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BACKGROUND: Evidence of the impact of genetic diagnosis on medical management in individuals with previously unexplained epilepsy is lacking in the literature. Our goal was to determine the impact of genetic diagnosis on medical management in a cohort of individuals with early-onset epilepsy. METHODS: We performed detailed phenotyping of individuals with epilepsy who underwent clinical genetic testing with an epilepsy panel and/or exome sequencing at Boston Children’s Hospital between 2012 and 2019. We assessed the impact of genetic diagnosis on medical management. RESULTS: We identified a genetic etiology in 152 of 602 (25%) individuals with infantile- or childhood-onset epilepsy who underwent next-generation sequencing. Diagnosis impacted medical management in at least one category for 72% of patients (110 of 152) and in more than one category in 34%. Treatment was impacted in 45% of individuals, including 36% with impact on antiseizure medication choice, 7% on use of disease-specific vitamin or metabolic treatments, 3% on pathway-driven off-label use of medications, and 10% on discussion of gene-specific clinical trials. Care coordination was impacted in 48% of individuals. Counseling on a change in prognosis was reported in 28% of individuals, and 1% of individuals had a correction of diagnosis. Impact was documented in 13 of 13 individuals with neurotypical development and in 55% of those with epilepsy onset after age two years. CONCLUSION: We demonstrated meaningful impact of genetic diagnosis on medical care and prognosis in over 70% of individuals, including those with neurotypical development and age of epilepsy onset after age two years.

We report an early childhood onset Stiff Limb Syndrome (SLS) in association with unusual polyautoimmunity of GAD-65, anti-islet cell, and Thyroid Peroxidase (TPO) autoantibodies, who has achieved a nearly complete neurological recovery following combined immunotherapy, symptomatic and physical therapy. The patient had normal MRIs of the brain and spinal cord and a negative paraneoplastic work-up. Subsequently, she developed hypothyroidism requiring levothyroxine supplementation. We then conducted an extensive review of literature and identified 52 previously reported pediatric Stiff Man Syndrome (SMS)/Stiff Person Syndrome (SPS) or SLS cases, which has demonstrated a common association with other systemic autoimmune conditions. In the available literature, screening for concurrent autoimmunity has only been reported infrequently. We found that a paraneoplastic process is extremely rare in pediatric cases. Timely diagnosis and initiation of immunotherapy are critical to a favorable outcome. Therefore, we recommend to include SMS/SPS or SLS as an important differential diagnosis for MRI-negative myelopathy. Further clinical and research efforts should be focused on understanding the role of both genetic predisposition and environmental insults in the autoimmunity of pediatric SMS/SPS or SLS.

One hypothesis is that the activation of innate immunity and release of cytokines breaks down the blood brain barrier (BBB) and causes neuroinflammation. Here, I present a case of COVID-19 associated MIS-C (multisystem inflammatory syndrome in children) with neurological complications manifesting as encephalopathy and a cytotoxic lesion of the corpus callosum (CLOCC) on the brain MRI, in association with extremely elevated levels of circulating interleukin-6 (IL-6), and soluble interleukin-2 receptor (sIL2R).