Abstracts

Rationale: Since the initial characterization of CACNA1A-related hemiplegic migraine (HM), the phenotypic spectrum has broadened from relatively mild episodes in neurotypical individuals to severe and even life-threatening episodes, which may include status epilepticus, prolonged paralysis, coma, and cerebral edema. Also, at baseline, the severe phenotype may have additional neurodevelopmental differences. While clinical histories have been well-described in individual case reports, there has not been a large-scale observational cohort analysis using clinical data from Electronic Medical Records (EMR). The paucity of longitudinal data hinders our understanding of the natural history and therapeutic considerations for this rare disorder.

Methods: We examined clinician-entered data for thirteen individuals with a documented pathogenic or likely-pathogenic variant in CACNA1A and a diagnosis of HM from three tertiary care children's hospitals. We reconstructed HM and seizure history for each individual within the cohort, retrospectively assigning frequency and severity of episodes over time. HM severity was defined across multiple dimensions, including the need for hospitalization, duration of hospitalization, associated clinical features, time to recovery to baseline, and associated abnormal imaging, where data were available. We retrieved data regarding preventative and abortive treatment for HM for eight individuals in our cohort, and anti-seizure medication in 12 individuals, which allowed us to describe the current treatment landscape and the presumed effectiveness of these agents in treating both CACNA1A-related HM and epilepsy.

Results: Our cohort consisted of patients aged three to 29 years, with data spanning 138 patient-years, and included nine unique and two recurrent variants (R1349Q and V1393M). We categorized phenotype along two clinical dimensions: 1. The severity of HM episodes (mild versus severe), and 2. The presence of comorbid neurodevelopmental features, including epilepsy, autism, ataxia, and developmental delay/intellectual disability (no plus versus plus). Of the 13 individuals, there were zero mild, one mild-plus, four severe, and eight severe-plus, with categorical homogeneity within recurrent variants. Most HM preventative treatments included acetazolamide, verapamil, topiramate, and the ketogenic diet. Home abortive treatments included acetazolamide, and hospital abortive treatments included intravenous acetazolamide and steroids, among others.

Conclusions: This study is the first longitudinal analysis of CACNA1A-related HM in a cohort greater than one. We illustrated the disease course in 13 individuals spanning 138 patient-years, highlighting the spectrum of the disorder both concerning HM severity and comorbid neurodevelopmental features and delineating individuals into distinct phenotypic categories. We demonstrated phenotypic homogeneity across genotypes. We described the current treatment landscape at three different institutions. Based on our novel findings, this study promises to inform future diagnostic considerations and treatment practices for mild and severe CACNA1A-related HM.

Funding: Supported in part by NIH NINDS 1R01NS127830