Dravet Syndrome

Demographics

Prevalence:

• 6.5/100,000 live births.

Age at onset:

• Median seizure onset: 5.7m (range: 1.5 - 20.6m) in a large cohort. 

Genetics: 

• 80-85% of patients with DS have SCN1A mutations.     
• Most pathogenic variants in SCN1A are de novo, up to 10% of patients have one parent who is mosaic for the variant.  This has important implications for genetic counselling.
• SCN1A may be found in other syndromes such as GEFS+ (Generalized Epilepsy with Febrile Seizures plus other seizure types) - Phenotypic variability.
• Other sodium genes (e.g. SCN1B), potassium and chloride genes, ligand-gated genes (e.g. GABRG2, GABRA1), as well as non-channels genes (e.g. STXBP1), can cause the phenotype of DS - Genotypic variability.
• Diagnosis of DS requires typical clinical features and cannot be made on the presence of a variant alone.
• A clinical diagnosis of DS can be made in the absence of a diagnosed gene variant.
• Family history of febrile seizures or other epilepsies may be seen in 30-50% of cases including GEFS+.

Signs | Symptoms

Seizures:

• Seizure onset is typically between 3-9m.
• Although seizure onset outside the above range is possible, seizure onset less than 2 months or over 15 months should alert the clinician to review the diagnosis.

Clues to early diagnosis in the first year of life (especially when multiple features are seen):

• Triggers (see list below) of focal clonic and generalized tonic-clonic seizures are integral to diagnosis.
• Age of onset of seizures <7 months.
• Prolonged seizures >10 mins and status epilepticus with no other cause.
• Generalized clonic seizures or focal to bilateral seizures, with or without fever.
• Presence of hemiconvulsions.
• Focal seizures.

Seizure precipitating factors (triggers):

• In the first year of life, particularly:
  • Fever.
  • Vaccination-related fever.
  • Hot bath.
• In early childhood onwards:
  • Physical activity.
  • Change in environmental patterns.
  • Photic stimulation.
  • Excitement.
  • Fever (less so than the first year of life).

Signs which go against the diagnosis of DS include:

• No history of prolonged seizures (i.e. >10 min) and
• Lack of fever sensitivity as a seizure precipitant.
• Epileptic spasms are exclusionary.

Recommendation: In the International consensus on diagnosis and management of Dravet syndrome, there was a strong consensus that infants 2-15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination - in the absence of another cause - should undergo genetic testing for DS. 

Course of illness:

• Drug-resistant epilepsy.
• Myoclonic and atypical absences appear between 1-4 years.
• In a large cohort of 205 patients (median age 8.5years), status epilepticus occurred in 93% (89% experienced convulsive status and 24% had non-convulsive status).
• Episodes of status are more frequent before 5 years.
• By adolescence, status and atypical absences are rare and seizures experienced (i.e. focal seizures with loss of awareness, clonic, generalized tonic-clonic, myoclonic) are brief.
• Nocturnal seizures (tonic and tonic-clonic) become the predominant seizure type.

Development and Neurology:

• At seizure onset, development (98%) and neurological exam are typically normal (significant delay, abnormal neurological exam, movement disorder or microcephaly at seizure onset, are red flags to an alternative diagnosis).
• From the second year of life, children demonstrate cognitive and behavioural impairments.
• Over time, most patients manifest a degree of intellectual disability ranging from mild to severe (50%).
• Gait abnormalities including a crouch gait are usually seen by late childhood, together with subtle pyramidal signs.
• Many patients develop behavioural disorders. Patients may have inattention and hyperactivity.

Differential Diagnosis

• Other developmental epileptic encephalopathies.
• Other syndromes: Protocadherin 19 (affects girls, clusters of seizures triggered by fever, starting in infancy).
• Structural focal epilepsies.

Investigations

EEG: 

• EEG is typically normal or slow in patient <2 years.
• In patients>2 years, slowing on the EEG is typical. Interictal discharges noted may include: focal, multi-focal, and generalized.
• A photic-paroxysmal response is seen in 15%.

MRI:

• Normal at seizure onset but may show atrophy over time.
• A minority have hippocampal sclerosis.

Prognosis

• The evolution of epilepsy (as described above) is an evolution of cognitive impairment and other comorbidities (for example change in gait).
• Behavioural issues often continue as may sleep difficulties.
• A subgroup of patients in adulthood develops signs and symptoms of Parkinson’s disease.
• Dysautonomia and gut motility issues may develop.
• In a review of mortality in Dravet Syndrome, it was concluded DS is characterized by high epilepsy-related premature mortality and a marked young age at death:
  • It was estimated that 10-20% of children with Dravet syndrome die before 10 years of age.
  • SUDEP was the leading reported cause of death in DS accounting for nearly half of the deaths, followed by status epilepticus as causative in one-third of the deaths, drowning or accidental death in 8%, and infections in 5%.  
  • Age at death was reported in 80% of cases with a mean of 8.7 (+/- 9.8 years).
  • 73% of deaths were before 10 years.

Management

The recommendations below reflect those of the first International DS Consensus, which included both expert physicians and caregivers, from all continents. Delphi methodology was used: 

• Valproic acid, clobazam, stiripentol and fenfluramine may be considered as first or second-line maintenance treatments.
• Cannabidiol of pharmacological grade was considered third-line. 
• Topiramate and ketogenic diet were considered fourth-line.
• Other modalities and drugs to consider:
  • Vagal nerve stimulation, levetiracetam, zonisamide, bromides, clonazepam and ethosuximide (for absences).
• Early diagnosis enables prompt use of the most appropriate drugs first.
• Sodium channel blockers, including carbamazepine, oxcarbazepine, phenytoin and lamotrigine should be avoided.
• Phenytoin may be helpful for status epilepticus, but should be avoided as maintenance treatment. 
• Lamotrigine may have a limited role in adults with refractory seizures but should be carefully monitored for seizure exacerbation.
• Contraindicated therapies may exacerbate seizures and adversely impact development.
• Several disease-modifying therapies are in clinical development. Provided they are safe and efficacious there is consensus for recommending their use in persons with DS:
  • STK-001, antisense oligonucleotide which restored Nav1.1 to wild-type levels and decreased both seizures and mortality (i.e. SUDEP) in Dravet mice, is currently in human trials (MONARCH: US and UK).
• Regarding comorbidities, including intellectual disability, attention problems, gait abnormalities and sleep problems, there is limited agreement on optimal management.
• There is modest support for use of melatonin for sleep problems.
• Autism appears to be unrecognized. Periodic evaluation by a neuropsychologist or developmental paediatrician is recommended.
• Careful and well-prepared transition pathways to informed adult health professionals are critical.

Discussion with family:

A seizure management plan and seizure emergency plan tailored to the patient is important.

• Safety
• Epilepsy Medical Record
• Drug handout
• Dravet Syndrome - parent information

References

• Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000;356(9242):1638-1642. https://doi.org/10.1016/s0140-6736(00)03157-3 
• Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. New England Journal of Medicine. 2017;376(21):2011-2020. https://doi.org/10.1056/NEJMoa1611618 
• Hattori, J., Ouchida, M., Ono, J., Miyake, S., Maniwa, S., Mimaki, N., Ohtsuka, Y. and Ohmori, I. (2008), A Screening test for the prediction of Dravet syndrome before one year of age. Epilepsia, 49: 626-633. https://doi.org/10.1111/j.1528-1167.2007.01475.x
• Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243-2254. https://doi.org/10.1016/S0140-6736(19)32500-0 
• Li, W, Schneider, AL, Scheffer, IE. Defining Dravet syndrome: An essential pre-requisite for precision medicine trials. Epilepsia. 2021; 62: 2205– 2217. https://doi.org/10.1111/epi.17015
• Miller I, Scheffer IE, Gunning B, et al. Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial [published correction appears in JAMA Neurol. 2020 May 1;77(5):655]. JAMA Neurol. 2020;77(5):613-621. https://doi.org/10.1001/jamaneurol.2020.0073  
• Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020;77(3):300-308. https://dpo.org/10.1001/jamaneurol.2019.4113 
• Shmuely S, Sisodiya SM, Gunning WB, Sander JW, Thijs RD. Mortality in Dravet syndrome: A review. Epilepsy Behav. 2016;64(Pt A):69-74. https://doi.org/10.1016/j.yebeh.2016.09.007 
• Wirrell EC, Hood V, Knupp KG, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761-1777. https://doi.org/10.1111/epi.17274 
• Xiaojing Xu, Yuehua Zhang, Huihui Sun, Xiaoyan Liu, Xiaoling Yang, Hui Xiong, Yuwu Jiang, Xinhua Bao, Shuang Wang, Zhixian Yang, Ye Wu, Jiong Qin, Qing Lin, Xiru Wu. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutation. Brain and Development. 2014;36(8):676-681. https://doi.org/10.1016/j.braindev.2013.10.004 
• Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1349-1397. https://doi.org/10.1111/epi.17239