GAD65+ Autoimmune Epilepsy Shows Evidence for Hippocampal Hyperexcitability and Inflammation: A Case Study Using HD Spatial Transcriptomics by 10X Genomics
Mary Benson1, Ken Jones1, Angus Toland2, Amanda Piquet1, Samuel Guzman1
1University of Colorado, 2Children's Hospital Colorado
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
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