Dravet Syndrome

Dravet syndrome is a severe developmental and epileptic encephalopathy beginning in infancy with prolonged febrile and afebrile hemiclonic or generalised seizures, followed by mixed seizure types, developmental regression and ataxia. It is mostly caused by loss-of-function variants in SCN1A.

The incidence is about 1 in every 15,000 to 40,000 births. About 80% of cases have SCN1A variants, most arising de novo.

Course. Onset is at about 6 months in a previously normal infant. Developmental slowing appears in the second year, with ataxia, crouch gait and behavioural problems. Mortality of 10 to 15% from status epilepticus, accidents and sudden unexpected death in epilepsy.

Triggers. Fever, hot baths, vaccination related fever, illness, exertion and photic or pattern stimulation.

Pathophysiology.

Loss of function of the Nav1.1 sodium channel in inhibitory interneurons reduces inhibition and produces network hyperexcitability.

Sodium channel blocking drugs further reduce interneuron firing and worsen seizures.

• First seizure at 3 to 9 months, often prolonged (over 15 minutes), unilateral or generalised, triggered by fever or a hot bath.
• Later myoclonic jerks, atypical absences, focal impaired awareness seizures and tonic seizures; convulsive and non-convulsive status.
• Developmental plateau and regression, ataxia, crouch gait, hypotonia, sleep problems, and autism like behaviour.
• Temperature sensitivity persists.

Red flags.

• Seizure lasting over 5 minutes.
• Non-convulsive status with reduced responsiveness.
• Worsening seizures after starting a sodium channel blocker.

• Clinical suspicion from the history; EEG is often normal early, with generalised and multifocal spikes later.
• SCN1A sequencing and deletion or duplication analysis; epilepsy gene panel; MRI is normal or shows non-specific change.
• Developmental assessment; swallowing, orthopaedic, sleep and behavioural assessments.

Differential diagnosis. Febrile seizures plus, other developmental and epileptic encephalopathies (PCDH19, CDKL5, SCN2A, SCN8A), Lennox-Gastaut syndrome, epilepsy with myoclonic atonic seizures and metabolic disease.

• Avoid sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin, lamotrigine, rufinamide) and vigabatrin, which can worsen seizures.
• Sodium valproate first line: initial 10 to 15 mg/kg orally daily in 2 divided doses, increased by 5 to 10 mg/kg weekly to a usual 20 to 30 mg/kg daily. Maximum 60 mg/kg daily. Monitor liver function, full blood count, platelets and weight. Avoid in liver disease, mitochondrial disease (including POLG variants), urea cycle disorders and porphyria. Contraindicated in girls and women of childbearing potential unless no alternative works and a pregnancy prevention programme is in place.
• Clobazam: body weight 30 kg or under, 5 mg orally daily, increased to 10 mg daily at day 7 and 20 mg daily at day 14; over 30 kg, 10 mg daily, increased to 20 mg daily at day 7 and 40 mg daily at day 14 (in 1 or 2 doses). Maximum 20 mg daily (30 kg or under) and 40 mg daily (over 30 kg). Monitor sedation, drooling, behaviour and respiration, tolerance and dependence. Start low in hepatic impairment and in poor CYP2C19 metabolisers; avoid abrupt withdrawal.
• Stiripentol add on to valproate and clobazam from 6 months: 50 mg/kg orally daily in 2 or 3 doses with a meal, titrated over 3 days. Maximum 4000 mg daily. Monitor full blood count, liver function, weight and growth; reduce clobazam by about 25% if sedation occurs. Avoid in severe hepatic or renal impairment; strong CYP interactions.
• Fenfluramine add on from 2 years: 0.1 mg/kg orally twice daily, increased weekly to 0.35 mg/kg twice daily (0.2 mg/kg twice daily with stiripentol). Maximum 26 mg daily (17 mg daily with stiripentol). Monitor echocardiography before treatment, every 6 months and 3 to 6 months after stopping (valvular heart disease and pulmonary hypertension), plus weight and appetite. Contraindicated in valvular heart disease, pulmonary hypertension and with monoamine oxidase inhibitors; reduce dose in severe hepatic or renal impairment.
• Cannabidiol add on for age 2 years and over: 2.5 mg/kg orally twice daily for 1 week, then 5 mg/kg twice daily, increased weekly in steps of 2.5 mg/kg twice daily to a maximum of 10 mg/kg twice daily. Monitor ALT, AST and bilirubin at baseline and at 1, 3 and 6 months. Reduce the dose in moderate hepatic impairment and avoid in severe impairment.
• Prolonged seizure rescue: midazolam oromucosal solution as a single dose of 2.5 mg (3 months to under 1 year), 5 mg (1 to under 5 years), 7.5 mg (5 to under 10 years) or 10 mg (10 to under 18 years), given for a seizure lasting over 5 minutes. Maximum 1 dose; call emergency services if the seizure continues after 10 minutes. Monitor breathing and sedation. Use caution in respiratory and hepatic impairment; avoid in myasthenia gravis.
• Non-drug therapy: ketogenic diet and vagus nerve stimulation; avoid triggers, use fever control and cooling; keep seizure action plans.

Monitoring. Review every 3 months; monitor growth, development, bone health and drug levels.

Referral and escalation. Paediatric epilepsy centre for all children with suspected Dravet syndrome; early genetic counselling.

Special groups. Adolescents and adults: transition to adult services; manage mood, sleep and mobility.