**3. Infantile spasms (IS) and West syndrome (WS)**

### **3.1 Overview**

West syndrome (WS) was first described by Dr. WJ West of Tunbridge, United Kingdom, in 1841, in a letter addressed to the editor of *The Lancet*. West reports the characteristic clinical features in his own son. In 1952, Gibbs and Gibbs describe hypsarrhythmia, the characteristic electroencephalographic feature of WS [1]. WS is an age-dependent epilepsy that usually starts in the first year of life, most frequently between the first 3 and 9 months of life; however spasms can also affect older children but rarely beyond the age of 2 years. Even though the triad of epileptic spasms in cluster, developmental regression, and hypsarrhythmia on the EEG defines WS, it is not always associated with the classical hypsarrhythmic EEG pattern, and patients do not always have developmental regression at the beginning of the disease [19]. The recent ILAE classification included the term "epileptic spasms" (ES), rather than "infantile spasms," when this seizure type is observed at other ages. Hypsarrhythmia can also be incidentally recorded in the absence of spasms.

### **3.2 Seizures: symptoms and semiology**

ES are a seizure type, characterized by short-term muscle contractions that affect predominate proximal and truncal muscles which lead to abrupt flexion, extension, or mixed movements. According to EEG-EMG polygraphy records, an epileptic spasm reaches the full contraction more slowly than myoclonia but faster than a tonic seizure [20]. Usually, ES occurs in clusters but may be isolated. Clusters of ES increase progressively in frequency and intensity, reach a peak, and then gradually decline before they stop.

Some ES are limited to making only grimaces, deviation of the eye, and nodding; they can also be subclinical; it's called "subtle" ES. On the other hand, ES may be asymmetric, or asynchronous, concomitant with various focal manifestations that may implicate the limbs, head, or eyes; sometimes ES may express with compartmental and vegetative features. If ES is preceded or followed by, or interspersed with, focal seizures, it suggests a focal lesion [21].

## **3.3 Electroencephalography**

## *3.3.1 Background*

Continuously abnormal during the wakefulness and sleep.

### *3.3.2 Interictal abnormalities*

A typical interictal presentation in WS, hypsarrhythmia, refers to a high-voltage (hypsos = height), disorganized, and chaotic (without any discernible normal background rhythm = arrhythmia) EEG pattern. At onset, hypsarrhythmia may be present only during the drowsiness and light sleep, but it soon grows into profuse during the wakefulness.

Sometimes epileptic discharges appear to be focal or multifocal, however, without a rhythmic or organized pattern. This electrical manifestation is almost continuous, although in initial stages, background activity can be observed intermittently. Hypsarrhythmia predominates in the posterior regions; rarely, posterior predominance is observed, especially after the first year of life [11]. This pattern of hypsarrhythmia reaches its peak in stage 1 of sleep, is less persistent in stages II and III of sleep (as multifocal spikes and sharp discharges), and disappears completely in REM sleep.

Different variants of hypsarrhythmia have been reported further than its typical presentation; these include (1) hypsarrhythmia with increased interhemispheric synchronization, (2) asymmetric hypsarrhythmia, (3) hypsarrhythmia with episodes of voltage attenuation, (4) hypsarrhythmia with a consistent focus of epileptic discharges or focal slowing, and others [22].

When the EEG shows atypical hypsarrhythmia, an underlying structural origin can be suspected; for example, predominating focal discharges or slow complexes could indicate a focal lesion, diffuse high-voltage theta-alpha activity may indicate lissencephaly or pachygyria, and persistent asymmetry or asynchrony may suggest a focal lesion or agenesis of the corpus callosum.

### *3.3.3 Ictal EEG*

Ictal activity associated with ES includes a diffuse high-amplitude triphasic slow wave, a low-amplitude brief fast discharge, or a short-lasting diffuse flattening of ongoing activity [13, 20]. A transient disappearing or reduction of the hypsarrhythmic pattern could be seen during a cluster of ES. Patients with brain lesions may show an asymmetry of the ictal high-amplitude slow wave because of the more involved hemisphere. Focal or unilateral fast discharges directly preceding the highvoltage slow wave are greatly suggestive of focal cortical lesion [11].

### **3.4 Etiology**

WS etiology can be genetic, structural or metabolic, or unknown. Prenatal and perinatal etiologies explain more than 40% of the cases; they include central nervous system malformations, neurocutaneous syndromes (especially tuberous sclerosis), metabolic disorders, hypoxic-ischemic encephalopathy, central nervous system infections, and other acquired conditions [23].

Underlying etiology may be genetic, either chromosomal abnormalities or single-gene defects. The mutations in specific genes are ARX, GAMT, ALG13, CDKL5, SCN2A, STXBP1, SCN1A, ALG13, GABRB3, DNM1, SCN8A, MAGI2, ACADS, WDR45, and GABRA1 [23, 24].

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*Epileptic Encephalopathies in Infants and Children DOI: http://dx.doi.org/10.5772/intechopen.85378*

The key short-term aims of therapy are the rapid abolition of ES and the elimination of hypsarrhythmia. Effective treatment is associated with better outcome, at least in patients where the underlying pathology is not responsible for significant neurological deterioration. Therefore, children with WS, who are developmentally normal prior to spasms, continue to be normal after successful early treatment; on the other hand, children with WS, who have some cognitive problems prior to spasms, remain to have cognitive deficits, even after successful treatment related to

Other factors that contribute to unfavorable outcome are onset at age < 3 months, psychomotor retardation, existence of other seizure types, persistence of abnormal EEG features, mild to gross neurologic deficits, significant computed tomography/MRI findings, and long duration of therapy. All unfavorable prognostic factors seem to relate to the underlying pathology; some symptomatic

With the exception of IS in the setting of tuberous sclerosis complex (TSC), there is relatively broad consensus that hormonal therapy is the most effective class of initial treatment for IS [27]; but the best agent, dose, and length of treatment are not clear. The most studied medications are natural adrenocorticotropic hormone (ACTH, a 39 amino acid peptide), synthetic ACTH (sACTH, a truncated peptide spanning the first 24 N-terminal residues), prednisolone, and prednisone (the

The highest short-term response rates (freedom from ES and hypsarrhythmia on treatment day 14) have been observed with ACTH administered at high

Although some authors reported that short-term response was far superior with this regimen of ACTH in comparison to prednisolone at dose of 2 mg/kg/day [29], a sequence of studies has suggested that higher dose regimens of prednisolone are as effective as ACTH. In the UKISS study, no difference in response rate between prednisolone (40–60 mg/day) and a "moderate" dose of sACTH (0.50–0.75 mg on alternate days) was observed, although treatment allocation was not randomized [30]. Likewise, in a debatably underpowered retrospective analysis, Kossoff and colleagues reported that efficacy of high-dose prednisolone (40–60 mg/day) was similar to historical experience with high-dose natural ACTH [31]. In other relatively small study evaluating short-term efficacy of very high-dose prednisolone (8 mg/kg/day; max 60 mg/day) followed by high-dose natural ACTH in prednisolone nonresponders, the EEG-confirmed response to prednisolone (63%) was analogous to the reported ACTH response in most

More recently, in a large-scale prospective observational study led by the National Infantile Spasms Consortium (United States) without randomized treatment distribution, Knupp and colleagues reported that response rates to natural

(most with high-dose prednisolone; 40–60 mg/day) were statistically indistinct [32]. In the only modern randomized controlled trial comparing high-dose prednisolone (40–60 mg/day) with moderate-dose sACTH (0.5–0.75 mg on alternate days), Wanigasinghe and colleagues found that response to prednisolone was superior,

Given the cost of a typical course of ACTH exceeds 100,000 USD, a typical course of prednisolone costs less than 100 USD; many of treatment protocols for WS begin with prednisolone/prednisone and leave ACTH as an alternative for

body surface areas per day, divided into two daily doses) [28].

/day) and oral corticosteroids

**3.5 Treatment and prognosis**

the underlying pathology [25].

prodrug of prednisolone).

dose (150 U/m<sup>2</sup>

current studies [25].

ACTH (most with high-dose protocol; 150 U/m<sup>2</sup>

patients without response to this drug.

though the response rate to sACTH was inexplicably low [33].

cases may develop autism or LGS [26].
