Different Forms Of Multiple Sclerosis Research Articles

What insights have new imaging techniques given into aggressive forms of MS – different forms of MS or different from MS?

“Aggressive” multiple sclerosis (MS) is still a challenging diagnosis, in spite of the relevant progresses concerning the comprehension of the disease mechanisms, especially through pathology studies and the advent of conventional magnetic resonance imaging (MRI). Some reviews have been already published on their clinical and therapeutical aspects, but no systematic review is available in literature about the neuroradiological features, using both conventional and advanced techniques. In particular, advanced MRI techniques, namely diffusion-weighted and tensor imaging, magnetization transfer imaging, and proton magnetic resonance spectroscopy, are giving new insights to find specific and appropriate radiological parameters that can help in targeting the diagnosis. We report a review of literature on the neuroradiological findings of aggressive forms of MS, focusing specifically on the role of advanced MRI techniques in the diagnostic phase and during follow-up.

Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.

Animal models of multiple sclerosis for the development and validation of novel therapies – potential and limitations

Various types of experimental autoimmune encephalomyelitis (EAE) reflect some of the pathogenetic, clinical, and therapeutic features of the different forms of multiple sclerosis (MS), thereby, providing some, albeit limited, insight into the molecular and cellular basis of the human disease. Specific questions of MS therapy including the search for new therapeutic targets and strategies and their validation require investigations in different available EAE models. A survey is given of experimental therapeutic approaches that are currently under study with the most promising examples of monoclonal antibodies, gene therapy, stem cell transplantation and orally applied small molecular weight disease-modifying drugs. Reasons for therapy failure and adverse side-effects of some experimental trials are discussed. Precaution is advised, if results of new experimental approaches are translated into clinical practice.

Induction of antiidiotypic immune response with autologous T-cell vaccine in patients with multiple sclerosis

Patients with different forms of multiple sclerosis were treated with a vaccine consisting of myelin-reactive T cells. It was found that after this treatment, lymphocytes from patients acquired the capacity to generate antiidiotypic proliferative response directed towards myelin-reactive T cells. The serum concentration of IFN-gamma decreased about 2-fold 1.5-2.0 years after the start of vaccine therapy, whereas the concentration of IL-4 increased 2-3 fold. Myelin-reactive proliferative activity of peripheral blood mononuclear cells also decreased. The results of the 2-year follow-up study revealed no side effect of T-cell vaccination in patients with cerebrospinal form of multiple sclerosis and demonstrated its possible clinical efficiency in the treatment of this disease at early stages.

Building Different Mouse Models for Human MS

Multiple sclerosis (MS) is a clinically and pathologically heterogeneous inflammatory/demyelinating disease of the central nervous system (CNS). Many patients first present with isolated optic neuritis. In some variants of MS, like Devic's disease or neuromyelitis optica (NMO), lesions are predominantly found in the optic nerves and spinal cord but not in the brain. The immunological bases of the different forms of MS are unknown. Here, we summarize our published findings on two mouse models: 2D2 myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic mice, which develop spontaneous isolated optic neuritis, and 2D2 mice crossed with MOG-specific IgH knockin (TH) mice, which spontaneously develop a severe form of experimental autoimmune encephalomyelitis (EAE) with a selective distribution of meningeal and parenchymal inflammatory lesions in the spinal cord and optic nerves similar to that found in human Devic's disease.

Interferon-β regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis

The mechanism of action of interferon (IFN)-β therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-β regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-γ, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-naïve patients secreted more IL-10 than healthy controls. During IFN-β therapy, however, T cells produced less IL-10. In vitro, IFN-β stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-β therapy increased BDNF levels in antidepressant-naïve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-β in vitro strongly induced IL-10 and IFN-γ in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-β effects are specific for disease state and immune subsets, possibly explaining why IFN-β therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes. Multiple Sclerosis 2007; 13: 459-470. http://msj.sagepub.com

Myelin oligodendrocyte glycoprotein–specific T and B cells cooperate to induce a Devic-like disease in mice

Multiple sclerosis (MS) is a clinically and pathologically heterogeneous inflammatory/demyelinating disease of the CNS. In the MS variant Devic disease, lesions are predominantly found in the optic nerves and spinal cord but not the brain. The immunological bases of the different forms of MS are unknown. We previously generated myelin oligodendrocyte glycoprotein-specific (MOG-specific) TCR transgenic mice (TCRMOG mice; also referred to as 2D2 mice) and reported that a large proportion of these mice develop spontaneous isolated optic neuritis. We have now crossed the TCRMOG mice with MOG-specific Ig heavy-chain knock-in mice (IgHMOG mice; also referred to as Th mice), in which one-third of the B cells are specific for MOG. In these mice, MOG-specific B cells are very efficient in presenting MOG to the transgenic T cells and undergo class switching to IgG1 in the presence of the transgenic T cells. Sixty percent of TCRMOG x IgHMOG mice spontaneously developed a severe form of experimental autoimmune encephalomyelitis (EAE). Histological examination of the CNS revealed a selective distribution of meningeal and parenchymal inflammatory lesions in the spinal cord and optic nerves. Thus, CNS antigen-specific T and B cells cooperate to induce a distinct clinicopathologic EAE pattern that closely replicates human Devic disease.

The spectrum of multiple sclerosis and treatment decisions

An increasing number of patients referred for neuroimaging studies unrelated to multiple sclerosis (MS) are found to have incidental lesions suggestive of MS in their nervous systems but many such patients do not develop clinical symptoms and signs and remain as “subclinical MS” (SCMS). MRI and cerebrospinal fluid (CSF) studies in monozygotic twins and siblings of MS patients, as well as necropsy studies in asymptomatic persons also reveal findings consistent with SCMS. Clinically isolated syndromes (CIS), acute disseminated encephalomyelitis (ADEM), benign MS, relapsing-remitting MS, primary and secondary progressive MS, optico-spinal MS, Balo's and Marburg's diseases, are considered different forms of MS by many because of their heterogeneous clinical, imaging and pathological features. Studies of disease susceptibility, type, course and severity have given different results in different populations, consistent with “genetic heterogeneity”. The various forms of the disease may change from one to another, and their clinical and imaging features became similar after a number of years. The current data support the concept that MS, whether it is a single disease or a group of disorders, is an immune-mediated disease of the CNS, with both inflammatory and degenerative features with available therapies being only partially and temporarily effective for the inflammatory phase of the disease. Making the diagnosis of MS may not be an absolute indication for early treatment with disease modifying agents. The use of new technology such as microarray and other techniques in diagnosing and understanding the MS spectrum may make it possible to recognize the different molecular subtypes of these diseases and develop better therapies.

Massive Apoptosis in Lymphoid Organs in Animal Models for Primary and Secondary Progressive Multiple Sclerosis

The mechanism(s) responsible for generating the different forms of multiple sclerosis, primary progressive (PP) and secondary progressive (SP) versus relapsing-remitting (RR), is not well understood. Using myelin oligodendrocyte glycoprotein (MOG)(92-106), we have established animal models that mimic the different types of multiple sclerosis. A.SW mice develop PP or SP-experimental allergic encephalomyelitis (EAE) with large areas of demyelination and high titers of MOG antibody whereas SJL/J mice develop RR-EAE with perivascular T cells and mild demyelination. In A.SW progressive EAE, we found atrophy of the thymus, spleen, and lymph nodes with depletion of T and B cells and massive apoptosis, as demonstrated by immunohistochemistry, terminal dUTP nick-end labeling, and DNA agarose gel electrophoresis. To test whether lymphoid apoptosis itself contributes to disease progression, we injected SJL/J mice with apoptotic thymocytes. Injection of apoptotic cells resulted in greater than 20% of mice developing SP-EAE with ataxia. SJL/J mice with SP-EAE had large areas of demyelination, high MOG antibody titers and atrophic lymphoid organs. Spleen cells from mice with progressive EAE produced less interferon-gamma than those from RR-EAE when stimulated with mitogen. We suggest that induction of lymphoid apoptosis alters the balance of Th1 versus Th2 immune responses and increases MOG antibody production, leading to exacerbation of demyelination and subsequent disease progression.

Mechanisms of normal appearing corpus callosum injury related to pericallosal T1 lesions in multiple sclerosis using directional diffusion tensor and 1H MRS imaging

Objectives: To investigate the extent of tissue damage in a region of normal appearing corpus callosum (NACC) for different forms of multiple sclerosis (MS) using diffusion tensor and proton magnetic...

The nature of multiple sclerosis

Multiple sclerosis (MS) has recently been classified according to its clinical course. Despite relapses and remissions, its course is invariably progressive, and the observed progression from the remitting-relapsing to the secondary progressive form represents the accumulation of permanent damage to the nervous system. Discussions of the nomenclatural position of Schilder’s, Marburg’s, and Baló’s diseases, ignore the fact that the unique, pathognomonic, sharp-edged plaque of MS, is also the pathologic end-result in the three variants. Devic’s disease or neuromyelitis optica (NMO) is quite different and with some exceptions, is a particular form of disseminated encephalomyelitis (DEM). There is no evidence that the ‘oriental form of MS’ is anything but NMO. The suggestion that MS and DEM are variants of the same condition is contradicted by the fact that the pathological characteristics of the two are quite different. While it is probable that the two share aspects of pathogenesis, the patients differ because of their genetic endowment. This was dramatically demonstrated in a group of Japanese patients who died after anti-rabies vaccination and were found to have the typical sharp-edged lesions of MS. The genetic determinant was also crucial in the marmoset in which EAE uniquely resulted in a chronic relapsing-remitting (RR) disease characterized by the classic sharp-edged lesions of MS. The question ‘ADEM: distinct disease or part of the MS spectrum?’ can be answered with a resounding no. A new classification is proposed separating the different forms of MS from the various types of DEM.

The use of animal models to investigate the pathogenesis of neuroinflammatory disorders of the central nervous system.

A major hurdle in the research of neuroinflammatory disorders of the central nervous system is the inaccessibility of the organ. Thus investigation is limited to end-stage disease and systemic changes that occur during disease progression, neither of which may reflect the pathological process in the central nervous system. These factors may explain the lack of effective therapies in multiple sclerosis, a common chronic inflammatory disease of the central nervous system. To overcome such limitations approaches using more relevant animal models have been developed to study pathological mechanisms as well as the design of rational therapeutic strategies. This review describes the animal models used to study pathological processes leading to inflammation within the central nervous system that may be operating in multiple sclerosis and the use of these models in the design of more rational therapeutic strategies. The clinical heterogeneity of multiple sclerosis as well as the finding of different pathological patterns suggests that multiple sclerosis may be a spectrum of diseases that may represent different pathological processes. This and the renewed interest in the extent of axonal damage has led to the development of more relevant animal models, such as those in nonhuman primates, that both reflect the spectrum of multiple sclerosis and allow the development of species-specific therapeutic approaches. While many animal models are available, the use of relevant animal models that mimic either the different forms of multiple sclerosis or the spectrum of multiple sclerosis is critical to examine those factors, for example genes or proteins, that are of pathogenic relevance and can be used as targets for therapy.

Equiluminant red-green and blue-yellow VEPs in multiple sclerosis.

The primate visual system is composed by two color-opponent pathways--red-green (R-G) and blue-yellow (B-Y)--subserved by the so-called parvo- and koniocellular streams respectively. The authors' aim was to compare the relative involvement of chromatic visual subsystems in multiple sclerosis (MS). In 30 MS patients with different forms of MS they recorded visual evoked potentials (VEPs) to onset (300 msec) and offset (700 msec) of equiluminant R-G and B-Y sinusoidal gratings of different contrast (90% and 25%). Equiluminance was established psychophysically by establishing the R-G and the B-Y color ratio at which chromatic gratings alternating at 15 and 10 Hz respectively had minimum visibility. The negative wave at stimulus onset with a peak latency of 120 to 160 msec was evaluated. Ordinary VEPs to luminance (LUM) contrast (black-white reversing checkerboards of 15' check size and 50% contrast) were also recorded for comparison. Latencies of R-G VEPs were abnormal in 53.3% and 58.3% of patients at 90% and 25% contrast respectively, whereas abnormal B-Y VEPs were 56.6% and 48.3%. Latencies of LUM VEPs were abnormal in 45% of patients. Interocular latency asymmetries were abnormal in 59.2% and 33.3% of patients for R-G, and 51.8% and 62.9% for B-Y. Latency asymmetries for LUM VEP were abnormal in 46.4% of patients. The higher rate of VEP abnormalities found with equiluminant chromatic stimuli compared with achromatic stimuli confirms the general vulnerability of color-opponent visual pathways in MS, even if the number of patients with abnormal findings was not significantly different when both test conditions were compared. VEPs to R-G and B-Y equiluminant stimuli appear to be involved approximately to the same extent.

Antibody association with a novel model for primary progressive multiple sclerosis: induction of relapsing-remitting and progressive forms of EAE in H2s mouse strains.

Multiple sclerosis (MS) can be divided into 4 clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP), and progressive relapsing (PR). Since PP-MS is notably different from the other forms of MS, both clinically and pathologically, the question arises whether PP-MS is immunologically similar to the other forms. The pathogenesis of the PP-MS remains unclear, partly due to a lack of highly relevant animal models. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic different forms of MS in 2 strains of H-2s mice, SJL/J and A.SW. We induced experimental allergic encephalomyelitis (EAE) using MOG92-106 in the presence or absence of supplemental Bordetella pertussis (BP). Although, SJL/J mice developed RR-EAE whether BP was given or not, A.SW mice developed PP-EAE without BP and SP-EAE with BP. Histologically, SJL/J mice developed mild demyelinating disease with T cell infiltration, while A.SW mice developed large areas of plaque-like demyelination with immunoglobulin deposition and neutrophil infiltration, but with minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody was detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of mice. We hypothesized that, in A.SW mice, a Th2 response favors production of myelinotoxic antibodies, leading to progressive forms with early death. Our new models indicate that a single encephalitogen could induce either RR-, PP-, or SP- forms of demyelinating disease in hosts with immunologically different humoral immune responses.

Patterns of oligodendroglia pathology in multiple sclerosis.

Patterns of inflammation, demyelination and oligodendrocyte pathology were studied in acute multiple sclerosis and during early and late exacerbations of chronic multiple sclerosis. Cells within lesions were identified by immunocytochemistry with markers for T lymphocytes, macrophages, oligodendrocytes and astrocytes. In addition, in situ hybridization for proteolipid protein mRNA was used to identify myelinating and myelin supporting oligodendrocytes. Degenerating cells in the lesions were detected by DNA fragmentation in cell nuclei. The inflammatory reaction in all three types of multiple sclerosis lesions was shown to be dominated by T lymphocytes and macrophages. In late chronic multiple sclerosis lesions, a significant increase in the number of immunoglobulin producing plasma cells was found in infiltrates as compared with acute and early multiple sclerosis lesions. In all three types of multiple sclerosis, confluent plaques of demyelination were found to be present. In acute multiple sclerosis, demyelination was found to be associated with extensive destruction of other tissue elements, including oligodendrocytes, astrocytes and axons, but even in these destructive lesions a considerable number of oligodendrocytes was preserved and at disposal therefore, for rapid remyelination. During early exacerbations of chronic multiple sclerosis, selective demyelination was associated with almost complete preservation of oligodendrocytes in the majority of cases. Correspondingly, a high number of remyelinating lesions was present at that stage of disease. In lesions developing late after onset of multiple sclerosis, demyelination generally accompanied extensive destruction and loss of oligodendrocytes. In these lesions, remyelination was sparse and restricted to lesional borders. The observed patterns of cell death suggest that in some cases oligodendrocytes, in others myelin sheaths are the primary target of the destructive process. Our data indicate that the type and amount of inflammation, de- and remyelination, and of tissue damage vary between different forms of multiple sclerosis and between different stages of the disease, possibly reflecting different pathogenic mechanisms in a disease spectrum.

Risk Factors by Onset Age in Multiple Sclerosis

Some investigators have suggested that there are different forms of multiple sclerosis (MS) based on onset age, and that each has a different etiology. 173 Canadian MS patients were matched to controls on age, gender, race and risk zone prior to age 15. Data were collected on: age at onset, gender, initial symptom, disability level, residence history and family background. Three onset age subgroups (early, intermediate and late) were derived. Matched-pair logistic regression analysis indicated that rural residence, use of well water and an MS family history distinguished between patients and controls overall, but showed no significant interaction with onset age. A family history of diabetes distinguished between patients and controls with evidence of age interaction, in that this risk factor decreased in importance as onset age increased.