**3.5 Treatment and prognosis**

*Epilepsy - Advances in Diagnosis and Therapy*

Continuously abnormal during the wakefulness and sleep.

epileptic discharges or focal slowing, and others [22].

a focal lesion or agenesis of the corpus callosum.

A typical interictal presentation in WS, hypsarrhythmia, refers to a high-voltage

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

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

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 high-

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

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,

voltage slow wave are greatly suggestive of focal cortical lesion [11].

system infections, and other acquired conditions [23].

ACADS, WDR45, and GABRA1 [23, 24].

(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

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

**3.3 Electroencephalography**

*3.3.2 Interictal abnormalities*

during the wakefulness.

in REM sleep.

*3.3.3 Ictal EEG*

**3.4 Etiology**

*3.3.1 Background*

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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 the underlying pathology [25].

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 cases may develop autism or LGS [26].

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 prodrug of prednisolone).

The highest short-term response rates (freedom from ES and hypsarrhythmia on treatment day 14) have been observed with ACTH administered at high dose (150 U/m<sup>2</sup> body surface areas per day, divided into two daily doses) [28]. 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 current studies [25].

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 ACTH (most with high-dose protocol; 150 U/m<sup>2</sup> /day) and oral corticosteroids (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, though the response rate to sACTH was inexplicably low [33].

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 patients without response to this drug.

All hormonal therapies exhibit similar—and important—adverse event profiles. The main risk is immunosuppression, which can be severe and potentially lethal, as well as hypertension, with the potential to yield congestive heart failure [34]. As such, avoidance of infectious contacts and screening for asymptomatic hypertension are key safety measures to be endorsed during any course of hormonal therapy. In addition, most clinicians prescribe antibiotic prophylaxis for pneumocystis pneumonia, screen for asymptomatic hyperglycemia, monitor serum potassium given modest risk of hypokalemia, and also screen for adrenal or pituitary insufficiency after a course of hormonal therapy.

Vigabatrin (VGB) is an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase, with proven efficacy in the treatment of IS in several randomized, controlled trials [35, 36]. Nevertheless, short-term response rates to VGB are considerably lower in comparison to the hormonal therapies. With respect to long-term outcomes, the superiority of hormonal therapy is not as clear [37, 38]. Although a large-scale trial of VGB versus high-dose hormonal therapy has not been undertaken in a TSC cohort, several studies indeed suggest that response to VGB is substantially higher among patients with WS associated with TSC in comparison to patients with other etiologies [39–41]. There is broad consensus that patients with IS in the setting of TSC should receive first-line treatment with VGB [27].

Overall, VGB is moderately effective (and highly effective in the setting of TSC) and confers moderate risk. The threat of visual field loss is relatively low and perhaps diminished by short courses of therapy; the risk of reversible and habitually asymptomatic MRI toxicity is moderately high and dose-dependent [41].

The hypothesis that combination therapy is superior to either therapy alone was proven in the International Collaborative Infantile Spasms Study (ICISS) [42], in which the investigators randomized new-onset patients with IS to receive either hormonal therapy (prednisolone or sACTH) alone or in combination with VGB. The combination therapy group exhibited superior response rates with respect to clinical outcome (parent-reported freedom from ES on days 14–42), electroclinical outcome, and time to cessation of ES.

A minority of children with IS are good candidates for surgical resection [43]. The etiologies best suitable to surgical resection include cortical dysplasia, cortical tubers in TSC, and various acquired structural lesions, for example, unifocal stroke or hemorrhage. The role of nonresective surgical approaches (e.g., corpus callosotomy) is not well established in these patients [43].

There are rare occasions in which a specific metabolic etiology of IS prompts a specific therapeutic intervention, either as an alternative or adjunct to first-line therapy [44]; the most notable examples include pyridoxine (vitamin B6) dependency (treated with pyridoxine or leucovorin), pyridoxal-5-phosphate deficiency (treated with pyridoxal-5-phosphate), glucose transporter type 1 (Glut1) deficiency (treated with the ketogenic diet), and nonketotic hyperglycinemia (ameliorated to some extent by sodium benzoate and other interventions to promote central glycine clearance) [45].

Other treatments are supported by very limited reports of efficacy. It includes traditional antiseizure drugs such as topiramate, zonisamide, valproic acid, felbamate, and benzodiazepines clonazepam and nitrazepam. Among nonpharmacologic therapies, numerous studies suggest substantial efficacy for treatment of IS with the ketogenic diet; most of these are retrospective, and none has utilized placebo controls or unbiased outcome assessment. Prognosis depends on etiology and is better in children without apparent structural cause. In nearly half of the patients, WS evolves into LGS or multifocal epilepsies.

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

**4.2 Seizures: symptoms and semiology**

which starts later [48].

**A.** Convulsive seizures

**4.1 Overview**

**4. Severe myoclonic epilepsy in infancy (Dravet syndrome)**

Severe myoclonic epilepsy of childhood was described in 1978 by Charlotte Dravet and included among epileptic encephalopathies in the 2001 proposal [3]. However, the acceptance that DS is a channelopathy of the SCN1A gene, as well as the presence of neurological deterioration in the early stages of the disease, has questioned whether the deterioration is really due to epileptic seizures or due to channelopathy [46]. Estimated prevalence of Dravet syndrome (DS) is about 1% of epilepsy syndromes in infancy and childhood, being more frequently in male. According to different descriptions of the natural course during of DS childhood, two phases have been identified: early phase (first year of life) and a steady phase (from 2 to 5 years of life); the electroclinical features are different between these phases. Early phase is characterized by long hemi- or generalized convulsive seizures, typically related with fever, while in the steady phase, seizures that predominate are myoclonic seizures (MS), atypical absences, and complex partial seizures (CPS); also, events of nonconvulsive status may occur. Cognitive development slows down progressively causing moderate/severe intellectual disability generally after the age of 4–5 years. Most patients develop ataxia, pyramidal signs, and hypotony, which persist to adulthood. Seizure behavior should vary in time; association between seizures and fever may be absent; also CPS and MS may begin in the early phase. Diagnosis of DS may be delayed because of the variability in evolution, the seizure polymorphism, and the non-specific EEG features. Long-term prognosis is always bad, pharmacoresistance is the rule, and most patients go on severely cognitively impaired.

The typical picture is previously healthy children who begin with seizures in the first year of life; its seizures should be unilateral or generalized convulsive (clonic or tonic-clonic), are commonly prolonged (more than 10 min), and could be progressed into status epilepticus (SE). Seizures are usually triggered by fever, or occur after immunization, but may also be afebrile. In the second or third year of life, other types of seizure, generally afebrile, can occur [47] in the absence of MS,

The seizure pattern changes over time; SE is the most problematic through the first 2 years of life and decreases in frequency after 5 years of age. In early childhood, frequent nonconvulsive seizures may negatively impact neurodevelopment. In the adolescent and adult years, brief but frequent nocturnal generalized convulsive seizures are the most common and place the patient at risk of sudden unexpected death in epilepsy (SUDEP). The details of seizures observed in DS are described then:

1.Unilateral with clear hemiclonic or tonic convulsions that may alternate sides

3.Falsely generalized (FG) and unstable seizures. FG are bilateral convulsive with asymmetric clonic or tonic movements and postures, at times predomi-

in the same patient can offer a significant sign to early diagnosis.

nating on one side or changing sides during the seizure.

2.Generalized tonic-clonic seizure (GTCS).
