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A 48-year-old Caucasian woman with history of multiple sclerosis (MS) presented with erythematous papulonodular lesions in her extremities and trunk. She was being treated with glatiramer acetate (GA) for the past 10 years and the glatiramoid, Glatopa, for 2 years prior to this presentation. A skin biopsy showed CD30+ lymphoproliferative disorder consistent with lymphomatoid papulosis (LyP). Three weeks after stopping Glatopa, her skin lesions were improved. It remains unclear whether GA’s or Glatopa’s capability to alter T-cell differentiation, may have a link with LyP. This case report is a reminder to be vigilant for skin lesions in patients with MS.

Background: Caring for individuals with progressive, disabling forms of multiple sclerosis (MS) presents ongoing, complex challenges in health care delivery, especially access to care. Although mobility limitations represent a major hurdle to accessing comprehensive and coordinated care, fragmentation in current models of health care delivery magnify the problem. Importantly, individuals with disabling forms of MS are exceedingly likely to develop preventable secondary complications and to incur significant suffering and increased health care utilization and costs. Methods: A house call program, Multiple Sclerosis at Home Access (MAHA), was implemented. The program was designed to provide comprehensive services and prevent common complications. Key aspects included monthly house calls, continuity among providers, and a multidisciplinary team led by a comprehensivist, a provider bridging subspecialty and primary care. A total of 21 adult patients (Expanded Disability Status Scale score ≥7.5) completed 1 full year of the program. Results: During the 2-year preevaluation and postevaluation period, half of the hospital admissions were related to secondary and generally preventable complications. Aside from a single outlying individual important to the evaluation, in the year after program implementation, decreases were found in number of individuals hospitalized, hospitalizations/skilled facility admissions, and hospital days; the total number of overall emergency department (ED) visits decreased; and ED-only visits increased (ie, ED visits without hospital admission). Patient satisfaction reports and quality indicators were positive. Fifty percent of patients participated in supplementary televisits. Conclusions: This program evaluation suggests that a house call–based practice is a viable solution for improving care delivery for patients with advanced MS and disability.

Multiple sclerosis (MS) is a demyelinating disease that results in a broad array of symptoms, including impaired motor performance. How such demyelination of fibers affects the inherent neurophysiological activity in motor circuits, however, remains largely unknown. Potentially, the movement errors associated with MS may be due to imperfections in the internal model used to make predictions of the motor output that will meet the task demands. Prior magnetoencephalographic (MEG) and electroencephalographic brain imaging experiments have established that the beta (15-30 Hz) oscillatory activity in the sensorimotor cortices is related to the control of movement. Specifically, it has been suggested that the strength of the post-movement beta rebound may indicate the certainty of the internal model. In this study, we used MEG to evaluate the neural oscillatory activity in the sensorimotor cortices of individuals with MS and healthy individuals during a goal-directed isometric knee force task. Our results showed no difference between the individuals with MS and healthy individuals in the beta activity during the planning and execution stages of movement. However, we did find that individuals with MS exhibited a weaker post-movement beta rebound in the pre/postcentral gyri relative to healthy controls. Additionally, we found that the behavioral performance of individuals with MS was aberrant, and related to the strength of the post-movement beta rebound. These results suggest that the internal model may be faulty in individuals with MS. Hum Brain Mapp 38:4009-4018, 2017. © 2017 Wiley Periodicals, Inc.

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.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, the most recognized type of autoimmune encephalitis, manifests with rapid cognitive decline, psychosis, and seizures that develop in 78–86% of patients. Recently, anti-NMDAR encephalitis was reported in association with demyelinating diseases which are accompanied by a characteristic clinical phenotype, imaging abnormalities, and the presence of antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) in bodily fluids. The patient presented herein suffered from bilateral optic neuritis followed by recurrent encephalitis with focal seizures and demonstrated anti-NMDAR and MOG-IgGs in the cerebrospinal fluid and serum, respectively. Her symptoms responded to immunotherapy and antiseizure medication. The recognition of the novel syndrome of MOG antibody-associated demyelination (MOGAD), encompassing the overlapping anti-NMDAR encephalitis and other MOG-IgG associated disorders, is important for the successful management of these patients., Highlights • Recurrent anti-N-methyl-d-aspirate (NMDA) receptor encephalitis with seizures may follow an acute demyelinating disease • In overlap syndrome, anti-NMDA receptor antibodies and antibodies against myelin oligodendrocyte glycoprotein may be detected in the bodily fluids • Recognition of the overlap syndrome is important to determine the optimal treatment and ensure the prevention of relapse

Purpose Fingolimod is among the first oral disease-modifying agents for the treatment of relapsing-remitting multiple sclerosis (MS). Despite its favorable safety profile, fingolimod may cause macular edema, a significant adverse event, which occurs within the first 4 months of therapy. Macular edema usually resolves upon discontinuation of fingolimod; however, the time required for resolution of this condition is unknown. Observations A 42-year-old white male with a history of relapsing-remitting MS presented with blurring of vision in his left eye 24 h after the first dose of fingolimod. Dilated fundus examination of the left eye revealed an increased retinal thickness and mild optic disc pallor. Spectral domain optical coherence tomography (SD-OCT) confirmed the diagnosis of cystoid macular edema. Topical nonsteroidal anti-inflammatory drug (NSAID) was initiated immediately after the diagnosis, and fingolimod therapy was discontinued shortly thereafter. Seven weeks after the initial presentation, intermediate uveitis was noted in the inferior periphery of the left eye, and SD-OCT revealed worsening of macular edema. Acetazolamide therapy was added to the topical NSAID to control the edema. Three weeks after initiation of acetazolamide, macular thickness reduced significantly. The patient then stopped all medications, and 3 weeks later macular edema rebounded. Systemic steroid was employed to control both the intermediate uveitis and macular edema. Conclusions and importance We report a case of acute and very rapid onset of fingolimod-associated macular edema (FAME). Acetazolamide may have a beneficial effect on macular edema secondary to fingolimod. It is unclear if intermediate uveitis is associated with the rapid development of FAME.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Ipilimumab is a monoclonal antibody that prolongs survival in patients with metastatic melanoma.1 It targets the coinhibitory receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 signaling induces a state of T-cell unresponsiveness, which facilitates tumor escape from immune surveillance. Blockade of CTLA-4 is believed to shift the immune status from T-cell exhaustion to a functional antitumor response. Anti-CTLA-4 therapy is associated with immune-related adverse events in 64% of patients. Autoimmunity involving the nervous system has a low incidence and manifests predominantly as peripheral inflammatory neuropathy.2 We report new-onset inflammatory CNS demyelination in an ipilimumab-treated melanoma patient (figure), confirmed by histology and associated with enhanced responses of myelin-reactive CD4+ T cells.

BACKGROUND AND PURPOSE The neuromuscular impairments seen in the ankle plantarflexors have been identified as a primary factor that limits the mobility and standing postural balance of individuals with multiple sclerosis (MS). However, few efforts have been made to find effective treatment strategies that will improve the ankle plantarflexor control. Our objective was to determine whether an intensive 14-week neurorehabilitation protocol has the potential to improve the ankle plantarflexor control of individuals with MS. The secondary objectives were to determine whether the protocol would also improve postural control, plantarflexion strength, and mobility. METHODS Fifteen individuals with MS participated in a 14-week neurorehabilitation protocol, and 20 healthy adults served as a comparison group. The primary measure was the amount of variability in the submaximal steady-state isometric torque, which assessed plantarflexor control. Secondary measures were the Sensory Organization Test composite score, maximum plantarflexion torque, and the spatiotemporal gait kinematics. RESULTS There was less variability in the plantarflexion torques after the neurorehabilitation protocol (preintervention, 4.15% ± 0.5%; postintervention, 2.27% ± 0.3%). In addition, there were less postural sway (preintervention, 51.87 ± 0.2 points; postintervention, 67.8 ± 0.5 points), greater plantarflexion strength (preintervention, 0.46 ± 0.04 Nm/kg; postintervention, 0.57 ± 0.05 Nm/kg), and faster walking speeds (preferred preintervention, 0.71 ± 0.05 m/s; preferred postintervention, 0.81 ± 0.05 m/s; fast-as-possible preintervention, 0.95 ± 0.06 m/s; postintervention, 1.11 ± 0.07 m/s). All of the outcome variables matched or trended toward those seen in the controls. DISCUSSION AND CONCLUSIONS The outcomes of this exploratory study suggest that the neurorehabilitation protocol employed in this investigation has the potential to promote clinically relevant improvements in the ankle plantarflexor control, standing postural balance, ankle plantarflexion strength, and the mobility of individuals with MS. Video abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A110).

During recent decades, the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD), once broadly classified under the umbrella of multiple sclerosis (MS), has been extended to include autoimmune inflammatory conditions of the central nervous system (CNS), which are now diagnosable with serum serological tests. These antibody-mediated inflammatory diseases of the CNS share a clinical presentation to MS. A number of practical learning points emerge in this review, which is geared toward the pattern recognition of optic neuritis, transverse myelitis, brainstem/cerebellar and hemispheric tumefactive demyelinating lesion (TDL)-associated MS, aquaporin-4-antibody and myelin oligodendrocyte glycoprotein (MOG)-antibody NMOSD, overlap syndrome, and some yet-to-be-defined/classified demyelinating disease, all unspecifically labeled under MS syndrome. The goal of this review is to increase clinicians’ awareness of the clinical nuances of the autoimmune conditions for MS and NMSOD, and to highlight highly suggestive patterns of clinical, paraclinical or imaging presentations in order to improve differentiation. With overlay in clinical manifestations between MS and NMOSD, magnetic resonance imaging (MRI) of the brain, orbits and spinal cord, serology, and most importantly, high index of suspicion based on pattern recognition, will help lead to the final diagnosis.

Diffuse leptomeningeal oligodendrogliomatosis is a rare, frequently fatal CNS malignancy that most often affects children.1 Although potentially treatable with chemotherapy and radiation, the radiologic findings are nonspecific and pathologic confirmation of the diagnosis is difficult. We describe an adult patient whose initial presentation mimicked neurosarcoidosis. Despite extensive imaging abnormalities, 3 biopsies were required before the diagnosis of diffuse leptomeningeal oligodendrogliomatosis was confirmed.

Objective. We are reporting two cases: a patient with steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) and another patient with secondary progressive multiple sclerosis (SPMS), both presenting with altered mental status (AMS) and later diagnosed with nonconvulsive atypical absence status epilepticus (AS), with atypical EEG changes. Methods. A report of two cases. Results. A patient with history of SREAT and the other with SPMS had multiple admissions due to AMS. For both, EEG revealed the presence of a high voltage generalized sharply contoured theta activity. A diagnosis of NCSE with clinical features of AS was made based on both clinical and EEG features. There was significant clinical and electrographic improvement with administration of levetiracetam for both patients in addition to sodium valproate and Solumedrol for the SREAT patient. Both patients continued to be seizure free on follow-up few months later. Conclusions. This is a report of two cases of atypical AS, with atypical EEG, in patients with different neurological conditions. Prompt clinical and EEG recovery occurred following appropriate medical treatment. We think that this condition might be underreported and could significantly benefit from prompt treatment when appropriately diagnosed.

Background:The corpus callosum (CC) is frequently compromised in patients with multiple sclerosis (MS). Structural and functional measurements of the CC may be useful to monitor the progression of the disease. The aim of this pilot study was to determine if bimanual tactile temporal thresholds correlates with CC volume. A tactile temporal threshold is the longest temporal interval that separates the onsets of two tactile stimuli when they are judged by the observer as simultaneous. Judgments to bimanual stimulations require interhemispheric transfer via the CC.Methods:Thresholds were examined in MS patients and matched controls. Magnetic resonance (MR) images were acquired on a 3T MR system within 48 hours of clinical assessment and measurement of thresholds.Results:Corpus callosum volume was assessed by using a semiautomatic livewire algorithm. The CC volume was smaller (by 21% on average, p < 0.01) and thresholds were higher (by 49% on average, p < 0.03) in MS patients when compared to controls. A significant correlation (r = -0.66, p = 0.01) between CC volume and thresholds emerged for the MS patients.Conclusion:Measuring treatment benefits of neuroprotective and repair therapies is a well recognized challenge in MS research. The overall findings of this study suggest that these measurements, which involve the transfer of information interhemispherically via the CC, may be promising outcome measures that warrant further scientific exploration to develop a model to measure recovery.

Background Disability is prevalent in individuals with multiple sclerosis (MS), leading to difficulty in care access, significant caregiver burden, immense challenges in self-care and great societal burden. Without highly coordinated, competent and accessible care, individuals living with progressive MS experience psychological distress, poor quality of life, suffer from life-threatening complications, and have frequent but avoidable healthcare utilizations. Unfortunately, current healthcare delivery models present severe limitations in providing easily accessible, patient-centered, coordinated comprehensive care to those with progressive MS. We propose a home-based comprehensive care model (MAHA) to address the unmet needs, challenges, and avoidable complications in individuals with progressive MS with disabling disease.Objective The article aims to describe the study design and methods used to implement and evaluate the proposed intervention. Method The study will use a randomized controlled design to evaluate the feasibility of providing a 24-month, home-based, patient-centered comprehensive care program to improve quality of life, reduce complications and healthcare utilizations overtime (quarterly) for 24 months. A transdisciplinary team led by a MS-Comprehensivist will carry out this project. Fifty MS patients will be randomly assigned to the intervention and usual care program using block randomization procedures. We hypothesize that patients in the intervention group will have fewer complications, higher quality of life, greater satisfaction with care, and reduced healthcare utilization. The proposed project is also expected to be financially sustainable in fee-for-service models but best suited for and gain financial success in valued-based care systems. Discussion This is the first study to examine the feasibility and effectiveness of a home-based comprehensive care management program in MS patients living with progressive disability. If successful, it will have far-reaching implications in research, education and practice in terms of providing high quality but affordable care to population living with severe complex, disabling conditions.

The 'Decade of the Brain' (1990-2000) saw unprecedented advances in neurosciences including multiple sclerosis. It could have not been more aptly named, as it produced a shift in the paradigm of multiple sclerosis management, making multiple sclerosis a treatable disorder with the availability of several therapeutic options. For a chronic progressive neurological disorder like multiple sclerosis, this change in the understanding and treatment touched the lives of hundreds of thousands of patients worldwide and many more who provided care and counsel as family and friends. Of the four agents available for the treatment of the most common type of multiple sclerosis - relapsing-remitting - three are beta-interferons and one is a noninterferon polypeptide of four amino acids (glatiramer acetate) with a distinct immunomodulating profile. Glatiramer acetate is now approved and available in North America, Europe and many other countries. It has been tested in pivotal trials as well as long term extension trials for almost 10 years (8 years published) providing remarkable evidence of efficacy and safety. This review will highlight the immune mechanisms and clinical data reported with glatiramer acetate in multiple sclerosis over the past three decades.