Dravet Syndrome: Symptoms, Types, Causes and Treatment

Dravet Syndrome is a rare, catastrophic form of epilepsy that predominantly begins in infancy. It challenges families and clinicians alike due to its severe seizures, developmental impacts, and complex management needs. In this comprehensive guide, we break down the symptoms, types, causes, and treatment options for Dravet Syndrome, drawing on the latest scientific research and clinical consensus.

Symptoms of Dravet Syndrome

Dravet Syndrome is more than just a seizure disorder—it’s a complex neurological condition that affects many aspects of a person’s life. Understanding the range of symptoms is crucial for early recognition and holistic care.

Symptom	Description	Onset/Progression	Source(s)
Seizures	Febrile/afebrile, prolonged, varied types	Onset in 1st year, recurrent	1 4 5 9
Cognitive Decline	Slowing of developmental/cognitive skills	Evident by 2nd–3rd year	1 4 5
Behavioral Issues	Inattention, perseveration, autistic traits	Develop over time	1 3 7
Motor Disturbances	Gait problems, crouch gait, ataxia	Emerge with disease course	3 4 15
Sleep Disturbance	Problems with sleep maintenance	Persistent	3 15
Appetite Issues	Poor appetite, eating difficulties	Ongoing	3 14
Autonomic Symptoms	E.g., temperature instability	Variable	3
SUDEP Risk	Sudden unexpected death in epilepsy	Ongoing risk	15

Table 1: Key Symptoms

Seizure Characteristics

• Onset: Typically, the first seizures emerge within the first year of life, often triggered by fever (febrile seizures) or without fever (afebrile). These are commonly clonic or tonic-clonic, generalized or unilateral, and frequently last more than 10 minutes. Seizures are often prolonged and can evolve into status epilepticus—a medical emergency where seizures do not stop on their own 1 4 9.

• Progression: Over time, multiple seizure types appear. These may include myoclonic (brief, shock-like jerks), atypical absences, and focal seizures. As the child grows, seizures generally become less frequent but remain resistant to standard treatments 1 4 5.

Cognitive and Developmental Impact

• Developmental Delay: Children typically show normal development before seizure onset, but a noticeable slowing or regression in cognitive and motor skills becomes evident by the second or third year of life 1 4 5.

• Cognitive Impairment: Intellectual disability is common, ranging from mild to severe, impacting learning, memory, and problem-solving skills 2 5 15.

Behavioral and Psychiatric Symptoms

• Behavioral Issues: Many children develop behavioral disorders, including inattention and perseveration. Autistic-like traits and social interaction deficits are also observed, though their frequency may vary depending on the underlying genetic mutation 3 7 15.

• Sleep and Appetite: Disturbed sleep patterns and appetite issues are reported in the majority of cases, significantly affecting quality of life for both the patient and their caregivers 3 14.

Motor and Autonomic Disturbances

• Gait and Motor Issues: Problems with walking, balance (ataxia), and a specific “crouch gait” are common as the disease progresses 3 4 15.

• Autonomic Symptoms: Some children experience symptoms like unstable body temperature, excessive sweating, or other autonomic dysfunctions 3.

Risk of SUDEP

• SUDEP: Patients with Dravet Syndrome are at a higher risk for sudden unexpected death in epilepsy, making careful monitoring essential 15.

Types of Dravet Syndrome

While Dravet Syndrome is often viewed as a single disorder, research has identified several related forms and overlapping syndromes, each with unique characteristics.

Type	Key Features	Genetic Link(s)	Source(s)
Core/Typical	Multiple, prolonged seizures, myoclonus	SCN1A (mainly)	1 4 5 7
Borderline	Absence or subtle myoclonic seizures	SCN1A, sometimes others	1 4
DS-like	Similar to DS, with some differences	PCDH19, GABRA1, STXBP1	7 8 10
SCN1A Spectrum	Milder to severe phenotypes	SCN1A	5 6 10

Table 2: Dravet Syndrome Types and Related Phenotypes

Core (Typical) Dravet Syndrome

• Definition: The classic form, previously known as Severe Myoclonic Epilepsy of Infancy (SMEI), includes all hallmark features: early onset of febrile and afebrile seizures, varied seizure types, myoclonus, and pronounced developmental delay 1 4 5.
• Genetics: Most often associated with pathogenic variants in the SCN1A gene 1 4 5.

Borderline Dravet Syndrome (SMEIB)

• Definition: Patients present with similar early seizures and developmental issues but lack prominent myoclonic seizures, or these are very subtle 1 4.
• Clinical Course: The absence of typical myoclonus may make diagnosis more challenging.

Dravet Syndrome-like Phenotypes

• Definition: Some patients exhibit a “Dravet-like” syndrome—clinical features mimicking Dravet Syndrome but with different or no SCN1A mutations.
• Genetics: Frequently associated with mutations in PCDH19 (especially in females), GABRA1, STXBP1, and other genes 7 8 10.
• Key Differences: For example, autistic traits are more prominent in patients with PCDH19 mutations compared to those with SCN1A variants 7.

The SCN1A Spectrum

• Phenotypic Continuum: Dravet Syndrome exists on a spectrum of severity linked to SCN1A mutations, from milder forms (e.g., Genetic Epilepsy with Febrile Seizures Plus, or GEFS+) to the severe classic presentation 5 6 10.
• Overlap with Other Disorders: Some other epilepsy syndromes, such as Doose, West, and Lennox–Gastaut, may overlap genetically or clinically with Dravet Syndrome, particularly in cases of “fragmented” phenotypes 5 6.

Causes of Dravet Syndrome

The root cause of Dravet Syndrome lies in genetic mutations that disrupt the function of brain cells, but there is a growing understanding of its genetic diversity.

Cause	Description	Frequency/Significance	Source(s)
SCN1A Mutation	Sodium channel α1 subunit gene mutation	70–80% of cases	1 5 6 9 10
Other Genes	PCDH19, GABRA1, STXBP1, SCN1B, GABRG2	Rare, but significant in DS-like	7 8 10 11
Inheritance	Most mutations de novo, some inherited	Familial or mosaic cases	5 9 10
Unknown	No mutation detected	~20% of cases	10

Table 3: Genetic Causes of Dravet Syndrome

SCN1A Mutations: The Primary Cause

• Gene Function: SCN1A encodes the alpha subunit of the voltage-gated sodium channel NaV1.1, essential for proper neuron firing and brain function 2 5 10.
• Mutation Types: Over 1,800 pathogenic variants have been identified, including truncating, missense, splice-site mutations, and large deletions. Truncating mutations are linked with earlier and more severe disease 5 6 10.
• Mechanism: Loss-of-function mutations impair inhibitory neurons, leading to brain-wide hyperexcitability, seizures, and cognitive deficits 2 12.

Other Genetic Causes

• PCDH19: Mutations especially in females can produce a Dravet-like syndrome with prominent autistic features and greater sensitivity to fever 7 10.
• GABRA1 and STXBP1: Recently identified as causes in SCN1A-negative patients, both are important for inhibitory neurotransmission 8.
• SCN1B and GABRG2: Rare mutations can result in Dravet or Dravet-like presentations, sometimes inherited in a recessive manner 10 11.

Inheritance Patterns

• De Novo Mutations: Most patients have new (de novo) mutations, but inherited forms exist, sometimes as somatic mosaicism (mutation present in only some cells) or with milder symptoms in parents 5 9 10.
• Familial Variation: Within families, severity and symptoms can vary widely, even among those with the same mutation 5.

Other Considerations

• Undetected Causes: About 20% of patients have no identifiable mutation, suggesting the involvement of other genes or mechanisms yet to be discovered 10.
• SCN1A and Related Disorders: SCN1A mutations can also cause other epilepsy syndromes, such as GEFS+, Doose syndrome, and West syndrome, supporting the concept of a genetic spectrum 6.

Treatment of Dravet Syndrome

Treating Dravet Syndrome is challenging due to the pharmacoresistant nature of the seizures and the need to address comorbidities. Management is multifaceted, involving medication, emergency planning, and holistic support.

Treatment	Role	Key Notes & Considerations	Source(s)
Valproate	First-line anti-seizure	Broad-spectrum, baseline agent	14 15 16 17
Clobazam	Adjunctive therapy	Often combined with valproate	14 15 17
Stiripentol	Add-on (EU/US approved)	With VPA/CLB; proven efficacy	14 16 17
Topiramate	Adjunctive, alternative	Useful, but watch for side effects	14 15 16 17
Cannabidiol (CBD)	Add-on (recently approved)	With/without CLB; liver monitoring needed	16 17
Fenfluramine	Add-on (recently approved)	Dose monitoring for heart safety	16 17
Ketogenic Diet	Dietary therapy	For refractory cases	14 15 16
Rescue Medications	Emergency seizure management	Benzodiazepines for status	13 14 15 16
Avoided Drugs	Exacerbate seizures	Carbamazepine, phenytoin, lamotrigine	14 15 17
Supportive Care	Multidisciplinary interventions	Therapists, psychologists, social work	15

Table 4: Dravet Syndrome Treatments

Mainstay Anti-Seizure Medications

• Valproate: The foundation for seizure management. It helps prevent recurrence of febrile and afebrile seizures but is often insufficient alone 14 15 17.
• Clobazam: Commonly used as adjunct therapy, often in combination with valproate 14 15 17.
• Stiripentol: A GABAergic agent, approved for use with valproate and clobazam; proven in controlled trials to reduce seizures. Monitor for side effects and drug interactions 14 16 17.

Newer and Adjunctive Therapies

• Topiramate: Can be effective as adjunct therapy but requires careful monitoring for cognitive and metabolic side effects 14 15 17.
• Cannabidiol (CBD): Recently approved, especially in combination with clobazam. Monitor for liver toxicity, especially if used with valproate 16 17.
• Fenfluramine: Shown to reduce seizures; requires cardiac monitoring due to historical concerns regarding heart valve effects 16 17.
• Ketogenic Diet: High-fat, low-carbohydrate diet that can be effective in refractory cases 14 15 16.

Acute and Emergency Management

• Rescue Medications: Benzodiazepines (oral, nasal, or rectal) are essential for treating prolonged seizures and status epilepticus. All families should have a seizure emergency plan 13 14 15 16.
• Status Epilepticus Protocols: Clear protocols must be in place for emergency care, both at home and in hospital settings 13 15.

Medications to Avoid

• Sodium Channel Blockers: Drugs like carbamazepine, oxcarbazepine, phenytoin, and lamotrigine can worsen seizures and should be avoided 14 15 17.

Holistic and Supportive Care

• Comprehensive Team: Management should involve physical, occupational, and speech therapy; neuropsychology; and social work to address the wide range of comorbidities 15.
• Lifestyle and Trigger Avoidance: Avoid known seizure triggers such as high temperatures, flashing lights, and illness 13 15.
• Monitoring: Regular blood work, cardiac monitoring (for fenfluramine), and drug level checks are part of ongoing care 17.

Emerging and Future Therapies

• Gene Therapy: Animal studies suggest that gene reactivation or correction could potentially reverse symptoms, opening doors for future therapeutic strategies 2 12.
• Other ASMs: Levetiracetam, bromides, and other antiepileptic drugs may be used in resistant cases, though evidence is less robust 14 15 16 17.

Conclusion

Dravet Syndrome remains one of the most challenging epilepsy disorders, both for families and clinicians. Early recognition, genetic diagnosis, and a multidisciplinary approach are the cornerstones of care. Here’s a summary of the main points:

• Symptoms: Early-onset, prolonged, and varied seizures; developmental and cognitive slowing; behavioral, motor, sleep, and appetite issues; high risk for SUDEP 1 3 4 5 15.
• Types: Core (typical), borderline, and Dravet-like syndromes, with a spectrum of genetic and clinical variability 1 4 5 7 8 10.
• Causes: Mostly SCN1A mutations, with other genes like PCDH19, GABRA1, and STXBP1 implicated in a minority of cases; most mutations are de novo, but familial cases occur 5 6 7 8 9 10 11.
• Treatment: Requires tailored combinations of anti-seizure medications (valproate, clobazam, stiripentol, etc.), emergency planning, trigger avoidance, and holistic support; newer therapies (CBD, fenfluramine) and gene therapy hold promise for the future 13 14 15 16 17.

Supporting those affected by Dravet Syndrome means not only managing seizures but embracing a comprehensive, compassionate, and adaptable approach to care.