Abstract Details

Title GAD65+ Autoimmune Epilepsy Shows Evidence for Hippocampal Hyperexcitability and Inflammation: A Case Study Using HD Spatial Transcriptomics by 10X Genomics

Topic Autoimmune Neurology

Presentation(s) P2 - Poster Session 2 (8:00 AM-9:00 AM)

Poster/Presentation
Number 8-015

Objective To investigate the pathological mechanisms underlying GAD65+ autoimmune epilepsy in a patient with refractory epilepsy, specifically focusing on observed neuronal hyperexcitability in the hippocampus through the use of novel HD Visium technology.

Background GAD65 autoimmune epilepsy is a rare, antibody-mediated condition that causes refractory seizures. Current therapies, including immunotherapy and antiseizure medications, have limited efficacy. In this case, a 21-year-old woman with refractory seizures underwent right temporal lobectomy for seizure control. However, she was later found to have GAD65+ autoimmune epilepsy and developed recurrent epilepsy shortly after resection.

Design/Methods

Neuropathologic evaluation of the hippocampus included histologic examination and standard validated immunohistochemistry (IHC) protocols. Stains of interest included GFAP, NeuN, CD68 and CD163. Spatial transcriptomics was performed by the HD Visium platform, profiling gene expression across various regions of the hippocampus.

Results

Analysis of the hippocampus revealed severe loss of pyramidal neurons in CA1 and CA4, granular neuron dispersion, and loss in the dentate gyrus by H&E. Increased inflammation around neurons and heavy reactive gliosis, supported by GFAP staining, was observed. NeuN staining supports loss of neurons in CA1 and CA4. Axonal swellings are identified in CA4 and CA1 in response to neuron loss, highlighted by neurofilament staining. Scattered microglial cells are identified throughout the hippocampus by CD68 and CD163 staining. These results indicate significant inhibition of GABA and significant glutamate overexpression. Dysregulated gene networks demonstrated significant excitotoxic effects, with oxidative stress and activation of cellular stress responses. These altered pathways affected several Gene Ontology pathways that may contribute to clinical phenotype.

Conclusions This case highlights the role of GAD65 autoantibodies in disrupting GABAergic signaling, promoting neuronal hyperactivity and inflammation within the hippocampus. The use of HD Visium allowed for detailed spatial gene expression profiling, which underscores the importance of understanding the molecular underpinnings of autoimmune epilepsy and may inform the development of targeted therapies

Authors/Disclosures
Samuel Aragon, BS (University of Colorado Anschutz Medical Campus) PRESENTER	Mr. Aragon has nothing to disclose.
Mary N. Gallanis, MD	Dr. Gallanis has nothing to disclose.
Ken Jones, PhD	Dr. Jones has stock in Bioinformatic Solutions, LLC. An immediate family member of Dr. Jones has stock in Bioinformatic Solutions. The institution of Dr. Jones has received research support from NIH.
Angus Toland, MD	Dr. Toland has received intellectual property interests from a discovery or technology relating to health care.
Amanda L. Piquet, MD, FAAN (University of Colorado)	The institution of Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech/Roche. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Kyverna . The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech/Roche. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kyverna. The institution of Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Sands Anderson PC. Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Joe Jones Law Firm. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cortez & Associates. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Falk Waas. The institution of Dr. Piquet has received research support from Rocky Mountain MS Center. The institution of Dr. Piquet has received research support from Roche/Genentech. The institution of Dr. Piquet has received research support from NYU. The institution of Dr. Piquet has received research support from Anokion. The institution of Dr. Piquet has received research support from UCB . The institution of Dr. Piquet has received research support from Foundation for Sarcoidosis. The institution of Dr. Piquet has received research support from Kyverna . Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Litigative Consultant with US-Dept HHS/DICP. Dr. Piquet has a non-compensated relationship as a Medical Advisory Board Member with Autoimmune Encephalitis Alliance (AEA) that is relevant to AAN interests or activities. Dr. Piquet has a non-compensated relationship as a Medical Advisory Board Member with Stiff Person Syndrome Research Foundation (SPSRF) that is relevant to AAN interests or activities.
Samuel Guzman	Samuel Guzman has nothing to disclose.

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