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Historical note and nomenclature

In a letter to Lancet in 1841, West first described the infantile spasms his son suffered. He emphasized the relentless nature, especially in terms of psychomotor retardation (West 1841). The condition was considered incurable until the serendipitous discovery that adrenocorticotropic hormone can control the seizures (Sorel and Dusaucy-Bauloxe 1958). In 1952 Gibbs and Gibbs first described the unique EEG pattern recorded in a large number of infantile spasm patients: hypsarrhythmia (hypsi, from Greek, meaning "high," arrythmia, from Greek, meaning "lack of rhythm"), which is characterized by random, high-voltage, nonsynchronous spikes and slow wave activity (Gibbs and Gibbs 1952). The triad of infantile spasms, mental retardation, and hypsarrhythmic EEG pattern has been collectively called West syndrome since the 1960s (Gastaut et al 1964). The identification of focal brain lesions, only detectable on functional imaging, was puzzling in an epilepsy considered as being generalized (Chugani et al 1990). The effect of vigabatrin was a new step in the treatment of West syndrome (Chiron et al 1990; Gram et al 1992). Evolution from early epileptic encephalopathy to West syndrome and to Lennox-Gastaut syndrome, thus, three types of age related epileptic encephalopathies, has been emphasized by Ohtahara (Ohtahara 1984).

Clinical manifestations

West syndrome comprises a triad of spasms in clusters, mental retardation, and diffuse and profound paroxysmal EEG abnormalities. The onset is insidious in either an otherwise normal or an already handicapped infant. It is an age-dependent epilepsy syndrome that begins in infancy, mostly between 4 months and 6 months of life, before the age of 12 months in over 90% of cases (Kellaway et al 1979). However, the later occurrence, up to 4 years of age, has been recently emphasized, it is easily overlooked and, therefore, inappropriately treated for many months before the diagnosis is done (Bednarek et al 1998). There is a slight male preponderance.

Infantile spasms are characterized by usually symmetrical, bilateral, brief, and sudden contractions of the axial muscle groups. The features of the seizures depend on whether the flexor or extensor muscles are predominantly affected and also on the number and distribution of the muscle groups involved. Thus, spasms may vary from extensive contractions of all flexor or extensor muscles to contractions of only neck muscles or abdominal recti (Hrachovy and Frost 1989). Spasms may be flexor, extensor, and mixed flexor-extensor. Mixed spasms are most common, followed by flexor spasms, with extensor spasms being the least common (Kellaway et al 1979). Most infants have more than one of these types, and the type observed at any given moment may be influenced by body positions.

The flexor spasm, though not the most common, is the most characteristic of West syndrome. When the abdominal flexor muscles are involved, the body may bend at the waist like a jackknife (jackknife seizure). When the upper extremities are involved, either abduction or adduction of the arms in a self-hugging motion will appear. The jackknife seizure plus the adduction of the upper extremities is reminiscent of the ritual of salaam, thus the term "salaam attacks." When only the neck flexor muscles are involved, the spasm may be a head nod. The involvement of the shoulder girdle may manifest as a shrug-like movement (Kellaway et al 1979). A behavioral arrest may also occur as a seizure without associated spasm. Spasms can be restricted to brief, vertical, ocular deviation or nystagmoid movements. Alteration in respiration is also a common associated phenomenon, whereas change in heart rate is rare (Kellaway et al 1979).

In fact, the type of spasms, whether in flexion, extension, or mixed does not seem to be affected by etiology or the prognosis. In contrast, whether the spasms are symmetrical or not is important because asymmetry contributes to indicate some kind of cortical brain damage (Fusco and Vigevano 1993). Asymmetrical spasms consist of lateral deviation of the head or eyes.

Spasms tend to occur soon after awakening or on falling asleep. Most of the spasms occur in clusters, ie, the interval between successive spasms is less than 60 seconds. Usually the intensity of spasms in a given cluster will peak gradually and then decline (Hrachovy and Frost 1989). The frequency of spasms varies from only a few times a day to several hundred a day (Kellaway et al 1979). They do not show a predilection for either day or night, although they appear to be temporally related to sleep. Sudden loud noises or tactile stimulation, but not photic stimulation, may precipitate them.

Following a spasm there may be periods of attenuated responsiveness. Crying may frequently follow a spasm, but this is not an ictal phenomenon. In walking children, drop attacks may be the first manifestation of the disorder.

In one-third the psychomotor development is normal before onset (Kurokawa et al 1980). In about two-thirds of the patients without any identifiable cause for the infantile spasms, there is some degree of neuropsychological impairment prior to onset of spasms without definitively contributing factors. Axial hypotonia and loss of hand grasping are the most frequently lost skill. Loss of eye contact has a negative prognostic significance.

The usual EEG abnormalities consist of diffuse, high amplitude, nonsynchronous paroxysmal and slow wave theta and delta activity with loss of background features that is continuous when awake and fragmented in sleep. This hypsarrhythmic pattern may be symmetrical or asymmetrical because of additional foci, or unilateral. In other conditions, it consists of one or several spike foci when awake with secondary generalization in sleep. Other patterns are specifically determined by particular causes.

The interictal EEG of infantile spasms is usually characterized by hypsarrhythmia with a continuous, irregular, random, ever-changing, disorganized, high-voltage spike and slow wave activity. This is sufficiently characteristic to be easily identified, and the term “chaos” may be inappropriate from this point of view. It may be present during wakefulness and non-REM sleep or may be present only during sleep (Watanabe et al 1993). During deep sleep, it may be discontinuous (Blume and Dreyfus-Brisac 1982). Hypsarrhythmia, however, is usually seen in the early stages of infantile spasms, most often in younger infants, and is present in approximately 66% of the cases (Blume and Dreyfus-Brisac 1982). The “chaotic” pattern becomes more organized with time (Hrachovy et al 1984; Watanabe et al 1993) and, between 2 years and 4 years of age, may evolve into the generalized slow sharp and slow-wave pattern of Lennox-Gastaut syndrome.

Several different ictal EEG patterns are associated with infantile spasms (Kellaway et al 1979). The most common one is a high-voltage, generalized, slow-wave transient followed by an attenuation of background activity that lasts more than 1 second, referred to as an electrodecremental response. In other instances, there is electrodecremental fast activity (Vigevano et al 1993). There is no correlation between the ictal pattern and the type of spasm. The duration of the ictal EEG ranges from 0.5 seconds to 106 seconds. The longer episodes are associated with behavioral arrest. In some instances, the ictal discharge combines focal discharge with the cluster of spasms (Bour et al 1986; Carrazana et al 1993), the focal discharge either preceding, following, or being in the middle of the cluster of spasms. This combination strongly indicates either brain malformation or focal brain lesion.

Clinical vignette

No information was provided by the author.

Etiology

Infantile spasms are either due to a variety of known etiological factors (symptomatic), or are without apparent causes (idiopathic/cryptogenic). Some authors suggest a distinction between cryptogenic and idiopathic: idiopathic referring to patients with a possible hereditary predisposition, such as a family history of epilepsy or febrile seizures or EEG genetic patterns, and cryptogenic referring to patients with a presumed underlying etiology, that cannot be demonstrated (van der Berg and Yerushalmy 1969; Dulac et al 1993b; Vigevano et al 1993).

Cryptogenic cases account for 9% to 15% of the cases, the rest being symptomatic (Matsumoto et al 1981; Riikonen 1982). Unless the etiology is a specific genetic disorder, such as tuberous sclerosis or twin pregnancy, familial recurrence is rare (Kurokawa et al 1980; Dulac et al 1993a). The symptomatic cases are associated with several prenatal, perinatal, and postnatal factors. Prenantal (CMV fetopathy) or perinatal (herpes virus or bacterial meninigitis) infection, neonatal ischemia following term (focal or diffuse) or premature delivery, or post-natal ischemia (near miss), various brain dysgenesis (lissencephaly, hemimegalencephaly, focal cortical dysplasia, septal dysplasia or callosal agenesis), chromosomal (including Down syndrome, del1p36) or single gene (ARX mutation) involvement, neurocutaneous syndrome (tuberous sclerosis, incontinentia pigmenti or Ito syndrome, neurofibromatosis, traumatic lesions are the most frequent, whereas inborn errors of metabolism are rare. Nevertheless, infantile spasms used to be observed with phenylketonuria, and may complicate tetrahydrobiopterine deficiency, and mitochondrial cytopathy is occasionally observed. It is particularly frequent in the course of Menkes disease.

During the past several decades, immunization with various vaccines, especially the diphtheria-pertussis-tetanus vaccine, has been frequently considered as a causative agent in infantile spasms. The relationship is speculative, because the diphtheria-pertussis-tetanus immunization is given at a time when infantile spasms have their peak occurrence (ie, less than 6 months of age). Current available evidence indicates that the association between infantile spasms and diphtheria-pertussis-tetanus immunization is coincidental and that the two are not causally related (Fukuyama et al 1977; Cody et al 1981; Bellman et al 1983; Anonymous 1991).

Pathogenesis and pathophysiology

In the cryptogenic cases, nonspecific degenerative changes have been reported in the cerebral cortex and white matter (Satoh et al 1984).

The pathogenesis of West syndrome is unknown. However, the following hypotheses have been advanced:

(1) Brainstem dysfunction of serotonergic neurons may cause infantile spasms (Hrachovy et al 1981; Silverstein and Johnston 1984). This hypothesis is based on the observation that patients with infantile spasms have decreased REM sleep duration, a sleep period during which there is normalization of the EEG with a decrease in the number of spasms. Brainstem serotonergic neurons are involved in sleep cycles and depletion of serotonin may decrease REM sleep. Langlais and colleagues provided data supporting a serotonin dysfunction hypothesis by demonstrating reduced levels of 5-HIAA, a metabolite of serotonin, as well as decreased levels of homovanillic acid and MHPG in patients with infantile spasms, but it is yet undetermined whether this is primary or secondary to West syndrome (Langlais et al 1991). In children who responded to adrenocorticotropic hormone treatment, there was a large increase in 5-HIAA following therapy, whereas in nonresponders, 5-HIAA levels decreased.

(2) An immunologic abnormality has also been postulated. Patients with infantile spasms have been reported to have an increased frequency of HLA-DRw52 and an increased number of activated B cells (Hrachovy et al 1985; 1988). However, the relationship remains to be verified.

(3) Alteration in the brain-adrenal axis in patients with infantile spasms has recently been suggested. Baram and colleagues demonstrated lower cerebrospinal fluid adrenocorticotropic hormone and increased corticotrophine releasing factor levels, although they failed to demonstrate any difference in cerebrospinal fluid cortisol or corticotropin-releasing hormone levels between infantile spasm patients and controls (Baram et al 1992). According to this hypothesis, excessive corticotrophine releasing factor due to stress or other precipitating factors could precipitate the occurrence of spasms.

(4) Overexpression of axonal collaterals and excitatory synapses that play a major role in the development of cortical functions determine major hyperexcitability of the developing brain cortex and could be responsible of continuous spiking activity, particularly in combination with some brain damage. Lack of myelin at that age would account for the absence of interhemispheric synchrony, thus producing the hypsarrhythmic pattern (Dulac et al 1994). Continuous paroxysmal activity would account for the cognitive decline. It would also determine subcortical disinhibition, with paroxysmal discharges in the basal ganglia (Chugani et al 1990). Thus, a loop including the cortex and basal ganglia would be involved in the genesis of West syndrome (Desguerre et al 2003). Any alteration at one level, either cortical lesion is the most frequent, or basal ganglia, particularly in inborn errors of metabolism. Maturation of the brain would reduce excitability and explain disappearance of the syndrome in a majority of cases, or determine in the intractable one, synchronization between hemispheres due to myelination, with occurrence of slow spike waves and tonic seizures, thus Lennox-Gastaut syndrome.

Epidemiology

The incidence of West syndrome is estimated to be about 1 per 2000 to 4000 live births (Hurst 1994). It is the most frequent type of epileptic encephalopathy, the group of conditions in which epilepsy determines cognitive deterioration.

Prevention

There is no known prevention. However, the question is open whether vigabatrin could prevent the occurrence of spasms when given from before the first spasms to a patient with tuberous sclerosis discovered early in life or before birth. In addition, some compound, mainly carbamazepine, may precipitate the occurrence of spasms (Talwar et al 1994), and this drug should, therefore, be used with major caution in infants with epilepsy due to a cause known to generate spasms, or without identified cause.

Differential diagnosis

Babies with infantile spasms are often misdiagnosed as having exaggerated startle responses. There should be a high degree of suspicion for epileptic spasms if exaggerated startle occur, especially on arousal.

Benign myoclonus of early infancy (benign nonepileptic infantile spasms) was first reported in 1977 (Lombroso and Fejerman 1977). Although it shares the similar age of onset and behavioral spasms with West syndrome, the prognosis is entirely different. In benign myoclonus of early infancy, the tonic spasms are associated with normal ictal and interictal EEGs during wakefulness and sleep. The spasms occur without any temporal relationship with sleep, in contrast to those of West syndrome. There is no mental or psychomotor involvement. It is usually associated with no or minor perinatal insults. There may or may not be family history of epilepsy (Dravet et al 1986). The spasms in benign myoclonus of early infancy usually disappear by a few years of age, with or without treatment.

Benign myoclonic epilepsy of infancy is another epilepsy syndrome with similar age of onset but a distinct seizure type. The latter are characterized by myoclonic jerks, usually involving only the arms and head. As in benign nonepileptic infantile spasms, the myoclonic episodes usually have no relationship to sleep, although drowsiness tends to increase their frequency. Interictal EEGs are usually normal, but the seizures are associated with a 1- to 3-second burst of spike-and-wave and polyspike-and wave-discharges. Photic stimulation may provoke the myoclonus. Psychomotor development remains normal, and these children do not evolve to have other seizure types (Roger et al 1993).

Sandifer syndrome is associated with of gastroesophageal reflux, with head cocking, or torticollis, and abnormal dystonic posturing of the body, including opisthotonus. There may be associated eye and limb movements. These spells, particularly the opisthotonic posturing, may be mistaken for spasms. Historical features can help establish the diagnosis, although not all babies with reflux will exhibit obvious signs such as vomiting, failure to thrive, and respiratory symptoms. Spells often occur in relation to feeding. EEG is normal. Barium esophagogram, esophagoscopy, or pH probe may demonstrate the reflux. The major risk is to overlook spasms in a child with reflux, a frequent condition in early infancy. Any doubt should indicate an EEG.

Diagnostic workup

Particularities of the EEG may contribute to etiological diagnosis. Some diffuse brain malformations such as lissencephaly or Aicardi syndrome exhibit specific EEG patterns (Dulac et al 1983). In tuberous sclerosis, the EEG is rarely hypsarrhythmic, whereas spike foci are frequent with secondary generalization in sleep. Suppression bursts are frequent in hemimegalencephaly, schizencephaly, or Aicardi syndrome. A slow wave focus is added to hypsarrhythmia in porencephaly, focal dysplasia, and other focal lesions. IV diazepam may contribute to disclose the focus by reducing hypsarrhythmia. In idiopathic cases, hypsarrhythmia is symmetrical.

Ictal pattern showing a combination of focal discharges before, during, or after the cluster of spasms usually results from a cortical malformation (Dalla Bernardina 1984; Ohtsuka et al 1998). Reappearance of hypsarrhythmia between spasms of a cluster is a feature of West syndrome (Dulac et al 1993b).

CT may be normal or reveal underlying focal of diffuse structural pathology (Singer et al 1982). MRI studies are more sensitive in detecting focal lesions, including areas of abnormal or delayed myelination, abnormal demarcation between gray and white matter, and focal areas of cortical dysplasia (van Bogaert et al 1993).

In some children, PET scans have revealed focal areas of hypometabolism, which often correlate with dysplastic cortex and white matter (Chugani et al 1992; 1993). Specific markers may be contributive, showing mainly the epileptogenic areas of the cortex in multifocal brain lesion, particularly tuberous sclerosis (Chugani et al 1998).

Prognosis and complications

The spasms and hypsarrhythmic EEG tend to disappear spontaneously before 3 years of age. However, up to 55% to 60% of children with infantile spasms will develop other types of seizures and epileptic syndromes, for example, Lennox-Gastaut syndrome (Jeavons et al 1973; Matsumoto et al 1981; Riikonen 1982).

The prognosis for West syndrome in terms of normal development is poor in spite of treatment. Overall, only about 5% to 12% of patients have normal mental and motor development. Approximately one-half are left with motor impairment and 70% to 78% are mentally retarded (Jeavons et al 1973; Matsumoto et al 1981; Riikonen 1982; Glaze et al 1988). The prognosis is better in the idiopathic or cryptogenic cases that have no known associated etiologic factor, no abnormality on neurologic examination, normal development before the onset of the spasm, and normal neuroimaging prior to therapy. Among this group of infants, 37% to 44% are neurologically and cognitively normal at long-term follow-up (Jeavons et al 1973; Matsumoto et al 1981; Riikonen 1982; Glaze et al 1988). In this subgroup of cryptogenic patients, a delay in initiation of treatment may be associated with worse outcome (Matsumoto et al 1981; Riikonen 1982). In older series there is no significant difference in long-term outcome between those who are responsive to adrenocorticotropic hormone/prednisone therapy and those who are not, although other investigators have found a good response to adrenocorticotropic hormone to be associated with good neurologic outcome (Riikonen 1982).

Unfortunately, because the precise condition of the patient before the first spasms is often not determined, the relative responsibility of the previous condition that determined the occurrence of West syndrome, and West syndrome itself, are usually not distinguished properly when defining the sequelae of West syndrome. Indeed, in many instances in which the symptomatic epilepsy is soon brought under control, the long term condition is not altered by the transient occurrence of West syndrome. On the contrary, lasting or early onset West syndrome is likely to produce sequelae by itself. It is now established for patients with West syndrome due to Down syndrome that delay to proper treatment contributes to generate intractability and the occurrence of autistic features (Eisermann et al 2003).

Within the group of patients without evidence of brain lesion by history or radiology, a subgroup can be identify at the onset on the basis of clinical and EEG characteristics, that has excellent outcome. It has no history prior to the first spasms, spasms are symmetrical, there is moderate loss of cognitive functions, particularly no loss of eye following, hypsarrhythmia is symmetrical and hypsarrhythmia recurs between spasms within a cluster (Dulac et al 1993b).

The prognosis is worst in the cases in which the syndrome is symptomatic of underlying degenerative brain diseases (Glaze et al 1988). The mortality rate used to be estimated as high as 25%. Recently, the mortality rate was reported to be reduced to 5%, which may be attributed to improved general medical care (Glaze et al 1988).

Management

Treatment of infantile spasms with adrenocorticotropic hormone or prednisone often results in cessation or amelioration of the seizures and disappearance of the hypsarrhythmic EEG pattern. A double-blind study comparing adrenocorticotropic hormone versus prednisone showed superiority of adrenocorticotropic hormone (Hrachovy et al 1983; Baram et al 1996). Snead and colleagues have demonstrated a significantly higher response rate, 90%, with high-dose adrenocorticotropic hormone (Snead et al 1989). This higher response rate may be related to a sustained rise in cortisol following high-dose adrenocorticotropic hormone, which does not occur with low-dose adrenocorticotropic hormone or oral prednisone.

Just as there is no consensus regarding the dose of steroids for the treatment of infantile spasms, duration of treatment also varies, usually ranging from 2 weeks to 6 weeks.

Previously, among antiepileptic drugs only valproic acid and nitrazepam were reported to be effective in treating patients with infantile spasms. Dreifuss and colleagues have suggested that nitrazepam and adrenocorticotropic hormone afford a similar degree of seizure control, although there is no general agreement (Dreifuss et al 1986). Recently, vigabatrin (gamma vinyl GABA), an antiepileptic medication available in Canada, Europe, South America, several countries in Asia, and the Middle East, has been used with success in the treatment of infantile spasms, as confirmed in two double-blind studies (Appleton et al 1999; Elterman et al 2001). A randomized study has shown better effect of vigabatrin than hydrocortisone in infantile spasms due to tuberous sclerosis (Chiron et al 1997).

Also in uncontrolled studies, human polyvalent immunoglobulins have been used intravenously to decrease the frequency of seizures, improve EEG patterns, as well as improve psychomotor performance (van Rijckevorsel-Harmant et al 1986).

High-dose pyridoxine (100 mg/kg to 300 mg/kg per day) has been beneficial in treating some patients with infantile spasms, with minimal toxicity (Blennow and Stark 1986; Pietz et al 1993). Those patients who respond tend to do so within the first 1 week to 2 weeks after initiation.

Some infants with medically intractable infantile spasms and focal lesions, either structural or on PET imaging, may benefit from resection of the focal abnormality (Chugani et al 1990; Holmes 1993). Persistent spasms not amenable to focal surgery and who suffer from drop attacks, may benefit from total callosotomy, whereas anterior callosotomy is ineffective probably for reasons related to maturation of the brain (Pinard et al 1999).

Pregnancy

Not applicable.

Anesthesia

Precautions must be taken regarding seizures.

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ILAE
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Abbreviations

5-HIAA:5-hydroxyindoleacetic acid

CT:computed tomography

EEG:electroencelpahlogram

GABA:gamma-aminobutyric acid

HLA-DR:human leukocyte antigen, locus DR

MHPG:3-methoxy-4-hydroxypheylglycol

MRI:magnetic resonance imaging

REM:rapid eye movement

ICD code

345.1

McKusick MIM number

308350

Synonyms

Infantile myoclonic seizures

Massive spasms

Wests syndrome

West’s syndrome

Associated disorders

Benign myoclonus of early infancy

Early epileptic encephalopathy

Lennox-Gastaut syndrome

Tuberous sclerosis

Major keyword descriptors

ACTH

adrenocorticotropic hormone

axial hypotonia

brainstem dysfunction of serotonergic neurons

carbamazepine

diphtheria-pertussis-tetanus vaccine

drop attacks

electrodecremental response

epileptic encephalopathy

flexion spasms

flexor spasms

human polyvalent immunoglobulin

hypoxia-ischemia

hypsarrhythmia

inborn error of metabolism

infantile spasms

intrauterine infection

jackknife seizures

loss of hand grasp

nitrazepam

prednisone

pyridoxine

salaam attacks

valproic acid

vigabatrin

Minor keyword descriptors

alteration in respiration

cerebral degenerative disorders

epilepsy

head nod

mental retardation

motor impairment

psychomotor retardation

seizures

Age of presentation

0-01 month

01-23 months

02-05 years

Age of typical presentation

01-23 months

(mainly 3 months to 12 months)

Population group(s) preferentially affected

none selectively affected

Occupation group(s) preferentially affected

none selectively affected

Sex

male>female, >1.5:1

Family history

family history may be obtained

Heredity

none

Permuted topic, synonyms, variants

West syndrome

syndrome, Wests

syndrome, West’s

spasms, Massive

myoclonic seizures, Infantile

seizures, Infantile myoclonic

Related topics

Atypical absences

Benign myoclonic epilepsy in infancy

Benign nonepileptic infantile spasms

Epilepsy

Lennox-Gastaut syndrome

Myoclonic-astatic epilepsy of childhood

Vigabatrin

Zonisamide

Differential diagnosis

exaggerated startle responses

benign myoclonus of early infancy

benign myoclonic epilepsy in infancy

benign nonepileptic infantile spasms

Sandifer syndrome