West Syndrome

Olivier Dulac

Bernardo Dalla Bernardina

Catherine Chiron

Introduction

The occurrence of clusters of axial movements in the first year of life, combined with major and subcontinuous electroencephalographic (EEG) paroxysmal activity called hypsarrhythmia, is the most frequent cause of psychomotor deterioration in infancy. This condition, usually termed either infantile spasms (IS) or West syndrome (WS), is a model for the study of epilepsy, because although the etiology, clinical and EEG expression, and outcome vary greatly from one patient to another, there is growing evidence that the etiology determines both expression and outcome in each given patient. The term IS denotes a specific age of onset and is therefore a syndromic concept. Because the concept of West syndrome usually includes hypsarrhythmia, this term should be considered more restrictive than the term IS. The clinical and EEG pattern is described in Chapter 54 (Spasms). This chapter concentrates on recent findings concerning correlation with etiology and the contribution of these findings to the understanding of pathophysiology.

Historical Perspectives

Over 160 years ago, West reported a condition that is probably the first epilepsy syndrome ever described. It was characterized by spasms as a particular seizure type not reported earlier and also by occurrence in infancy and mental deterioration. The condition did not become widely recognized as an epilepsy syndrome until 100 years later, however, when the particular EEG pattern was defined. Nevertheless, epileptic spasms were not recognized as a particular type of seizure and were therefore not included in the international classification,⁸⁰ although it is clear that their occurrence is not restricted to West syndrome, and they may occur beyond infancy.

Basic Mechanisms

A large variety of cerebral lesions may cause IS. Classic concepts of basic mechanisms suggest that IS are generated in subcortical structures, with ascending activity producing hypsarrhythmia and descending activity producing the seizures, a concept very similar to that of so-called centrencephalic epilepsy.³⁹^,⁴³ This view fails to take in account the predominantly cortical lesions determined radiologically and by neuropathologic studies. According to a newer concept, based on the potential recovery following removal of cortical lesions, the subcortical structures supposedly producing hypsarrhythmia and spasms are triggered by discharges in the cortical lesion.¹⁰^,¹⁵ During an ictal event, electrocorticography recording detects a focal spike triggering the fast-wave burst² and near-infrared spectroscopy multiple cortical areas activated simultaneously or sequentially.⁷⁰ However, this hypothesis does not clarify the age relationship, the variability of outcome, and especially the correlation of clinical and EEG pattern with etiology. The neurobiologic characteristics of the developing brain cortex, including age-dependent hyperexcitability and anteroposterior gradient of maturation, are the features most likely to contribute to the clinical and EEG pattern, including variations in outcome of epilepsy and cognitive disorders.²⁶ According to this hypothesis, continuous paroxysmal activity in the cortex, resulting from cortical damage, age-related functional instability, or both, produces nonconvulsive status epilepticus, accounting for the psychomotor deterioration, and determines the disinhibition of subcortical structures that generate the spasms. A model based on an unbalanced maturational pattern in brain structures leading to developmental desynchronization has recently been proposed for IS.³⁸ A transient developmental particularity is also the key of Baram’s hypothesis at the origin of IS: The excessive secretion by hypothalamus of a highly convulsant peptide in immature brain, cortico-releasing factor, would be reduced by feedback using adrenocorticotropic hormone (ACTH) as treatment of IS.⁴

Clinical Characteristics of the Syndrome

For these, see also Chapter 54.

Seizures

Epileptic spasms consist of axial contractions that may occur in flexion, extension, or both, and that may be symmetric or asymmetric. Asymmetry may involve the upper limbs, head, or eyes, and video recording is often required for detailed analysis. The contractions are usually brief and differ from myoclonic and tonic fits. They occur in clusters, occasionally combined with a focal discharge. Between spasms of a cluster, the interictal EEG pattern may or may not recur, which distinguishes “independent” from “nonindependent” spasms. Other types of seizures—myoclonic, tonic, or partial—may occur before, in combination with, or after the cluster of spasms.

Psychomotor Development

Psychomotor development can be been normal or abnormal before the first spasms. Deterioration at onset of spasms is a usual feature. However, some patients do not deteriorate and may even make further progress in development after onset of the disorder.

Interictal Electroencephalogram

The interictal EEG pattern is quite variable. Hypsarrhythmia as defined by Gibbs and Gibbs,⁴⁰ consisting of more or less continuous activity of high-amplitude, asynchronous spikes-and-slow-waves without any physiologic activity, involves only a
small proportion of cases. Other patterns consist of asymmetric hypsarrhythmia, focal or multifocal spikes with secondary generalization during sleep, and patterns that are more specific to particular causes of the disorder, including suppression bursts.

Age of Onset

Onset of IS usually occurs in the middle of the first year of life. Onset is rare before 3 months and after 1 year of age, which is considered to be the upper limit of occurrence of the syndrome in the classification of epilepsy syndromes.⁸⁰ In one series, however, >2% of patients with IS had their first seizure after the age of 12 months, and cases with onset in the fourth year of life are on record.⁵

Outcome

The range of outcomes is wide; spontaneous recovery may occur in 6% to 16% of patients. Others still have spasms after the end of the first decade of life. Different types of seizure disorders may occur, including partial epilepsy with one or more foci, Lennox-Gastaut syndrome, and other types of symptomatic generalized epilepsy. Mental retardation and various types of specific cognitive disorders are involved.

Thus, the pattern of IS is extremely variable from patient to patient in terms of clinical and EEG features and outcome. Etiology seems to be the major factor determining the characteristics of each component. Whatever the cause, age of onset and seizure type are similar among patients. The syndrome can therefore either be subdivided according to specific patterns or considered as a single disorder. The following discussion will show that both approaches are productive in terms of understanding clinical expression and outcome.

Pattern of Infantile Spasms According to Etiology

Malformations

Aicardi Syndrome

Aicardi syndrome is characterized by IS, chorioretinal lacunae, and callosal agenesis. Although often overlooked, the presence of widespread polymicrogyria probably contributes to the severe epilepsy; paraventricular heterotopia and occasional plexus papilloma are also frequently observed.

Initial seizures occur before 3 months of age in 68% of patients and before 1 month in 23%. Partial seizures usually precede epileptic spasms by 1 to 6 weeks, and spasms most often are characterized by asymmetry of contraction of the upper limbs and lateral deviation of the head and eyes.

Interictal EEG is characterized by asymmetry or asynchrony of both hemispheres with unilateral hypsarrhythmia, a pattern called split brain³⁴; it is now clear, however, that the pattern does not result from callosal agenesis, because patients with callosal agenesis and IS of other etiology do not exhibit a similar pattern. At disease onset, patients often have a diffuse, asymmetric, or unilateral suppression-burst pattern. Focal discharges may arise from the smaller or more malformed hemisphere.²¹ Electroencephalographic recordings of ictal events demonstrate that in many instances the cluster of spasms is combined with a focal discharge.⁹^,¹⁰ Spasms prove to be extremely resistant to treatment, and they often persist after the end of the first decade. Most patients exhibit severe mental retardation and remain bedridden, and the mortality rate is high. However, some patients acquire the ability to walk.⁶⁵

Agyria, Pachygyria, and Laminar Heterotopia

Various forms of diffuse disorders of cortical development, ranging from the four-layered cortex of agyria to laminar heterotopia, may produce IS. Agyria with microcephaly resulting from chromosomal deletion of 17p13 and agyria-pachygyria with no obvious chromosomal deletion produce IS in most cases.⁸^,²⁴ Laminar heterotopia mainly involves female infants and rarely produces IS.⁷⁴^,⁷⁵ A few families have been reported with girls exhibiting laminar heterotopia and boys agyria, with X-linked dominant transmission.²²^,⁷⁸

In cases of agyria and pachygyria, epilepsy may be manifested by early partial seizures before epileptic spasms occur. Interictal EEG demonstrates diffuse, high-amplitude rhythmic activity in the theta or alpha range that becomes discontinuous during sleep.³² A similar pattern is occasionally seen in laminar heterotopia. Polygraphic recording shows the disappearance of high-amplitude interictal activity between spasms of a cluster. A functional imaging study with single-photon emission computed tomography (SPECT) showed no anteroposterior gradient of cerebral blood flow and no modification with age, in contrast with the maturation observed in normal infants, thus demonstrating the lack of normal maturation of the cortex.¹⁴ This is correlated with the persistence of spasms, which may last beyond the end of the first decade.

Hemimegalencephaly, Focal Cortical Dysplasia, and Hamartoma

In hemimegalencephaly, one hemisphere and the corresponding lateral ventricle are larger than the other, and the cortex on the affected side is thick with giant neurons and abnormal lamination.⁸³ In focal cortical dysplasia, similar but less extensive histologic abnormalities are observed.

Epileptic spasms occur in half of cases of hemimega- lencephaly.¹⁰⁴ During a spasm, contraction of the upper limbs is asymmetric. The period of IS is usually preceded and followed by partial seizures. A similar pattern may be produced by focal cortical dysplasia, particularly when it is located in the occipital lobe⁵⁸ or recently individualized as hemi-hemimegalencephaly if extended to the posterior quadrant.²⁰ Here, the asymmetry involves eye deviation rather than the upper limbs. Electroencephalographic findings may include triphasic spikes in the first week of life. During the period of IS, EEG usually demonstrates an asymmetric suppression-burst pattern.⁷³ Detection of focal cortical dysplasia may be difficult, even on new-generation magnetic resonance imaging (MRI machines). Functional imaging is helpful,¹⁶ but IS are often associated with transient cortical, especially occipital, hypometabolic foci that are not necessarily associated with structural lesions and do not indicate a poor prognosis.

Several cases of prepeduncular hamartoma have been reported with IS.³⁷

Bilateral Perisylvian Microgyria

Bilateral perisylvian microgyria appears to result from some ischemic event related to rapid growth of the perisylvian area in the second trimester of gestation. A small proportion of patients are affected with IS.⁵⁶ The EEG pattern consists of asymmetric hypsarrhythmia.

Neurocutaneous Syndromes

Tuberous Sclerosis

Half of all patients with tuberous sclerosis have IS, and tuberous sclerosis is the major cause of IS,⁴⁹ accounting for 7% to 25% of cases. The IS are often asymmetric or are preceded by or combined with partial seizures. Most patients with partial seizures in the first month of life progress to IS. This pattern is rare when partial seizures begin after 6 months of age.²⁷ Interictal EEG demonstrates diffuse spike-and-slow-wave activity that is rarely of the typical hypsarrhythmic pattern type. Waking traces usually show one or several spike-and-slow-wave foci with generalization during sleep. During drowsiness, spikes associated with physiologic hypnagogic hypersynchrony simulate the hypsarrhythmic pattern.²⁷ Even patients who exhibit true hypsarrhythmia have focal spikes or slow waves in a significantly higher proportion than do patients with cryptogenic West syndrome, particularly after administration of diazepam. Polygraphic recordings show that clusters of spasms may be initiated by a tonic or a focal discharge. The tracing between spasms does not return to the pattern seen before the onset of the cluster. Few spasms are isolated. Video recording shows that during the spasm the eyes or head may turn to the side opposite the interictal focus.

In 75% of patients, epileptic foci are correlated with the topography of large cortical tubers, suggesting that these malformations are the main epileptogenic cause.¹⁷ The correlation is stronger for occipital than for frontal foci⁹⁶ because frontal foci are rare before the age of 2 years and because bilateral synchrony predominates in the frontal regions.¹⁶ A functional imaging study in 25 patients used SPECT and MRI and showed that cortical tubers are hypoperfused, even before the first seizure occurs.¹¹ In active epilepsy, the area of hypo- perfusion may be wider than that of the corresponding tuber. Patients with intractable epilepsy exhibit hypoperfused areas without corresponding cortical tubers, localized mostly in the temporal regions. This suggests that secondary epileptogenic foci contribute to intractability.

In the past, more than two thirds of patients with tuberous sclerosis and IS were left with mental retardation and behavioral disorders, and more than half exhibited autistic traits,⁴⁵ a rate twice that for all patients with IS. Mental retardation is linked to the number of tubers together with IS.⁷¹ Intellectual outcome is significantly improved by the control of spasms and subsequent seizures.⁴¹^,⁴⁸ Early treatment with vigabatrin, which controls spasms in >90% of cases,¹³ prevents the development of autistic features in most instances, even in patients who still have intractable partial seizures.⁴⁷ Topography of tubers also plays a major role. Autistic traits with TS were linked to bilateral and combined anterior and posterior tubers,⁴⁹ whereas mental retardation is associated more with other generalized seizures in patients with bilateral anterior tubers. Patients with selective cognitive defects had had either transient IS rapidly controlled by therapy or infrequent partial seizures, and they had a single detectable cortical tuber.

Neurofibromatosis

The combination of neurofibromatosis and West syndrome is not coincidental.⁶⁹ Spasms are usually symmetric, with a typical hypsarrhythmic EEG, “independent” spasms on ictal EEG and no focal features. This is the only symptomatic condition having the clinical and EEG characteristics of “idiopathic West syndrome” in most patients. A single case of hemimegalencephaly with neurofibromatosis has been reported.¹⁸

Perinatal Hypoxia-Ischemia

Severe hypoxia-ischemia in full-term newborns producing convulsions in the neonatal period and IS in infancy has become a rare condition in developed countries. Electroencephalographic features are a markedly depressed tracing followed by a progressive return to normal or near normal before focal or multifocal spikes or sharp waves appear and foretell hypsarrhythmia.¹⁰⁷ The outcome of the spasms is rarely favorable,¹⁰³ and partial epilepsy with multiple foci or generalized epilepsy may occur in more than half of patients.

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