Authors :
Presenting Author: Philippa Karoly, PhD – Biomedical Engineering, University of Melbourne
Nicholas Winterling, ME – The University of Melbourne
Ewan Nurse, PhD – Seer Medical
Sophie Russ-Hall, BSc, MD (candidate) – University of Melbourne
Oliva Adrian, BS – Austin Health
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Rationale: Despite a distinctive
age-related electroclinical and developmental course in patients with Dravet syndrome, there remains a lack of quantitative evidence establishing the natural history of convulsive seizures from onset in infancy until later adult life.
This study aimed to identify demographic, genetic, and other variables correlated with lifetime seizure severity in SCN1A Dravet syndrome.Methods: This observational study tracked seizures from comprehensive seizure diaries over many years in 79 individuals with
SCN1A-Dravet syndrome (median age 5.5 y, range 2 m - 52.4 y), who underwent detailed phenotyping.
Outcome measures included seizure frequency and duration of convulsive seizures and convulsive status epilepticus (CSE, defined as at least 30 minutes
). Linear mixed models were used to assess the effect of age and mutation type (truncation vs missense) on seizure outcomes.
Results: Over 18,000 seizures were recorded across a total recording time of 352 years, with an average diary duration per person of 4.5 y (range: 3 m - 24.9 y). The 79 patients had an average of 160 days with reported convulsive seizures over the duration of their seizure diaries (range: 0 – 7900 seizure days).
The incidence of CSE significantly decreased with age, by 22% with each year of age until 12 years (95% CI: 14% to 30%, p < 0.001 using linear mixed effects model), while the incidence of all convulsive seizures remained constant until adulthood (18 years). CSE was infrequent after 6 years old (5 people reported any CSE between 6 – 12 y, with 2 people having >1 CSE/year).
Seizure rates were highly variable both within and between individuals, with individual mean frequency ranging from 0.1 - 10 seizures/month and standard deviation increasing linearly with mean (indicative of extreme fluctuations in monthly seizure counts).
Individuals’ median duration of convulsive seizures (excluding CSE) significantly decreased with age, from 8 minutes in infants (0 – 2 y), 3 minutes in early childhood (2 – 6 y), to 1.8 minutes in late childhood (6 – 12 y).
Conclusions: This study provides a benchmark quantifying both intra- and inter-individual variability in the natural history of seizures in Dravet syndrome. Findings will guide clinical management and prognosis of Dravet syndrome. Importantly, they will inform the development of Dravet syndrome-specific inclusion criteria for drug trials to allow the inclusion of the majority of individuals with Dravet syndrome, rather than just a small subset, in precision therapy trials.
Funding: This research was supported by an Australian Government National Health & Medical Research Council Grant (APP1178220)