Pharmacological treatment of pain in multiple sclerosis (MS) is challenging due to the many underlying pathophysiological mechanisms. Few controlled trials show adequate pain control in this ...population. Emerging evidence suggests that pain might be more effectively classified and treated according to symptoms and underlying mechanisms. The new mechanism-based classification we propose here distinguishes nine types of MS-related pain: trigeminal neuralgia and Lhermitte’s phenomenon (paroxysmal neuropathic pain due to ectopic impulse generation along primary afferents), ongoing extremity pain (deafferentation pain secondary to lesion in the spino-thalamo-cortical pathways), painful tonic spasms and spasticity pain (mixed pains secondary to lesions in the central motor pathways but mediated by muscle nociceptors), pain associated with optic neuritis (nerve trunk pain originating from
nervi nervorum
), musculoskeletal pains (nociceptive pain arising from postural abnormalities secondary to motor disorders), migraine (nociceptive pain favored by predisposing factors or secondary to midbrain lesions), and treatment-induced pains. Identification of various types of MS-related pain will allow appropriate targeted pharmacological treatment and improve clinical practice.
Although pregnancy in women with multiple sclerosis (MS) is not generally considered high risk, there are some associated therapeutic challenges. The pregnancy‐associated reduction in the relapse ...rate, especially in the third trimester, is followed by a sharp increase in the first few months postpartum. Nevertheless, retrospective evidence for pregnant women with and without MS followed for up to 10 years indicates that pregnancy has no perceptible effect on long‐term disease course or disability progression. Likewise, MS has no apparent effects on the pregnancy course or fetal outcomes. All disease‐modifying therapies (DMTs) have potential adverse effects on fertility and pregnancy outcomes, but the level of risk varies amongst agents. There is some support for continued use of interferon‐β and glatiramer acetate throughout pregnancy to reduce the risk of relapse. Use of DMTs during breastfeeding is best avoided if possible. Close evaluation of drug safety information is imperative when managing women with MS who are pregnant or wish to become pregnant. Decision‐making should be a shared experience between patient and physician, and the approach must be individualized for each patient.
This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with ...relapsing-remitting multiple sclerosis (RRMS).
464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated.
The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥ 1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema.
Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RRMS is under consideration.
NCT01006265.
Background: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo‐controlled study of an oral antispasticity ...agent to use an enriched study design.
Methods: A 19‐week follow‐up, multicentre, double‐blind, randomized, placebo‐controlled, parallel‐group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add‐on therapy, in a single‐blind manner for 4 weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12‐week randomized, placebo‐controlled phase.
Results: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4 weeks of single‐blind treatment, and 241 were randomized. The primary end‐point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention‐to‐treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P = 0.0002). Secondary end‐points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols.
Conclusions: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.
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Background and purpose: To define the predictive value of clinical and magnetic resonance imaging (MRI) characteristics in identifying relapsing‐remitting multiple sclerosis (RR‐MS) patients with ...sustained disability progression during interferon beta (IFNB) treatment.
Methods: All patients receiving treatment with one of the available IFNB formulations for at least 1 year were included in this single‐centre, prospective and post‐marketing study. Demographic, clinical and MRI data were collected at IFNB start and at 1 year of therapy; patients were followed‐up at least yearly. Poor clinical response was defined as the occurrence of a sustained disability progression of ≥1 point in the Expanded Disability Status Scale (EDSS) during the follow‐up period.
Results: Out of 454 RR‐MS patients starting IFNB therapy, data coming from 394 patients with a mean follow‐up of 4.8 (2.4) years were analysed. Sixty patients were excluded because of too short follow‐up. Less than 1/3 (30.4%) of the patients satisfied the criterion of ‘poor responders’. Patients presenting new lesions on T2‐weighted MRI scan after 1 year of therapy (compared with baseline) had a higher risk of being poor responder to treatment with IFNB during the follow‐up period (HR 16.8, 95% CI 7.6–37.1, P < 0.001). An augmented risk increasing the number of lesions was observed, with a 10‐fold increase for each new lesion.
Conclusions: Developing new T2‐hyperintense lesions during IFNB treatment was the best predictor of long‐term poor response to therapy. MRI scans performed after 1 year of IFNB treatment may be useful in contributing to early identification of poor responders.
BACKGROUND AND PURPOSEConventional MR imaging explains only a fraction of the clinical outcome variance in multiple sclerosis. We aimed to evaluate machine learning models for disability prediction ...on the basis of radiomic, volumetric, and connectivity features derived from routine brain MR images. MATERIALS AND METHODSIn this retrospective cross-sectional study, 3T brain MR imaging studies of patients with multiple sclerosis, including 3D T1-weighted and T2-weighted FLAIR sequences, were selected from 2 institutions. T1-weighted images were processed to obtain volume, connectivity score (inferred from the T2 lesion location), and texture features for an atlas-based set of GM regions. The site 1 cohort was randomly split into training (n = 400) and test (n = 100) sets, while the site 2 cohort (n = 104) constituted the external test set. After feature selection of clinicodemographic and MR imaging-derived variables, different machine learning algorithms predicting disability as measured with the Expanded Disability Status Scale were trained and cross-validated on the training cohort and evaluated on the test sets. The effect of different algorithms on model performance was tested using the 1-way repeated-measures ANOVA. RESULTSThe selection procedure identified the 9 most informative variables, including age and secondary-progressive course and a subset of radiomic features extracted from the prefrontal cortex, subcortical GM, and cerebellum. The machine learning models predicted disability with high accuracy (r approaching 0.80) and excellent intra- and intersite generalizability (r ≥ 0.73). The machine learning algorithm had no relevant effect on the performance. CONCLUSIONSThe multidimensional analysis of brain MR images, including radiomic features and clinicodemographic data, is highly informative of the clinical status of patients with multiple sclerosis, representing a promising approach to bridge the gap between conventional imaging and disability.
Abstract There is evidence that gender influences the clinical course of Multiple Sclerosis (MS). Symptom prevalence as well as characteristics differs between the sexes. These differences can be, at ...least partly, explained by gender differences in the characteristics of tissue damage and disease progression measured by Magnetic Resonance Imaging (MRI). The interaction between sex hormones and MS damage, supported by both MRI and clinical evidence, seems to play an important role in the clinical and sub-clinical gender bias in MS. Experimental data testing directly the effects of sex hormones on brain damage and their clinical relevance show that sex hormones have the potential of exerting anti-inflammatory and protective effects on brain tissue. Both data in experimental models and patient studies discussed in this review encourages a gender-based approach to MS.
Background and objective:
To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural ...brain damage, as assessed by diffusion tensor imaging, and clinical impairments.
Methods:
Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons.
Results:
Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity.
Conclusions:
Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.
The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for ...many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.
We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.
A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).
Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.
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