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Fumarate targets pyroptosis A form of inflammatory cell death called pyroptosis depends on the caspase-mediated cleavage of gasdermin D (GSDMD), the fragments of which assemble into permeability pores that then kill the cell. The mechanisms regulating this important cellular process are not yet fully understood. Humphries et al. now report that the tricarboxylic acid cycle intermediate fumarate can act as an inhibitor of pyroptosis (see the Perspective by Pickering and Bryant). Both endogenous fumarate and exogenously delivered dimethyl fumarate (DMF) convert the cysteines in GSDMD to S-(2-succinyl)-cysteines (a process called succination) to prevent its interaction with caspases and subsequent processing and activation. Administration of DMF to mice alleviated inflammation in models of multiple sclerosis and familial Mediterranean fever. These findings may explain the efficacy of DMF as a treatment for multiple sclerosis and other inflammatory diseases and offer insights into future anti-inflammatory drug design. Science , this issue p. 1633 ; see also p. 1564

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

Background: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.

Alemtuzumab; Efficacy; Safety Alemtuzumab; Eficacia; Seguridad Alemtuzumab; Eficàcia; Seguretat Background Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]). Methods Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years). Results Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22–0.24 vs. 0.38–0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%–92% vs. 62%–88%; achievement of 6-month confirmed disability improvement [CDI]: 20%–31% vs. 13%–25%), increased proportions free of MRI disease activity (70%–86% vs. 42%–63% per year), and slowed brain volume loss (BVL; –0.45% to –0.87% vs. –0.50% to –1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%–2.2% vs. >45 years: 8.1%) and deaths (0%–1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts. Conclusions Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed. The study was supported by Sanofi and Bayer HealthCare Pharmaceuticals.

BackgroundA sensitive test reflecting subtle sensorimotor changes throughout disease progression independent of mobility impairment is currently lacking in progressive multiple sclerosis.ObjectivesWe examined non-ambulatory measures of upper and lower extremity sensorimotor function that may reveal differences between relapsing–remitting and progressive forms of multiple sclerosis.MethodsCutaneous sensitivity, proprioception, central motor function and mobility were assessed in 32 relapsing–remitting and 31 progressive multiple sclerosis patients and 30 non-multiple sclerosis controls.ResultsCutaneous sensation differed between relapsing–remitting and progressive multiple sclerosis at the foot and to a lesser extent the hand. Proprioception function in the upper but not the lower extremity differed between relapsing–remitting and progressive multiple sclerosis, but was different for both upper and lower extremities between multiple sclerosis patients and non-multiple sclerosis controls. Foot-tap but not hand-tap speed was slower in progressive compared to relapsing–remitting multiple sclerosis, suggestive of greater central motor function impairment in the lower extremity in progressive multiple sclerosis. In addition, the non-ambulatory sensorimotor measures were more sensitive in detecting differences between relapsing–remitting and progressive multiple sclerosis than mobility assessed with the 25-foot walk test.ConclusionThis study provides novel information about changes in sensorimotor function in progressive compared with relapsing–remitting forms of multiple sclerosis, and in particular the importance of assessing both upper and lower extremity function. Importantly, our findings showed loss of proprioceptive function in multiple sclerosis but also in progressive compared to relapsing–remitting multiple sclerosis.

Background: The importance of supporting pregnancy-related decisions in multiple sclerosis (MS) patients has increasingly been recognized and hence the need for prospective data on pregnancy and pediatric outcomes in this patient population. Objective: To assess prospective growth and developmental outcomes of infants born to mothers with multiple sclerosis (IMS). Methods: PREG-MS is a prospective multicenter cohort study in New England, United States. We followed 65 women with MS and their infants with up to 12 months consistent pediatric follow-up. Pediatric, neurologic, and demographic information was obtained via structured telephone interviews and validated with medical records. Results: No differences in infant weights and lengths with World Health Organization (WHO) 50th percentile standards were observed ( p > 0.05). However, larger head circumference (HC) measurements than WHO standards were reported in cohort infants ( p Conclusion: This first prospective study on pediatric anthropometry in IMS suggests a possible increase in HC compared to WHO standards without an increase in irreversible developmental abnormalities. The observations are exploratory and require confirmation with larger prospective studies in diverse groups of MS patients.

Background:We developed a preference assessment tool to help assess patient goals, values, and preferences for multiple sclerosis (MS) management. All preference items in the tool were generated by people with MS. The aim of this study was to evaluate this tool in a national sample of people with MS.Methods:English-speaking patients with MS aged 21 to 75 years with access to the internet were recruited. Participants completed the preference tool online, which included separate modules assessing three core preference areas: treatment goals, preferences for attributes of disease-modifying therapies, and factors influencing a change in treatment. The tool generated a summary of participants' treatment goals and preferences. Immediately after viewing the summary, participants were asked to evaluate the tool. Rankings of preference domains were compared with rankings obtained in another study.Results:In 135 people with MS who completed the tool and evaluation, the highest ranked goal was brain health (memory, thinking, brain), followed by disability concerns (walking, strength, vision). Rankings were highly similar to those in the referent study. Nearly all participants reported that the tool helped them understand their goals and priorities regarding MS and that the summary appropriately reflected what is important to them. Most participants (87%) wanted to discuss their treatment goals and priorities with their clinician.Conclusions:This preference assessment tool successfully captured patients' goals, values, and preferences for MS treatment and could potentially be used to help patients communicate their preferences to their clinician.

Background. Most people with multiple sclerosis (MS) want to be involved in medical decision making about disease-modifying therapies (DMTs), but new approaches are needed to overcome barriers to participation. Objectives. We sought to develop a shared decision-making (SDM) tool for MS DMTs, evaluate patient and provider responses to the tool, and address challenges encountered during development to guide a future trial. Methods. We created a patient-centered design process informed by image theory to develop the MS-SUPPORT SDM tool. Development included semistructured interviews and alpha and beta testing with MS patients and providers. Beta testing assessed dissemination and clinical integration strategies, decision-making processes, communication, and adherence. Patients evaluated the tool before and after a clinic visit. Results. MS-SUPPORT combines self-assessment with tailored feedback to help patients identify their treatment goals and preferences, correct misperceptions, frame decisions, and promote adherence. MS-SUPPORT generates a personal summary of their responses that patients can share with their provider to facilitate communication. Alpha testing (14 patients) identified areas needing improvement, resulting in reorganization and shortening of the tool. MS-SUPPORT was highly rated in beta testing (15 patients, 4 providers) on patient-provider communication, patient preparation, adherence, and other endpoints. Dissemination through both patient and provider networks appeared feasible. All patient testers wanted to share the summary report with their provider, but only 60% did. Limitations. Small sample size, no comparison group. Conclusions. The development process resulted in a patient-centered SDM tool for MS that may facilitate patient involvement in decision making, help providers understand their patients’ preferences, and improve adherence, though further testing is needed. Beta testing in real-world conditions was critical to prepare the tool for future testing and inform the design of future studies.

Multiple sclerosis (MS) is a chronic and progressive neurological disease characterized by recurrent episodes of inflammatory demyelination of the brain and spinal cord. Alemtuzumab has been previously shown in large phase III trials to be an effective therapy in reducing MS clinical flares as well as new radiological activity and atrophy rates. The purpose of this study was to examine real-world effectiveness and safety data from a large cohort of people treated with alemtuzumab at an academic medical center, including those who failed B-cell depletion therapy. Over an average of 2.6 years follow-up, there were small but significant improvements in neurological disability scores, and a 61% rate of the composite "No Evidence of Disease Activity" (NEDA-3) outcome at 2-year follow-up. There were no substantial safety issues encountered in our review; rates of adverse events were similar or below those reported in Phase III trials. We compare and contrast our results to other available real-world data using alemtuzumab in multiple sclerosis.

Background Rapid tapping tests have been shown to be reliable measures of upper motor neuron disease, and effectively examine motor function differences between multiple sclerosis (MS) and non-MS controls (CON), and between relapsing-remitting and progressive MS subtypes. To successfully perform rapid repetitive movements such as tapping, a person must be able to consistently turn on and off motor units to switch between the up and down movement phases. However, it is not clear which specific movement phase that occurs during tapping is different between MS subtypes. The objective of this study was to quantify and characterize performance differences during rapid hand- and foot-tapping tests between relapsing-remitting (RRMS) and progressive (PMS) forms of MS, as well as how both subtypes differ from non-MS controls. Methods Participants in this study included 30 non-MS controls, 32 RRMS, and 31 PMS. Participants wore inertial sensors on all hands and feet and were instructed to tap as fast as possible for 10 s. Angular velocity from the gyroscope was used to quantify inter-tap interval (ms), coefficient of variation of inter-tap interval (COV), and up- and down-movement characteristics (duration (ms), COV, peak angular velocity (rad/s)). Differences between groups were examined with ANOVA and independent t-tests. Inter-tap interval was examined for its ability to distinguish between RRMS and PMS by a binary logistic regression analysis. Up-down movement characteristics were further evaluated for within-group directional differences (up- vs. down-phase movement components) with paired-sample t-tests. Results Inter-tap interval for both hand- and foot-tapping differed between controls and MS, but only foot tapping was different between RRMS and PMS (RRMS = 286.7 ± 83.0 ms; PMS = 379.5 ± 170.9 ms; mean difference (d) = -92.8 ms). Logistic regression analysis showed foot-tap interval but not hand-tap interval has the potential to distinguish between RRMS and PMS (Area under the ROC = 0.71). Both up- and down-movement duration differences were consistent with the results for inter-tap interval, but up-movement duration showed larger mean group differences than down-movement differences. No significant group differences in overall inter-tap interval COV were detected for either hand- or foot-tapping; however, up-movement foot-tapping variation (CON = 18.7 ± 6.1; RRMS = 25.5 ± 11.2; PMS = 23.3 ± 8.6; CON vs RRMS d = -6.8; CON vs PMS d = -4.7), but not down-movement variation was different between controls and MS. Up- and down-peak angular velocity during foot-tapping were different between controls and PMS (CON Up = 1.4 ± 0.5 rad/s; PMS Up = 1.0 ± 0.4 rad/s; Up d = 0.4 rad/s; CON Down= 1.5 ± 0.6 rad/s; PMS Down = 1.2 ± 0.5 rad/s; Down d = 0.3 rad/s), and up-movement peak angular velocity differences showed larger mean group differences than the down-movement peak angular velocity between controls and PMS. Conclusion Foot-tapping differs between MS disease subtypes and has greater potential than hand-tapping to distinguish between subtypes. Performance in the up-movement showed larger group differences than the down-movement, suggesting that the anti-gravity up-movement during tapping may be more important diagnostically. Future studies should be conducted on the nature of the physiological mechanisms underlying impairments in anti-gravity movements in people with MS.

Post-Epstein-Barr virus (EBV) cerebellitis is very rare complication of infectious mononucleosis and only a few adult cases are reported in literature. We present a 23-year-old patient who was admitted to the neurology service with worsening ataxia, nystagmus and dysarthria, 1 week after infectious mononucleosis. Imaging and cerebrospinal fluid studies were normal, serum studies revealed acute transaminitis and positive EBV viral capsid IgM and IgG. The patient underwent a 5-day course of intravenous immunoglobulins with rapid resolution of all his symptoms and was safely discharged home. The pathophysiology of post-EBV cerebellitis involves autoreactive antibodies, rather than a direct viral insult. Antineuronal antibodies might be the result of a mimicry between EBV proteins and neuronal antigens or they can be secreted by the EBV-transformed lymphocytes themselves. Many reports stress the benign, self-limiting nature of this syndrome; however, immunotherapy might de facto decrease the severity and duration of illness.

Background We have previously demonstrated that cerebrospinal fluid-derived B cells from early relapsing–remitting multiple sclerosis (RRMS) patients that express a VH4 gene accumulate specific replacement mutations. These mutations can be quantified as a score that identifies such patients as having or likely to convert to RRMS. Furthermore, we showed that next generation sequencing is an efficient method for obtaining the sequencing information required by this mutation scoring tool, originally developed using the less clinically viable single-cell Sanger sequencing. Objective To determine the accuracy of MSPrecise, the diagnostic test that identifies the presence of the RRMS-enriched mutation pattern from patient cerebrospinal fluid B cells. Methods Cerebrospinal fluid cell pellets were obtained from RRMS and other neurological disease (OND) patient cohorts. VH4 gene segments were amplified, sequenced by next generation sequencing and analyzed for mutation score. Results The diagnostic test showed a sensitivity of 75% on the RRMS cohort and a specificity of 88% on the OND cohort. The accuracy of the test in identifying RRMS patients or patients that will develop RRMS is 84%. Conclusion MSPrecise exhibits good performance in identifying patients with RRMS irrespective of time with RRMS.

Background. Patients facing a high-stakes clinical decision are often confronted with an overwhelming array of options. High-quality decisions about treatment should reflect patients’ preferences as well as their clinical characteristics. Preference-assessment instruments typically focus on pre-selected clinical outcomes and attributes chosen by the investigator. Objective. We sought to develop a patient-centered approach to elicit and compare the treatment goals of patients with multiple sclerosis (MS) and healthcare providers (HCPs). Methods. We conducted five nominal group technique (NGT) meetings to elicit and prioritize treatment goals from patients and HCPs. Five to nine participants in each group responded silently to one question about their treatment goals. Responses were shared, consolidated, and ranked to develop a prioritized list for each group. The ranked lists were combined. Goals were rated and sorted into categories. Multidimensional scaling and hierarchical cluster analysis were used to derive a visual representation, or cognitive map, of the data and to identify conceptual clusters, reflecting how frequently items were sorted into the same category. Results. Five NGT groups yielded 34 unique patient-generated treatment goals and 31 unique HCP-generated goals. There were differences between patients and HCPs in the goals generated and how they were clustered. Patients’ goals tended to focus on the impact of specific symptoms on their day-to-day lives, whereas providers’ goals focused on slowing down the course of disease progression. Conclusions. Differences between the treatment goals of patients and HCPs underscore the limitations of using HCP- or investigator-identified goals. This new adaptation of cognitive mapping is a patient-centered approach that can be used to generate and organize the outcomes and attributes for values clarification exercises while minimizing investigator bias and maximizing relevance to patients.

Objective To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). Methods We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon β-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. Results JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging–detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4+ and CD8+ T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p = 0.05) and B cells (p = 0.03). Interpretation Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment. ANN NEUROL 2014;75:925–934

This article reviews and discusses the approved and emerging therapies for multiple sclerosis (MS). MS is a chronic and disabling immune-mediated disease of the central nervous system (CNS) that affects mainly young adults. MS imposes a huge economic burden on healthcare systems and the society. Although the last 20 years have brought a continuous expansion in therapeutic options, there are still unmet needs in MS management. Available MS drugs have varying degrees of efficacy in reducing relapse risk. The long-term term effects of these treatments are incompletely known. New therapies, along with variations of currently available treatments, may prove more effective and tolerable than the available drugs. Treatments for MS differ with respect to the mode of administration, tolerability and likelihood of treatment adherence, side effects, and risk of major toxicity. The armamentarium of approved disease-modifying therapies in MS and those in development include: (1) the first approved, moderately effective, injectable interferon-β and glatiramer acetate; (2) oral drugs (fingolimod, laquinimod, teriflunomide, dimethyl fumarate); (3) monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab); and (4) immunosuppressive agents (e.g. mitoxantrone). The place of each drug in the therapeutic algorithm is dependent on its specific risk-benefit profile. Patients' clinical and paraclinical phenotypes and biomarker profile may help to elucidate disease subtypes and response to therapy in the future, thus allowing treatment individualization.

A 55-year-old man presented with brief seizure with associated acute aphasia, right head turn and subsequent generalised convulsion. On imaging, he was found to have patchy juxtacortical and cortical T2 hyperintensity with high radiographic suspicion for subacute multifocal leukoencephalopathy. Serum and cerebrospinal fluid testing were unremarkable. Clinically, the patient recovered completely and had no recurrence of symptoms. On follow-up MRI 1 month later, the T2 hyperintensity had resolved almost entirely while hypointensity on susceptibility-weighted angiography MRI remained, suggesting isolated cortical venous thrombosis.

Lymphomatosis cerebri (LC) is a rare variant of a primary central nervous system non-Hodgkin's lymphoma (PCNSL) characterised by diffuse infiltration of tumour cells throughout the brain parenchyma. We present a 68-year-old immunocompetent woman with headaches, dizziness, blurred vision, localised right leg weakness and rapidly progressive dementia. A brain MRI demonstrated diffuse T2 hyperintense white matter lesions that did not enhance with contrast. The clinical differential diagnosis of these lesions included metastatic disease, infectious or inflammatory process such as sarcoidosis, lymphoma, demyelinating disease and less likely vascular aetiology, such as vasculitis or ischaemic stroke. A right frontal stereotactic brain biopsy was non-diagnostic. The patient eventually died from aspiration pneumonia following a pneumonectomy for a primary lung adenocarcinoma. The diagnosis of LC was established on postmortem examination of the brain.

Objectives Multiple Sclerosis (MS) is known to be associated with a wide range of psychiatric symptoms, particularly with affective disorders. However, a link to psychotic disorders has not been fully established. Methods A systematic review of the PubMed/MEDLINE database was performed to identify cases of MS presenting with psychotic symptoms. Variables analyzed included patient demographics, clinical presentation, imaging characteristics and treatment. Results Ninety-one cases were identified. The mean age was 34.4, and there was a female predominance. The majority of patients did not have a prior history of MS or psychiatric disease. The majority of cases could be classified as having either Psychotic Disorders or Mood Disorders with psychotic features. Most patients received some type of antipsychotic therapy, with variable success. At least 26 patients were treated with corticosteroids in the acute phase of their psychotic symptoms, and the majority responded favorably. Imaging data was available for 50 patients. Of these, 60% had predominantly fronto-temporal lesions, and most had contrast enhancing lesions. Conclusions MS can present with a variety of psychotic symptoms. The presence of enhancing lesions and steroid-responsiveness suggests these could be characterized as flares.

Clinical observations of mood instability in multiple sclerosis (MS) have led to the hypothesis that bipolar disorder (BD) may be more prevalent in persons with MS than in the general population. This cross-sectional study assesses the prevalence of BD among patients with MS using standardized psychiatric diagnostic interviews and evaluates quality of life. This study demonstrates a higher prevalence of BD in patients with MS compared with the general population. It also reveals the negative impact of BD on quality of life, raises the concern that BD can occur before the onset of neurological symptoms in MS, and suggests that, in some cases, BD may delay diagnosis of MS.

Objective In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Methods Fifteen secondary-progressive MS (SPMS) and 12 relapsing-remitting MS (RRMS) cases, and 14 matched healthy controls underwent 11C-PBR28 MR-PET. MS subjects underwent 7 Tesla T2*-weighted imaging for cortical lesions segmentation; neurological and cognitive evaluation. 11C-PBR28 binding was measured using normalized 60-90-minutes standardized uptake values and volume of distribution ratios. Results Relative to controls, MS subjects exhibited abnormally high 11C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. Interpretation In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, and closely linked to poor clinical outcome and, at least partly, to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. This article is protected by copyright. All rights reserved.

Whipple’s disease is a systemic illness caused by an infection with a bacterium of the Actinomycetes species called Tropheryma whipplei. The infection primarily causes gastroenteritis and malabsorption; however, it could also infect other target organs including the central nervous system (CNS). CNS involvement manifests as a wide spectrum of symptoms such as change in mental status, myoclonus, ophthalmoplegia, and ataxia. Whipple’s disease is rare and mostly presents with nonspecific symptoms, therefore requiring a high clinical suspicion for prompt diagnosis. Early initiation of antibiotherapy could prevent bacterial dissemination and produce a complete resolution of symptoms.

There are only six cases in literature that describe development of dystonia with Sjogren’s syndrome (SS). We describe a case of a 43-year-old woman who presented with symptoms including movement disorder, sensory neurogenic bladder, sensory loss and neuropathic pain, migraine like headaches, musculoskeletal pain, Raynaud’s phenomenon and dysautonomia. Symptoms started in 2000, with weakness that progressed to dystonia in 2003. Diagnostic work-up was inconclusive with negative inflammatory serologies, cerebrospinal fluid and MRI for many years. After patient developed sicca syndrome with dry eyes and mouth in 2009, her rheumatoid factor titre was elevated (550 IU/mL), erythrocyte sedimentation rate, anti-Sjogrens syndrome-related antigen A (anti-Ro/SSA) and anti-SSB/La: anti-Sjogrens syndrome-related antigen B (anti-La/SSB) became positive. Lip biopsy confirmed diagnosis of SS. She was diagnosed with primary SS with neurological involvement. Her symptoms responded well to intravenous methylprednisolone. Symptoms stabilised with trials of immune-suppressive therapy. This is a case that demonstrates the delay of diagnosing SS with preceding unique neurological association.

There are only three cases in the literature that describe development of neurosarcoidosis in a patient who is on tumour necrosis factor α inhibitors. We describe a case of a 33-year-old woman with a history of juvenile rheumatoid arthritis and refractory uveitis (with previous treatment trials of adalimumab, infliximab, mycophenolate, methotrexate) who had been stable for 2 years on etanercept. She was diagnosed with biopsy-proven systemic sarcoidosis with meningeal and parenchymal neurosarcoidosis. She was switched to infliximab and methotrexate, with clinical and imaging improvements. This is a case that demonstrates the difficulty of choosing tumour necrosis factor α (TNF-α) inhibitors when treating patients with multiple clinical autoimmune entities. It is also a case where a change in the mechanism of TNF-α inhibition pathway can still be used to treat refractory sarcoidoisis and rheumatoid arthritis. It is still unclear what the exact difference between the TNF-α blockers and their neurological complications is, and who the patients at risk of developing neurological complications are.

Summary A 52-year-old woman with a 10-year history of relapsing-remitting multiple sclerosis (RRMS) was started on natalizumab after she developed side effects for interferon β-1a and glatiramer acetate. The patient presented with acute severe infusion reaction after the third treatment with natalizumab, developing whole-body purpura. Laboratory testing revealed progressive worsening thrombocytopenia up to 3 weeks following natalizumab discontinuation. Platelet antibodies to platelet-specific antigen as well as antibodies against natalizumab were positive. Bone marrow biopsy was negative. The patient was diagnosed with drug-induced immune thrombocytopenia (DITP) as a rare case of natalizumab side effect which was treated with intravenous methylprednisolone followed by rituximab with successful resolution of thrombocytopenia. The patient had a stable course of RRMS with no relapses and no brain MRI changes at 2 years after initiation of rituximab.

Objective: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development. Methods: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features. Results: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report. Conclusions: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is an inducer of matrix metalloproteinases and has roles in leukocyte activation and migration. We reported previously that in MS and its animal model, experimental autoimmune encephalomyelitis, cell surface-associated EMMPRIN was significantly elevated in leukocytes around inflammatory perivascular cuffs in the CNS. In this study we report that activated T-cells can secrete soluble form of EMMPRIN (sEMMPRIN) upon activation. As sEMMPRIN is also present in biological fluids, we determined whether sEMMPRIN is altered in the CSF and sera of MS subjects. Sera from individuals without neurological conditions served as controls, while CSFs collected from subjects undergoing discectomy, and without evidence of CNS pathology, were used as a comparator group. We found that serum levels of sEMMPRIN from clinically stable MS patients or other inflammatory conditions did not differ from control subjects. Paired serum and CSF samples demonstrated poor correlation of sEMMPRIN. Interestingly, sEMMPRIN levels were approximately 60% higher in CSFs compared to sera. sEMMPRIN CSF levels were significantly higher in secondary progressive compared to primary progressive subjects. Thus we conclude that measurement of sEMMPRIN in serum is not informative for disease activity in MS. The differential expression of sEMMPRIN in the CSF of primary and secondary progressive MS invites hypotheses of the still undefined roles of EMMPRIN in the CNS.

Brachial amyotrophic diplegia (BAD) is a rare segmental form of motor neuron disease which presents with asymmetric lower motor neuron weakness largely confined to the upper extremities (UE). In the case being reported, a 62-year-old gentleman on antiretroviral treatment since 1993, presented with left-arm weakness in 2007 that quickly progressed to involve the right arm. Complete HIV-viral load suppression had been achieved since 2003. Examination revealed lower motor neuron weakness in both UEs, worse proximally than distally and normal strength in the lower extremities (LEs). Nerve conduction studies showed reduced amplitudes of bilateral median and ulnar nerves’ motor responses. Needle electromyography of bilateral UE showed active and chronic denervation/reinnervation changes with normal findings in both LEs. MRI of the cervical spine showed cord atrophy. This is the first case report describing a patient who presented with BAD in the setting of complete HIV-viral load suppression for many years.