Australian neurologists have developed a new definition of the criteria for Dravet syndrome to encompass a wider spectrum of patients, which they says is necessary for early diagnosis and improve involvement in precision medicine trials.
Writing in Epilepsia, clinicians at Austin Health and the Epilepsy Research Centre, Melbourne University say that Dravet syndrome has broader phenotypic limits than often recognized, with many patients having atypical features resulting in diagnostic delay and inappropriate therapy.
And with the emergence of precision medicine they say earlier diagnosis would help identify patients in readiness for trials of new therapies.
They therefore reviewed the clinical data for 205 patients with Dravet syndrome and pathogenic pathogenic variants in genes such as SCN1A diagnosed by three experts.
The review showed that the median seizure-onset age was 5.7 months, but ranged up to 20 months.
About half of initial seizures (52%) were tonic-clonic (52%) and 35% hemiclonic.
Notably only 55% of initial seizures in Dravet syndrome were associated with fever and 3% never had fever.
On third (34%) of patients presented with status epilepticus and 7% of patients never had status epilepticus.
The median time between first and second seizure was 30 days (range 4 hours to 8 months), and 5% of patients had at least six months between initial and subsequent seizures.
Median ages at onset of second and third seizure types were 9.1 months (range 3 months–25.4 years) and 15.5 months (range 4 months–8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.
The investigators, led by Dr Li Wenhui and Professor Ingrid Scheffer, said the review had challenged many of the assumptions made around Dravet syndrome including age at onset, fever at onset, the most common type of seizure at onset and onset of convulsive seizures after initial nonconvulsive seizures.
The findings also challenged the teaching that infants with Dravet syndrome present with status epilepticus and the timing of the first three seizures. The earlier age at onset of other seizure types also suggested a rethink was needed on recognition of additional seizures, they said.
Based on their review, the study authors produced a list of the most frequent features:
- SCN1A pathogenic variant in all (inclusion criteria)
- Hemiclonic or tonic-clonic seizures (all patients)
- Seizure onset <12 months (98%)
- Normal development prior to seizure onset (98% patients with adequate data)
- Developmental impairment prior to 5 years (98% patients with adequate data)
- Fever-sensitive seizures (97% patients with adequate data)
- Tonic-clonic seizures (96% patients with adequate data)
- Intellectual disability (93% patients with adequate data)
- Status epilepticus (93% patients with adequate data)
“We provide data to delineate the broader limits of Dravet syndrome so that evidence-based criteria can be developed and assist less-expert clinicians in making an earlier Dravet syndrome diagnosis,” they concluded.