Consensus recommendations for diagnosis and treatment of Multiple Sclerosis: 2023 revision of the MENACTRIMS guidelines.

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.

Alternative diagnoses in patients referred to specialized centers for suspected MS.

OBJECTIVES: The aim of this study is to explore the frequency, type, and predictors of alternative diagnoses among patients referred with a recent diagnosis of multiple sclerosis (MS) to two specialized MS centers in the Middle East. METHODS: This is a retrospective review of a prospectively followed cohort of MS patients at 2 University specialized MS centers. All patients referred for MS were included. The final diagnosis was recorded and demographic, clinical, laboratory, electrophysiological and radiological variables were collected. RESULTS: A total of 554 patients were included in this study of which 431 were referred for diagnostic confirmation. The final diagnosis of MS was confirmed in 300 (70%), while 114 (26%) turned out to have an alternative diagnosis and 15 (3.5%) fulfilled criteria for radiologically isolated syndrome (RIS). The most common alternative diagnoses were psychogenic (16.3%), non-specific MRI white matter lesions (14.7%), NMO (9.5%), migraine (8.6%) and systemic autoimmune disorders (8.6%). The strongest predictors of a final diagnosis of MS were: younger age, presence of oligoclonal bands in the CSF, periventricular, corpus callosum, spinal (P<0.0001), or enhancing lesions (P<0.005) on MRI. CONCLUSIONS: Our study shows that 30% of patients referred for a suspicion of MS end up with a different diagnosis. The most common alternative diagnoses of MS in the Middle East are not different from what has been described in Western countries. Age, MRI and CSF findings can help with the differential diagnosis.

The impact of lesion in-painting and registration methods on voxel-based morphometry in detecting regional cerebral gray matter atrophy in multiple sclerosis.

BACKGROUND AND PURPOSE: VBM has been widely used to study GM atrophy in MS. MS lesions lead to segmentation and registration errors that may affect the reliability of VBM results. Improved segmentation and registration have been demonstrated by WM LI before segmentation. DARTEL appears to improve registration versus the USM. Our aim was to compare the performance of VBM-DARTEL versus VBM-USM and the effect of LI in the regional analysis of GM atrophy in MS. MATERIALS AND METHODS: 3T T1 MR imaging scans were acquired from 26 patients with RRMS and 28 age-matched NC. LI replaced WM lesions with normal-appearing WM intensities before image segmentation. VBM analysis was performed in SPM8 by using DARTEL and USM with and without LI, allowing the comparison of 4 VBM methods (DARTEL + LI, DARTEL - LI, USM + LI, and USM - LI). Accuracy of VBM was assessed by using NMI, CC, and a simulation analysis. RESULTS: Overall, DARTEL + LI yielded the most accurate GM maps among the 4 methods (highest NMI and CC, P < .001). DARTEL + LI showed significant GM loss in the bilateral thalami and caudate nuclei in patients with RRMS versus NC. The other 3 methods overestimated the number of regions of GM loss in RRMS versus NC. LI improved the accuracy of both VBM methods. Simulated data suggested the accuracy of the results provided from patient MR imaging analysis. CONCLUSIONS: We introduce a pipeline that shows promise in limiting segmentation and registration errors in VBM analysis in MS.

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study.

Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P=0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P=0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P=0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P=0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells.

BACKGROUND: Natalizumab is an antibody directed against integrin alpha4 that reduces disease activity in patients with multiple sclerosis (MS) by blocking migration of T and B cells into the CNS. The goal of this study was to characterize the effects of natalizumab treatment on cytokine production and expression of activation markers, costimulatory molecules, and trafficking determinants on CD4+ and CD8+ T cells. METHODS: In a longitudinal study, we investigated the expression of surface makers and cytokine expression on peripheral blood lymphocytes from 28 patients with MS who started natalizumab treatment and were followed for 1 year. A mixed effects model was used to compare pretreatment to on-treatment measurements. RESULTS: The frequency of CD4+ T cells producing interferon-gamma, tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation increased 6 months after initiation of natalizumab treatment and remained elevated throughout the follow-up. The frequency of CD4+ T cells expressing CD25, HLA-DR, and CCR6 ex vivo was increased at one or more time points during treatment. Among CD8+ T cells, the frequency of cells producing IL-2 and IL-17 after stimulation was increased during natalizumab treatment, as was the frequency of CD8+ T cells expressing CD58 and CCR5 ex vivo. The increase in the frequency of activated cells could not be replicated by in vitro exposure to natalizumab. CONCLUSION: Natalizumab treatment increases the percentage of activated leukocytes producing proinflammatory cytokines in blood, presumably due to sequestration of activated cells in the peripheral circulation.

Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study.

OBJECTIVE: To determine the rate of treatment failure in patients outside of a controlled treatment trial and to ascertain the factors physicians used to make this decision. METHODS: One hundred and thirty four patients with the diagnosis of relapsing-remitting (RR) multiple sclerosis (MS) or clinically isolated symptom (CIS) enrolled in the CLIMB study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital) were treated with either interferon beta or glatiramer acetate as their initial treatment for MS. RESULTS: The probability of failing initial treatment within 3 years was 30%. Clinical activity, defined as relapses and/or progression in disability, determined treatment failure in 35.7% (n=10) of nonresponders. New T2 hyperintense or gadolinium-enhancing lesions on MRI was used to define treatment failure in 28.6% (n=8) and new MRI lesions were used in combination with clinical activity in 35.7% (n=10). Treatment failures had a higher T2 hyperintense lesion volume (p=0.015) and number of gadolinium-enhancing lesions (p=0.0001) on the enrollment MRI than responders. CONCLUSIONS: These observations demonstrate that treating physicians use both clinical and MRI parameters to define a response to treatment and initiation of a treatment change and that baseline MRI identified those with increased risk of treatment failure.

Daclizumab in treatment of multiple sclerosis patients.

BACKGROUND: Daclizumab is a humanized monoclonal antibody (mAb) that blocks the interleukin-2 receptor alpha subunit (IL-2R-alpha chain; CD25) expressed on activated T cells leading to the inhibition of T-cell expansion, thus strongly reduces brain inflammation in patients with multiple sclerosis (MS). Another mechanism is significant expansion of CD56 (bright) natural killer (NK) cells that in turn inhibit T-cell survival. OBJECTIVE: At the Partners MS center, we have been using Daclizumab in an open-label fashion in patients who fail first line therapy or non-standard immunosuppressive treatment. Our aim was to assess its safety and tolerability in our patient population.

CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial.

BACKGROUND: The modulation of costimulatory pathways represents an original therapeutic approach to regulate T cell-mediated autoimmune diseases by preventing or reducing autoantigen-driven T-cell activation in humans. Autoreactive CD4(+) T cells play a critical role in initiating the immune response leading to the chronic inflammation and demyelination characteristic of multiple sclerosis (MS). METHODS: We used IV infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway in a phase 1 dose-escalation study in MS. Sixteen patients with relapsing-remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. In an extension study, four additional subjects received four doses of CTLA4Ig. RESULTS: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon-gamma production by MBP-specific lines. CONCLUSIONS: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.

Medulla oblongata volume: a biomarker of spinal cord damage and disability in multiple sclerosis.

BACKGROUND AND PURPOSE: While brain MR imaging is routinely performed, the MR imaging assessment of spinal cord pathology in multiple sclerosis (MS) is less frequent in clinical practice. The purpose of this study was to determine whether measurements of medulla oblongata volume (MOV) on routine brain MR imaging could serve as a biomarker of spinal cord damage and disability in MS. MATERIALS AND METHODS: We identified 45 patients with MS with both head and cervical spinal cord MR imaging and 29 age-matched and sex-matched healthy control subjects with head MR imaging. Disability was assessed by the expanded disability status scale (EDSS) and ambulation index (AI). MOV and upper cervical cord volume (UCCV) were manually segmented; semiautomated segmentation was used for brain parenchymal fraction (BPF). These measures were compared between groups, and linear regression models were built to predict disability. RESULTS: In the patients, MOV correlated significantly with UCCV (r = 0.67), BPF (r = 0.45), disease duration (r = -0.64), age (r = -0.47), EDSS score (r = -0.49) and AI (r = -0.52). Volume loss of the medulla oblongata was -0.008 cm(3)/year of age in patients with MS, but no significant linear relationship with age was found for healthy control subjects. The patients had a smaller MOV (mean +/- SD, 1.02 +/- 0.17 cm(3)) than healthy control subjects (1.15 +/- 0.15 cm(3)), though BPF was unable to distinguish between these 2 groups. MOV was smaller in patients with progressive MS (secondary- progressive MS, 0.88 +/- 0.19 cm(3) and primary-progressive MS, 0.95 +/- 0.30 cm(3)) than in patients with relapsing-remitting MS (1.08 +/- 0.15 cm(3)). A model including both MOV and BPF better predicted AI than BPF alone (P = .04). Good reproducibility in MOV measurements was demonstrated for intrarater (intraclass correlation coefficient, 0.97), interrater (0.79), and scan rescan data (0.81). CONCLUSION: MOV is associated with disability in MS and can serve as a biomarker of spinal cord damage.

Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis.

Cognitive dysfunction is common in patients with multiple sclerosis (MS), and has been associated with MRI measures of lesion burden and atrophy. Little is known about the prevalence of cognitive impairment in patients with early MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course are also unclear. This study used a brief battery of cognitive tests to determine the prevalence and pattern of cognitive impairment in patients with clinically isolated syndromes or newly diagnosed MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course were also examined. Ninety-two patients with clinically isolated syndromes or the diagnosis of MS within the last 3 years participating in the CLIMB study underwent a neurologic examination, neuropsychological evaluation and MRI at 1.5 T. Forty-nine percent of patients were impaired on one or more cognitive measures. There were no significant correlations between cognitive scores and MRI measures of disease severity including total T2 lesion volume, normal appearing white matter volume, grey matter volume, and brain parenchymal fraction. These findings suggest that cognitive impairment may predate the appearance of gross structural abnormalities on MRI and serve as an early marker of disease activity in MS.

Predicting short-term disability in multiple sclerosis.

OBJECTIVE: To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits. METHODS: Semiannual EDSS scores were prospectively collected in 218 relapsing-remitting (RR) and clinically isolated syndrome (CIS) patients as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. Baseline brain parenchymal fraction (BPF) and T2 lesion volume were available on 205 patients. A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits. A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented. RESULTS: The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS. Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression. In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume. CONCLUSIONS: Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with multiple sclerosis.

At the interface of the immune system and the nervous system: how neuroinflammation modulates the fate of neural progenitors in vivo.

Neural stem and progenitor cells express a variety of receptors that enable them to sense and react to signals emanating from physiological and pathophysiological conditions in the brain as well as elsewhere in the body. Many of these receptors and were first described in investigations of the immune system, particularly with respect to hematopoietic stem cells. This emerging view of neurobiology has two major implications. First, many phenomena known from the hematopoietic system may actually be generalizable to stem cells from many organ systems, reflecting the cells' progenitor-mediated regenerative potential. Second, regenerative interfaces may exist between diverse organ systems; populations of cells of neuroectodermal and hematopoietic origin may interact to play a crucial role in normal brain physiology, pathology, and repair. An understanding of the origins of signals and the neural progenitors' responses might lead to the development of effective therapeutic strategies to counterbalance acute and chronic neurodegenerative processes. Such strategies may include modifying and modulating cells with regenerative potential in subtle ways. For example, stem cells might be able to detect pathology-associated signals and be used as "interpreters" to mediate drug and other therapeutic interventions. This review has focused on the role of inflammation in brain repair. We propose that resident astroglia and blood-born cells both contribute to an inflammatory signature that is unique to each kind of neuronal degeneration or injury. These cells play a key role in coordinating the neural progenitor cell response to brain injury by exerting direct and indirect environmentally mediated influence on neural progenitor cells. We suggest that investigations of the neural progenitor-immunologic interface will provide valuable data related to the mechanisms by which endogenous and exogenous neural progenitor cells react to brain pathology, ultimately aiding in the design of more effective therapeutic applications of stem cell biology. Such improvements will include: (1) ascertaining the proper timing for implanting exogenous neural progenitor cells in relation to the administration of anti-inflammatory agents; (2) identifying what types of molecules might be administered during injury to enhance the mobilization and differentiation of endogenous and exogenous neural progenitor cells while also inhibiting the detrimental aspects of the inflammatory reaction; (3) divining clues as to which molecules may be required to change the lesioned environment in order to invite the homing of reparative neural progenitor cells.

Therapeutic strategies to prevent neurodegeneration and promote regeneration in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability that is the ultimate outcome of the disease. Axonal degeneration may be the primary determinant of fixed neurological deficits in MS. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair of CNS components in multiple sclerosis.

Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is mediated by myelin-specific CD4(+) T cells secreting Th1 cytokines, while recovery from disease is associated with expression of Th2 cytokines. Investigations into the role of individual cytokines in disease induction have yielded contradictory results. Here we used animals with targeted deletion of the STAT4 or STAT6 genes to determine the role of these signaling molecules in EAE. The STAT4 pathway controls the differentiation of cells into a Th1 phenotype, while the STAT6 pathway controls the differentiation of cells into a Th2 phenotype. We found that mice deficient in STAT4 are resistant to the induction of EAE, with minimal inflammatory infiltrates in the central nervous system. In contrast, STAT6-deficient mice, which have a predominantly Th1 phenotype, experience a more severe clinical course of EAE as compared with wild-type or STAT4 knockout mice. In addition, adoptive transfer studies confirm the regulatory functions of a Th2 environment in vivo. These novel data indicate that STAT4 and STAT6 genes play a critical role in regulating the autoimmune response in EAE.

Increased percentage of IL-12+ monocytes in the blood correlates with the presence of active MRI lesions in MS.

Interleukin (IL)-12 is a cytokine thought to play a major role in the pathogenesis of multiple sclerosis (MS). We have previously shown that patients with progressive MS have a high percentage of IL-12-producing monocytes in the blood compared to normal individuals. We analyzed 269 blood samples from 189 MS patients for the percentage of IL-12-producing monocytes. We found that the increased IL-12 expression correlates with disability, as measured by the Expanded Disability Status Scale (EDSS), and with disease activity, measured by the presence of gadolinium-enhancing magnetic resonance imaging (MRI) lesions.

Oral salbutamol decreases IL-12 in patients with secondary progressive multiple sclerosis.

IL-12 is a key cytokine for Th1 cell development and may be important in the pathogenesis of multiple sclerosis (MS). The beta2-agonist salbutamol is known to decrease IL-12 production in monocytes of normal individuals through increased intracellular cAMP. In a prospective open-label study, we investigated by flow cytometry the effect of a 2-week long oral salbutamol treatment on monocyte IL-12 production in 21 secondary progressive MS patients. Baseline IL-12 production was higher in patients than in healthy controls. The treatment induced a significant decrease in the percentage of IL-12-producing monocytes and dendritic cells that lasted up to 1 week after treatment interruption. This first report on the use of salbutamol in MS shows that this drug has immunomodulatory properties both in vivo and in vitro, and may be beneficial in the treatment of MS.

Ondansetron versus dehydrobenzoperidol and metoclopramide for management of postoperative nausea in laparoscopic surgery patients.

BACKGROUND: In this prospective, randomized, double-blind study, we compared the efficacy of ondansetron versus dehydrobenzoperidol (droperidol) or metoclopramide in the treatment of established postoperative nausea and vomiting in 200 adult patients undergoing laparoscopic surgery under general anesthesia. METHODS: One hundred seventy-three American Society of Anesthesiologists (ASA) I and II patients satisfied inclusion criteria. Fifty-seven patients received ondansetron 4 mg (group O), 57 patients were given droperidol 1.25 mg (group D), and 59 patients received metoclopramide 10 mg (group M). Antiemetic efficacy was compared at 10 minutes and 30 minutes after the administration of the study drug. RESULTS: At 10 minutes, nausea scores in group O dropped from 8.3 to 3.7, in group D from 8.5 to 5, and in group M from 8.4 to 6.7; (P < 0.05 between the three groups). At 30 minutes, nausea scores were 1.3 in group O, 1.7 in group D, and 5 in group M; (P < 0.05 between group M and the other two groups). In the droperidol group, 25% of patients developed sedation. Patient satisfaction was best with ondansetron. CONCLUSIONS: Both ondansetron and droperidol were more effective in the treatment of established postoperative nausea and vomiting than was metoclopramide. However, patients were satisfied best with ondansetron, which acts faster and causes less sedation than droperidol.

Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

CD28-independent induction of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated disease initiated by antigen-specific CD4(+) T cells. Signaling through CD28 is a critical second signal for activation of T cells, and CD28 knockout (CD28KO) mice have been reported to be resistant to induction of EAE. We now report that CD28KO mice have no intrinsic defect in mediating disease, because they developed EAE after passive transfer of primed T cells. After immunization, peripheral T cells from CD28KO mice were primed and developed memory phenotype, but had decreased antigen-specific IFN-gamma production as compared with cells from wild-type (WT) animals. Reimmunization of CD28KO mice brought out clinical disease and increased IFN-gamma production in vitro. Pathologically, there were cellular infiltrates in the central nervous system, in contrast to single-immunized mice. We show furthermore that blocking B7-1 or CTLA4, but not B7-2, in CD28KO mice induces disease after a single immunization. Thus, EAE can be induced in animals lacking CD28-dependent costimulation, suggesting that alternative costimulatory pathways were used. Blocking the OX40-OX40L costimulatory pathway differentially affected disease induction in CD28KO mice as compared with WT controls. Our data show that EAE may develop in the absence of CD28 T-cell costimulation. These findings have implications for therapies aimed at blocking costimulatory signals in autoimmune diseases.