticosteroids. 69
Transient Brain Shrinkage. Increases in subarachnoid space and ven-
tricular size on CT scan have been reported after hormonal treatment of
infantile spasms. 7. 28, 52. 56. 57 These findings have been reported to be
reversible. 28. 52. 57 In our study, however, the increases persisted for 4 to 6
weeks following discontinuance of therapy in 44 per cent of those patients
who developed such changes. 24 The precise mechanism underlying these
changes and the possible hazard to the infant are not known.

ANTICONVULSANT THERAPY

Of the various traditional anticonvulsants that have been used to treat

patients with infantile spasms, only valproic acid 2 , 16 and the benzodiaze-
pines, particularly nitrazepam,15, 20, 26, 27, 39, SO, 59 have been reported to be
effective. These studies suffer from the same methodologic shortcomings
outlined previously in the discussion of hormonal therapy. The study of
Dreifuss et al. 15 deserves special comment. This was the first attempt to
evaluate the relative effectiveness of nitrazepam versus ACTH in a random-
324 RICHARD A. HRACHOVY AND JAMES D. FROST, JR

ized, controlled study in which response was determined objectively by

utilizing 24-hour polygraphic/video monitoring. The authors concluded from
this study that there was no significant difference in effectiveness between
ACTH and nitrazepam. This conclusion was based on evaluation of mean
seizure frequency and not on total cessation of spasms, however. Therefore,
the clinical significance of these data is difficult to assess in light of the
natural variability in seizure occurrence over time. 31 There is also some
question concerning what clinical events were considered to be spasms.
The authors stated that some patients had the onset of new seizure activity,
described as nystagmus, and that the new-onset seizures usually occurred
in patients with good or excellent control. It is not clear whether these
ocular events were truly new seizures or were minimal expressions of
infantile spasms. The ictal EEG changes associated with these eye move-
ments were not described. In addition, the effect of nitrazepam therapy on
the interictal EEG activity was not presented. This latter point is critical,
because the EEG improvement seen in patients who respond to nitrazepam
has been reported to be less striking than that encountered during steroid
therapy. 59 Finally, although the authors stated that they performed sleep
staging during the 24-hour monitoring studies, the effect of nitrazepam
therapy on REM sleep was not presented. It is important to know whether
nitrazepam therapy produces the marked increase in REM sleep that occurs
when patients respond to hormonal therapy.32
Thus, at present, there is no clear evidence that standard anticonvulsant
therapy is of benefit in treating infantile spasms. This issue will not be
resolved until appropriately designed and objectively evaluated studies are
performed.

PYRIDOXINE THERAPY

Pyridoxine has been reported to be beneficial in treating a small

number of patients with infantile spasms. 4, 6,17.71 The results of these studies
are difficult to interpret, however. None of the studies were controlled,
and no objective methods for determining seizure frequency were used.
The dosages of pyridoxine varied significantly, as did the route of adminis-
tration, with some patients receiving the drug intravenously, some intra-
muscularly, some orally, and others in various combinations. The number
of doses of pyridoxine required to produce an effect is unclear. In some
patients, a response was reported to occur within minutes of a single
intravenous dose,4, 17 whereas in others a response might not occur for
many days after institution of therapy.6, 71
Thus, although anecdotal reports suggest that pyridoxine may be
effective in a small number of infantile spasm patients (presumably with B6
dependency), a definite statement regarding its efficacy in treating this
disorder cannot be made until appropriately designed and controlled studies
are performed.
INFANTILE SPASMS 325
MORTALITY RATE
Past studies of infantile spasms have reported a significant mortality
(1l-23 per cent).50 In a recent study of long-term outcome, however, we
documented a mortality rate of only 5 per cent,25 a finding probably related
to the availability of better general medical care in today's society.

OTHER SEIZURE TYPES

The occurrence of other types of seizures in patients who stopped
having infantile spasms has ranged from 35 to 60 per cent.42. 43. 50. 75 The
most common types of seizures observed are tonic, simple partial, and
generalized tonic-clonic. In our recently completed prospective study of
long-term outcome, other types of seizures occurred in 53 per cent.25 None
of the cryptogenic patients who responded to hormonal therapy had other
types of seizures.

SUMMARY
Infantile spasms constitute a relatively rare disorder of infancy and
early childhood; their onset is usually within the first 6 to 8 months of life.
A large percentage of patients with this disorder (85-90 per cent) show
various degrees of retardation. Infantile spasms typically occur in clusters
immediately on arousal, or soon thereafter, but rarely occur while the
infant is actually asleep. The usual interictal EEG pattern associated with
infantile spasms is hypsarrhythmia, but infantile spasms may occur in the
absence of this EEG pattern. The pathophysiology of infantile spasms is
not known, but recent evidence suggests that certain regions in the brain
stem that are associated with sleep cycling may be responsible for the
clinical and EEG manifestations of this disorder. At present, the only
known effective treatment for infantile spasms is ACTH or corticosteroids.
The therapeutic efficacy of these two agents is relatively equal, and one
drug may be effective if the other drug fails. The effectiveness of certain
traditional anticonvulsants (valproic acid and the benzodiazepines) and
pyridoxine in the treatment of infantile spasms has not been adequately
assessed. The long-term mental and developmental outcome of patients
with infantile spasms is poor. The only factor that appears to be important
in terms of long-term outcome is whether the patient is initially classified
as cryptogenic or symptomatic, with the cryptogenic patients having the
better outcomes. Approximately half of the infantile spasm patients will
continue to have other types of seizures after their spasms stop.

Supported by grant NSll535 from the National Institute of Neurological and Communicative
Disorders and Stroke, National Institutes of Health.

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Section of Neurophysiology
Department of Neurology
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030