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      The immune system and metabolic products in epilepsy and glioma-associated epilepsy: emerging therapeutic directions

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          Abstract

          Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. Metabolic modulation of the IDH1-mutant pathway provides a dual pathway for reversing immune suppression and dampening seizure activity. Elucidating the relationship between neurons and immunoreactivity is an area for the prioritization and development of the next era of ASMs.

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          ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology

          Ingrid Scheffer, Samuel Berkovic, Giuseppe Capovilla … (2017)
          The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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            Synaptic pruning by microglia is necessary for normal brain development.

            Rosa Paolicelli, Giulia Bolasco, Francesca Pagani … (2011)
            Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
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              Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.

              Wei Xu, Hui Yang, Ying Liu … (2011)
              IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Shashwat Tripathi
                Cody L. Nathan
                Jessica W. Templer:
                ORCID: http://orcid.org/0000-0003-1850-8868
                Joshua M. Rosenow
                Timothy L. Sita
                Benjamin Deneen
                Stephen D. Miller:
                ORCID: http://orcid.org/0000-0002-9556-0718
                Amy B. Heimberger:
                ORCID: http://orcid.org/0000-0002-9970-8695
                Journal
                Journal ID (nlm-ta): JCI Insight
                Journal ID (iso-abbrev): JCI Insight
                Journal ID (publisher-id): JCI Insight
                Title: JCI Insight
                Publisher: American Society for Clinical Investigation
                ISSN (Electronic): 2379-3708
                Publication date (Electronic, pub): 9 January 2024
                Publication date (Electronic, collection): 9 January 2024
                Publication date PMC-release: 9 January 2024
                Volume: 9
                Issue: 1
                Electronic Location Identifier: e174753
                Affiliations
                [1 ]Department of Neurological Surgery,
                [2 ]Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center,
                [3 ]Department of Neurology,
                [4 ]Department of Pathology, and
                [5 ]Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
                [6 ]Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA.
                [7 ]Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
                Author notes
                Address correspondence to: Amy B. Heimberger, Northwestern University; SQ6-516; 303 E. Superior Street Chicago, Illinois 60611, USA. Phone: 312.503.3805; Email: Amy.heimberger@ 123456northwestern.edu .
                Author information
                http://orcid.org/0000-0003-1850-8868
                http://orcid.org/0000-0002-9556-0718
                http://orcid.org/0000-0002-9970-8695
                Article
                Publisher ID: 174753
                DOI: 10.1172/jci.insight.174753
                PMC ID: 10906461
                PubMed ID: 38193532
                SO-VID: 63813590-c2b1-47d3-a2f0-3b65eecc3b0a
                Copyright © © 2024 Tripathi et al.
                License:

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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