Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis DEC 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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14 Hot Topics in Multiple Sclerosis [December 2017] R E V I E W INTRODUC TION Since first described by Charcot almost two centuries ago, 1 the field of multiple sclerosis (MS) witnessed enormous advancements. Not only do we know more about the pathophysiology of the disease but also the different risk factors, clinical subtypes, and how attenuate the pathophysiological processes are that lead to neuronal demise. The success cannot be seen better than in the field of relapsing remitting multiple sclerosis (RRMS), where more than six medications got approved by the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) since 2010. 2 However, primary progressive multiple sclerosis (PPMS) remains a considerable challenge. Despite having more than one study fulfilling its primary endpoint 3,4 at the time of this article, we still do not have any approved medication. Nevertheless, the recent focus on progressive MS forms (PPMS and SPMS) leads to a deep insight in the different pathological aspects driving the disease. In this article, we summarize the recent developments and integrate the different aspects to provide a framework that explains the sequence of events leading to the clinical picture. PATHOPHYSIOLOGY OF MS Genetic factors. The genetic p redisposition for MS is based on observations highlighting the role of maternal genes and epigenetic factors. 5 Half siblings from the same mother and first-degree relatives have a higher MS incidence. 6 HLA-DR2 haplotype demonstrated association and linkage to MS. 7 HLA-DRB1*15:01 allele is associated with lower age of onset, white matter lesions (WMLs) volume, and reduction of parenchymal volume in RRMS. 8 Lack of difference in HLA-status between RRMS and PPMS patients suggests that DRB1- related mechanisms are contributing to both phenotypes. 7 Furthermore, many loci variants outside MHC have been correlated to MS risk and involve pathways of like kappa-light-chain- enhancer's of activated B-cells (NF- KappaB) mediated cytokine release and activation of immune cells both in the periphery and inside the central nervous system (CNS). 9,10 Different loci variants might correlate with relapse rate 11 and A B S T R A C T The focus of multiple sclerosis (MS) research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors, such as genetic susceptibility, age, and Epstein–Barr virus (EBV) infection, might interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter, as well as of the meninges, with inflammatory cells, such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis (RRMS) basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a Phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies might be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future. KEYWORDS: Primary progressive multiple sclerosis, pathophysiology, treatment, Epstein–Barr virus, risk factors Primary Progressive Multiple Sclerosis: Putting Together the Puzzle by AHMED ABDELHAK, MARTIN S. WEBER, and HAYRETTIN TUMANI Mr. Abdelhak is with the Department of Neurology at Ulm University in Ulm, Germany. Mr. Weber is with the Department of Neuropathology and Department of Neurology, University Medical Center, at Georg August University in Gottingen, Germany. Mr. Tumani is with the Department of Neurology at Ulm University in Ulm, Germany, and the Specialty Clinic of Neurology Dietenbronn in Schwendi, Germany. Front Neurol. 2017;8:234 FUNDING: No funding was provided. DISCLOSURES: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors, HT, and states that the process nevertheless met the standards of a fair and objective review. CORRESPONDENCE: Ahmed Abdelhak, Email: ed.mlu-inu@kahledba.demha

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