Abstracts

Rationale: Refractory status epilepticus (RSE) affects about 30% of status epilepticus (SE) patients, with continuous seizures lasting over 30 minutes despite benzodiazepines and at least one antiepileptic drug (AED). Super-refractory status epilepticus (SRSE) persists for over 24 hours post-anesthesia or recurs post-withdrawal, linked to significant neurological dysfunction and high mortality. Identifying RSE and SRSE etiology is challenging, delaying recognition and limiting treatment options. While RSE is often linked to autoimmune encephalitis (ASE), this case highlights a genetic syndrome causing new-onset RSE. Rapid whole exome sequencing (WES) is crucial in acute RSE cases without an initial etiology, especially in young patients. This report underscores genetic testing's significance in new-onset SRSE, resembling autoimmune encephalitis, while detailing Gould syndrome's EEG characteristics.


Methods: A female born at 36 weeks with panhypopituitarism, mild developmental delays, and limited speech presented at 16 months with her first complex febrile seizure. At 22 months old, she had a 45-minute convulsive seizure treated with Ativan and Keppra, then within 24 hours, had frequent seizures with biphasic status epilepticus and SRSE, necessitating multiple AEDs, burst suppression therapy, and ketogenic diet. Typical seizures included focal myoclonic and clonic seizures with unresponsiveness and desaturations. Initial continuous video EEG revealed focal slowing with delta brush suggestive of anti-NMDA receptor encephalitis. IV methylprednisolone and IVIG were administered for presumed autoimmune encephalitis after neuroimaging and CSF testing, but genetic testing identified a de novo COL4A2 variant, highlighting epilepsy syndromes mimicking autoimmune encephalitis. A tracheostomy and G-tube were placed due to prolonged hospitalization, frequent seizures, and feeding difficulties. Outpatient follow-up revealed rare myoclonic seizures, severe hypotonia, and developmental delay, managed with Onfi, Fycompa, and ketogenic diet, with gradual improvements.


Results: Rapid trio WES identified a heterozygous de novo COL4A2 variant (c.826-1G >T) disrupting the AG splice acceptor site and interfering with normal splicing, along with a maternally inherited variant of uncertain significance in the RYR3 gene (c.355-1G >T). No clinically relevant copy number variants were detected. This underscores genetic testing's importance in avoiding unnecessary immunotherapies and enabling earlier targeted treatment.


Conclusions: Gould Syndrome 1 and 2 are rare autosomal dominant variants linked to COL4A1 and COL4A2 genes, encoding extracellular matrix proteins forming heterotrimers across organ basement membranes. Clinical features include childhood onset epilepsy, refractory epilepsy, cortical malformations, vascular defects, ocular dysgenesis, myopathy, and renal pathology. Our patient's presentation mimicked autoimmune encephalitis, but rapid WES revealed a genetic syndrome. Early genetic diagnosis could avoid unnecessary immunotherapies. This report also presents the first known case of Gould Syndrome associated with panhypopituitarism and new-onset SRSE, necessitating further exploration.


Funding: N/A