Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis MAR 2018

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

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13 Hot Topics in Multiple Sclerosis [March 2018] R E V I E W BACKGROUND The average rate of brain volume loss per year is significantly higher in patients with multiple sclerosis (MS) (range 0.5– 1.3%, median 0.7–0.8%) than in healthy gender- and age-matched controls (range 0.1–0.3%, median 0.2%) 1–4 and it's currently accepted that brain volume decline in MS mainly reflects gray matter (GM) atrophy rather than white matter (WM) loss. Indeed, while WM volume shows a mild reduction during the course of disease, GM volume significantly and progressively decreases. 5–13 Recently, a parenchymal loss of at least 0.4 percent per year was proposed as "pathological atrophy rate" in patients with MS. 14 GM atrophy, especially cortical atrophy, can be demonstrated early in patients with clinically isolated syndrome suggestive of MS (CIS) and rapidly progresses during the relapsing remitting MS (RRMS) disease course, becoming particularly evident in the frontal, temporal, and parietal lobes, 5,7,10,11,15–19 although it's in different degrees and with significant regional variation among patients. 19–24 Moreover, deep GM nuclei are a site of relevant atrophy as well, i.e., compared to matched healthy subjects, up to 25 percent loss of the thalamus volume has been demonstrated in RRMS. 24–28 GM atrophy becomes more widespread and severe in secondary progressive MS (SPMS) and primary progressive MS (PPMS) 29–37 and, in some patients, might undertake a dramatic acceleration, i.e., up to 14-fold compared to age-matched healthy individuals. 16,36 Although PPMS and SPMS show similar extent of total GM atrophy, different regional atrophy distribution was described in these two types of MS, 34–37 and some correlations between regional WM lesion load and GM atrophy were more often observed in SPMS compared to PPMS, a finding somehow expected given the differences in the WM lesion load that characterize these two MS types. On the other hand, a very weak relationship between WM pathology and GM atrophy is generally found in patients with progressive forms of MS, 38 a finding that might be explained with the different rates of evolution of inflammation and neurodegeneration in the more advanced phases of the disease. All the data above summarized strongly A B S T R A C T Progressive brain atrophy is a major feature of multiple sclerosis (MS) pathology and is actually considered a major determinant of the progressive accumulation of physical and cognitive disability in patients with MS. Although brain atrophy might have different pathological substrates, several lines of evidence suggest that in disease modifying drug (DMD)-treated patients with MS, the higher the anti-inflammatory effect of the DMD, the lower the progression of brain volume loss, gray matter atrophy, and accumulation of disability. Magnetic resonance imaging (MRI)-based measurements of inflammation (focal white matter and gray matter lesions) and neurodegeneration (decrease in brain volume, cortical and deep gray matter atrophy) are currently included among the primary or secondary endpoints of Phase II and III randomized clinical trials (RCT). This review summarizes literature data on the effects of DMDs on either whole brain or gray matter atrophy emerged from RCT and from post-marketing studies. Taken all together, literature data show that DMDs are able to reduce brain inflammation significantly and, although with different degrees of effectiveness, to slow down global brain and/or gray matter atrophy progression. Moreover, the comparison between early and delayed treatments clearly points out that the most relevant effects on brain and gray matter atrophy are observed when DMDs are initiated in the very early disease phases. KEYWORDS: Multiple sclerosis (MS), brain atrophy, gray matter atrophy, disease-modifying drugs (DMD), magnetic resonance imaging (MRI) Effects of Disease Modifying Therapies on Brain and Gray Matter Atrophy in Relapsing Remitting Multiple Sclerosis by ALICE FAVARETTO, ANDREA LAZZAROTTO, MONICA MARGONI, DAVIDE POGGIALI, and PAOLO GALLO Dr. Favaretto, Ms. Lazzarotto, Ms. Margoni, Mr. Poggiali, and Mr. Gallo are with the Multiple Sclerosis Centre, Department of Neurosciences, DNS, University Hospital of Padua in Padova, Italy. Multiple Sclerosis and Demyelinating Disorders. 2018;3:1 FUNDING: No funding was provided. DISCLOSURES: During the past three years, Professor P. Gallo has had a financial relationship (lecturer, member of advisory boards and/or consultant or investigator) with Biogen Italy, TEVA, Merck-Serono, Novartis Farma, Sanofi-Genzyme, Roche, and Almirall. Dr. A. Favaretto has received funding for travel and speaker honoraria in the last three years from Teva, Novar- tis, Biogen Italy, and Genzyme. A. Lazzarotto, M. Margoni, and D. Poggiali have nothing to disclose. CORRESPONDENCE: Paolo Gallo, Email:

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