**4.1 Overview**

*Epilepsy - Advances in Diagnosis and Therapy*

ficiency after a course of hormonal therapy.

electroclinical outcome, and time to cessation of ES.

tomy) is not well established in these patients [43].

patients, WS evolves into LGS or multifocal epilepsies.

VGB [27].

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 insuf-

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

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),

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 calloso-

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

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

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clearance) [45].

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.

## **4.2 Seizures: symptoms and semiology**

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, which starts later [48].

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 in the same patient can offer a significant sign to early diagnosis.
	- 2.Generalized tonic-clonic seizure (GTCS).
	- 3.Falsely generalized (FG) and unstable seizures. FG are bilateral convulsive with asymmetric clonic or tonic movements and postures, at times predominating on one side or changing sides during the seizure.

Sensitivity to photic or pattern stimulation is noted in approximately 40% of patients, particularly in younger children.

Worsening of seizures or SS may be provoked by blocking sodium channels AEDs, such as carbamazepine, phenytoin, lamotrigine, and vigabatrin.

In adults, seizures are more frequent during sleeping, especially long-lasting clonic seizures or short tonic-clonic seizures, while MS, AA, and focal seizures have a tendency to remit.

### **4.3 Electroencephalography**

EEG abnormalities are non-specific, but interictal EEG is useful for differential diagnosis; however sequential EEG recordings may show the evolution of DS, whereas ictal recordings with EMG polygraphy document seizure polymorphism [11].

### *4.3.1 Background*

In wakefulness state background activity is normal at onset, despite the frequent seizures; diffuse or asymmetric slowing may be seen if EEG is performed immediately after a seizure or may remain on for a few days. During sleeping normal patterns, initially after the first year, there is usually a gradual slowing of the background activity, more obvious if seizures are frequent. Physiological sleep phenomena and organization mostly remain conserved, except numerous nocturnal seizures occur.

### *4.3.2 Interictal abnormalities (IA)*

It may be present at the beginning (22% of patients) and grow during the evolution (77%) [48]. Generalized focal and multifocal abnormalities, spikes, and spike-wave or polyspike-wave discharges, symmetric or not, predominate over the frontal and central areas, but occur over the temporal and occipital areas, too. IA is typically greater during sleeping [48, 49]. The evolution of the EEG aspects with age is not always similar and being dependent on the number and duration of seizures.

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

predominant over the frontal areas.

seizures, in unstable seizures [47].

2–3.5 Hz, lasting 3–10 seconds.

frontal-central areas.

**4.5 Treatment and prognosis**

**4.4 Etiology**

seizure [47].

• Unilateral seizures. The ictal discharge is characterized by rhythmic (2–3/ second) bilateral slow waves of higher amplitude over the hemisphere contralateral to the clinical manifestations and intermixed with 10/second recruiting rhythms. In others, the EEG pattern can onset over the frontal or frontal-central regions of one hemisphere, or with bilateral asymmetric onset, but always

• Falsely generalized and unstable seizures. In this type of seizures, the EEG discharge is of bilateral symmetric or asymmetric onset with a slow spike, occasionally followed by a brief attenuation, and fast activities intermixed with slow waves. Whereas, the ictal discharge change topographically in a same

• In CPS ictal EEG consists of a rhythmic sequence of fast polyspikes intermixed with theta activity during the last part of the seizure, involving the temporal-parietal-occipital region of one hemisphere for the duration of the

• MS are accompanied by generalized spike or polyspike-wave discharges at 3 Hz or more, lasting 1–3 seconds and of higher voltage over the central-parietal areas.

• AA are linked with generalized regular or irregular spike-wave discharges at

• In obtundation status EEG background activity is substituted by diffuse delta slow waves, superimposed with multifocal spikes and spike-waves, sharp waves, and generalized spike-and-wave discharges preponderating over

• Tonic seizures are associated with diffuse discharges of polyspikes at 8–9 Hz [15].

DS is a channelopathy due to mutation in the SCN1A gene which encodes the alpha 1 subunit of the voltage-gated sodium (Nav1.1) channel reported in 80% of patients [50]. Almost half of SCN1A mutations are truncations, and most DS SCN1A mutations are de novo [51]. SCN1A mutations are not pathognomonic of DS; it could be observed in a spectrum of febrile epilepsy syndromes, which ranges from genetic epilepsy with febrile seizures plus (GEFS+) to DS. The mutations in the SCN1A gene also constitute a risk factor for SUDEP by causing cardiac and respiratory dysfunctions [52]. Another gene implicated in DS is GABRA1 [53].

The aim of treatment in patients with DS is reducing seizure frequency, minimizing comorbidities, limiting antiepileptic drug toxicity, and avoiding seizurerelated injury and SUDEP [54]. A greater degree of cognitive and behavioral impairment has been associated to higher frequencies of seizures [55, 56].

It is prominent that seizures are triggered by hyperthermia and less frequently by photosensitivity or pattern sensitivity; thus antipyretics for fever, minimizing

*4.3.3 Ictal EEG*

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