Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of ...fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop.
Summary Multiple sclerosis is a chronic disease of the CNS that leads to substantial disability in most patients. The early phase is characterised by relapses and the later phase by progressive ...disability. Results from immunological, genetic, and histopathological studies and treatment trials have shown that the immune system plays a key part in the disease course. Findings from animal models and immunological studies of patients with multiple sclerosis suggest a change in the involvement of the immune system during disease initiation and progression. These findings suggest that a peripheral immune response targeting the CNS drives the disease process during the early phase, whereas immune reactions within the CNS dominate the progressive phase. These concepts for the differential involvement of immune responses in the early and progressive phase of this disease have important implications for future research in the pathogenesis and treatment of multiple sclerosis.
Abstract Multiple sclerosis (MS), is a chronic disease of the central nervous system (CNS) characterized by loss of motor and sensory function, that results from immune-mediated inflammation, ...demyelination and subsequent axonal damage. MS is one of the most common causes of neurological disability in young adults. Several variants of MS (and CNS demyelinating syndromes in general) have been nowadays defined in an effort to increase the diagnostic accuracy, to identify the unique immunopathogenic profile and to tailor treatment in each individual patient. These include the initial events of demyelination defined as clinically or radiologically isolated syndromes (CIS and RIS respectively), acute disseminated encephalomyelitis (ADEM) and its variants (acute hemorrhagic leukoencephalitis-AHL, Marburg variant, and Balo's concentric sclerosis), Schilder's sclerosis, transverse myelitis, neuromyelitis optica (NMO and NMO spectrum of diseases), recurrent isolated optic neuritis and tumefactive demyelination. The differentiation between them is not only a terminological matter but has important implications on their management. For instance, certain patients with MS and prominent immunopathogenetic involvement of B cells and autoantibodies, or with the neuromyelitic variants of demyelination, may not only not respond well but even deteriorate under some of the first-line treatments for MS. The unique clinical and neuroradiological features, along with the immunological biomarkers help to distinguish these cases from classical MS. The use of such immunological and imaging biomarkers, will not only improve the accuracy of diagnosis but also contribute to the identification of the patients with CIS or RIS who, are at greater risk for disability progression (worse prognosis) or, on the contrary, will have a more benign course. This review summarizes in a critical way, the diagnostic criteria (historical and updated) and the definitions/characteristics of MS of the various variants/subtypes of CNS demyelinating syndromes.
Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on multiple sclerosis is supported by the reduced ...risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiple sclerosis. In this study, we measured 1,25 (OH)2 Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patients separated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)2 Vitamin D on ex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatory mechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosis were studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressive multiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH)D3 and 1,25(OH)2D3, measured by ELISA were significantly lower in relapsing–remitting patients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primary progressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)2D3. Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was induced by 1,25(OH)2D3 in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D3 into biologically active 1,25(OH)2D3, since T cells express α1-hydroxylase constitutively. Finally, 1,25(OH)2D3 also increased the expression and biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these data suggest that 1,25(OH)2D3 plays an important role in T cell homeostasis during the course of multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.
During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates ...and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.
Gray matter brain structures, including deep nuclei and the cerebral cortex, are affected significantly and early in the course of multiple sclerosis and these changes may not be directly related to ...demyelinating white matter lesions. The hippocampus is an archicortical structure that is critical for memory functions and is especially sensitive to multiple insults including inflammation. We used high-resolution MR imaging at 3.0 T to measure hippocampal volumes in relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients and controls. We found that both groups of MS patients had hippocampal atrophy and that this volume loss was in excess of global brain atrophy. Subregional analysis revealed selective volume loss in the cornu ammonis (CA) 1 region of the hippocampus in RRMS with further worsening of CA1 loss and extension into other CA regions in SPMS. Hippocampal atrophy was not correlated with T2-lesion volumes, and right and left hippocampi were affected equally. Volume loss in the hippocampus and subregions was correlated with worsening performance on word-list learning, a task requiring memory encoding, but not with performance on the Paced Auditory Serial Addition Task (PASAT), a test of information processing speed. Our findings provide evidence for selective and progressive hippocampal atrophy in MS localized initially to the CA1 subregion that is associated with deficits in memory encoding and retrieval. The underlying histopathological substrate for this selective, symmetric and disproportionate regional hippocampal vulnerability remains speculative at this time. Further understanding of this process could provide targets for therapeutic interventions including neuroprotective treatments.
Objective
To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data ...used in clinical trials have long‐term prognostic value.
Methods
This is a prospective study of 517 actively managed MS patients enrolled at a single center.
Results
More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long‐term outcomes that were no different from those of the cohort as a whole. 25‐OH vitamin D serum levels were inversely associated with short‐term MS disease activity; however, these levels had no association with long‐term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval CI = 7.2–14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5–22.5%) evolved from relapsing MS to secondary progressive MS (SPMS).
Interpretation
Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2‐year endpoint was not a predictor of long‐term stability. Finally, the data call into question the utility of annual MRI assessments as a treat‐to‐target approach for MS care. Ann Neurol 2016;80:499–510
Novel insights from basic and translational studies are reshaping concepts of the immunopathogenesis of multiple sclerosis and understanding of the different inflammatory responses throughout the ...disease course. Previously, the cellular immunology of relapsing multiple sclerosis was considered to be principally T-cell driven; however, this process is now understood to involve multiple cell types and their functionally distinct subsets. Particularly, relapsing multiple sclerosis appears to involve imbalanced interactions between T cells, myeloid cells, B cells, and their effector and regulatory subpopulations. The major contributors to such imbalances differ across patients. Several emerging techniques enable comprehensive immune cell profiling at the single-cell level, revealing substantial functional heterogeneity and plasticity that could influence disease state and response to treatment. Findings from clinical trials with agents that successfully limit new multiple sclerosis disease activity and trials of agents that inadvertently exacerbate CNS inflammation have helped to elucidate disease mechanisms, better define the relevant modes of action of current immune therapies, and pave the way for new therapeutic strategies.
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a membrane-bound receptor expressed by microglia and macrophages. Engagement of TREM-2 on these cells has been reported to reduce ...inflammatory responses and, in microglial cells, to promote phagocytosis. TREM-2 function is critical within the CNS, as its genetic deficiency in humans causes neurodegeneration with myelin and axonal loss. Blockade of TREM-2 worsened the mouse model for multiple sclerosis. In the present study, a soluble form of TREM-2 protein has been identified by immunoprecipitation and by ELISA. Soluble TREM-2 protein (sTREM-2) was detected in human CSF, and was compared among subjects with relapsing-remitting multiple sclerosis (RR-MS; n = 52), primary progressive multiple sclerosis (PP-MS; n = 21), other inflammatory neurologic diseases (OIND; n = 19), and non-inflammatory neurologic diseases (NIND; n = 41). Compared to NIND subjects, CSF sTREM-2 levels were significantly higher in RR-MS (P = 0.004 by ANOVA) and PP-MS (P < 0.001) subjects, as well as in OIND (P < 0.001) subjects. In contrast, levels of sTREM-2 in blood did not differ among the groups. Furthermore, TREM-2 was detected on a subset of CSF monocytes by flow cytometry, and was also highly expressed on myelin-laden macrophages in eight active demyelinating lesions from four autopsied multiple sclerosis subjects. The elevated levels of sTREM-2 in CSF of multiple sclerosis patients may inhibit the anti-inflammatory function of the membrane-bound receptor suggesting sTREM-2 to be a possible target for future therapies.
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