Year: 2021
Type: dissertation
Study design: Observational Study
Abstract: The neuromyelitis optica spectrum comprises chronic inflammatory disorders of the central nervous system (CNS). In 55 % of the patients, optic neuritis is the primary clinical manifestation. Longitudinally extensive transverse myelitis (LETM) including three or more vertebral segments and brainstem syndromes are other important hallmarks of neuromyelitis optica spectrum disorders (NMOSD). The NMOSD-specific antibody targets aquaporin-4 (AQP4-IgG), an astrocytic water channel, and can be detected in serum of up to 80 % of the patients. It has been proposed that accumulation of irreversible disability in AQP4-IgG seropositive NMOSD occurs exclusively in response to attacks. Nevertheless, recent data from animal experiments and human autopsy studies also suggest attack-independent changes, possibly mediated by astrocytic degeneration, in AQP4-IgG seropositive NMOSD. In a subset of AQP4-IgG seronegative patients, myelin-oligodendrocyte-glycoprotein-antibodies (MOG-IgG) can be detected. It is still under debate whether MOG-IgG seropositive disease is part of the NMO-spectrum or rather a separate disease entity. The aim of this work was to evaluate and to quantify attack-independent alterations of the afferent visual system in AQP4-IgG seropositive NMOSD and to characterize different retinal disease patterns in AQP4-IgG and MOG-IgG seropositive patients. Therefore, modern imaging techniques, such as optical coherence tomography and diffusion weighted imaging based probabilistic tractography were applied. First, these methods were established and evaluated for investigations in the afferent visual system. Second, by utilizing the established methods, microstructural attack-independent changes in the afferent visual system of AQP4-IgG seropositive NMOSD patients were investigated cross-sectionally as well as longitudinally. Key findings were an attack-independent thinning of the fovea and microstructural changes of the optic radiation as well as a longitudinal ganglion cell layer thinning as a potential marker of neuro-axonal damage in comparison to healthy controls. The localization and extent of these changes suggested a widespread astrocytopathy of the CNS with subsequent neuro-axonal degeneration. Lastly, a similar retinal neurodegeneration after optic neuritis but no longitudinal ganglion cell loss was found in MOG-IgG seropositive patients. The results reported in this thesis challenge the paradigm of pure attack-dependent tissue damage in AQP4-IgG NMOSD and favor the notion that AQP4-IgG and MOG-IgG disorders may represent distinct disease entities. These findings demand - if further substantiated - an adaption of therapeutic strategies, which are at the moment very similar between both patient groups and usually solely based on attack frequency. The functional and diagnostic relevance of the reported findings as well as their translatability to other functional systems of the CNS still needs to be elucidated.
Author: Oertel, Frederike Cosima
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Sanofi, Biogen, Teva Pharmaceutical Industries, Alexion Pharmaceuticals, Guthy-Jackson Charitable Foundation, European Committee for Treatment and Research in Multiple Sclerosis, Arthur Arnstein Stiftung, Multiple Sclerosis Society, Bayer HealthCare, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Austrian Science Fund, Bundesministerium für Wirtschaft und Technologie, Fondation pour la Recherche Médicale, Bundesministerium für Wissenschaft, Forschung und Wirtschaft, Technische Universität München, Dietmar Hopp Stiftung, Friedrich-Baur-Stiftung, Sydney Eye Hospital Foundation, Berlin Institute of Health, Novartis Pharma, Chugai Pharmaceutical, Sanofi Genzyme, Bayer Vital
Awards: G1067930796, G7912391034
OpenAlex ID: W3134026065