MRI-based analysis of the natalizumab therapeutic window in multiple sclerosis.

The recommended natalizumab dosage is 300 mg every 4 weeks. We evaluated radiological activity at various times from the last natalizumab infusion by examining 386 magnetic resonance imaging (MRI) scans from 166 natalizumab-treated patients with relapsing-remitting MS. Of 113 scans performed >4 weeks after last natalizumab infusion, 26 were active (i.e. had ≥1 contrast-enhancing lesions). Risk of radiological activity increased by 1.34 fold for each week of delay with respect to the recommended 4-week dosing interval, compared with schedule-adherent patients (p<0.0001). Our data suggest that an increased MRI activity ≥7 weeks from the last infusion of natalizumab should be considered in cases of therapy discontinuation.

Observations during an elective interruption of natalizumab treatment: a post-marketing study.

In this prospective post-marketing study, 21 patients with multiple sclerosis treated with natalizumab for 24 consecutive months elected a trial of treatment interruption (90-180 days). During a mean duration of treatment interruption of 111.5 days 4 patients (19.0%) experienced a relapse and 9 out of 19 (47.4%) had MRI activity. Number of contrast-enhancing lesions at baseline was lower than during treatment interruption, but the difference was not significant. These findings suggest that disease activity may return after the last infusion of natalizumab. Patients should have regular MRI assessment during treatment interruption to rapidly identify any return of disease activity. The aim of this study was to determine the optimal duration for temporary interruption of natalizumab therapy in patients who have received continuous therapy with natalizumab for 24 months.

Advances in preventing adverse events during monoclonal antibody management of multiple sclerosis.

INTRODUCTION: Decades of pharmacological research in Multiple Sclerosis (MS) led to the development of therapeutic Monoclonal Antibodies (MAbs) with many different mechanisms of action (MoA), potentially able to improve disability outcome but also determining a more complex management of patients. Areas covered: When clinicians select MS treatments, they should consider adverse events (AEs) on individual basis to minimize patients' risks. Some AEs are common and can be easily handled, but rare complications should also be taken into account. The aim of this review is to summarize existing evidence and provide practical recommendations for the management of therapeutic MAbs in MS. Expert opinion: The introduction of MAbs revolutionized MS treatment with an improvement in effectiveness. Unfortunately, this has been coupled with a more complex array of AEs needing a tighter surveillance strategy. A close interaction between general practitioners, neurologists, and other specialists is the key for a safer use of such effective drugs.

Tp-Te interval predicts heart rate reduction after fingolimod administration in patients with multiple sclerosis.

BACKGROUND: FTY720 (Fingolimod) is an immunosuppressive drug, which provides favourable effects in patients with multiple sclerosis (MS), albeit it induces heart rate (HR) and blood pressure (BP) reductions. Therefore, we tested potential factors able to predict HR response in MS patients treated with fingolimod. METHODS: We analysed patients with MS followed at our Neurology Outpatient Clinic from May 2013 to June 2015. All patients underwent BP measurements and 12-lead ECG before and 6-h after drug administration. At these time intervals, conventional and new ECG indexes for cardiac damage, including Tp-Te interval, were measured. Univariate and multivariate analyses were performed to test the outcome of HR reduction more than median difference between baseline and final observations. RESULTS: 69 outpatients with MS (46 males, age 35.1±9.4years, BP 119.0±12.7/73.0±9.3mmHg, HR 73.5±11.4bpm) were included. No relevant adverse reactions were reported. Fingolimod induced progressive systolic (P=0.024) and diastolic (P<0.001) BP, as well as HR (P<0.001) reductions compared to baseline. Prolonged PQ (150.4±19.5 vs. 157.0±19.5ms; P<0.001), QT (374.9±27.0 vs. 400.0±25.8ms; P<0.001), Tp-Te (1.8±0.3 vs. 1.9±0.3mm; P=0.021), and reduced QTc (414.4±24.4 vs. 404.5±24.5ms; P<0.001) intervals were also recorded at final observation. Baseline HR, QT and Tp-Te intervals provided prognostic information at univariate analysis, although Tp-Te interval resulted the best independent predictor for HR reduction at multivariate analysis [0.057 (0.005-0.660); P=0.022]. CONCLUSIONS: This study firstly demonstrates that prolonged Tp-Te interval may identify those MS patients treated with fingolimod at higher risk of having significant, asymptomatic HR reduction during clinical observation.

Predictors of freedom from disease activity in natalizumab treated-patients with multiple sclerosis.

PURPOSE: To identify baseline predictors of the response to natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We prospectively collected clinical and magnetic resonance imaging (MRI) data of RRMS patients treated with natalizumab and followed-up for 24 months. They were categorized according to different outcomes of response to natalizumab: (i) "full" responders, i.e. those having no relapses, no sustained disability worsening on Expanded Disability Status Scale (EDSS), and no MRI activity; (ii) "partial" responders, i.e. those having MRI activity, but not relapses and/or EDSS worsening; and (iii) "poor" responder, i.e. those experiencing relapses and/or EDSS worsening. RESULTS: We analysed data of 210 RR-MS patients (147 F, 63 M); at the end of the 24-month study period, 120 (57.1%), 36 (17.1%), and 54 (25.8%) patients were defined as "full", "partial" or "poor" responders, respectively. Thirty-two (89%) patients classified as "partial" responders experienced MRI activity at the 6-month scan; the majority of them had >2 contrast-enhancing lesions at baseline MRI scan or >2 relapses in the year prior to starting therapy. A "full" response to natalizumab was found more likely in patients with ≤ 2 relapses in the year prior to treatment start (OR=3.68; p=0.002), and in those with an EDSS score ≤ 2.5 at baseline (OR=3.60; p<0.001). Accordingly, patients with >2 relapses in the year prior to treatment start, or those with an EDSS score ≥ 3.0 at baseline were more likely to be classified as "poor responders". These figures were replicated even after excluding 20 patients who developed anti-natalizumab antibodies. CONCLUSION: Our results suggest that natalizumab may lead to a complete remission of MS if started in patients with less aggressive disease (i.e. few relapses and mild disability), thus suggesting its possible role as first switching option, or even first-line therapy, at least in JCV-negative patients. We also support the recommendation against an immediate discontinuation of despite the occurrence of MRI activity in the first few months of treatment, since the freedom from clinical disease activity could be still achieved.

Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: a functional and anatomical study.

Functional MRI (fMRI) studies have shown increased activation of ipsilateral motor areas during hand movement in patients with multiple sclerosis (MS). We hypothesized that these changes could be due to disruption of transcallosal inhibitory pathways. We studied 18 patients with relapsing-remitting MS. Conventional T1- and T2-weighted images were acquired and lesion load (LL) measured. Diffusion tensor imaging (DTI) was performed to estimate fractional anisotropy (FA) and mean diffusivity (MD) in the body of the corpus callosum (CC). fMRI was obtained during a right-hand motor task. Patients were studied to evaluate transcallosal inhibition (TCI, latency and duration) and central conduction time (CCT). Eighteen normal subjects were studied with the same techniques. Patients showed increased MD (P < 0.0005) and reduced FA (P < 0.0005) in the body of the CC. Mean latency and duration of TCI were altered in 12 patients and absent in the others. Between-group analysis showed greater activation in patients in bilateral premotor, primary motor (M1), and middle cingulate cortices and in the ipsilateral supplementary motor area, insula, and thalamus. A multivariate analysis between activation patterns, structural MRI, and neurophysiological findings demonstrated positive correlations between T1-LL, MD in the body of CC, and activation of the ipsilateral motor cortex (iM1) in patients. Duration of TCI was negatively correlated with activation in the iM1. Our data suggest that functional changes in iM1 in patients with MS during a motor task partially represents a consequence of loss of transcallosal inhibitory fibers.