Dravet Syndrome

Dravet Syndrome – 13 Interesting Facts

DS (Dravet syndrome) is a rare, severe childhood epilepsy syndrome characterized by drug-resistant seizures, intellectual disability, and high mortality
Cause is de novo variant resulting in SCN1A pathologic variant associated with disease in a large majority of patients
Median age of seizure onset is 6 months (range 1-20 months) usually with hemiclonic or generalized tonic-clonic seizures, often associated with fever and often prolonged
Features that develop with time include drug-resistant epilepsy, development of multiple seizure types, developmental delay, cognitive deterioration, and behavioral disorders
Diagnosis is made clinically in conjunction with serum SCN1A testing
Prolonged hemiclonic or tonic-clonic seizure with fever or after vaccination in a developmentally normal infant without an underlying etiology on neuroimaging or initial laboratory workup is highly suggestive of a diagnosis of DS and should trigger genetic testing
Most used antiseizure drugs are valproate and clobazam, but new FDA-approved medications include cannabidiol, stiripentol, and fenfluramine
Ketogenic diets can be also helpful in medication-refractory cases
Abortive medications including rectal and intranasal diazepam, and intranasal midazolam are an important aspect of DS care
Maintain an individualized seizure action plan detailing patient specific measures when first line abortive measures fail
Common comorbidities include gait abnormalities, cognitive decline, and behavioral abnormalities
Most patients develop moderate to severe cognitive disability and continue to experience seizures throughout adulthood
Risk of mortality due to SUDEP (sudden unexpected death in epilepsy) is higher in children with DS than other forms of epilepsy

Alarm Signs and Symptoms

Presence of repeated events of status epilepticus and nocturnal seizures may suggest a higher chance of SUDEP

Basic Information

Terminology

DS (Dravet syndrome) (OMIM #607208)¹ is a rare and severe infantile-onset developmental and epileptic encephalopathy²
Condition was previously referred to as severe myoclonic epilepsy of infancy

Background Information

Median age of seizure onset is 6 months (range 1-20 months) usually with hemiclonic or generalized tonic-clonic seizures, often associated with fever and often prolonged⁷
Features that develop with time include drug-resistant epilepsy, cognitive delay, and behavioral disorders after about age 1 year³
SUDEP (sudden unexpected death in epilepsy) is more common in children with DS
Mortality rate in DS ranges from 15% to 20%³

Epidemiology

Incidence is estimated at 1 in 17,500 to 20,000 children⁹

Etiology and Risk Factors

Etiology

At least 80% of disease is caused by a pathologic variant resulting in loss of function of SCN1A located on chromosome 2q24³
Loss of function involving a single copy of SCN1A results in decreased Nav1.1 voltage-gated sodium channel function in GABAergic (γ-aminobutyric acid) inhibitory interneurons causing neuronal network hyperexcitation
Most patients have de novo variants¹
Other pathologic variants involving different genes than SCN1A that result in similar phenotype (eg, GABRG2, PCDH19, CHD2, HCN1, SCN1B, GABRA1, STXBP1) are reported
Note that SCN1A variants (OMIM #182389)¹² are also noted in patients with generalized epilepsy with febrile seizures plus (OMIM #604403)¹³ and non-DS developmental and epileptic encephalopathy

Risk Factors

Family history is positive for epilepsy or febrile seizures in 30% to 50% of patients¹⁴

Risk Models and Risk Scores

Validated prediction model is available to aid in determining risk for development of DS versus genetic epilepsy with febrile seizures plus¹⁵
- Prediction model uses clinical (eg, age at onset) and genetic biomarkers (eg, SCN1A genetic score)
- Early and accurate determination of disease trajectory may aid in prognostic counseling and treatment decisions

Diagnosis

Approach to Diagnosis

Suspect diagnosis based on history and physical examination
- Typical history involves first seizure at about age 6 months (range 1-20 months) in an otherwise developmentally normal child; seizures are often hemiconvulsive or generalized tonic-clonic, often associated with fever and often prolonged; first EEG is typically normal²
- Recurrent febrile and afebrile seizures develop; caregivers characteristically identify triggers (eg, vaccination, heat, hot baths, fevers, excitement, exercise)
- Seizures are often medication refractory, EEG begins to show abnormalities, and neurodevelopmental delay and neurologic disability develop
DS (Dravet syndrome) is largely a clinical diagnosis established by development of clinical features over time
Genetic testing is recommended for patients with suspected DS; confirm genetic diagnosis by identification of a pathologic variant responsible for disease⁶
- Early identification of pathologic variant responsible for disease may diminish additional extensive workup and help guide treatment decisions (eg, avoidance of certain anticonvulsants)
Obtain CBC and comprehensive metabolic profile as baseline for monitoring with antiseizure medication management, as indicated
Initial evaluation after diagnosis may include:¹¹
- Cognitive and behavioral neuropsychiatric assessments
- Consultation with a clinical geneticist or genetic counselor

Diagnostic Criteria

International League Against Epilepsy diagnostic criteria for DS¹⁶
- Seizure onset between 1 and 20 months, most in first year
- Normal development before seizure onset
- Prolonged febrile or afebrile hemiclonic or generalized tonic-clonic seizures
- Cognitive and behavioral impairment after age 24 months
- Onset of other seizure types including myoclonic, absence, and focal seizures between age 1 and 4 years; development of drug-resistant epilepsy
- EEG—background slowing after age 2 years with focal, multifocal, and/or generalized discharge, often with early photosensitivity
- Normal MRI at seizure onset
- Appearance of subsequent ataxia, crouch gait, and pyramidal signs by mid to late childhood

Workup

History

Clinical disease evolves with time and progression of disease tends to manifest in 3 overlapping phases
- Seizure-onset phase
  - First manifestation is often a seizure within the first year of life, with average age of onset around age 6 months (range 1-20 months), in an otherwise developmentally normal infant²
  - Initial seizure type is often described as generalized tonic-clonic or hemiclonic activity
  - Seizures may be febrile or afebrile in nature and often are prolonged in duration
  - First EEG and MRI, when obtained, are characteristically normal
- Worsening phase
  - With time, seizures recur, and multiple other seizure types develop (eg, myoclonic, absence, focal)
    - Note that hemiclonic seizures often switch sides from seizure to seizure
  - Parents typically report triggers (eg, vaccination, heat, hot baths, fevers, excitement, emotional stress, eating, exercise or overexertion, flashing lights or visual patterns, sleep deprivation)⁶
  - Seizures are typically prolonged (ie, more than 15 to 30 minutes)⁷ and require rescue medication to stop
  - Seizures become medication refractory, and trials of sodium channel antiseizure drugs (eg, oxcarbazepine, lamotrigine) characteristically worsen seizures
  - Interictal EEG abnormalities become apparent
  - Psychomotor developmental slowing or plateauing is often notable several months after initial onset of seizures¹⁷
- Stabilization phase
  - Between ages 5 and 10 years, seizures become shorter and less frequent, but often multiple types emerge (if not previously)³
  - By adolescence and adulthood, brief nocturnal convulsive seizures are usually the most prominent seizure type
  - Cognitive, especially language, deterioration becomes a major aspect of this phase
  - Children may develop walking abnormalities with a crouching gait and ataxia
  - MRI may begin to show atrophy and/or mesial temporal sclerosis
Family history is frequently significant for epilepsy or febrile seizures

Physical Examination

Examination findings may be normal early on
With time, subtle finding may develop including:
- Gait abnormalities (eg, wide-based gait, tiptoeing, hunched over position with gait)
- Hypotonia
- Delays in fine motor control
- Subtle cerebellar signs (eg, ataxia, incoordination)

Laboratory Tests

SCN1A testing
- SCN1A variants identified in more than 80% of patients⁵
- Note that the diagnosis of DS (Dravet syndrome) does not require a positive SCN1A test
- Multigene epilepsy panel is the preferred testing method for pathologic variants associated with the disease
  - Panels that include SCN1A and other genes of interest are most likely to identify underlying genetic cause while decreasing the risk of detecting variants of uncertain significance¹¹
  - Genetic testing (free of cost to patient) is available for young children up to age 8 years with epilepsy and includes testing for SCN1A pathologic variants associated with disease¹⁸
- Genetic testing for DS is highly recommended by the International DS Consensus Panel for infants and children aged 2 to 15 months with either a first prolonged hemiclonic seizure or convulsive status epilepticus of unknown cause, with fever or after vaccination²
  - Expert panel notes that although strong consensus exists where diagnosis of DS should be considered, this does not preclude testing in other settings as DS may present up through age 19 months with afebrile brief seizures in the setting of developmental delay
- Discrete indications for genetic testing as recommended by the North American Consensus Panel include the following in otherwise developmentally normal children without causal lesion identified on MRI with unknown seizure etiology:⁶
  - Age younger than 12 months with 2 or more prolonged (more than 15 minutes) focal febrile seizures, affecting opposite sides of the body
  - Age younger than 12 months with more than 2 prolonged (more than 15 minutes) focal febrile seizures, affecting the same side of the body
  - Age younger than 12 months with 2 or more prolonged (more than 15 minute) febrile seizures, of which at least 1 being focal and 1 generalized in nature
  - Age 12 to 25 months with 1 or more prolonged (more than 15 minutes) febrile seizures or 2 or more febrile seizures (all brief) before age 18 months and myoclonic and/or atypical absence seizures refractory to 1 or more antiseizure medication

Imaging Studies

MRI
- Obtain at epilepsy onset to exclude a focal structural lesion
- MRI findings consistent with DS characteristically include:
  - First MRI obtained during first years of life is typically normal
  - With time, typically between ages 5 and 10 years, generalized cerebral atrophy may develop and mesial temporal sclerosis is sometimes noted¹

Diagnostic Tools

EEG
- EEG findings usually evolve with time
- First EEG obtained after initial seizure(s) is often normal
- Background slowing is often seen by age 2 years and present in most by age 5 years²
- With time, follow-up EEG begins to show abnormalities as seizures become prolonged and medication refractory
- Epileptiform abnormalities may include generalized spike-wave, multiple spike-and-wave, and multifocal spike discharges¹¹
- Photoparoxysmal responses (spikes with flashing lights) may be apparent
- Ictal EEG findings vary depending on seizure type
Polysomnography
- Sleep study may be indicated if obstructive or central sleep apnea is suspected

Differential Diagnosis

Table

Table 1. Differential Diagnosis: Dravet syndrome.

Condition	Description	Differentiated by
Febrile seizures	Common and benign condition characterized by seizures triggered only by fever in children ages 6 months to 5 years¹⁹Simple (versus complex) febrile seizures are generalized, last no longer than 15 minutes, and do not occur more than once in a given febrile illness²⁰	Does not progress, persist, or worsenChildren affected are typically developmentally normal with normal intellectEEG is usually normal and no other seizure types develop
Intracranial infection	Infections such as meningitis, encephalitis, and intracranial abscess may present with seizures in association with feverMental status is usually significantly impaired in between seizures, and meningeal signs are often noted on examination	Suspect based on presenting clinical featuresCNS imaging is indicated (before LP) in patients with concern for increased ICP clinically or focal findings on examinationDiagnose meningitis by characteristic CSF findingsEncephalitis is often determined by supportive MRI and CSF findings
Structural lesions leading to focal epilepsy	CNS structural lesions may present with febrile or afebrile seizuresFocal seizures and focal findings on examination are particularly concerning for potential CNS mass	Suspect based on presenting clinical featuresCNS imaging is indicated in patients with concern for increased ICP clinically or focal findings on examination to assess for mass lesion
GEFS+²¹	Spectrum of genetically and phenotypically heterogenous familial seizure disorders characterized by focal and generalized seizuresFebrile seizure may begin before age 6 months and persist beyond age 6 yearsMost common seizure type is generalized tonic-clonic; however, other seizure types may occur (eg, absence, myoclonic, atonic, focal)Seizures not related to fever do occur, often after age 6 years²²Associated with strong family history of febrile seizure in 2 or more family members (autosomal dominant inheritance with variable penetrance)Abnormal EEG often shows abnormalitiesCan have SCN1A-positive status¹¹	No progression or worsening of seizures over time, seizures usually short, and seizures often stop by late childhoodDevelopment and neurocognitive abilities are usually normalStrong family history (not usually present in DS)Diagnosis is often suspected in children with febrile seizures outside typical age range from simple febrile seizuresGenetic diagnosis may be established by identification of 1 of several pathologic variants associated with disease. Children may have SCN1A variants as well
PCDH19-related epilepsy²³	Febrile seizures at onset, onset primarily before age 3 years, often medication resistant, and often occur in clusters as opposed to prolonged single febrile seizuresMany seizure types develop and may not be triggered by feverDevelopmental delay, cognitive impairment, autistic traits, and behavioral problems are common	Females only; seizures notable for screaming during ictusGenetic testing shows abnormality different from DS. Genetic abnormality (PCDH19 gene) is on X chromosome
EMAS²⁴(also referred to as Doose syndrome)	Young onset (6 months-6 years), neurodevelopmentally normal at onset of seizuresBoys affected more than girlsFamily history may be positive for seizure disorderFirst seizure is often generalized tonic-clonic and may be associated with feverMyoclonic-atonic and atonic seizures develop, but the most characteristic are myoclonic atonic seizuresFindings of EEG similar to those of DS	Fever not usually a trigger, highly responsive to ketogenic diets, and genetic testing usually negativeMRI is usually normalSome children exhibit some developmental impairment with time but are less impaired than DS patients
Lennox-Gastaut syndrome	Epileptic encephalopathy present in infants and young children with multiple types of drug-resistant seizures and intellectual disabilityProlonged seizures and behavioral problems are common.Underlying causes are diverse and may include structural and genetic abnormalities responsible for development of condition²⁵EEG pattern is specific with slow background with bursts of frontal predominant slow spike-wave complexes and generalized paroxysmal fast activity in sleep²²	Suspect by clinical presentation with distinctions being that tonic seizures are prominent and prolonged hemiclonic seizures do not occur²²EEG findings are distinct from DS (slow spike-wave without normal backgrounds)Diagnosis is often clinical (eg, multiple seizure types, cognitive impairment, characteristic EEG findings)²⁶Supportive findings may be noted on MRI and by identification of a genetic pathologic variant associated with disease
Mitochondrial disorders	Complex and heterogenous group of heritable metabolic disorders that may present with multiple seizure types early in infancy and childhoodPathologic variants of nuclear DNA and mitochondrial DNA may cause disease (typically autosomal recessive and X-linked inheritance)²⁷Involvement of multiple organ systems is characteristic of many mitochondrial disorders	Involvement of multiple organ systems, elevations in lactate level, and characteristic MRI abnormalities often help discriminateGenetic testing can help characterize and confirm disease
Multiple other forms of epilepsy and epilepsy syndromes²⁸	Varied, different ages of onset but some do include infancy	Clinical criteria and genetic testing

Caption: DS, Dravet syndrome; EMAS, epilepsy with myoclonic atonic seizures; CNS, central nervous system; CSF, cerebrospinal fluid; GFFS+, genetic epilepsy with febrile seizures plus; ICP, intracranial pressure; LP, lumbar puncture; PCDH19, protocadherin 19.