Predictors of Outcome in SCN1A-positive Dravet Syndrome

Abstract & Commentary

By Sotirios Keros, MD, PhD. Instructor, Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medical College. Dr. Keros reports no financial relationships relevant to this field of study.

Synopsis: Early seizures and EEG abnormalities as well as status epilepticus predicts worse outcome in SCN1A-positve Dravet syndrome in this new, large cohort of patients.

Source: Brunklaus A, et al. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 2012;135(Pt 8):2329-2336.

Severe myoclonic epilepsy in infancy (dravet syn-drome) represents approximately 5% of epilepsy syndromes that begin in infancy and is strongly associated with mutations in the sodium channel alpha 1 subunit gene (SCN1A). However, not all patients with SCN1A mutations have Dravet. Dravet syndrome is currently defined by the International League Against Epilepsy to have the following criteria: family history of seizures; normal development before onset; seizures that begin during the first year of life as generalized or unilateral febrile clonic seizures followed by later onset of myoclonic jerks and also often other partial, generalized and absence seizures; and EEG with generalized spike-waves and polyspike-waves, with early photosensitivity and focal abnormalities. In addition, the seizures in Dravet syndrome tend to be highly refractory to medication, status epilepticus is common, seizures exacerbate with hyperthermia, ataxia and pyramidal signs are common, and most children eventually will develop moderate to profound learning disabilities.

This study identified 355 Dravet cases pooled from a total of 1023 patients referred for SCNA1 testing. Patient information was obtained from a structured form submitted by the referring clinician. Of the children meeting criteria for Dravet, 241 (68%) had an SCN1A mutation and were included in further analysis. The authors estimate an incidence of 1 in 40,000 births in the United Kingdom. Missense mutations were the most common (46%), followed by nonsense (19%), and frameshift (8%). Twenty-nine percent had a family history positive for seizures. De novo mutations accounted for 104/115 (90%) of cases with parental data. Status epilepticus was noted in 80% and 72% had an episode of febrile seizures lasting longer than 10 minutes. The incidence of identified seizure types included generalized tonic-clonic seizures (94%), hemiclonic (72%), myoclonic (61%), complex partial (61%), and atypical absence (51%). The first seizure was precipitated by fever or illness in 58%, vaccination in 7%, bath in 2%, and 33% had no obvious precipitant.

Only 8/47 (17%) EEGs performed during the first 6 months of life were abnormal. In contrast, 30/38 patients (79%) had an abnormal EEG during the third year of life. Photosensitivity was present in 16% of all patients. The MRIs were normal in 89%. MRI abnormalities were mostly non-specific atrophy and temporal lobe changes. Valproate was most commonly reported to reduce seizure frequency (51%), followed by clobazam or clonazepam (34%) and topiramate (28%). Carbamazepine (60%) and lamotragine (43%) were reported to increase seizure frequency.

As expected, behavioral problems and developmental delay were common. Nearly all infants were classified as normal during infancy, and the median age at which developmental delay was first noted was 18 months. At the fifth year of life, however, only 10% of patients had normal development, and 70% had moderate or profound disability. By 15 years of age nearly all patients had, at minimum, moderate disability (15%) with the rest having severe (65%) or profound (20%) learning disability.

Using logistic regression, the authors found that the following clinical features predicted a worse developmental outcome: status epilepticus, interictal EEG abnormalities found during the first year of life, presence of a motor disorder, and early focal seizures with impairment of awareness. Mutation class, seizure precipitant, or MRI abnormalities did not contribute to predicting outcome.

Commentary

Previous reports of prognostic information in Dravet syndrome have been relatively small with somewhat contradictory findings. Although limited by the reliance on structured referral forms as the main source of data, this study provides useful new information, particularly that status epilepticus, earlier seizures, and EEG abnormalities predict worse outcomes. Mutations in the sodium channel encoded by the SCN1A gene may be directly responsible for the cognitive dysfunction.1 Thus, it still is not clear whether seizures are causative for encephalopathy or merely a marker of a more severe phenotype. In absence of other approaches, however, aggressive prevention and treatment of seizures in Dravet is warranted. In addition, this study adds yet more weight to using valproate as first-line therapy, although it is important to note that only stiripentol has been validated (as add-on therapy to valproate and clobazam) for use in Dravet in blinded, placebo-controlled studies.

Mutation type did not predict outcome, which is consistent with other studies that failed to show any genotype/phenotype correlations and is evidence of other genetic or environmental disease-modifying factors. Gene mutations besides SCN1A, for example protocadherin 19, also can cause Dravet syndrome, and it is likely that many more genetic causes of Dravet and other epileptic encephalopathy syndromes will be discovered.

Reference

1. Bender AC, et al. SCN1A mutations in Dravet syndrome: Impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav 2012;23:177-186.