Abstracts

Rationale: The etiology of infantile spasms (IS) is unknown in one third of patients despite investigation for structural, metabolic and chromosomal conditions. IS of unknown etiology is typically thought to have a better prognosis than IS with a known etiology. We report the clinical features of the largest reported cohort of patients with IS of unknown etiology. Methods: Participants were enrolled in the Epilepsy Phenome/Genome Project (EPGP) Infantile Spasms Project, a multi-center study. Inclusion criteria included history of infantile spasms of unknown etiology, and EEG showing hypsarrhythmia or a hypsarrhythmia variant. Exclusion criteria included developmental delay of greater than 50% prior to onset of IS, prematurity (<32 weeks gestation) or a malformation other than focal cortical dysplasia on brain imaging. The full criteria can be found at www.epgp.org. For this study, medical records were reviewed by two independent reviewers. EEG and MRI brain imaging were reviewed. Patients were excluded if an etiology (including focal cortical dysplasia) was identified. Results: Of 107 patients with IS of unknown etiology, 61 (57.0%, p= 0.18) were male and 46 (43.0%) had a family history of epilepsy. The median age at last follow-up was 2.5 years (range 0.25-20 years). IS onset occurred at a median age of 5.3 months (range 2-14 months). Treatment was initiated within one month in 64 (59.8%) patients; corticosteroids were first line therapy in 71 (66.3%) patients. 31 (29.0%) had resolution of IS (defined as seizure freedom for at least six months) with the first medication used. Seizures antecedent to the IS occurred in 10 (9.4%). 61 (57.0%) of patients had other seizure types subsequent to the IS. Developmental delay occurred prior to IS in 24 (22.4%). At most recent assessment, only 20 (18.7%) had normal development. Normal developmental outcome was seen in 19/58 (32.8%) of patients with normal development prior to the onset of IS. 17/64 (26.6%) of patients who were treated with corticosteroids within one month and 13/31 (41.9%) of patients who had resolution of IS with the first medication used had a normal developmental outcome. Conclusions: This large cohort of patients with IS of unknown etiology shows significant heterogeneity of developmental and seizure outcomes. The majority of patients had an unfavourable developmental outcome despite the presence of factors previously identified to predict good prognosis including normal development prior to IS and prompt initiation of and response to treatment, and despite having excluded from the cohort those with severe delay before onset of spasms. The variable clinical outcomes suggest that the causes are also likely heterogenous. Whole exome sequencing of these patients will take place under the auspices of the Epi4K Project. Identification of the genetic bases of IS will allow better prognostication in individual patients as well as a greater understanding of the mechanisms underlying the development of IS, and will be the first step in the development of targeted therapies.