This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available diseasemodifying treatments and this will be a major focus for future development.KEYWORDS : Diagnostic criteria , epidemiology , multiple sclerosis , progressive multiple sclerosis , treatments What is multiple sclerosis?Multiple sclerosis (MS) is an acquired disabling neurological disease of young adults, affecting approximately 2.3 million people worldwide. It is most prevalent in North America (140 cases per 100,000) and Europe (108 cases per 100,000); the prevalence is lowest in sub-Saharan Africa (2.1 cases per 100,000) and East Asia (2.2 cases per 100,000).1 Overall, there are approximately 120,000 people with MS in the UK. 2MS is an inflammatory disease of the central nervous system (CNS), which causes a heterogeneous array of symptoms and signs because of differential involvement of motor, sensory, visual and autonomic systems. Optic neuritis (inflammation of the optic nerve), Uhthoff's phenomenon (transient fluctuation or worsening of MS symptoms with a rise in body temperature) and Lhermitte's phenomenon (an abnormal electric-shock like sensation down the spine or limbs on neck flexion) are characteristic of MS.3-5 MS relapses occur because of focal areas ABSTRACTMultiple sclerosis, a treatable disease of demyelination evolving over 24 hours and persisting for days or weeks before generally, though not exclusively, improving.4,6

Background Neurodegeneration is the pathological substrate that causes major disability in secondary progressive multiple sclerosis. A synthesis of preclinical and clinical research identified three neuroprotective drugs acting on different axonal pathobiologies. We aimed to test the efficacy of these drugs in an efficient manner with respect to time, cost, and patient resource. Methods We did a phase 2b, multiarm, parallel group, double-blind, randomised placebo-controlled trial at 13 clinical neuroscience centres in the UK. We recruited patients (aged 25-65 years) with secondary progressive multiple sclerosis who were not on disease-modifying treatment and who had an Expanded Disability Status Scale (EDSS) score of 4•0-6•5. Participants were randomly assigned (1:1:1:1) at baseline, by a research nurse using a centralised web-based service, to receive twice-daily oral treatment of either amiloride 5 mg, fluoxetine 20 mg, riluzole 50 mg, or placebo for 96 weeks. The randomisation procedure included minimisation based on sex, age, EDSS score at randomisation, and trial site. Capsules were identical in appearance to achieve masking. Patients, investigators, and MRI readers were unaware of treatment allocation. The primary outcome measure was volumetric MRI percentage brain volume change (PBVC) from baseline to 96 weeks, analysed using multiple regression, adjusting for baseline normalised brain volume and minimisation criteria. The primary analysis was a complete-case analysis based on the intention-to-treat population (all patients with data at week 96). This trial is registered with ClinicalTrials. gov, NCT01910259.

This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24‐hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

IntroductionThe major unmet need in multiple sclerosis (MS) is for neuroprotective therapies that can slow (or ideally stop) the rate of disease progression. The UK MS Society Clinical Trials Network (CTN) was initiated in 2007 with the purpose of developing a national, efficient, multiarm trial of repurposed drugs. Key underpinning work was commissioned by the CTN to inform the design, outcome selection and drug choice including animal models and a systematic review. This identified seven leading oral agents for repurposing as neuroprotective therapies in secondary progressive MS (SPMS). The purpose of the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) will be to evaluate the neuroprotective efficacy of three of these drugs, selected with distinct mechanistic actions and previous evidence of likely efficacy, against a common placebo arm. The interventions chosen were: amiloride (acid-sensing ion channel antagonist); fluoxetine (selective serotonin reuptake inhibitor) and riluzole (glutamate antagonist).Methods and analysisPatients with progressing SPMS will be randomised 1:1:1:1 to amiloride, fluoxetine, riluzole or matched placebo and followed for 96 weeks. The primary outcome will be the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalisation, of Atrophy method. With a sample size of 90 per arm, this will give 90% power to detect a 40% reduction in PBVC in any active arm compared with placebo and 80% power to detect a 35% reduction (analysing by analysis of covariance and with adjustment for multiple comparisons of three 1.67% two-sided tests), giving a 5% overall two-sided significance level. MS-SMART is not powered to detect differences between the three active treatment arms. Allowing for a 20% dropout rate, 110 patients per arm will be randomised. The study will take place at Neuroscience centres in England and Scotland.Ethics and disseminationMS-SMART was approved by the Scotland A Research Ethics Committee on 13 January 2013 (REC reference: 13/SS/0007). Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numbersNCT01910259; 2012-005394-31; ISRCTN28440672.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

Secondary progressive multiple sclerosis (SPMS) is diagnosed retrospectively and involves a clinical course characterized by a progressive accumulation of neurological disability, independent of relapses, following an initial relapsing-remitting (RR) phase. Our incomplete understanding of the pathological mechanisms underlying neurodegeneration in multiple sclerosis (MS) may explain why, to date, there is no definitive imaging or laboratory test that is able to inform us when the disease is clearly entering into a progressive phase and why the vast majority of clinical trials testing immunosuppressant and immunomodulating drugs in SPMS patients has so far yielded disappointing or mixed results. Here we discuss the definition(s) of SPMS and how it may vary, outcome measurements (current and emerging) and modern trial design.

This article reviews our current understanding and modern treatment of multiple sclerosis (MS). MS is a disabling condition resulting in devastating social and economic impacts. As MS can affect any part of the central nervous system, the presentation is often diverse; however, there are key features that can be useful in the clinic. We comment on the diagnostic criteria and review the main subtypes of MS, including clinically isolated syndrome, relapsing remitting MS, secondary progressive MS and primary progressive MS. Although the underlying aetiology of MS is still not known, we summarise those with most evidence of association. Finally, we aim to present treatment strategies for managing the acute relapse, disease-modifying therapies and MS symptoms. This review highlights that progressive MS is an area where there is currently a paucity of available diseasemodifying treatments and this will be a major focus for future development.KEYWORDS : Diagnostic criteria , epidemiology , multiple sclerosis , progressive multiple sclerosis , treatments What is multiple sclerosis?Multiple sclerosis (MS) is an acquired disabling neurological disease of young adults, affecting approximately 2.3 million people worldwide. It is most prevalent in North America (140 cases per 100,000) and Europe (108 cases per 100,000); the prevalence is lowest in sub-Saharan Africa (2.1 cases per 100,000) and East Asia (2.2 cases per 100,000).1 Overall, there are approximately 120,000 people with MS in the UK. 2MS is an inflammatory disease of the central nervous system (CNS), which causes a heterogeneous array of symptoms and signs because of differential involvement of motor, sensory, visual and autonomic systems. Optic neuritis (inflammation of the optic nerve), Uhthoff's phenomenon (transient fluctuation or worsening of MS symptoms with a rise in body temperature) and Lhermitte's phenomenon (an abnormal electric-shock like sensation down the spine or limbs on neck flexion) are characteristic of MS.3-5 MS relapses occur because of focal areas ABSTRACTMultiple sclerosis, a treatable disease of demyelination evolving over 24 hours and persisting for days or weeks before generally, though not exclusively, improving.4,6

Objectives:To explore the relationship between slowly expanding lesions (SELs) on MRI and disability in secondary progressive multiple sclerosis (SPMS).Methods:We retrospectively studied 345 patients with SPMS enrolled in the MS-SMART trial (NCT01910259). They underwent brain MRI at baseline, 24 and 96 weeks. Definite SELs were defined as concentrically expanding T2 lesions, as assessed by non-linear deformation of volumetric T1-weighted images. Associations of SEL volumes with other MRI metrics and disability were assessed through Pearson correlations and regression analyses.Results:Averaged across patients, 29% of T2 lesions were classified as being definite SELs. A greater volume of definite SELs correlated with a higher total baseline T2 lesion volume (r=0.55, p<0.001), and percentage brain volume reduction (r=-0.26, p<0.001), a higher number of new persisting T1 black holes (r=0.19, p<0.001) and, in a subset of 106 patients, with a greater reduction in magnetization transfer ratio (adjusted difference=0.52, p<0.001). In regression analyses, a higher definite SEL volume was associated with increasing disability, as assessed by the Expanded Disability Status Scale (beta=0.23, p=0.020), z-scores of the Multiple Sclerosis Functional Composite (beta= -0.47, p=0.048), Timed 25 Foot Walk Test (beta= -2.10, p=0.001), Paced Auditory Serial Addition Task (beta= -0.27, p=0.006), and increased risk of disability progression (odds ratio=1.92, p=0.025).Conclusions:Definite SELs represent almost one third of T2 lesions in SPMS. They are associated with neurodegenerative MRI markers and related to clinical worsening, suggesting that they may contribute to disease progression and be a new target for therapeutic interventions.