Gad-antibody Associated Temporal Lobe Epilepsy: T Cells Kill Neurons, and Plasma Cells and Antibodies Are Bystanders
Abstract number :
2.361
Submission category :
14. Neuropathology of Epilepsy
Year :
2022
Submission ID :
2204662
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Christian Bien, MD – Bielefeld University; Anna Tröscher, PhD – Kepler University Hospital Linz; Katharina Mair, MD – Medical University of Vienna; Laia Verdu de Juan, Mrs – Medical University of Vienna; Ulrike Köck, Mrs – Medical University of Vienna; Anja Steinmaurer, Mrs – Medical University of Vienna; Hartmut Baier, MD – Epilepsy Centre Bodensee; Albert Becker, PhD – University of Bonn; Ingmar Blümcke, PhD – Erlangen University; Martin Finzel, MD – Epilepsy Centre Kleinwachau; Christian Geis, PhD – Jena University Hospital; Romana Höftberger, PhD – Medical University of Vienna; Christian Mawrin, PhD – University of Magdeburg; Tim von Oertzen, MD – Kepler University Hospital Linz; Julika Pitsch, PhD – University of Bonn; Rainer Surges, PhD – University of Bonn; Berthold Voges, MD – Protestant Hospital Alsterdorf; Serge Weis, PhD – Kepler University Hospital Linz; Michael Winklehner, MD – Medical University of Vienna; Friedrich Woermann, MD – Bielefeld University; Jan Bauer, PhD – Medical University of Vienna
Rationale: GAD-antibody associated temporal lobe epilepsy is different from, e.g., temporal lobe seizures due to anti-LGI1 encephalitis. It is a chronic condition, and response to immunotherapy (and anti-seizure medication or epilepsy surgery) is mostly unsatisfying. A better understanding of the evolving pathophysiology may help to improve the timing of immunotherapy.
Methods: We retrospectively assessed MRI courses and CSF-serum pairs. We collected formalin-fixed paraffin-embedded mediotemporal brain samples of 15 patients and compared them to a control cohort (n=8) by performing histopathology and whole-genome transcriptomics.
Results: During early stages, patients showed mediotemporal volume and signal increase on MRI and intrathecal IgG- or GAD antibody-synthesis. Eleven patients developed MRI evidence of hippocampal sclerosis, three already within the first two years. In cases with a short disease duration, CD3+CD8+GranzymeB+ cytotoxic T-cells were elevated in the brain parenchyma. T cell numbers decreased with longer disease duration. Transcriptomics revealed upregulated T cell genes in patients with high T cell counts. In such cases, also B cell- and complement-associated pathways were overrepresented. This was paralleled by high numbers of plasma cells in the perivascular space of blood-vessels as well as in the parenchyma. These cases, however, showed no neural IgG deposition or complement activation. In cases with short disease duration, loss of hippocampal neurons and APP+ axonal bulbs indicated acute neural damage.
Conclusions: Early in the disease course, cytotoxic T cells damage neurons. Subsequently, plasma cells enter the brain but there are no signs of antibody-mediated pathology. This early encephalitic period can be recognized by MRI scans showing mediotemporal swelling with signal increase and CSF studies revealing intrathecal antibody synthesis. The early irreversible neural destruction may explain incomplete responses to delayed immunosuppressive therapy and calls for early immunotherapy before irreversible brain damage has ensued (i.e., within the first 1-2 years).
Funding: This project was financially supported by the Austrian Science Fund (project numbers P 26936-B27 to JB), P 34864-B, DOC 33-B27 to MW and RH, and I4685-B SYNABS to RH. ART was supported by a grant from the Alexander von Humboldt Foundation. CG was supported by the Schilling foundation and DFG: German Research Council GE 2519/8-1 and 11-1.
Neuropathology of Epilepsy