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Dravet syndrome: Genetics, clinical features, and diagnosis

Dravet syndrome: Genetics, clinical features, and diagnosis
Authors:
Danielle M Andrade, MD, MSc, FRCPC.
Fabio A Nascimento, MD
Section Editor:
Douglas R Nordli, Jr, MD
Deputy Editor:
John F Dashe, MD, PhD
Literature review current through: Dec 2022. | This topic last updated: Nov 08, 2022.

INTRODUCTION AND DESCRIPTION — Dravet syndrome (DS) (OMIM # 607208), previously known as severe myoclonic epilepsy of infancy (SMEI), is a rare early-onset epilepsy syndrome characterized by refractory epilepsy and neurodevelopmental problems beginning in infancy.

DS was first described by Charlotte Dravet in 1978 and was found to have a genetic basis in 2001, with discovery of pathogenic variants in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene [1,2]. DS is classified as a genetic epilepsy syndrome and a developmental and epileptic encephalopathy, defined as an epilepsy syndrome associated with encephalopathic features that present or worsen after the onset of epilepsy [3,4]. (See "ILAE classification of seizures and epilepsy".)

The epidemiology, genetics, clinical features, and diagnosis of DS are reviewed here. Management and prognosis of DS are reviewed separately. (See "Dravet syndrome: Management and prognosis".)

The initial evaluation of febrile and afebrile seizures in infants and children more generally, as well as other epilepsy syndromes of childhood, are reviewed elsewhere. (See "Epilepsy syndromes in children" and "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Clinical features and evaluation of febrile seizures".)

GENETICS AND PATHOPHYSIOLOGY

SCN1A pathogenic variants — A genetic basis for DS was first identified in 2001, when de novo pathogenic variants in the SCN1A gene located on chromosome 2q24 were identified in seven out of seven unrelated patients with DS [2]. In subsequent studies, SCN1A pathogenic variants have been identified in approximately 70 to 80 percent of patients with DS [5,6].

More than 700 pathogenic variants, randomly distributed along the SCN1A gene, have been identified. The most common genomic abnormalities are nonsense variants, missense variants, in-frame deletions [7], and splice site changes [8]. Some patients who test negative for SCN1A abnormalities on sequencing are found to have exonic deletions or chromosomal rearrangements involving the same gene. Rare duplications and amplifications affecting the SCN1A gene have also been reported [5,8-11].

Approximately 90 percent of pathogenic variants arise de novo. Familial or germline pathogenic variants, usually missense in nature, account for approximately 5 to 10 percent of cases [2,12-14]. Parental mosaicism has been identified in up to two-thirds of familial cases and likely accounts for unaffected or mildly affected parental phenotype [15]. Variations in noncoding regions of SCN1A have been shown to reduce the level of expression of full-length SCN1A protein [16].

SCN1A pathogenic variants have also been identified in patients with genetic epilepsy with febrile seizures plus (GEFS+) [17], as well as in infants with early infantile epileptic encephalopathy [18]. The determinants of this broad phenotypic spectrum are not fully understood and may be related to the type and location of the genetic variant, whether the variant leads to gain or loss of function, and the presence of yet-to-be-determined modifier genes. (See "Clinical features and evaluation of febrile seizures", section on 'Genetic epilepsies with febrile seizures'.)

Other pathogenic variants — Twenty to 30 percent of patients with DS do not have identifiable pathogenic variants in SCN1A. Many of these patients remain without a molecular diagnosis, and other genes are likely to be implicated.

Additional genes that have been identified in patients with a DS phenotype include PCDH19, SCN1B, GABRA1, STXBP1, CHD2, SCN2A, and, rarely, HCN1, KCNA2, and GABRG2 [19-29]. Notably, PCDH19 pathogenic variants have been described in approximately 5 percent of all patients with DS [19]. It is unclear if these patients were followed long enough to ensure that they did not have PCDH19 clustering epilepsy, a syndrome characterized by cluster febrile seizures and cognitive decline that mainly affects females and can imitate DS in the first years of life [30]; however, the long-term evolution of these diseases can be very different [31]. (See "Overview of infantile epilepsy syndromes", section on 'PCDH19 clustering epilepsy'.)

Genotype-phenotype correlations — Consistent genotype-phenotype correlations have not been firmly established in DS, although data are evolving. In general, it is not possible to predict an individual's phenotype based solely on the specific SCN1A pathogenic variant.

Truncating variants, by definition, are expected to cause premature termination of protein translation, leading to haploinsufficiency. Therefore, virtually all SCN1A truncating variants result in a DS phenotype. Compared with missense variants, truncating variants have been associated with earlier age at the onset of myoclonic seizures (16 versus 19 months), atypical absence seizures (17 versus 27 months), [32] and an increased rate of cognitive decline [33].

By contrast, clinically significant missense variants in SCN1A are likely to be located within the four conserved homologous domains (D1 to D4), which represent the main ion transport sequence of the neuronal sodium channel (figure 1). Each of these domains consists of six transmembrane segments, S1 to S6. Missense variants appear to occur most frequently in segment S4, which accounts for most of the gating charge of the voltage sensor [32,34,35], and S6, which forms the inner pore lining the sodium channel [36]. One recurrent missense variant has been reported in a small number of patients in association with a particularly severe phenotype of early infantile epileptic encephalopathy [18].

Nonsense variants or variants affecting the pore-forming region of the sodium channel appear to associate closely with gait deterioration, specifically crouched gait [37].

Despite these observations, there can be remarkable variability in epilepsy severity and clinical phenotype among family members harboring the same pathogenic variant [12,38-42]. Proposed mechanisms to explain this variability include modifier genes such as SCN9A [43], genetic background, environmental factors, and somatic or germline mosaicism.

Interneuron hypothesis — Dysfunction of inhibitory interneurons has been proposed as a pathophysiologic mechanism in DS.

In mouse models, the protein product of the SCN1A gene (Nav1.1) is the primary voltage-gated sodium channel in several classes of gamma-aminobutyric acid (GABA)-ergic interneurons [44,45]. Nav1.1 is specifically located in cell bodies and dendrites [46,47]. Impairment of Nav1.1 channels results in loss of firing of GABAergic neurons and consequent disinhibition of selected neural circuits.

Haploinsufficiency of Nav1.1 as a result of pathogenic variants in SCN1A, leading to dysfunction of inhibitory interneurons, is therefore hypothesized to be the underlying mechanism of epilepsy, as well as comorbid ataxia, in DS [48-51].

EPIDEMIOLOGY — DS is a rare disorder, affecting an estimated 1 in 15,700 to 1 in 40,000 live births [52-54]. It affects males and females in equal proportions [55].

In one study, DS accounted for 3 percent of cases of epilepsy among children presenting with a seizure within the first year of life [56]. In another study, DS accounted for 7 percent of epilepsy cases with seizure onset in the first three years of life [57].

CLINICAL FEATURES AND EEG FINDINGS

Core features — The clinical features of DS evolve over time, including seizure phenotypes and ictal electroencephalography (EEG) patterns [58]. Core features include refractory epilepsy characterized by multiple different seizure types, neurodevelopmental delay and neurologic disability that begin after seizure onset, and cognitive and motor system dysfunction persisting into adulthood (table 1) [59].

Onset in infancy — Seizure onset most often occurs within the first year of life, usually between five and eight months (range 1 to 21 months), in a previously healthy infant [8,59-63]. As a rule, infants with DS have had normal physical and psychomotor development at the time of their first seizure.

First seizure — The typical initial seizure in DS is tonic-clonic, more often bilateral (52 percent), and less frequently unilateral (hemiclonic; 35 percent), and is often associated with fever [62]. Seizures are often prolonged, lasting more than 10 minutes, sometimes evolving into status epilepticus.

In a report of 241 patients with DS, the most common initial identified seizure precipitants were [61]:

Fever/illness (58 percent)

Immunization within the preceding 48 hours (7 percent)

Bathing (2 percent)

No precipitants were identified in 33 percent.

Uncommonly, patients with DS present initially with myoclonic or focal seizures with impaired awareness. Some patients experience focal myoclonic jerks, which may or may not be recognized as epileptic in origin, days or weeks prior to the first convulsive seizure [8,64].

The prolonged duration of the first seizure may be the first clue of a more severe neurologic disorder. In most patients with DS, febrile and or afebrile seizures, including episodes of status epilepticus, recur repeatedly in the weeks to months after the initial event, despite antiseizure medication therapy [60]. Psychomotor impairment is initially observed in the months following the first seizure.

Initial findings — The initial neurologic examination, laboratory studies, EEG, and brain imaging are usually normal (see 'Neuroimaging' below). Thus, the first seizure is often classified as a complex febrile seizure. Many patients have relatives with mild forms of epilepsy or a history of simple febrile seizures [1,64,65].

Interictal EEG performed in the early phase of the disease is usually normal during both wakefulness and sleep, with background activity that is appropriate for age as well as normal organization and sleep patterns. In a five-year follow-up study of 22 patients with DS, EEG was normal at onset in 77 percent of patients [66].

Less commonly, there is rhythmic theta activity (4 to 5 Hz) over the rolandic and vertex areas during wakefulness [67,68]. EEG performed shortly after a prolonged seizure can show either diffuse or focal slowing of background activity. Rarely, brief diffuse spike-wave discharges are present [69]. Up to one-quarter of patients in the first year of life exhibit generalized spike-and-wave discharges triggered by intermittent photic stimulation [67,70].

Interictal EEG findings evolve over time in patients with DS, becoming progressively abnormal during early childhood.

One to five years of age

Seizure characteristics — Young children with DS have a multitude of seizure types, which as a rule are refractory to antiseizure treatment. Patients characteristically have a low epileptic threshold to both external and internal stimuli, especially during the early childhood years. Common stimuli include fever/hyperthermia, emotional stress or excitement, flashing lights, and contrasting lights and visual patterns. Eating and overexertion can also trigger seizures in some patients [59].

Convulsive seizures – Convulsive seizures are present in virtually all patients and tend to persist throughout the lifespan. Seizures may be generalized tonic-clonic, generalized clonic, and alternating hemiclonic. They may be prolonged and evolve into status epilepticus. Importantly, generalized seizures can be either generalized at onset or focal at onset, progressing to bilateral tonic-clonic. In some cases, the focal onset is brief and easily missed [8].

Hemiclonic seizures can affect either side in the same patient. This alternating pattern is somewhat characteristic of DS and can be helpful diagnostically. Postictally, patients usually have asymmetric EEG signs and may have temporary paralysis.

Myoclonus and myoclonic seizures – Myoclonus, both epileptic and nonepileptic, occurs frequently in patients with DS [63]. Myoclonus can be segmental, multifocal, or generalized. Consciousness is preserved during the events, except in the context of multiple consecutive seizures or long clusters [64,71,72].

Body distribution – Myoclonic seizures may involve the axial muscles only, at times manifesting as rhythmic movements referred to as "head nodding." Myoclonic seizures may involve only the arms and shoulders. Others may become generalized, massive myoclonic jerks.

Temporal distribution – Myoclonic seizures may be isolated, or they may occur in brief clusters of two or three myoclonic jerks. They may evolve into long runs of repeated myoclonic jerks for several seconds or into convulsive seizures.

Triggers – Myoclonic seizures can be spontaneous or triggered by photic stimulation, eye closure, variation in light intensity, or fixation on patterns.

On EEG, epileptic myoclonus is usually associated with fast polyspikes with a generalized distribution but higher in amplitude over the frontocentral regions. Consecutive runs of myoclonic jerks can be associated with repeated fast polyspikes or spike-and-wave discharges with generalized distribution, as well as bifronto-central predominance; at times, a stable 3 Hz or higher frequency can be observed.

Absence seizures – Most patients with DS have atypical absence seizures manifested as abrupt impairment of consciousness, usually lasting 3 to 10 seconds, with or without a myoclonic component involving the head, eyelids, and sometimes the arms [60,69]. EEG during these events shows slow generalized spike waves with a frequency ≤3 Hz. Typical absence seizures with generalized spike-wave discharges at 3 Hz or higher are rare in patients with DS [73]. (See "Childhood absence epilepsy", section on 'Seizure semiology'.)

Absence status epilepticus can occur, characterized by progressive impairment of consciousness with fluctuating intensity, without motor phenomena. EEG during absence status shows discontinuous sequences of slow polyspike or spike-wave discharges that fluctuate in intensity and are diffusely distributed but with an anterior predominance [8].

Obtundation status – Obtundation status is a subtype of nonconvulsive status epilepticus that consists of varying degrees of long-lasting impairment of consciousness (obtundation) along with segmental, erratic myoclonia affecting limbs and face. Recurrent massive myoclonic jerks may be interspersed. Convulsive seizures can initiate, terminate, or even occur during these events. Obtundation status can last from a few hours up to several days and may be temporarily interrupted by strong sensory stimuli.

The EEG during obtundation status typically shows diffuse slow waves, intermixed with focal as well as diffuse spikes, sharp waves, and spike-wave discharges, of higher voltage in the anterior regions and the vertex [8,69,71,73]. There is no time correspondence between the spikes and the myoclonic jerks, except during some of the massive myoclonic jerks.

Focal seizures – Focal seizures can appear at any time from four months to four years of age. Both focal motor seizures and focal seizures with impaired awareness may be seen, and any type of focal seizure may evolve to a bilateral tonic-clonic seizure.

Focal motor seizures in patients with DS can be characterized by versive or clonic movements limited to an extremity or hemiface, whereas focal unaware seizures consist of impairment of consciousness and prominent autonomic phenomena (pallor, cyanosis, respiratory changes, drooling, sweating), as well as oral automatisms, hypotonia, and sometimes eyelid or distal myoclonus.

The EEG during focal unaware seizures usually shows rhythmic fast polyspikes followed by theta activity towards the end of the seizure. Ictal onset can be seen anywhere in the cortex but frequently involves the temporo-parieto-occipital region of one hemisphere or, less frequently, one of the frontal regions [69].

Tonic seizures – Tonic seizures are infrequent in children with DS. They have variable electroclinical features but are somewhat similar to the axial tonic seizures of Lennox-Gastaut syndrome (LGS), occasionally with an additional myoclonic component.

Ictal EEG generally shows either a flattening of the background activity of short duration (two to three seconds) or a rapid, diffusely distributed recruiting rhythm, at times interrupted by a flattening, followed by slow waves or irregular diffuse spike-wave discharges [8,69,74].

Evolving EEG — From one to five years of age, interictal EEG during wakefulness shows normal background activity, or slight slowing, in approximately one-half of patients in this stage. In the other half, background activity becomes overtly slow and poorly organized. Slowing of background activity does fluctuate over time and is influenced by recent seizure activity as well as various pharmacologic therapies [8,69].

Interictal epileptiform discharges in DS include generalized spike waves, isolated or in brief bursts, predominating in the frontocentral regions, as well as brief discharges of fast polyspike waves, diffuse or involving mainly the frontocentral regions, which may be induced by eye closure.

Eye closure and fixation on patterns may elicit subclinical or clinical discharges in the form of spikes and spike-and-wave discharges in approximately one-fourth of patients; photosensitivity may persist in a small percentage of patients [69].

Recorded seizures can be "falsely generalized," meaning that changes may appear bilateral on EEG early in a seizure that is clinically focal or may appear bilateral at onset and then become and remain asymmetric [63]. Recorded seizures may be "unstable," meaning that the epileptiform discharge changes topographically, moving from one brain region to another during the same seizure.

Focal neurologic signs — Neurologic signs gradually appear throughout this stage. Typical findings include [12,67,68,71,72,75-77]:

Hypotonia, detectable at around one year of age and present in most patients.

Ataxia and incoordination, usually noted when patients start to walk and present in 50 to 83 percent of patients. Patients start to walk at a typical age but then develop an unsteady gait shortly thereafter.

Pyramidal signs (eg, spasticity, hyperreflexia), reported at varying frequencies across different series. Fine motor abilities do not develop well.

Patients with DS also have more dysautonomic events than controls, including a tendency to overheat, decreased sweating, and problems with regulation of distal extremity temperature [78].

Developmental delay — Neurodevelopmental impairment typically begins shortly after seizure onset within the first year of life and becomes progressively evident from the second year onward [79]. In most children with DS, developmental impairment is due to stagnation (ie, lack of or slower progression) rather than regression [63]. In some cases, status epilepticus can lead to loss of previously acquired skills. Language tends to emerge at an appropriate age but then progresses slowly, to the extent that many patients fail to reach the stage of constructing elementary sentences.

This arrest of development is most evident up to five or six years of age, resulting in cognitive impairment of variable degrees, after which there seems to be a general trend towards stabilization (plateauing phase) but no significant recovery [80,81]. (See 'Cognitive impairment' below.)

Behavioral disturbances — The most common behavioral disturbances during early childhood are attention deficit, hyperactivity, autistic traits, and relational difficulties. Irritability, aggressiveness, and opposition also occur. These features, in addition to motor and cognitive impairments, may significantly impact adaptive behavior and social life [8,65,80].

Five years of age to adulthood — The vast majority of patients with DS have lifelong persistent and refractory seizures as well as moderate to severe cognitive impairment. Importantly, however, a minority of patients have milder intellectual disability and relatively better seizure outcomes [37,82,83].

Epilepsy — Convulsive seizures generally persist throughout life. In adulthood, they tend to occur mainly during sleep, either isolated or in clusters. In long-term follow-up studies, there seems to be a progressive reduction in the frequency of both convulsive seizures and convulsive status epilepticus, especially after the third decade. Atypical absence, myoclonic, and focal seizures tend to decrease in frequency or even disappear in adulthood [84].

Fever sensitivity is found in up to 50 percent of adult patients, whereas photic and pattern sensitivity are usually no longer present [37,82,83,85-87].

EEG in older children and adults — From five years of age to adulthood, the background EEG activity remains normal (ie, occipital alpha rhythm) in one- to two-thirds of patients with DS. An increase in theta activity in the central regions and vertex may be elicited by eye closure [69,85,86]. This activity is particularly enhanced in patients with significant motor deterioration.

Interictal paroxysmal abnormalities, including focal and multifocal spikes, spike-and-wave discharges, sharp waves, and, rarely, generalized spike-and-wave discharges, often appear during sleep but may disappear or become sporadic during wakefulness. Photosensitivity progressively decreases with age, although it can still be seen in a minority of adult patients [69].

Sleep architecture is usually normal, except in the context of a preceding nocturnal seizure, and the cyclic organization of sleep remains preserved. Even among patients with abnormal sleep architecture, it is still possible to distinguish between rapid eye movement (REM) and non-REM sleep [69,85,86].

Motor system dysfunction — Motor system dysfunction is present in most patients with DS. In small observational series, a range of abnormalities has been described, including [37,83,85-87]:

Ataxia – 30 to 50 percent

Tremor and clumsiness of fine movements – 28 to 42 percent

Dysarthria – 40 percent

Pyramidal signs, including spasticity and hyperreflexia – 40 percent

Parkinsonian signs, including rigidity, dystonic posturing, postural instability, and dystonic as well as parkinsonian gait – 15 to 90 percent

Parkinsonism (bradykinesia, asymmetric cogwheel rigidity) has been observed in adults with DS who had never received antipsychotic medications [87,88]. Antecollis (figure 2), camptocormia (also known as bent-spine syndrome) (figure 3), and hoarding behavior have also been reported. A prospective study showed that these symptoms worsened in adults over a five-year span [89]. These features, which can also be seen in Parkinson disease, suggest that the pathophysiology of DS involves basal ganglia dysfunction [90].

Gait impairment — A "crouched gait" pattern, characterized by increased hip and knee flexion and ankle dorsiflexion throughout the stance phase of gait, with minimal or no associated spasticity, has been described in up to 50 percent of adults with DS and SCN1A pathogenic variants, particularly those with either nonsense variants or variants in the pore-forming region of the alpha-1 subunit [37]. Another study identified crouched gait in 5 out of 10 children with DS between the ages of 6 and 12 years and in 8 out of 9 older patients [91]. (See 'Genotype-phenotype correlations' above.)

Other types of gait abnormalities are also common in adults with DS, including dystonic or wide-based gait, small steps, tiptoeing, festinating, and tonic lateral flexion of the trunk (Pisa syndrome) (figure 4) [83,85,87]. Gait abnormalities progressively worsen with age. A study using instrumental gait analysis (IGA) found that all gait parameters analyzed were abnormal in a cross-sectional group of 17 patients (mean age 31 years) with DS, and their gait performance was worse than an older healthy control group (mean age 62 years) [89]. In the prospective arm of the same study, six adult patients with DS showed progressive worsening of gait over a five-year span, and the two older patients who were previously ambulatory could no longer walk after five years.

Patients may also develop skeletal abnormalities such as kyphosis, kyphoscoliosis, and claw and flat feet [85,91,92].

Cognitive impairment — After the age of five to six years, there is no clear evidence of further cognitive decline, but patients tend to progress no further or to progress slowly (ie, stagnation). Consequently, over time, the gap between acquired and expected skills increases and cognitive performance decreases.

Cognitive impairment is seen in the majority of patients, mostly in the moderate to severe range [80,82,93,94]. Attention, visual motor integration, visual perception, and executive functions tend to be more impaired than language [81].

The cause of cognitive impairment is likely multifactorial. Epilepsy characteristics usually correlate with cognitive outcomes. Worse cognitive outcomes have been associated with higher frequency of convulsive seizures [93], presence of status epilepticus and interictal EEG abnormalities in the first year of life [61], early appearance of myoclonus and absence seizures [95], and early dyscognitive seizures [96]. The presence of a motor disorder (including hypotonia, ataxia, spasticity, and dyskinesia) early in life [61] and SCN1A pathogenic variants have also been associated with poor cognitive outcomes [96].

The use of sodium channel blockers (eg, lamotrigine, phenytoin, carbamazepine, eslicarbazepine, oxcarbazepine, vigabatrin) may have a negative impact on the cognitive outcome of patients with DS. (See "Dravet syndrome: Management and prognosis", section on 'Drugs to avoid'.)

The possible effects of different levels of stimulation and parental educational levels have not been systematically evaluated.

Psychiatric comorbidity — Many of the behavioral disturbances associated with DS in early childhood seem to improve over time [87]. Importantly, behavioral issues in children with DS may be underdiagnosed and therefore left untreated [63]. In fact, many adults with DS are very affectionate and seek contact with others.

However, the prevalence of depression and anxiety increases with age, and these conditions affect most adults with DS [63]. Perseveration and hoarding behaviors are commonly observed. Some adults with DS exhibit obsessiveness, agitation, bouts of aggressiveness, and, rarely, acute psychiatric episodes [8,97].

All ages

Premature mortality — DS is associated with an increased risk of premature mortality. Premature death may happen at any age, but it occurs more frequently during childhood. The most common causes of death appear to be sudden unexpected death in epilepsy (SUDEP) and status epilepticus. (See "Dravet syndrome: Management and prognosis", section on 'Prognosis' and "Sudden unexpected death in epilepsy".)

Cardiac dysfunction — Cardiac investigations have found an increased resting heart rate and decreased heart rate variability (HRV) in patients with DS compared with patients on antiseizure medications who have other epilepsies and compared with healthy controls [98,99]. This predominance of adrenergic tone could be connected to high rate of SUDEP seen in DS. In some studies, patients with DS show an increased rate of peri-ictal corrected QT (QTc) lengthening >60 ms compared with controls (epilepsy patients with other forms of drug-resistant epilepsy) [100,101]. Although this could be explained by unstable repolarization, it could also represent a response to ictal hypoxemia [101].

Neuroimaging — Infants with DS have normal brain magnetic resonance imaging (MRI) at the time of presentation [59]. As children age, the MRI typically remains normal. Rare reported abnormalities in older children and adults with DS include hippocampal sclerosis, cerebellar and cerebral atrophy, enlarged ventricles, focal cortical dysplasia, and increased white matter signal [67,85,102,103]. While cortical atrophy may develop over time, serial MRIs are not usually obtained for patients with DS; thus, cortical atrophy may not be recognized [104].

EVALUATION AND DIAGNOSIS

When to suspect Dravet syndrome — DS is a clinical diagnosis that should be suspected in previously healthy infants presenting with drug-resistant seizures, often in the setting of fever, beginning before 15 to 18 months of age (usually between 5 and 8 months) and associated with neurodevelopmental regression after the onset of seizures [104].

The key clinical features that suggest the diagnosis of DS differ according to age of presentation, as shown in the table (table 1) [59].

Investigations — Infants and children with suspected DS should have testing with neuroimaging, preferably with MRI, and EEG at a minimum. Genetic testing is recommended to confirm the diagnosis [104].

Clinical diagnosis — DS is one of several recognized epilepsy syndromes of infancy according to the International League Against Epilepsy (ILAE) classification system [104,105]. As such, DS is a clinical diagnosis that can be reliably made based on the clinical and EEG characteristics reviewed above. (See 'Clinical features and EEG findings' above.)

Genetic testing — Genetic testing for SCN1A and other pathogenic variants is recommended for most patients in whom the diagnosis of DS is suspected [59,106]. To facilitate early diagnosis, a 2022 international consensus panel recommended genetic testing for DS in developmentally normal infants 2 to 15 months of age who present with a single prolonged (5 to 29 minutes) hemiclonic seizure or focal/generalized status epilepticus (≥30 minutes) of unknown etiology in the setting of vaccination or fever [63].

It is more cost effective to use an epilepsy gene panel or whole exome sequencing rather than testing each possible candidate gene. This is particularly true early in the course of disease, when the phenotypic spectrum may overlap with many other syndromes. The composition of such epilepsy panels may vary, and clinicians should confirm that the genes described above are included in the panel being requested. Testing should include both sequencing and deletion/duplication analyses. Negative genetic testing does not rule out the diagnosis of DS in a patient with otherwise typical clinical features. (See 'SCN1A pathogenic variants' above and 'Other pathogenic variants' above.)

Identification of a pathogenic variant enables early confirmation of the diagnosis at a time when clinical and EEG features may not yet be fully expressed, thereby avoiding further extensive etiologic testing [107]. Early identification of a pathogenic variant also aids in selection of antiseizure medication therapy, including avoidance of sodium channel-blocking drugs that may worsen seizures and cognition, and facilitates access to adjuvant therapies and family and caregiver support networks [108]. However, SCN1A pathogenic variants can be seen in conditions other than DS, including genetic epilepsy with febrile seizures plus (GEFS+) and early infantile developmental and epileptic encephalopathy (EIDEE) [18]. Therefore, the mere detection of an SCN1A pathogenic variant is not enough to tell if the patient will develop DS.

The detection of variants of uncertain significance (VUS) in SCN1A does not exclude or confirm the diagnosis of DS. When VUS are identified, a referral to a geneticist (or genetic counselor) is advisable.

Prediction models have been proposed to calculate the risk of DS depending on the SCN1A variant [109], but these models need to be validated not only in European but also in other populations. (See "Dravet syndrome: Management and prognosis".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of DS varies depending on specific phases of the disease. It is very difficult to correctly diagnose DS after the first or only a few febrile seizures. Adult patients, who may no longer have the typical myoclonus and myoclonic seizures, are also difficult to properly diagnose, especially if previous medical records describing the first few years of disease in detail are not available.

For the most common forms of DS (those associated with intractable epilepsy and important intellectual disability), diagnosis is more easily made on a clinical basis between the second year of life and the plateau phase. In general, the differential diagnosis of DS includes febrile seizures, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic-atonic seizures (EMAtS), progressive myoclonus epilepsy (PME), and PCDH19 clustering epilepsy.

The most important tools to distinguish among these diagnoses are a detailed epilepsy and developmental history in conjunction with EEG and neuroimaging.

Febrile seizures – Seizure onset in DS is usually associated with fever, and it is therefore of great importance to distinguish DS from febrile seizures or even genetic epilepsy with febrile seizures plus (GEFS+) to plan initiation of antiseizure medication. Although this is not always possible at the time of the first febrile seizure, useful differentiating features in patients with DS include the following [60]:

The onset of DS is almost always between the first 5 and 15 months of life. Despite overlap, the mean age of seizure overlap differs between DS and SCN1A-related GEFS+. In a retrospective study to develop and validate a prediction model for the early diagnosis of SCN1A-related epilepsies, patients with DS had mean seizure onset at 6.0 months (standard deviation [SD] 3.0 months], while patients with GEFS+ had mean seizure onset at 14.8 months (SD 11.8 months) [109].

Seizure type with DS is typically clonic and often unilateral, whereas the majority of febrile seizures are generalized.

Fever-induced seizures can last longer (>10 to 15 minutes) and may evolve into status epilepticus.

The temperature necessary to induce seizure does not need to be very high.

The clinical features and diagnostic evaluation of febrile seizures are reviewed in detail separately. (See "Clinical features and evaluation of febrile seizures".)

Lennox-Gastaut syndrome – Similar to DS, LGS is an epilepsy syndrome characterized by severe childhood onset seizures with intellectual disability. Nonetheless, these two syndromes can be differentiated on electroclinical grounds. Seizures in LGS can occur de novo or may occur after an earlier presentation of infantile seizures, West syndrome, or other severe seizure disorders. Age of onset for LGS is later than that for DS, usually between three and five years but sometimes much later. The most important seizure types in LGS are atonic seizures (drop attacks), axial tonic seizures, and atypical absence seizures. Specific interictal EEG features include diffuse slow (<2.5 Hz) spike waves and bursts of generalized fast rhythms (around 10 Hz) during sleep [110]. (See "Lennox-Gastaut syndrome".)

Epilepsy with myoclonic-atonic seizures – This syndrome, previously known as epilepsy with myoclonic-astatic seizures, or Doose syndrome, is a generalized electroclinical syndrome of early childhood characterized by multiple seizure types (drop attacks, myoclonic, myoclonic-atonic, and generalized tonic-clonic seizures) with onset between six months and six years. The two main distinguishing features between EMAtS and DS are that many, but not all, patients with DS exhibit focal seizures and focal findings on EEG that are not present in EMAtS and that drop attacks, one of the cardinal seizure types in EMAtS, can be present but are not the main seizure type seen in DS [111].

Progressive myoclonus epilepsy – PME is a distinct disorder characterized by progressive intellectual decline, tremor and ataxia in the context of myoclonus, myoclonic seizures, and generalized tonic-clonic seizures. Early-onset PMEs, such as neuronal ceroid lipofuscinoses, differ from DS based on the presence of visual loss, fundus abnormalities, and results of genetic testing [112]. Furthermore, PMEs with onset in infancy or early childhood are not expected to have a plateau phase, as is seen in DS, and this can be distinguishing with passage of time. (See "Symptomatic (secondary) myoclonus", section on 'Progressive myoclonic epilepsy and progressive myoclonic ataxia'.)

PCDH19 clustering epilepsy – PCDH19 clustering epilepsy is characterized by childhood-onset focal and/or generalized seizures, commonly fever induced and in clusters, as well as behavioral and psychiatric comorbidity and varying degrees of intellectual disability [19,31,113,114]. The differentiation between this syndrome and DS can be very difficult due to significant phenotypic overlap as well as the fact that PCDH19 pathogenic variants can cause both syndromes. Nonetheless, PCDH19 clustering epilepsy patients have comparatively fewer myoclonic and absence seizures, fewer episodes of convulsive status epilepticus, and less photosensitivity compared with patients with DS [19]. These observations, in addition to the fact that PCDH19 clustering epilepsy affects mainly females, may be used to clinically distinguish these two syndromes. (See "Overview of infantile epilepsy syndromes", section on 'PCDH19 clustering epilepsy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

Description and epidemiology – Dravet syndrome (DS) is a rare genetic epilepsy syndrome characterized by refractory seizures beginning before the age of one year and poor neurodevelopmental outcome. It accounts for less than 5 percent of cases of epilepsy presenting in the first year of life. (See 'Introduction and description' above and 'Epidemiology' above.)

Genetics – Pathogenic variants in the SCN1A gene are identified in 70 to 80 percent of patients with DS. (See 'Genetics and pathophysiology' above.)

Clinical features – The clinical features of DS evolve over time. (See 'Clinical features and EEG findings' above.)

Birth to one year – The most common presenting symptom is a hemiclonic or generalized seizure, often precipitated by fever, in an otherwise healthy infant between five and eight months of age. Early seizures tend to be prolonged and recurrent and may evolve into status epilepticus. Neurodevelopmental decline typically begins shortly after seizure onset. (See 'Onset in infancy' above.)

One to five years – Between one and five years of age, patients with DS have refractory epilepsy characterized by multiple types of seizures, both febrile and afebrile, including convulsive seizures, myoclonic seizures, atypical absence seizures, and focal seizures. Neurologic signs include hypotonia, ataxia, pyramidal signs, myoclonus, and behavioral disturbances. (See 'One to five years of age' above.)

Five years to adult – Older children and adults with DS tend to have improved seizure control but persistent, moderate to severe intellectual disability and motor system abnormalities, including crouch gait, antecollis, and other parkinsonian features. (See 'Five years of age to adulthood' above.)

Premature mortality – There is an increased risk of premature mortality, due primarily to sudden unexpected death in epilepsy (SUDEP) and status epilepticus. (See 'Premature mortality' above.)

EEG findings

Interictal – The interictal EEG is often normal at the time of seizure onset but gradually evolves to show slowed background activity and interictal epileptiform abnormalities, including generalized spike-and-wave discharges, polyspike waves, and focal or multifocal discharges.

Ictal – The ictal EEG patterns in patients with DS vary according to seizure type and are described above. (See 'Seizure characteristics' above.)

Diagnosis – DS is a clinical diagnosis, based on a combination of clinical and EEG features (table 1). Genetic testing is recommended for developmentally normal infants 2 to 15 month of age who present with a single prolonged hemiclonic seizure or focal/generalized status epilepticus of unknown etiology in the setting of vaccination or fever. Genetic testing enables early identification of the disease, influences treatment selection, and facilitates access to adjuvant therapies and patient and family/caregiver support networks. (See 'Evaluation and diagnosis' above.)

Differential – The differential diagnosis of DS varies depending on the phase of the disease and includes febrile seizures, Lennox-Gastaut syndrome (LGS), epilepsy with myoclonic-atonic seizures (EMAtS), progressive myoclonus epilepsy (PME), and PCDH19 clustering epilepsy. (See 'Differential diagnosis' above.)

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References