Group leader: Inflammatory Mechanisms of epileptogenic Neurodegeneration
Moorenstrasse 5 40225 Düsseldorf
According to the World Health Organization (WHO), epilepsy is one of the major serious neurological disorders with regard to lifetime, disability, mortality and life years lost. Epilepsy is frequently associated with cognitive and psychobehavioral comorbidities, and a decrease in quality of life, social and economic participation. Currently, approximately 70 million people worldwide have epilepsy, and about 1/3 of patients – mostly with focal epilepsy – have inadequate seizure control with anti-seizure medication (ASM) (pharmacoresistant epilepsy). Today, such patients can only be treated by epilepsy surgery. The most frequent causes of pharmacoresistant focal epilepsy treated by epilepsy surgery include congenital, static malformations of cortical development (MCD, including focal cortical dysplasia type I-III), acquired low-grade epilepsy associated tumors (LEAT) and hippocampal sclerosis (HS).
A shift of the excitatory-inhibitory (EI) balance towards cortical hyperexcitability (HE) is the hallmark of epilepsy. Not only the cardinal symptom - the epileptic seizure - but also interictal epilepsy-characteristic EEG discharges (IED) are based on massive synchronized discharges of neurons organized in cerebral networks. Our understanding of underlying mechanisms and consequences of HE in epilepsy is incomplete. While the neuronal mechanisms of epileptic HE have been studied extensively, recent findings suggest that extra-neuronal mainly inflammatory, immune and vascular mechanisms play a major contributing role for development and progression of HE in epilepsy and its cognitive and psychobehavioral comorbidities.
On the one hand, autoimmune encephalitis (AIE) i.e. primary adaptive and innate immune responses and associated alterations of the blood-brain-barrier (BBB) and neurovascular unit may by itself cause acute HE and precede, precipitate and propagate the development of HS and other cortical scars with chronic HE. On the other hand, HE associated with MCD and LEAT may be accompanied by secondary adaptive and innate immune responses and alterations of the BBB and neurovascular unit thereby potentially modulating their epileptogenicity and sometimes also lead to HS and other cortical scars (“dual pathology”). These findings highlight the impact of adaptive and innate immune mechanisms and associated alterations of BBB and the neuro-vascular unit on cortical excitability and vice versa, suggesting a dynamic complex interplay between these factors in epileptogenesis in general.
Cognitive comorbidity, which is highly relevant for patients´ quality of life, can result from the formation of HS (memory dysfunction) and other cortical scars but also from the perturbation of physiological neuronal network activity by propagation of interictal and ictal activity.
- Performs experimental, translational and clinical research on the interaction of immunity, neurovascular function and cortical excitability as major determinants of epileptogenesis and neurodegeneration.
- Is a founding member of the GErman NEtwork for REsearch on AuToimmune Encephalitis – GENERATE funded by the Federal Ministry of Education and Research (BMBF) as well as the Germany Society of Epileptology (DGfE) and the Epilepsy Surgery Working-Group. We are centrally involved in planning and conducting national and international clinical studies and guidelines on these topics.
- Runs the academic outpatient clinic on Autoimmune Encephalitis and Epilepsy and provide clinical service on specialized inpatient clinics at the Department of Neurology of the Heinrich Heine University Düsseldorf.
- Gallus M, Roll W, Dik A, Barca C, Zinnhardt B, Hicking G, Mueller C, Naik VN, Anstotz M, Kramer J, Rolfes L, Wachsmuth L, Pitsch J, van Loo KMJ, Räuber S, Okada H, Wimberley C, Strippel C, Golombeck KS, Johnen A, Kovac S, Gross CC, Backhaus P, Seifert R, Lewerenz J, Surges R, Elger CE, Wiendl H, Ruck T, Becker AJ, Faber C, Jacobs AH, Bauer J, Meuth SG, Schafers M, Melzer N (2023) Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis. Sci Adv 2023 Jun 9;9(23):eabq7595.doi: 10.1126/sciadv.abq7595. Epub 2023 Jun 9. PubMed
- Räuber S, Schroeter CB, Strippel C, Nelke C, Ruland T, Dik A, Golombeck KS, Regner-Nelke L, Paunovic M, Esser D, Munch C, Rosenow F, van Duijn M, Henes A, Ruck T, Amit I, Leypoldt F, Titulaer MJ, Wiendl H, Meuth SG, Meyer Zu Horste G, Melzer N (2023) Cerebrospinal fluid proteomics indicates immune dysregulation and neuronal dysfunction in antibody associated autoimmune encephalitis. J Autoimmun 2023 Feb;135:102985.doi: 10.1016/j.jaut.2022.102985. Epub 2023 Jan 6. PubMed
- Strippel C, Herrera-Rivero M, Wendorff M, Tietz AK, Degenhardt F, Witten A, Schroeter C, Nelke C, Golombeck KS, Madlener M, Ruber T, Ernst L, Racz A, Baumgartner T, Widman G, Doppler K, Thaler F, Siebenbrodt K, Dik A, Kerin C, Räuber S, Gallus M, Kovac S, Grauer OM, Grimm A, Pruss H, Wickel J, Geis C, Lewerenz J, Goebels N, Ringelstein M, Menge T, Tackenberg B, Kellinghaus C, Bien CG, Kraft A, Zettl U, Ismail FS, Ayzenberg I, Urbanek C, Suhs KW, Tauber SC, Mues S, Kortvelyessy P, Markewitz R, Paliantonis A, Elger CE, Surges R, Sommer C, Kumpfel T, Gross CC, Lerche H, Wellmer J, Quesada CM, Then Bergh F, Wandinger KP, Becker AJ, Kunz WS, Meyer Zu Horste G, Malter MP, Rosenow F, Wiendl H, Kuhlenbaumer G, Leypoldt F, Lieb W, Franke A, Meuth SG, Stoll M, Melzer N, German Network for Research on Autoimmune E (2023) A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies. Brain 2023 Mar 1;146(3):977-990.doi: 10.1093/brain/awac119. PubMed
- Räuber S, Heming M, Repple J, Ruland T, Kuelby R, Schulte-Mecklenbeck A, Gross CC, Arolt V, Baune B, Hahn T, Dannlowski U, Meuth SG, Melzer N, Wiendl H, Meyer Zu Horste G (2021) Cerebrospinal fluid flow cytometry distinguishes psychosis spectrum disorders from differential diagnoses. Mol Psychiatry 2021 Dec;26(12):7661-7670.doi: 10.1038/s41380-021-01244-5. Epub 2021 Aug 6. PubMed
- Gross CC, Schulte-Mecklenbeck A, Madireddy L, Pawlitzki M, Strippel C, Räuber S, Kramer J, Rolfes L, Ruck T, Beuker C, Schmidt-Pogoda A, Lohmann L, Schneider-Hohendorf T, Hahn T, Schwab N, Minnerup J, Melzer N, Klotz L, Meuth SG, Meyer Zu Horste G, Baranzini SE, Wiendl H (2021) Classification of neurological diseases using multi-dimensional CSF analysis. Brain 2021 Oct 22;144(9):2625-2634.doi: 10.1093/brain/awab147. PubMed
- Pitsch J, van Loo KMJ, Gallus M, Dik A, Kamalizade D, Baumgart AK, Gnatkovsky V, Muller JA, Opitz T, Hicking G, Naik VN, Wachsmuth L, Faber C, Surges R, Kurts C, Schoch S, Melzer N, Becker AJ (2021) CD8(+) T-Lymphocyte-Driven Limbic Encephalitis Results in Temporal Lobe Epilepsy. Ann Neurol 2021 Apr;89(4):666-685.doi: 10.1002/ana.26000. Epub 2021 Jan 15. PubMed
- Brandle SM, Cerina M, Weber S, Held K, Menke AF, Alcala C, Gebert D, Herrmann AM, Pellkofer H, Gerdes LA, Bittner S, Leypoldt F, Teegen B, Komorowski L, Kumpfel T, Hohlfeld R, Meuth SG, Casanova B, Melzer N, Beltran E, Dornmair K (2021) Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABAA receptor encephalitis. Proc Natl Acad Sci U S A 2021 Mar 2;118(9):e1916337118.doi: 10.1073/pnas.1916337118. PubMed
- Gerwien H, Hermann S, Zhang X, Korpos E, Song J, Kopka K, Faust A, Wenning C, Gross CC, Honold L, Melzer N, Opdenakker G, Wiendl H, Schafers M, Sorokin L (2016) Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier. Sci Transl Med 2016 Nov 9;8(364):364ra152.doi: 10.1126/scitranslmed.aaf8020. PubMed
- Schneider-Hohendorf T, Mohan H, Bien CG, Breuer J, Becker A, Gorlich D, Kuhlmann T, Widman G, Herich S, Elpers C, Melzer N, Dornmair K, Kurlemann G, Wiendl H, Schwab N (2016) CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing. Nat Commun 2016 Apr 4;7:11153.doi: 10.1038/ncomms11153. PubMed
- Melzer N, Torres-Salazar D, Fahlke C (2005) A dynamic switch between inhibitory and excitatory currents in a neuronal glutamate transporter. Proc Natl Acad Sci U S A 2005 Dec 27;102(52):19214-8.doi: 10.1073/pnas.0508837103. Epub 2005 Dec 19. PubMed