Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy)

Definition and Overview

Dravet syndrome is a rare, catastrophic, genetic form of epilepsy that begins in the first year of life with frequent and/or prolonged seizures. It is characterized by multiple types of seizures, developmental delays, and other health problems throughout life.

Epidemiology

• Incidence: Approximately 1:15,700 to 1:40,000 live births
• Gender distribution: Slightly higher prevalence in males
• Accounts for about 7% of all severe epilepsies beginning before age 3
• Represents approximately 1% of all epilepsy cases

Genetic Basis

Primary genetic cause: Mutations in the SCN1A gene (sodium voltage-gated channel alpha subunit 1)

• 80-85% of cases involve SCN1A mutations
• 90% of mutations are de novo
• 10% inherited in autosomal dominant pattern
• Other rare genetic variants:
  • GABRA1
  • GABRG2
  • SCN1B
  • HCN1

Clinical Presentation

Early Phase (First Year)

• Normal development before seizure onset
• First seizure typically between 4-8 months
• Initial seizures often triggered by fever
• Prolonged hemiclonic or generalized tonic-clonic seizures

Evolution Phase (1-5 years)

• Multiple seizure types emerge:
  • Myoclonic seizures
  • Focal seizures
  • Absence seizures
  • Tonic seizures (less common)
• Development begins to slow or plateau
• Emergence of behavioral issues

Stabilization Phase (>5 years)

• Seizure frequency may decrease
• Nocturnal seizures become prominent
• Intellectual disability becomes evident
• Gait abnormalities manifest

Common Seizure Triggers

Environmental Triggers	Physical Triggers	Other Factors
Temperature changes Visual patterns Bright lights Warm baths	Fever Physical exertion Infections Vaccinations	Emotional stress Excitement Sleep deprivation

Diagnostic Criteria

Required Features:

• Normal development before seizure onset
• Seizure onset in first year of life
• Multiple seizure types
• Prolonged seizures
• Refractory to standard anticonvulsants

Supporting Features:

• SCN1A mutation
• Family history of epilepsy/febrile seizures
• Normal initial EEG
• Normal initial development
• Normal initial neuroimaging

Treatment Approach

First-Line Medications

• Valproate (VPA)
• Clobazam (CLB)
• Stiripentol (STP)
• Fenfluramine (FFA)
• Cannabidiol (CBD)

Medications to Avoid

• Sodium channel blockers:
  • Carbamazepine
  • Oxcarbazepine
  • Lamotrigine
  • Phenytoin

Emergency Management

• Rescue medications:
  • Midazolam (buccal/intranasal)
  • Diazepam (rectal)
• Emergency protocols for prolonged seizures
• Temperature management

Non-Pharmacological Interventions

• Ketogenic diet
• Vagus nerve stimulation
• Developmental therapy
• Physical therapy
• Occupational therapy
• Speech therapy

Monitoring and Follow-up

• Regular developmental assessments
• EEG monitoring
• Growth monitoring
• Cardiac evaluation
• Bone health assessment
• Quality of life measures

Complications and Comorbidities

Neurological	Non-neurological	Behavioral/Cognitive
Status epilepticus Crouch gait Ataxia	Growth problems Sleep disorders Immunological issues	Intellectual disability Autism spectrum features ADHD symptoms

Prognosis

• Mortality rate: 15-20% by adulthood
• Common causes of death:
  • SUDEP (Sudden Unexpected Death in Epilepsy)
  • Status epilepticus
  • Accidents/drowning
• Long-term outcomes:
  • Persistent seizures in most cases
  • Varying degrees of intellectual disability
  • Most require lifelong care

Note: This document represents current medical knowledge as of 2024. Treatment protocols may vary by region and should be tailored to individual patients. Regular consultation of updated guidelines and research is recommended.

Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy)

1. What is Dravet Syndrome?
   Dravet Syndrome is a severe, genetic epileptic encephalopathy that begins in infancy and is characterized by frequent, prolonged seizures and developmental delays.
2. What gene is most commonly associated with Dravet Syndrome?
   Mutations in the SCN1A gene, which encodes a sodium channel subunit, are found in approximately 80% of patients with Dravet Syndrome.
3. At what age do seizures typically begin in Dravet Syndrome?
   Seizures in Dravet Syndrome typically begin within the first year of life, often around 6 months of age.
4. What is the typical first seizure type in Dravet Syndrome?
   The first seizure in Dravet Syndrome is often a prolonged, hemiclonic or generalized tonic-clonic seizure, frequently associated with fever.
5. How does the seizure pattern evolve in Dravet Syndrome?
   As the syndrome progresses, patients develop multiple seizure types including myoclonic, focal, and absence seizures, as well as status epilepticus.
6. What triggers are commonly associated with seizures in Dravet Syndrome?
   Common seizure triggers in Dravet Syndrome include fever, changes in body temperature, visual patterns, and excitement.
7. How does Dravet Syndrome affect cognitive development?
   Dravet Syndrome typically leads to cognitive impairment, with slowing of development usually evident from the second year of life.
8. What is the range of intellectual outcomes in Dravet Syndrome?
   The range of intellectual outcomes in Dravet Syndrome varies from mild to severe intellectual disability, with most patients having moderate to severe impairment.
9. What non-seizure symptoms are common in Dravet Syndrome?
   Common non-seizure symptoms include ataxia, crouch gait, language impairment, behavioral problems, and sleep disturbances.
10. How is Dravet Syndrome diagnosed?
    Diagnosis is based on clinical presentation, EEG findings, and genetic testing for SCN1A mutations.
11. What are the typical EEG findings in Dravet Syndrome?
    EEG findings in Dravet Syndrome are often normal early on, but later show generalized spike-wave and polyspike-wave discharges, focal and multifocal discharges, and photosensitivity.
12. What antiepileptic drugs are typically used as first-line treatment for Dravet Syndrome?
    Valproate, clobazam, and stiripentol are often used as first-line treatments for Dravet Syndrome.
13. Why are sodium channel blockers generally avoided in Dravet Syndrome?
    Sodium channel blockers (e.g., carbamazepine, oxcarbazepine) are generally avoided because they can exacerbate seizures due to the underlying sodium channel dysfunction.
14. What is the role of the ketogenic diet in treating Dravet Syndrome?
    The ketogenic diet can be an effective adjunctive treatment for Dravet Syndrome, potentially reducing seizure frequency and improving cognition.
15. What is the prognosis for patients with Dravet Syndrome?
    The prognosis is generally poor, with persistent seizures, cognitive impairment, and increased risk of sudden unexpected death in epilepsy (SUDEP).
16. How does fenfluramine work in the treatment of Dravet Syndrome?
    Fenfluramine, approved in 2020, works by modulating serotonin signaling and has shown significant efficacy in reducing seizure frequency in Dravet Syndrome.
17. What is the role of cannabidiol (CBD) in treating Dravet Syndrome?
    CBD has been shown to be effective in reducing seizure frequency in Dravet Syndrome and is FDA-approved for this indication.
18. How does Dravet Syndrome affect life expectancy?
    Dravet Syndrome is associated with increased mortality, with a significant risk of SUDEP and status epilepticus.
19. What precautions should be taken for patients with Dravet Syndrome during illnesses?
    During illnesses, aggressive fever management and close monitoring are crucial to prevent prolonged seizures and status epilepticus.
20. How does Dravet Syndrome affect motor development?
    Motor development is often affected, with many patients developing ataxia, coordination problems, and sometimes a characteristic crouch gait.
21. What is the inheritance pattern of Dravet Syndrome?
    Dravet Syndrome is typically an autosomal dominant disorder, often caused by de novo mutations in the SCN1A gene.
22. How does genetic testing aid in the management of Dravet Syndrome?
    Genetic testing can confirm the diagnosis, guide treatment choices (e.g., avoiding sodium channel blockers), and facilitate genetic counseling.
23. What is the role of vagus nerve stimulation (VNS) in Dravet Syndrome?
    VNS can be considered as an adjunctive treatment in Dravet Syndrome, particularly in patients with drug-resistant seizures.
24. How does Dravet Syndrome affect sleep?
    Sleep disturbances are common in Dravet Syndrome, including insomnia, sleep fragmentation, and sometimes sleep-related seizures.
25. What behavioral issues are commonly associated with Dravet Syndrome?
    Common behavioral issues include hyperactivity, attention deficits, autistic-like features, and sometimes aggressive behavior.
26. How does Dravet Syndrome impact families?
    Dravet Syndrome can have significant psychosocial impacts on families, including high caregiving burden, financial stress, and effects on siblings.
27. What is the importance of rescue medications in Dravet Syndrome?
    Rescue medications (e.g., rectal diazepam, buccal midazolam) are crucial for managing prolonged seizures and preventing status epilepticus at home.
28. How does photosensitivity manifest in Dravet Syndrome?
    Photosensitivity is common in Dravet Syndrome, with seizures potentially triggered by flashing lights, contrasting patterns, or transitions from dark to light environments.
29. What is the role of early developmental interventions in Dravet Syndrome?
    Early developmental interventions, including physical, occupational, and speech therapies, are important to maximize developmental potential and manage comorbidities.
30. How does Dravet Syndrome differ from Lennox-Gastaut Syndrome?
    Dravet Syndrome typically begins earlier, has a known genetic cause (SCN1A mutations), and often includes temperature-sensitive seizures, whereas Lennox-Gastaut Syndrome typically begins later and has characteristic EEG patterns.

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