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Brain Health: Translating Scientific Evidence Into BRAIN HEALTH: TRANSLATING SCIENTIFIC EVIDENCE INTO CLINICAL PRACTICE IN MULTIPLE SCLEROSIS This satellite symposium took place on 29th May 2016, as part of the 2nd Congress of the European Academy of Neurology (EAN), Copenhagen, Denmark Chairperson Per Soelberg Sørensen1 Speakers Heinz Wiendl,2 Andreas Lysandropoulos,3 Andrew Chan4 1. Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark 2. Department of Neurology, University Hospital of Münster, Münster, Germany 3. Neuroimmunology Unit, Department of Neurology, University Hospital Erasme, Brussels, Belgium 4. Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany Disclosure: Prof Per Soelberg Sørensen has received personal compensation for serving on scientific advisory boards, steering committees, or independent data monitoring boards for Biogen, Merck Serono, Novartis, Genzyme, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, medDay Pharmaceuticals, and Forward Pharma and has received speaker honoraria from Biogen, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme, and Novartis. His department has received research support from Biogen Merck Serono, TEVA, Sanofi-Aventis/Genzyme, Novartis, Bayer, RoFAR, Roche, the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, and Genomics and Biotechnology for health. Prof Heinz Wiendl has received honoraria for lecturing and travel expenses for attending meetings from Bayer Healthcare, Biogen, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Sanofi Genzyme, and Teva Neuroscience, has received compensation for serving as a consultant for Biogen, Merck Serono, Novartis Pharma, and Sanofi Genzyme, and research support from Bayer Schering Pharma, Biogen, Elan Corporation, Merck Serono, Novartis, Novo Nordisk, and Sanofi Genzyme. Dr Andreas Lysandropoulos has received educational grants and honoraria as a speaker and member of advisory boards for Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and Teva. Prof Andrew Chan has received personal compensation (speakers honoraria and advisory board) from Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Roche, and Teva, and research support from Biogen, Sanofi Genzyme, and Novartis. Acknowledgements: Writing assistance was provided by Dr Joan Thomas of ApotheCom. Support: The symposium and publication of this article was sponsored by Sanofi Genzyme. Authors received honoraria for preparation and delivery of their presentations. The views and opinions expressed are those of the authors and not necessarily Sanofi Genzyme. Citation: EMJ Neurol. 2016;4[1]:36-44. MEETING SUMMARY Brain volume loss (BVL) progresses more rapidly in patients with multiple sclerosis (MS) than in healthy individuals, and brain atrophy begins early in the course of the disease. The objective of this symposium was to emphasise the importance of care and preservation of the brain within treatment protocols for MS so that early and appropriate management can be initiated to preserve brain volume and function. Prof Per Solberg Sørensen chaired the symposium and welcomed the speakers. Prof Heinz Wiendl gave a presentation on BVL in MS and described its underlying pathophysiology. Dr Andreas Lysandropoulos illustrated how information on BVL is clinically relevant and can be taken from clinical studies to assist clinical practice and decision-making. The final presentation was given by Prof Andrew Chan who highlighted the important role of brain atrophy in decision-making for early treatment and presented recent data for two treatments for MS: teriflunomide and the monoclonal antibody alemtuzumab. The symposium was concluded by a short question and answer session. 36 NEUROLOGY • July 2016 EMJ EUROPEAN MEDICAL JOURNAL NEUROLOGY • July 2016 EMJ EUROPEAN MEDICAL JOURNAL 37 Brain Volume Loss in Multiple Sclerosis: autoreactive antibodies via several well-defined Underlying Pathophysiology mechanisms including complement activation, phagocytosis by macrophages, and recruitment Professor Heinz Wiendl of autoreactive T cells.7,8 Remyelination is not uncommon in early lesions, although it fails in MS has traditionally been regarded as a white later stages of MS.9 Other mechanisms that matter disease and identifying lesions using may contribute to demyelination include the conventional magnetic resonance imaging (MRI) activities of cytotoxic CD8+ T lymphocytes and has become essential in the early diagnosis activated macrophages, hypoxia-like injury and management of the disease.1 More recently, leading to oligodendrocyte apoptosis, and grey matter disease has emerged as an important primary oligodendrocyte degeneration.8 As an component of MS and has been suggested to MS plaque progresses from acute to chronic, early correlate better with specific disability outcomes.1 inflammation and oedema resolve and astrocytes Healthy individuals lose between 0.1% and produce a glial scar.10 Gliosis may confound 0.3% of brain volume per year.2 BVL in people assessments of BVL in multiple ways including with MS, however, is typically 3-times this rate maintenance of volume in the event of axonal throughout the course of the disease.3 The rate injury9 and contraction of astrocyte volume as of grey matter volume loss increases with the the lesion matures.11 The volume of astrocytes is stage of the disease, from 3.4-fold in relapsing- reduced, which represents a physical and chemical remitting MS (RRMS) to 14-fold in secondary barrier to axon regeneration.12 Perhaps the progressive MS.3 most destructive mechanism of MS is axonal The application of different technologies can loss/neurodegeneration. Axonal loss has been be useful in identifying loss of white and grey demonstrated in both acute (new active) and matter. Cortical extrinsic curvature (CEC) is a chronic active (older reactivated) lesions in MS novel measure of white matter loss and is a more patients with disease duration from 2 weeks sensitive indicator of ‘pure’ white matter loss to 27 years.13 Axonal density is reduced up to than conventional MRI methods.4 Based on CEC 80% in chronic plaques.10 Axonal pathology measures, white matter atrophy appears to occur has been demonstrated in normal-appearing early in MS and may occur as early as clinically white matter as well as demyelinated lesions, isolated syndrome (CIS). An increase in CEC in indicating that factors other than inflammation patients with MS correlates significantly with loss can contribute to neurodegeneration.10,14 Potential of white matter integrity in the corpus callosum mechanisms include Wallerian degeneration as as assessed by fractional anisotropy, supporting well as retrograde and anterograde transneuronal the validity of CEC.4 There is increasing interest in degeneration.9,14 Different mechanisms contribute nuclear regions of the brain such as the thalamus, to this degeneration, including cytotoxic CD8+ which are affected early in the course of MS. T cells, which may directly destroy axons,14,15 A recent study evaluating early thalamic atrophy possibly via granule-mediated death. in patients with CIS and RRMS demonstrated Recent in vivo microscopy studies evaluating the that loss of relative thalamic volume correlated dynamics of neuronal reaction in response to significantly with disease duration.5 Patients with an inflammatory trigger demonstrate that acute RRMS and CIS with disease duration ≤24 months axonal transection is an early indicator of already had a reduced relative thalamic volume neurodegeneration in MS.15-17 Neuronal reactions versus healthy controls. The alterations in can occur in the absence of visible demyelination white matter in these patients could not be in which acute neuroinflammation induces a explained by the distribution of white matter pervasive state of reversible axonal dysfunction.16 lesions and it was concluded that early thalamic Ultrastructural axonal damage may occur with atrophy is mainly due to silent microstructural or without demyelination and may recover thalamic alterations.5 spontaneously.17 Transition from RRMS to secondary Pathological processes that underlie BVL include progressive MS occurs when the central nervous demyelination, gliosis, and axon loss. Focal loss of system (CNS) can no longer compensate for myelin tissue, particularly within overt white matter neuronal loss, resulting in progressive disability.15 lesions, is a contributing factor of brain atrophy.6 This important information demonstrates Demyelination is facilitated, at least in part, by that any type of inflammatory mechanism 36 NEUROLOGY • July 2016 EMJ EUROPEAN MEDICAL JOURNAL NEUROLOGY • July 2016 EMJ EUROPEAN MEDICAL JOURNAL 37 could eventually lead to neuronal dysfunction. Lost in Translation? Brain Atrophy from This has also been demonstrated in studies in Clinical Studies to Clinical Practice which it was shown that chronically demyelinated axons lacking Na+/K+ ATPase are incapable Doctor Andreas Lysandropoulos of nerve transmission.18 Thus, demyelination is one Evidence has shown that BVL is correlated with, possibility for axonal destruction or dysfunction and is predictive of, disability worsening in MS.21 but it is not the only one. Chronic CNS Popescu et al.21 showed that early BVL is strongly inflammation therefore involves several different correlated to clinical outcomes 10 years later. pathological mechanisms that lead to neuroaxonal Interestingly, in RRMS, the correlation is stronger damage by apoptosis and necrosis.
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