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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R E V I E W 16 Hot Topics in Multiple Sclerosis [March 2018] of teriflunomide on the MRI parameters of WM inflammation that suggests a possible direct effect of teriflunomide on gray matter atrophy. Dimethyl fumarate . Reductions in brain atrophy with dimethyl fumarate (DMF) in comparison to placebo did not reach statistical significance in the CONFIRM study, 103 while in the DEFINE study a relative reduction in the progression of brain atrophy from baseline to Year 2 (21% reduction; p=0.0449) and from Month 6 to Year 2 (30% reduction; p=0.0214) was observed and was statistically significant. 104 Recently, a retrospective analysis 105 in a small group of 20 patients with RRMS followed for up to one year, the DMF group showed a lower rate of whole brain atrophy compared to no-DMT group (PBVC: −0.37±0.49% vs. -1.04±0.67%, p=0.005). Although the DMF-treated group had less change in putamen volume (−0.06±0.22 vs. -0.32±0.28mL, p=0.02), no significant on-study differences between groups in caudate, globus pallidus, thalamus, total deep gray matter volume, T2 lesion volume, EDSS, or T25FW (all p >0.20) were demonstrated, probably because of the very low number of patients enrolled in the study. Fingolimod . In the two Phase III studies FREEDOMS and FREEDOMS II, 106,107 fingolimod was found to reduce the PBV loss in patients with RRMS by 36 percent (p <0.001) and 33 percent (p=0.0002), respectively. Whether this effect on PBV was mediated through the anti-inflammatory effects of the drug on WM focal inflammatory damage or was primarily a direct effect on the diffuse neurodegenerative damage, has been investigated in a post-hoc analysis in which patients with no evidence of focal disease activity from the two studies were pooled. 108 This analysis disclosed that fingolimod was able to significantly reduce PBV change by 65.5 percent over 12 months (fingolimod vs. placebo: −0.16 vs. −0.45; p=0.001) and by 48.2 percent over 24 months (−0.42 vs. -0.81; p=0.004). An absolute difference in PBV change of −0.27 percent (p <0.001) in favor of fingolimod versus placebo over 24 months was still evident in the pooled intention to treat (ITT) population, after adjusting for active lesions and on- study relapses. The regression model suggested that 54% (−0.27%/−0.51%) of the effect of fingolimod on PBV change was independent of its effects on visible focal WM damage. Thus, the effect of fingolimod on diffuse damage seems partly independent of its anti- inflammatory effect, suggesting that this drug positively affects both the inflammatory and the neurodegenerative components of MS. In a post hoc analysis of studies assessing fingolimod efficacy, brain volume loss was found to correlate with disease severity at baseline and disease activity during the course of the study. 109 This supports the concept that inflammatory activity, lesion load, and number of relapses contribute to atrophy, and that treatment of this activity has a beneficial effect on atrophy rates. Natalizumab . The controversial available data on the effects of natalizumab on brain atrophy can be primarily explained with the strong anti-inflammatory effect (i.e., marked pseudo-atrophy effect) of this monoclonal antibody and by the clinical and radiological features of the majority of the patients treated with this drug (i.e., patients with RRMS with very high disease activity, frequently coming from first-line treatment failure). Indeed, in a recent study on 62 patients with MS, 110 having a mean age of 34.7±8.3 and a mean disease duration of 10.4±6.6 years, the presence of gadolinium-enhancing lesions at baseline was associated with a strong pseudoatrophy effect. Indeed, the larger PBV decrease (p=0.005) were observed in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). On the contrary, the decrease in PBV in patients having no evidence of active brain inflammation was about one percent in the two years, a figure very close to that of normal subjects. Thus, baseline inflammation of patients with RRMS with very high disease activity strongly affects brain volume measures up to 24 months after natalizumab initiation. A marked pseudoatrophy effect of natalizumab therapy was confirmed in a 18-month study where the PBV of natalizumab-treated patients was found to dramatically decrease especially in the first 12 months of treatment. 111 In a recently published study aimed at investigating whether cerebrospinal fluid (CSF) markers of inflammation or neurodegeneration were associated with PBV change in natalizumab- treated MS and whether this change was reflected in non-lesional WM metabolites (analyzed by proton magnetic resonance spectroscopy, 1H–MRS), 25 natalizumab-treated patients with RRMS were followed for three years. The mean decline in PBV was three percent at the three-year follow-up, but mean 1H–MRS metabolite levels in non-lesional WM were unchanged. Interestingly, CSF levels of neurofilaments and tau at baseline correlated negatively with PBV change over three years (r= −0.564, p=0.012, and r= −0.592, p=0.010, respectively), suggesting their possible use for evaluating treatment response in MS. 112 In order to study the effect of natalizumab on GM atrophy avoiding the marked pseudo-atrophy effect of the drug on brain parenchymal volume, we analyzed the cortical thickness of patients with RRMS treated with natalizumab for up to four years. Thirty patients non- responsive to IFN, having had a mean annualized relapse rate of 1.5±1.0 (range 1–4) in the year prior to natalizumab initiation, evidence of disease activity at brain MRI and mean EDSS score of 3.0±1.6 were enrolled in the study. CTh was measured by Freesurfer on 3DT1 images obtained at study entry and then annually for four years. At the end of the study, natalizumab-treated patients had a mean loss of CTh of 2.09 ± 3.3 percent, corresponding to mean annual CTh loss of 0.5 percent, a higher value compared to age-matched normal controls, but significantly lower compared to untreated patients with MS. 100 Our finding are particularly interesting since they indicate

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