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The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Background To report the long-term results of the blinded extension phase of the randomized, controlled study of the combined use of interferon beta-1a (IFN) 30 μg IM weekly and glatiramer acetate (GA) 20 mg daily compared to each agent alone in relapsing-remitting multiple sclerosis (RRMS). Methods 1008 RRMS patients were followed on protocol until the last participant enrolled completed 3 years, allowing some subjects to be followed for up to 7 years. The primary endpoint was reduction in annualized relapse rate. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics. Results Similar to the core study, combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed EDSS worsening or change in MSFC. Also similar to the core result, the combination was superior to either agent alone in reducing new lesion activity, but the 3 year MRI result did not presage a clinical benefit over the extended observation interval. Conclusion Combining GA & IFN did not produce a significant clinical benefit over the entire study duration. The earlier effect on reducing MRI activity did not result in a later clinical advantage. The combination showed a sustained advantage in reducing disease activity free status.

BACKGROUND: Despite significant interest in diet by the MS community, research on this topic is limited; there are no published studies evaluating associations between diet and neuroimaging in MS. METHODS: We utilized baseline data from the RADIEMS cohort of early MS (diagnosed

In subjects with multiple sclerosis (MS), pathology is more frequent near the inner and outer surfaces of the brain. Here, we sought to explore if in subjects with primary progressive MS (PPMS) cortical lesion load is selectively associated with the severity of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging. To this aim, twenty-four subjects with PPMS and twenty healthy controls were included in the study. Using diffusion data, skeletonized mean diffusivity (MD) NAWM maps were computed excluding WM lesions and a 2 mm-thick peri-lesional rim. The supra-tentorial voxels between 2 and 6 mm of distance from the lateral ventricles were included in the periventricular NAWM mask while the voxels between 6 and 10 mm from the lateral ventricles were included in the deep NAWM mask; mean MD values were then computed separately for these two masks. Lastly, cortical lesions were assessed on phase-sensitive inversion recovery (PSIR) images and cortical thickness was quantified on volumetric T1 images. Our main result was the observation in the PPMS group of a significant correlation between periventricular NAWM MD values and cortical lesion load, with a greater cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no correlation between cortical lesion load and deep NAWM MD values or periventricular WM lesions. Our data thus suggest that a common – and relatively selective - factor plays a role in the development of both cortical lesion and periventricular NAWM abnormalities in PPMS., Highlights • In PPMS, pathology is more frequent near the inner and outer brain surfaces. • We evaluated the association between cortical lesions and periventricular damage. • Cortical lesion load directly correlated with periventricular NAWM damage severity. • Cortical lesion load did not correlate with periventricular lesions. • A common factor seems to modulate cortical lesions and periventricular NAWM damage.

Background Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. Objective This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. Methods This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×106 cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×106 cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Results Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score >0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. Conclusion PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose.

Objectives Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS. Methods Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline. Results Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved. Conclusion In this observational study at a tertiary care MS center, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.

A comprehensive analysis of the global and regional values of cortical thickness based on 3D magnetic resonance images was performed on 250 relapsing remitting multiple sclerosis (MS) patients who participated in a multi-center, randomized, phase III clinical trial (the CombiRx Trial) and 125 normal controls. The MS cohort was characterized by relatively low clinical disability and short disease duration. An automatic pipeline was developed for identifying images with poor quality and artifacts. The global and regional cortical thicknesses were determined using FreeSurfer software. Our results indicate significant cortical thinning in multiple regions in the MS patient cohort relative to the controls. Both global cortical thinning and regional cortical thinning were more prominent in the left hemisphere relative to the right hemisphere. Modest correlation was observed between cortical thickness and clinical measures that included the extended disability status scale and disease duration. Modest correlation was also observed between cortical thickness and T1-hypointense and T2-hyperintense lesions. These correlations were very similar at 1.5 T and 3 T field strengths. A much weaker inverse correlation between cortical thickness and age was observed among the MS subjects compared to normal controls. This age-dependent correlation was also stronger in males than in females. The values of cortical thickness were very similar at 1.5 T and 3 T field strengths. However, the age-dependent changes in both global and regional cortical thicknesses were observed to be stronger at 3 T relative to 1.5 T., Highlights ► Cortical thinning is observed in multiple cortical regions in MS subjects. ► Cortical thinning shows only moderate to weak correlation with lesion load. ► Age-dependent cortical thickness in MS is weaker than in normal controls. ► Age-dependent cortical thickness is stronger in males compared to females. ► Stronger age-dependent cortical thickness is seen at 3 T compared to 1.5 T.

Background Ocrelizumab (OCR) is a humanized monoclonal antibody that targets CD20+B cells. Selective depletion of CD20+B cells may potentially preserve the capacity for B-cell reconstitution and preexisting humoral immunity. Objective To assess the effect of OCR on specific humoral immunity in 2 identical Phase III, randomized, double- blind, double-dummy, IFN-beta-1a (IFN β -1a)-controlled trials in relapsing multiple sclerosis (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomized 1:1 to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44 μ g three-times weekly over the 96-week study treatment period. Prior to study enrollment, physicians were advised to review patient immunization status and follow local guidance for vaccination; immunizations were to be completed ⩾ 6 weeks prior to treatment. Measurements of antibody (Ab) titers against mumps, rubella, varicella, and Streptococcus pneumoniae were taken at baseline and at Weeks 12, 24, 48, 72, and 96. The proportion of patients with Ab levels that could be considered protective was assessed for each treatment group over time. Results The pooled safety analysis of the OPERA I and OPERA II studies included 826 IFN β -1a-treated and 825 OCR-treated patients. At baseline, 94.1% and 93.6% of the IFN β -1a and OCR groups, respectively, had positive levels of mumps Ab; this proportion ranged (min–max) 92.7–94.8% and 91.8–93.5% over the 6 measurements taken during the 96-week study treatment period. Positive rubella Ab levels were seen among 87.9% and 89.0% of the IFN β -1a and OCR groups, respectively, at baseline and ranged 89.8–90.8% and 88.7–89.4% over the treatment period. Positive varicella Ab levels were seen in 95.5% of both treatment groups at baseline and ranged 96.2–97.5% and 94.8–95.6% over the treatment period in the IFN β -1a and OCR groups, respectively. Among the evaluable patients, the mean (standard deviation) level of S. pneumoniae Ab was 53.67 (54.13) mg/L and 55.35 (67.00) mg/L at baseline; at 96 weeks, the mean change from baseline was −1.13 (40.25) mg/L and −1.99 (59.60) mg/L in the IFN β -1a and OCR groups, respectively. Conclusions In OPERA I and OPERA II, Ab titers against common viral and bacterial antigens were similar between the IFN β -1a and OCR groups at baseline and were maintained during the 96-week study treatment period. Treatment with OCR does not appear to affect preexisting humoral immunity. This study is sponsored by F. Hoffmann-La Roche Ltd.

The understanding of the mechanisms that lead to MS exacerbations continues to produce novel treatments for patients with relapsing forms of MS. However, even with the most potent agents available, the exacerbations remain a distinct possibility and a source of concern for patients and clinicians. Therefore, the treatment of acute MS exacerbations remains an indispensable element of MS care. Reviewed here are the available treatment options, their implementation, side effects, and evidence supporting their efficacy in promoting recovery from MS relapses.

Modern diagnosis of multiple sclerosis (MS) is accomplished using a combination of clinical history, neurologic examination, and paraclinical tools (MRI, evoked potentials, and cerebrospinal fluid analysis). The clinical course and features of MS result from the immunopathogenesis and pathologic consequences of inflammatory demyelination/degeneration.

Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs interferon beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44 μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p = 0.0001), and from Week 24 to Week 96 by 22.8% ( p = 0.0042) and 14.9% ( p = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p = 0.0024); in OPERA II, there was no difference ( p = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and can be characterized by acute exacerbations or gradual worsening of neurological function and disability. The course of the disease is highly variable and unpredictable, however, there are short and long-term favorable and unfavorable predictive factors, which may provide some information about the future pattern of the disease. Palliative care in MS is directed at symptom management, psychosocial support, and rehabilitation. The goal in palliative care is to achieve a high quality of life. The disease modifying agents, interferon beta, Glatiramer acetate and Mitoxantrone are the mainstay of treatment in MS. Symptomatic relief and counseling of patients with MS have a strong impact on quality of life.

In order to define the immunologic response to central nervous system tumors in a controlled fashion, we compared xenogeneic, allogeneic and syngeneic transplants of JC virus-induced neural tumor cell aggregates implanted into anterior ocular chambers of mice. Semiquantitative assessment of the level of leukocyte common antigen (CD45) of the transplants by immunohistochemistry was used to gauge rejection. Reticulin staining was used to monitor vascularization. Immunoreactivity to the viral oncoprotein, T-antigen, was confirmed by immunohistochemistry and immunoprecipitation/Western blot analysis. The results demonstrated that transplants were viable at all time-points and developed vascularization as early as three days after transplantation. Xenotransplants, 13-days post-transplantation, and allogeneic transplants, 25 days post-transplantation were infiltrated with polymorphonuclear leukocytes. Fewer CD45 positive cells were demonstrated in syngeneic transplants. High levels of JCV T-antigen stimulated rejection in syngeneic transplants. These results establish a model for further investigation of the natural and induced immunologic response to central nervous system tumors.

Both heterogeneity and restricted heterogeneity of the encephalitogenic myelin basic protein (MBP) peptide-specific T cell receptors (TCRs) were demonstrated in inbred animals depending on the strain-specific genetic characteristics, the stage of the disease, the compartment of the lymphocytes obtained and the methodology used. Nevertheless, the similar features of some MBP-specific TCRs demonstrated across species suggest that conservation of these autoantigen-specific molecules undoubtedly exists, even though the degree of this conservation is controversial. However, the unequivocal heterogeneity of the immune response directed at one of the most important myelin constituents, proteolipid lipoprotein (PLP), which occurs either as a primary or a secondary event during experimental allergic encephalomyelitis (EAE), indicates the complexity of the in vivo situation. Intramolecular and intermolecular spreading of antigen specificity during the course of the disease indicates that a TCR directed therapy may not be the choice of intervention in established disease even in individual strains of laboratory animals with restricted heterogeneity of the primary MBP-specific response. Studying the sequence of events, the recruited regulatory cells and cytokines, and the stromal factors controlling persistence or death of activated, memory cells in the tissue lesion, may reveal new therapeutic modalities with more universal applicabilities.

This activity will review recent advances in treatment options for patients with multiple sclerosis (http://courses.elseviercme.com/msard/597). Expert faculty will discuss the mechanism of MS in terms of the clinical and pathological worsening of the disease. The diagnosis of MS will be broken down into clinical subtypes, with emphasis on the new disease courses. The safety and efficacy and emerging therapeutic options will be analyzed and clinical trials will be discussed. The faculty will provide insight to physicians on how to personalize MS treatment for their patients, including risk factors and when to treat. This program will allow individuals who care for MS patients to optimize their treatment strategies, allowing for an improved quality of life in these individuals.

The interaction between encephalitogenic lymphocytes and the cerebral microvascular lining is considered to be an important initial step in the recruitment of immune cells into the central nervous system (CNS) under pathological conditions such as multiple sclerosis (MS) and its investigative analog, experimental allergic encephalomyelitis (EAE). This study was conducted in order to examine whether differences in microvascular endothelial cell expression of several molecules involved in lymphovascular interactions correlate with the strain and organ-specific development of EAE. Cerebral and epididymal microvascular endothelial cells (EC) were isolated from SJL and B10.S mice, which, despite MHC-compatibility (H-2s), differ in their ability to develop EAE. The subcultured cells were then analyzed by flow cytometry for their ability to express class I MHC, class II MHC and ICAM-1 molecules in response to treatment with murine recombinant interferon-γ (IFN-γ). Over a range of doses and times, cerebral EC cultures derived from EAE-susceptible SJL mice expressed two-fold higher levels and higher cell surface densities of class II molecules than cerebral EC cultures derived from EAE-resistant B10.S mice, whereas class I and ICAM-1 molecules were comparably upregulated on both SJL and B10.S cerebral EC. In contrast, both SJL and B10.S epididymal EC cultures expressed lower but comparable levels of class II molecules in response to IFN-γ. Class I and ICAM-1 molecules, however, were upregulated to at least the same degree as that observed on cerebral EC derived from both strains. The strain and site-dependent variations in microvascular endothelial cell inducible class II expression suggest a potential role for this molecule at the cerebral vascular lining in determining susceptibility to the development of EAE in this murine model.

Interleukin-6 (IL-6) induction, as detected by bioassay and Northern analysis, was examined in vitro in endothelial cells or astrocytes derived from BALB/c (susceptible) or SJL (resistant) mice following exposure to mouse hepatitis virus (MHV-4) or UV inactivated MHV-4 (UV-MHV-4). In BALB/c endothelial cells, up to 16-fold more IL-6 (> 640 U/ml) was induced, compared to SJL cells which showed a minimal response (40 U/ml), relative to basal levels (< 20 U/ml). In contrast, both BALB/c and SJL astrocytes showed a substantial IL-6 response to MHV-4 and UV-MHV-4 exposure, although a strain difference persisted. Despite strain and cell specific differences in released IL-6, equivalent levels of IL-6 mRNA were induced in all cell types following exposure to MHV-4 or UV-MHV-4.

Seven patients with multiple sclerosis who were receiving subcutaneous injections of recombinant interferon beta had pain followed by ulceration at the injection site. An eighth patient had a pustular flare of her usually mild psoriasis. No evidence of infection, or contaminated medication was found.

A heterotopic transplant paradigm was developed for its potential usefulness in dissecting genetically determined immune and central nervous system (CNS) components in the induction of experimental allergic encephalomyelitis (EAE). EAE is a cell-mediated, organ-specific, autoimmune disease producing inflammatory demyelination in the CNS. Susceptibility to EAE is determined by multiple genes and reflects both immune competence and target tissue responses. Syngeneic fetal CNS was heterotopically transplanted into the anterior chamber of the eye or beneath the capsule of the kidney of adult SJL or (SJL × BALB c )F 1 mice. Transplants usually survived better in the eye than the kidney. Six to eight weeks after transplantation, some mice were immunized for EAE. Immunized mice developed clinical and pathological signs of EAE in 12 to 15 days. The placement of CNS tissue into the eye or kidney prior to immunization did not suppress induction of EAE. Transplants in either location, in immunized mice, manifested perivascular inflammation and demyelination similar to that seen in the host CNS. However, transplants in mice not immunized for EAE, but maintained an equal time period after transplantation, did not demonstrate these features. The ability to produce the specific pathologic lesions of EAE in CNS tissue transplanted outside the CNS allows the design of studies of the tissue localization of genetic restrictions to development of EAE.

The effect was studied of varying the dosage of mycobacteria and pertussis vaccine in the immunization emulsion on the development of delayed, relapsing experimental allergic encephalomyelitis (DR-EAE) in SJL/J mice. DR-EAE could be induced with dosages of mycobacteria from 0.2 mg to 1.0 mg per mouse. Animals given pertussis vaccine from different batches and different sources all developed DR-EAE with similar percentages of animals sick, animals relapsing, and delay to onset. Mice immunized without pertussis vaccine also developed DR-EAE but had fewer relapses and a longer delay to onset. The role of antigens and adjuvants in relapsing EAE and analogies with multiple sclerosis are discussed.