Current state of the epilepsy drug and device pipeline.

The field of epilepsy has undergone substantial advances as we develop novel drugs and devices. Yet considerable challenges remain in developing broadly effective, well-tolerated treatments, but also precision treatments for rare epilepsies and seizure-monitoring devices. We summarize major recent and ongoing innovations in diagnostic and therapeutic products presented at the seventeenth Epilepsy Therapies & Diagnostics Development (ETDD) conference, which occurred May 31 to June 2, 2023, in Aventura, Florida. Therapeutics under development are targeting genetics, ion channels and other neurotransmitters, and many other potentially first-in-class interventions such as stem cells, glycogen metabolism, cholesterol, the gut microbiome, and novel modalities for delivering electrical neuromodulation.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

BACKGROUND: Distinct genetic alterations determine glioma aggressiveness, however, the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of the disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability. METHODS: A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n = 1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n = 206). Hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. Cross-validated discriminant analysis models trained exclusively on recurrent somatic mutations were used to identify variants associated with hyperexcitability. RESULTS: The distribution of WHO grades and tumor mutational burdens were similar between patients with and without hyperexcitability. Discriminant analysis models classified the presence or absence of EEG hyperexcitability with an overall accuracy of 70.9%, regardless of IDH1 R132H inclusion. Predictive variants included nonsense mutations in ATRX and TP53, indel mutations in RBBP8 and CREBBP, and nonsynonymous missense mutations with predicted damaging consequences in EGFR, KRAS, PIK3CA, TP53, and USP28. This profile improved estimates of hyperexcitability in a multivariate analysis controlling for age, sex, tumor location, integrated pathologic diagnosis, recurrence status, and preoperative epilepsy. Predicted somatic mutation variants were over-represented in patients with hyperexcitability compared to individuals without hyperexcitability and those who did not undergo continuous EEG. CONCLUSION: These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.

Challenges and directions in epilepsy diagnostics and therapeutics: Proceedings of the 17th Epilepsy Therapies and Diagnostics Development conference.

Substantial efforts are underway toward optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trial execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, although seizures represent one critical therapeutic target, targeting nonseizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves and other nonseizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics, from drug discovery to translational application.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures is uncertain. In a large cohort of patients with sequenced gliomas (n=1716), we used discriminant analysis models to identify somatic mutation variants associated with electrographic hyperexcitability in a subset with continuous EEG recording (n=206). Overall tumor mutational burdens were similar between patients with and without hyperexcitability. A cross-validated model trained exclusively on somatic mutations classified the presence or absence of hyperexcitability with an overall accuracy of 70.9%, and improved estimates of hyperexcitability and anti-seizure medication failure in multivariate analysis incorporating traditional demographic factors and tumor molecular classifications. Somatic mutation variants of interest were also over-represented in patients with hyperexcitability compared to internal and external reference cohorts. These findings implicate diverse mutations in cancer genes associated with the development of hyperexcitability and response to treatment.

Ischaemic stroke in a patient with myasthaenic crisis and antiphospholipid antibody syndrome.

While autoimmune diseases have been frequently found to coexist in the same patients, the co-occurrence of myasthaeniagravis and antiphospholipid antibody syndrome (APAS) has only been reported in eight cases. We present a case of a 46-year-old Filipina who developed ischaemic stroke while admitted at the neurocritical unit for myasthaenic crisis. She was successfully thrombolysed with intravenous recombinant tissue plasminogen activator (rTPA), given a regimen of intravenous Ig and a dose of cyclophosphamide prior to discharge. Extensive workup revealed APAS to be the aetiology of her stroke. Twenty-one months into her follow-up, she is doing well with a modified Rankin Score of 0. Our case suggests that rTPA followed by immunomodulators may be given safely in myasthaenic crisis patients who develop ischaemic stroke. We emphasise the importance of doing a comprehensive neurological evaluation in agitated patients in the critical care unit.