Recognized as a syndrome by the International League Against Epilepsy in the last classification,¹ severe myoclonic epilepsy of infancy (SMEI) has been placed among the “epileptic encephalopathies”, defined as conditions in which the epileptiform abnormalities are believed to contribute to a progressive disturbance in cerebral function, whether seizures are generalized, localized, symptomatic, idiopathic or cryptogenic.² Since 2001³ its etiology is regarded to be genetic as the majority of affected patients carry a mutation in the sodium-channel gene SCN1A. However, it remains unproven whether the cognitive decline observed in the first stages of the disease is a consequence of the epilepsy. In this new scheme, SMEI is renamed “Dravet syndrome” because of the lack of myoclonic seizures in many patients.

The frequency in the general population is not well known but has been estimated at 1/40,000 births.⁴ Since 1990, knowledge of the disease has grown considerably and it is likely its frequency is higher, but there is no other epidemiological data.

The typical features of the core syndrome are present in the majority of the patients, although variations exist in semiology and outcome.

ONSET

Seizures typically begin in the first year of life in a normal infant without pathological antecedents. A family history of epilepsy and febrile seizures is frequent. Seizures begin between ages 4 and 9 months, accompanied by mild hyperthermia, and last longer than the simple febrile seizures (10 minutes or more). They are clonic, generalized, unilateral or predominating on one side of the body, and change from one seizure to the next. They may have localized onset. In some patients, isolated episodes of focal myoclonia are observed before the appearance of the first convulsive seizure. Purely focal complex seizures are exceptional at the onset.

The first convulsive seizure can be afebrile, after a vaccination, a bath, or during a cold. Usually, afebrile seizures are quickly associated with febrile seizures. This first seizure is considered as an occasional seizure that does not require a treatment. But, shortly thereafter, other seizures occur, with or without fever, and persist in spite of the institution of a chronic treatment.

STEADY STATE

Seizure frequency increases during the second year of life. Affected patients have many upper respiratory tract infections and are repeatedly hospitalized. Some seizures are resistant to acute treatment and evolve to status epilepticus (SE) requiring intensive care. Other seizure types appear and psychomotor development slows.

Ictal Semiology

Convulsive seizures are reported to be generalized by the parents but have variable features. They may be truly generalized, clonic or tonic clonic. Others are “falsely generalized” or “unstable” with some focal elements, clinical or EEG, and localize to different areas during the course of the same seizure (Fig. 14–1). The most typical variants are unilateral and hemiclonic. Myoclonic seizures appear between ages 1 and 5 years in approximately 85% of the cases. They are generalized, involving the body axis and the proximal parts of the limbs. They occur several times a day and may be focal or secondarily generalized. Seizures are accompanied by diffuse spike-waves (SWs) in the EEG and are often associated with interictal segmental myoclonia.

Atypical absences may present up to age 12 years. Their frequency is difficult to assess due to a frequent myoclonic component that makes them difficult to differentiate from myoclonic seizures. Atonic components with a head drop are not uncommon and are accompanied by more or less regular diffuse spike-wave discharges and slow waves (Fig. 14–2). Peculiar obtundation status is observed in 40% of cases and consists of impaired consciousness accompanied by segmental and fragmentary erratic myoclonia, involving the limbs and the face, sometimes associated with a slight increase in the muscular tone. According to their degree of consciousness, patients may react to stimuli and continue simple activities (e.g., eat, manipulate toys). They last from 30 minutes to several hours and can be intermixed with short episodes of complete loss of consciousness or convulsive seizures. Clinically they may be difficult to distinguish from focal complex SEs, which are rarer and usually shorter. The EEG is associated with mixed diffuse slow waves, notched slow waves, sharp waves and spike-wave discharges without rhythmicity or less commonly, repeated diffuse spike-wave discharges (Fig. 14–3).

Focal seizures with and without loss of awareness appear between ages 4 months to 4 years or later. SPS are either versive seizures, with or without clonic jerks limited to a limb or one hemiface, or a combination of the two. CPS are characterized by loss of consciousness, autonomic phenomena (pallor, cyanosis, rubefaction, respiratory changes, drooling, sweating), oral automatisms, hypotonia, rarely stiffness, sometimes eyelid or distal myoclonia. When the symptomatology is mild, they are difficult to distinguish from atypical absences without concomitant EEG and the parents report them as “absences”.

Tonic seizures are exceptional and were recorded in nine patients.⁵ They differ from the tonic seizures of Lennox–Gastaut syndrome as they are sporadic, do not repeat in series and have variable EEG features.

Parents rarely describe polymorphic paroxysmal events which do not fit with usual epileptic seizures and which remain unclassifiable.

Triggering Factors

Fever and Temperature Variations Sensitivity

Patients are remarkably sensitive to infections and may experience numerous hyperthermic episodes accompanied by epileptic seizures. However, seizures can also be triggered by slight variations of body temperatures that do not rise above 38°C and are not caused by infection. Thus, it is more appropriate to substitute the term “temperature variation” for “fever”. Patients are also sensible to the ambient temperature, having more seizures when it is hot. The triggering effect of hot baths was first noted in Japan where hot baths are a custom.⁶ Physical exercise is also a frequent triggering factor.

Photosensitivity

can appear at different stages, from infancy to adolescence. It is not constant in the same patient and can disappear either transiently or definitively. Patients may present with myoclonia, absences and convulsive seizures when exposed to a bright environment, particularly after a dark one. A discrepancy between the EEG response to intermittent photic stimulation (IPS) and clinical photosensitivity has been observed. The quantity of light may have a more important role than wavelength.⁷ Patients with constant light sensitivity represents the most treatment-resistant form of SMEI. Eye closure, patterns, and television are also recognized as triggering factors; autostimulation may aggravate the situation.

Interictal Semiology

The interictal EEG is usually normal at the onset. It may display a diffuse or unilateral slow background if recorded after a prolonged seizure. In some patients, generalized spike-wave discharges are elicited by intermittent photic stimulation. Rhythmic 4–5-Hz theta activity may be present in the centroparietal areas and the vertex.⁸ The EEG changes progressively with the appearance of generalized, focal and multifocal abnormalities; specific features are lacking.

The waking background is either near-normal with slowing present only after a seizure, or constantly slow and poorly organized. Rhythmical theta activity may be present, but paroxysmal abnormalities are highly variable and consist of notched slow waves, sharp waves, spikes, spike-wave discharges and multispike-wave discharges. Discharges may be generalized or localized, mainly in the frontocentral and vertex areas, but also in the temporal and occipital areas, and may spread throughout the hemisphere. Eye closure facilitates their occurrence. The sleep EEG is usually well organized, with physiological patterns and cyclic organization, except after nocturnal seizures. In photosensitive patients, the IPS provokes generalized discharges (Fig. 14–4).

Psychomotor Development

Psychomotor delay becomes evident after age 2 years. Children begin walking at the normal age of 12–18 months, but an unsteady gait persists for an unusually long time. About 60% of the children are ataxic and 20% show mild pyramidal signs. Language begins at the normal time (lallation and first words) but progresses slowly and often does not reach the stage of elementary sentence construction. Affected patients develop hyperactivity, oppositional behavior and major learning problems. Relationships with adults and other children are often bizarre and autistic features may appear. In a single neuropsychological study of 20 patients^9,10 the neuropsychological deficits were global with motor, linguistic and visual abilities being more strikingly affected. Deterioration was related to the severity of the epilepsy during the first two years of life. However, no genetic analysis was performed and establishing a link to the SCN1A mutation was not possible.

We recently studied 11 patients aged 15 months to 9 years who were regularly followed with neuropsychological evaluations.¹¹ Slowing of psychomotor development was observed between ages 2 to 4 years and was more evident in eye–hand coordination, visual attention, expressive language, memory and executive functions. Partial recovery of language functions and, to a lesser degree, visual attention occurred subsequently. Only one girl has reached a borderline IQ level at the age of eight and could write, read and count. All patients older than age 3 years evidenced motor impairment and behavior disorders. Distractibility, hyperactivity, and oppositional behaviors were observed in all patients at first evaluation, which subsequently improved. Signs of withdrawal were present in only two patients, and one girl was psychotic.

Comorbidities

Comorbid conditions are frequent in SMEI and include orthopedic conditions (including pes planus/pes valgus, foot deformities, and neurogenic scoliosis), chronic upper respiratory infections, otitis media, low humoral immunity, and growth and nutrition issues.

Until recently, magnetic resonance imaging (MRI) was reported as normal, even when serially repeated. In 2005, Siegler et al¹² found hippocampal sclerosis (HS) in 10 of 14 investigated patients. However, a more recent study¹³ of 58 patients, 60% carrying SCN1A mutations, investigated by MRI after the age of 4, found only one case of HS. In one Argentinian study,¹⁴ signs compatible with unilateral HS were found in 3/53 patients. In this series one patient presented with unilateral brain atrophy following unilateral febrile SE.

Atypical or borderline presentations of Dravet syndrome were first reported by Japanese investigators.¹⁵ The presentations were characterized by a lack of one or several signs, mainly myoclonic seizures. Subsequently it was noted that patients lacking myoclonic seizures who were otherwise similar shared the same prognosis: 21% for Dravet et al,¹⁶ However, most of those lacking myoclonic seizures had interictal segmental myoclonus which compromised their motor abilities. In other patients myoclonic fits were transitory. A report of two siblings, one with and the other lacking myoclonic seizures has been reported^15,16 suggesting that both presentations are part of the same disorder.

With the advent of genetic investigations, it is now apparent that patients with borderline presentations also harbor the SCN1A mutation, although generally less severe and less frequent. Conversely, patients with only refractory grand mal seizures described in Japan^17,18 and Germany¹⁹ should not be included in SMEI, even if the genetic studies reveal the SCN1A mutation in some, demonstrating that they are a part of the GEFS+ syndrome.

In 2001, Claes and colleagues found new mutations in the sodium-channel gene SCN1A in all seven probands with SMEI.³ Subsequent studies have confirmed the presence of this mutation in most, but not all patients. Approximately 70% of patients are mutationally positive.²⁰ Frameshift and nonsense mutations are most frequent. Correlations between phenotype and genotype suggest a higher frequency of truncating mutations in the typical patients, including patients with myoclonia.^21,22 Mutations have also been identified in borderline forms²³ but are less frequent (7/27) than in the typical forms (19/31) and less severe (no truncating mutations). Likewise, missense mutations were found in patients presenting exclusively with refractory grand mal seizures.¹⁸

More often, mutations are de novo, but may be detected in one of the parents.^21,24,25 Parental mosaïcism was recently demonstrated.^26,27 With other more sensitive techniques (multiplex ligation-dependent probe amplification, multiplex amplicon quantification), approximately 15% of screened negative cases were found to carry a deletion or duplication of pathogenic significance on the SCN1A gene.²⁸ Recently, mutations in PCDH19, the gene encoding the protocadherin 19 on the X chromosome, were discovered in SCN1A-negative female patients presenting with a clinical picture resembling the borderline SMEI.²⁹ The authors estimated that 16% or 25%, if only females were included in the calculation, of their SCN1A-negative SMEI patients had PCDH19 mutations and that this gene might overall account for 5% of SMEI. Clinical similarities between PCDH19 mutation positive patients and SMEI, including febrile and afebrile seizures, occurrence of hemiclonic seizures, regression following seizure onset, suggest that PCDH19 should be tested in those patients in whom no SCN1A abnormalities can be found. Further studies should elucidate the possible role of other genes or of SCN1A promoters in the pathogenesis of this syndrome.