Multiple Sclerosis Disease Process Research Articles

New Hypointense Lesions on MRI in Relapsing-Remitting Multiple Sclerosis Patients

Background: Preliminary observational studies with multiple sclerosis (MS) patients have reported strong correlations between an increase in hypointense lesion load (black holes) on T1-weighted spin echo images, and an increase in disability. Objective: We assessed the relationship of hypointense lesions to the clinical course of disease among 50 relapsing-remitting MS patients in the controlled setting of a randomized clinical trial. Methods: Fifty patients with relapsing-remitting disease were enrolled in a randomized double-blind two-arm (cladribine vs. placebo) clinical trial of 1-year duration. All patients had monthly clinical evaluations and MRIs over the course of the trial. Multivariate techniques were used to identify predictors of clinical severity from information on exacerbations, MRIs, baseline clinical parameters, and demographics. Results: At baseline, clinical severity is weakly related to counts of black holes, with rank correlations between counts and clinical scores (EDSS and SNRS) of absolute magnitude 0.3. Rates of appearance of new black holes over the course of the trial are higher for patients with more severe disease at baseline (EDSS ≥ 4) than for the less severe patients. Changes in clinical severity over the course of the trial are best predicted by baseline neurologic scores and numbers of exacerbations, with black holes adding no further improvement in prediction. Conclusions: Numbers of exacerbations seem more critical to short-term clinical outcomes in relapsing-remitting MS, as reflected by patients’ clinical scores, rather than black holes. Various imaging methods and MRI indices capture complementary information relating to MS disease processes. The determination of which processes are affected by different drugs should lead to more effective treatment of MS patients.

The pathology of multiple sclerosis and its evolution

The pathology of multiple sclerosis (MS) was defined more than a century ago as a chronic inflammatory process which is associated with widespread primary demyelination and glial scarring. In this short review we discuss controversial issues on (i) the relationship between inflammation and demyelination, (ii) the various possible mechanisms of myelin destruction, and (iii) axonal involvement in this disease. We suggest that the disease process of MS is more complex that previously believed.

Analysis of gene expression in mutiple sclerosis lesions using cDNA microarrays.

In multiple sclerosis (MS) patients, a coordinated attack of the immune system against the primary constituents of oligodendrocytes and/or the myelin sheath of oligodendrocytes results in the formation of lesions in the brain and spinal cord. Thus far, however, a limited number of genes that potentially contribute to lesion pathology have been identified. Using cDNA microarray technology, we have performed experiments on MS tissue monitoring the expression pattern of over 5,000 genes and compared the gene expression profile of normal white matter with that found in acute lesions from the brain of a single MS patient. Sixty-two differentially expressed genes were identified, including the Duffy chemokine receptor, interferon regulatory factor-2, and tumor necrosis factor alpha receptor-2 among others. Thus, cDNA microarray technology represents a powerful new tool for the identification of genes not previously associated with the MS disease process.

Value of Magnetic Resonance Imaging in Assessing Efficacy in Clinical Trials of Multiple Sclerosis Therapies

Magnetic resonance imaging (MRI) has become an important technique for monitoring the effectiveness of putative treatments for multiple sclerosis (MS) because of its high sensitivity, objectivity, and noninvasive nature. Its importance as a surrogate measure of disease, however, is an issue that is more difficult to validate than might seem to be the case. In this review, we describe the role of MRI in the assessment of putative therapies for MS. New magnetic resonance techniques and methods of image analyses aimed at better demonstrating the nature and extent of disease are discussed, and the role of MRI in published MS therapeutic trials is examined. MRI is a frequently used secondary outcome measure for putative treatment strategies for MS. Although it is sensitive to changes in the inflammatory component of the MS disease process, poor correlation has been noted between MRI findings and long-term patient outcome. There is a widespread expectation that new magnetic resonance techniques--such as fluid-attenuated inversion recovery, magnetization transfer imaging, and magnetic resonance spectroscopy--will ultimately be useful for characterization of pathologic changes within the MS lesion and more generally of the MS disease process. Whether magnetic resonance changes seen in experimental therapies predict the long-term clinical course of the disease remains to be determined.

Intravenous immunoglobulin G therapy: effects of acute and chronic treatment in multiple sclerosis.

High dose intravenous immunoglobulin (IVIG) exerts several effects on the immune system that could have a beneficial influence on the disease processes in multiple sclerosis (MS). IVIG may be useful in treatment of acute exacerbations, in prevention of new relapses, and in promotion of remyelination. Presently, the clinical evidence of effect of IVIG in MS is based on the results of small open trials, some of which, however, have been encouraging. Confirmation of a beneficial effect of IVIG must await the results of placebo-controlled, double-blind trials currently ongoing in several centers. If effective, IVIG administration would be a valuable supplement to the existing treatment of MS.

Herpes Simplex Virus in Postmortem Multiple Sclerosis Brain Tissue

Herpes simplex virus (HSV) is a common neurotropic virus that is capable of long latencies. It can cause focal demyelination in animals. To test for the presence of HSV-1 and -2 in postmortem brain samples from patients with multiple sclerosis (MS) and controls using polymerase chain reaction and Southern blot hybridization. Dissected plaque tissue classified as active or inactive and unaffected white matter (WM) and gray matter (GM) from 37 cases of MS were screened for HSV using polymerase chain reaction and Southern blot hybridization. White matter and GM from 22 cases of Alzheimer's disease, 17 cases of Parkinson's disease, and 22 cases without neurologic disease served as controls. Forty-six percent (17/37) of the MS cases and 28% (17/61) of the control cases had samples that were positive for HSV (P = .11). Forty-one percent (9/22) of active plaques and 20% (6/30) of inactive plaques were positive for HSV. Twenty-four percent (9/37) and 14% (5/37) of MS cases and 23% (14/61) and 13% (8/61) of non-MS cases had HSV in WM and GM, respectively. No significant differences were found among all subgroups (P = .10). Herpes simplex virus was present in more MS cases than control cases and in more active plaques than inactive plaques. The presence of HSV in WM and GM in cases of MS as well as in control cases makes an etiologic association to the MS disease process uncertain, but cellular localization of HSV and its relationship to oligodendrocytes and latency may reveal such an association in future studies.

Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis.

The presence of T lymphocytes bearing the gamma delta T-cell receptor (TCR gamma delta) has been studied immunocyto-chemically in central nervous system (CNS) tissue from 13 patients with multiple sclerosis (MS), 4 with inflammatory non-MS CNS disorders, 6 with other neurological diseases, and 3 with nonneurologic conditions. Twenty-eight of 43 MS lesions contained TCR gamma delta cells and these were most frequently found in chronically demyelinated areas, in contrast to the previously studied CD4+, CD8+ (TCR alpha beta) population, which predominated in more active lesions. Some TCR gamma delta lymphocytes had an unusual morphology with long dendritic processes, which were sometimes interconnected forming a network. Because it is generally believed that TCR gamma delta lymphocytes function in a cytotoxic fashion in association with heat shock proteins (hsp), we examined the colocalization of TCR gamma delta cells with 65- and 70-kDa hsp (hsp65 and hsp70) in MS lesions. Hsp65 was expressed on immature oligodendrocytes at the margins of chronic lesions containing TCR gamma delta lymphocytes. The coexpression of these molecules might imply functional relationships perhaps of significance to the chronicity of the MS disease process and the failure of CNS remyelination.

Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study.

To compare the abnormalities shown by magnetic resonance imaging of the brain in three clinically distinct groups of patients with multiple sclerosis, and to correlate the extent of abnormality with the degree of clinical disability in the three groups. All patients underwent magnetic resonance imaging and full neurological examination, and their disability was scored according to the expanded Kurtzke disability state scale. National Hospital for Nervous Diseases (Multiple Sclerosis NMR Research Group). Three groups of patients with confirmed multiple sclerosis were studied: 12 patients with minimal disability despite a long (greater than 10 years) duration of illness (benign multiple sclerosis), 16 who had developed progressive disability after a relapsing and remitting course (secondary progressive multiple sclerosis), and 13 who had had progressive disability from the onset of the disease (primary progressive multiple sclerosis). Number and size of lesions in 17 anatomically defined sites; total lesion load, estimated with an arbitrary scoring system weighted for the size of lesions; and disability score. Magnetic resonance imaging showed that all 41 patients had abnormalities. These were extensive in the groups with secondary progressive and benign disease compared with the group with primary progressive disease. The lesions in the patients with secondary progressive disease were larger and more confluent than those in the two other groups (p = 0.007). Most lesions (85%) in the patients with primary progressive disease were under 5 mm in diameter; this percentage was higher than that in the two other groups (p = 0.032). Consequently the patients with primary progressive disease had the lowest mean lesion load (36.7); that in the patients with benign disease was 52.7 and that in the patients with secondary progressive disease 64.6 (p = 0.05). No correlation existed between disability and total lesion load. The distribution of brain lesions and of detectable lesions of the spinal cord, and the frequency of cortical atrophy, were similar in all groups. No relation was found between the degree of clinical disability and the extent of abnormality shown by magnetic resonance imaging: patients with clinically benign disease often had extensive abnormalities and those with primary progressive disease had surprisingly few lesions. Though magnetic resonance imaging increases knowledge of the disease process in multiple sclerosis and is invaluable in diagnosis, it is not helpful in predicting disability in individual patients.

Peripheral blood T lymphocyte changes in multiple sclerosis: a marker of disease progression rather than of relapse?

A serial study of peripheral blood T lymphocytes in 27 patients with clinically definite multiple sclerosis and 11 healthy controls was carried out over a 12 month period. This showed that contrary to many previous reports, relapses were not consistently associated with reduced numbers of peripheral blood suppressor T lymphocytes or any other T cells. Persistently low T cells numbers, including both the helper and suppressor T cell subsets, were, however, associated with disease activity as measured by the development of increased disability during the course of the study. This was true both for the patients with relapsing/remitting disease and those with progressive disease. The importance of carrying out a serial study was emphasised by the consistent and significant differences that were detected between individuals in both the control and the patient groups. A serial study is the most reliable means by which clinical events can clearly be correlated with laboratory estimations. The association in this study between the development of increased disability and persistently low levels of peripheral blood T lymphocytes suggest that both may be related to the underlying disease process in multiple sclerosis.

Intrathecal Interferon in the Treatment of Multiple Sclerosis

Follow-up observations on patients with multiple sclerosis who were treated with human fibroblast interferon (interferon beta) administered intrathecally for six months revealed a persisting beneficial effect in terms of a reduction in exacerbation rates. At the time of our last report in 1982, ten interferon beta recipients had shown a reduction in their mean exacerbation rate from 1.8/yr before the study to 0.2/yr during the study while ten control patients with multiple sclerosis showed no change in their rates during the study (0.69/yr) compared with before it (0.68/yr). That report was based on observations made for means of 1.9 years in the recipients and 1.6 years in the controls. The recipient patients have now been followed up for 4.4 years (mean) and their exacerbation rates have continued to decrease to a current mean level of 0.16/yr. The control patients were "crossed over" and began receiving interferon beta intrathecally after they had been in the study for two years without showing any change in their rate. During the 2.0 years since crossover they also have shown a reduction in exacerbation rate to a mean of 0.30/yr. The toxic side effects of interferon beta administered intrathecally were acceptable in view of the benefit achieved. Interferon was identified in the cerebrospinal fluid (but not the serum) of two patients prior to treatment, which is probably a manifestation of de novo production of interferon by the central nervous system in response to the multiple sclerosis disease process.

A T lymphocyte subpopulation in multiple sclerosis patients bearing Fc receptors for both IgG and IgM1.

Abnormally low proportions of total T lymphocytes were found in peripheral blood lymphocytes (PBL) of patients with multiple sclerosis (MS) accompanied by high proportions of T lymphocytes with Fc receptors (FcR) for IgG (T gamma cells). Seventy-five percent of the MS patients had greater than 40% T gamma in the T lymphocyte-enriched population. In 6 out of 16 cases, T mu were also elevated. This elevation, however, did not seem to correlated with disease stage. By mixed rosetting and direct observation with an indirect immunofluorescence test, 30 to 50% of the T gamma cells in MS PBL were also shown to bear FcR for IgM. This population bearing FcR for IgG and IgM, designated T gamma mu, was usually found to be 10% or less of the T gamma population in normal controls. The significance of this T gamma mu population for the MS disease process requires further evaluation.