Clinically Definite Multiple Sclerosis Research Articles

Screening of Cerebrospinal Fluid and Blood Sera of Multiple Sclerosis Patients for Oligoclonal Immunoglobulins by Capillary Electrophoresis

Multiple sclerosis (MS) is an autoimmune disease characterized by the production of specific types of immunoglobulins into the central nervous system. These immunoglobulins appear as oligoclonal bands (OCBs) in agarose isoelectric focusing (IEF) of cerebrospinal fluid (CSF). Among the cases with clinically definite MS, up to 95% have oligoclonal IgG bands in their CSF. In this report, we describe a micellar electrokinetic capillary chromatography (MEKC) method for the separation of CSF and serum proteins. MEKC was performed using 25 mM borate buffer, pH 10, containing 25 mM SDS at 20 kV and normal polarity. High values of repeatability in migration times and of reproducibility in peak areas were obtained (R.S.D. values were less than 2%). Calibration graphs were linear up to 2000 mg L−1. LOQ was 6.5 mg L−1 and LOD determined as a signal to noise ration of 3:1 was 4.5 mg L−1. Analysis of CSF and serum samples from patients with clinical definite MS and healthy individuals demonstrated the presence of two peaks migrating as γ-globulins in the CSF samples of patients. These peaks were absent from controls and the serum of the same patients. Correlation of the data obtained from IEF and MEKC analysis for 25 patients showed that the diagnostic sensitivity and specificity of MEKC were ca 89% and 92% respectively. The obtained results indicate that this MEKC method may be helpful for the diagnosis of multiple sclerosis. Capillary electrophoresis compared to flat bed IEF provides reproducible results, requires shorter analysis time, and allows direct quantitative determination.

Temporal variations of adhesion molecules and matrix metalloproteinases in the course of MS

Thirty patients with clinically isolated syndromes (CIS) were evaluated at the onset of neurological symptoms and when they developed clinically definite MS (CDMS). Surface expression of LFA-1α, VLA-4 and intercellular adhesion molecule-1 (ICAM-1) on PBMC and CSF cells was evaluated using flow cytometry. Serum and CSF concentrations of soluble vascular cell adhesion molecules-1 (VCAM-1), ICAM-1 and E-Selectin, as well as MMP-9 and MMP-2 serum concentrations were assayed using ELISA. Surface expression of LFA-1α and VLA-4 molecules on peripheral blood and CSF T cells and monocytes from CIS and CDMS was significantly increased compared with control subjects. Moreover, LFA-1α and VLA-4 expression was significantly higher in patients who developed CDMS compared with those with CIS. Similar changes were observed in the serum levels of MMP-9. Furthermore, patients with CIS and CDMS had significantly higher levels of CSF sVCAM and s-E-Selectin than control subjects. These data suggest that VLA-4, LFA-1α and MMP-9 play a leading role in the evolution of inflammatory demyelinating lesions in patients with CIS who develop CDMS.

Approach to discriminate subgroups in multiple sclerosis with cerebrospinal fluid (CSF) basic inflammation indices and TNF-α, IL-1β, IL-6, IL-8

Lumbar CSF and serum pairs of untreated multiple sclerosis patients (MS; n=47) were analyzed on admission. On average, higher CSF leukocyte (lymphocyte and monocyte) counts, IgG index, CSF IgG contents, but not of TNF-α, IL-1β, IL-6, IL-8 in CSF and serum, were revealed in all MS or patients with long disease course (LO-MS) compared with controls. In primary progressive MS (PP-MS) cell counts were low, but IgG contents were high, when compared to relapsing-remitting MS (RR-MS). In clinically probable MS (CP-MS) both contents were low, in clinically definite MS (CD-MS) high. Spearman’s correlation with the four monokines and the basic indices in CSF revealed activation patterns known for microglia/macrophages in the four MS subgroups, for astrocytes in CP-MS and RR-MS, for CSF lymphocytes in CP-MS and PP-MS, for cells of blood–brain barrier (BBB) in CP-MS, for intrathecal IgG synthesis in PP-MS and for lymphocyte transfer in CD-MS. Correlations between CSF and serum parameters indicated CNS disease processes to be associated with systemic processes of inflammation (acute, chronic) in CD-MS, RR-MS, and PP-MS in different ways. CSF IgG content, IgG index and systemic markers of inflammation correlated with overall disability scores in LO-MS; increasing levels may indicate a bad outcome.

Predicting multiple sclerosis at optic neuritis onset.

Using multivariate analyses, individual risk of clinically definite multiple sclerosis (CDMS) after monosymptomatic optic neuritis (MON) was quantified in a prospective study with clinical MON onset during 1990-95 in Stockholm, Sweden. During a mean follow-up time of 3.8 years, the presence of MS-like brain magnetic resonance imaging (MRI) lesions and oligoclonal immunoglobulin (Ig) G bands in cerebrospinal fluid (CSF) were strong prognostic markers of CDMS, with relative hazard ratios of 4.68 [95% confidence interval (CI) 2.21-9.91] and 5.39 (95% CI 1.56-18.61), respectively. Age and season of clinical onset were also significant predictors, with relative hazard ratios of 1.76 (95% CI 1.02-3.04) and 2.21 (95% CI 1.13-3.98), respectively. Based on the above two strong predictors, individual probability of CDMS development after MON was calculated in a three-quarter sample drawn from a cohort, with completion of follow-up at three years. The highest probability, 0.66 (95% CI 0.48-0.80), was obtained for individuals presenting with three or more brain MRI lesions and oligoclonal bands in the CSF, and the lowest, 0.09 (95% CI 0.02-0.32), for those not presenting with these traits. Medium values, 0.29 (95% CI 0.13-0.53) and 0.32 (95% CI 0.07-0.73), were obtained for individuals discordant for the presence of brain MRI lesions and oligoclonal bands in the CSF. These predictions were validated in an external one-quarter sample.

Time course of T-cell responses to MOG and MBP in patients with clinically isolated syndromes

CD4 + T-cell lines (TCLs) from patients with clinically isolated syndromes (CIS) were selected with purified human myelin basic protein (MBP) and recombinant human myelin oligodendrocyte glycoprotein (rhMOG), at onset of neurological symptoms and when patients developed clinically definite multiple sclerosis (CDMS). The epitope specificity of each TCL was mapped with overlapping synthetic peptides. TCLs were assessed for their ability to secrete IFN-γ, IL-4, and IL-6. Diverse patterns of epitope recognition were observed: (a) recognition of a broad spectrum of MBP peptide epitopes with evidence of shifts over time; (b) an initial T-cell response focused to a restricted segment of the MBP molecule (83–102) that broadened over the course of disease; and (c) persistence of a focused anti-MOG T-cell response. CIS patients who failed to develop CDMS maintained a focused epitope response against two to six MBP epitopes. Most MBP peptide-specific TCLs secreted considerable amounts of IFN-γ and low amounts of IL-4 and IL-6, whereas anti rhMOG Igd peptide-specific TCLs secreted preferentially IL-4 and IL-6. These data raise important issues for the pathogenesis and treatment of multiple sclerosis (MS).

Acute demyelinating optic neuritis.

Acute demyelinating optic neuritis associated with multiple sclerosis (MS) is the most common cause of inflammation of the optic nerve. The Optic Neuritis Treatment Trial (ONTT) has provided important clinical data on the use of corticosteroids, and demonstrated that patients with characteristic inflammatory lesions within the brain on magnetic resonance imaging had a greater chance of developing clinically definite MS (CDMS). The current approach to patients with optic neuritis has been modified by the results of the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS). Patients with an initial clinical episode of demyelination (optic neuritis, incomplete transverse myelitis, or brain-stem/cerebellar syndrome) and at least two characteristic demyelinating lesions within the brain were randomized to receive interferon beta-1a or placebo after initial treatment with intravenous corticosteroids. At the 3-year point patients treated with interferon beta-1a showed a 50% less risk of CDMS. The results of this study have set the standard for patients with a first bout of demyelinating optic neuritis.

Multiple sclerosis in Malta in 1999: an update

Objectives: To ascertain the prevalence of multiple sclerosis (MS) in the islands of Malta and compare it with a previous study undertaken 21 years earlier, when a remarkably low prevalence...

Expansion of CD5 - B cells in multiple sclerosis correlates with CD80 (B7-1) expression.

The pathogenetic role of autoantibodies in multiple sclerosis (MS) is uncertain. CD5+ B cells commonly produce autoantibodies, but CD5 expression has also been implicated in B-cell tolerance. We studied B-cell subsets, anti-myelin protein antibody-secreting cells in cerebrospinal fluid (CSF) and a panel of serum autoantibodies in patients with clinically isolated syndromes (CIS), suggestive of MS and patients with clinically definite MS (CDMS). Patients with CDMS had a higher percentage of CD5- B cells in CSF than did control subjects (P = 0.02). CIS patients with immunoglobulin G (IgG) oligoclonal bands in CSF or multiple lesions on magnetic resonance imaging (MRI) had a higher percentage of CD5- B cells in CSF than did the remaining CIS patients (P = 0.03). The percentage of CD5- and CD80+ B cells correlated positively and the percentage of CD5+ B cells correlated negatively with the number of CSF cells secreting anti-myelin basic protein (anti-MBP) antibodies. The prevalence of serum autoantibodies was comparable in the three patient groups. We conclude that intrathecal expansion of CD5- B cells appears to be more characteristic in MS patients, and CD5+ B cells may be associated with a lower prevalence of anti-myelin antibody production.

Treatment of acute demyelinating optic neuritis

Patients with typical acute monosymptomatic demyelinating optic neuritis should receive gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and orbits to determine if they are at high risk for the subsequent development of clinically definite multiple sclerosis (CDMS). The presence of ≥2 white matter lesions (≥3 mm in diameter, at least 1 lesion periventricular or ovoid) indicates high risk for CDMS; the following treatment should be considered for such patients: 1. Intravenous methylprednisolone sodium succinate (1 gram IV/day for 3 days) followed by oral prednisone (1 mg/kg/day for 11 days) with 4-day taper (20 mg on day 1, 10 mg on days 2 and 4); 2. Interferon beta 1-a (Avonex 30μg intramuscularly [IM] weekly, or Rebif 22μg subcutaneously [SQ] weekly). These two drugs have been shown to reduce the short-term risk of CDMS in high risk monosymptomatic patients. In monosymptomatic patients with <2 white matter lesions, and in patients for whom CDMS has been established, IV methylprednisolone treatment followed by oral prednisone should be considered on an individual basis. Treatment in these patients may hasten visual recovery, but does not affect long-term visual outcome. Oral prednisone alone, without prior treatment with IV methylprednisolone, may increase the risk for recurrent optic neuritis and should be avoided.

Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS.

To evaluate and compare the capacity of oligoclonal bands (OB) and three sets of MR imaging criteria to predict the conversion of clinically isolated syndromes (CIS) to clinically definite multiple sclerosis (CDMS). One hundred and twelve patients with CIS were prospectively studied with MR imaging and determination of OB. Based on the clinical follow-up (conversion or not conversion to CDMS), we calculated the sensitivity, specificity accuracy, positive and negative predictive value of the OB, and MR imaging criteria proposed by Paty et al, Fazekas et al and Barkhof et al. CDMS developed in 26 (23.2%) patients after a mean follow-up of 31 months (range 12-62). OB were positive in 70 (62.5%) patients and were associated with a higher risk of developing CDMS. OB showed a sensitivity of 81%, specificity of 43%, accuracy of 52%, positive predictive value (PPV) of 30% and negative predictive value (NPV) of 88%. Paty and Fazekas criteria showed the same results with a sensitivity of 77%, specificity of 51%, accuracy of 57%, positive predictive value of 32% and negative predictive value of 88%. Barkhof criteria showed a sensitivity of 65%, specificity of 70%, accuracy of 69%, PPV of 40% and NPV of 87%. The greatest accuracy was achieved when patients with positive OB and three or four Barkhof's criteria were selected. We observed a high prevalence of OB in CIS. OB and MR imaging (Paty's and Fazekas' criteria) have high sensitivity. Barkhof's criteria have a higher specificity. Both OB and MR imaging criteria have a high negative predictive value.

Magnetic resonance imaging findings predicting subsequent disease course in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.

This review summarizes the main contributions given by magnetic resonance imaging (MRI) to predict disease evolution in patients at presentation with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). In these patients, the extent of lesions on T2-weighted scans of the brain is a robust predictor of the subsequent development of clinically definite MS (CDMS), moderate to severe disability and new MRI lesions. The risk of developing CDMS in patients with CIS is further increased when some of these lesions are enhancing or when additional lesions are seen on T2-weighted scans of the spinal cord. Recent studies using new MRI techniques have shown that irreversible tissue disruption is an early event in the course of MS and that subtle normal-appearing white matter changes occur in patients with CIS and are associated with an increased risk of developing CDMS. These findings are changing our views of how to monitor early MS evolution and of early MS treatment strategy.

Optic Neuritis.

Patients with signs and symptoms consistent with acute monosymptomatic optic neuritis should undergo evaluation with gadolinium-enhanced MRI of the brain and orbits to determine whether or not they are at high risk for the development of clinically definite multiple sclerosis (CDMS). The presence of two or more white matter lesions (3 mm or larger in diameter, at least one lesion periventricular or ovoid) suggests high risk for CDMS, and should prompt immediate treatment as follows: Intravenous methylprednisolone sodium succinate (1 g intravenously per day for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) with a 4-day taper (20 mg on day 1, 10 mg on days 2 and 4). Interferon beta 1-a, which has been demonstrated to significantly reduce the 3-year probability of the development of CDMS and the development of clinically silent MRI lesions in high-risk patients with acute optic neuritis, should be considered following IV methylprednisolone treatment (30 &mgr;g intramuscularly weekly). In monosymptomatic patients with fewer than two white matter lesions by MRI, and in patients for whom a diagnosis of CDMS has been established, treatment with IV methylprednisolone followed by oral prednisone (as outlined), should be considered on an individual basis and may hasten visual recovery, but has not been demonstrated to affect long-term visual outcome. In all cases of typical acute monosymptomatic demyelinating optic neuritis, oral prednisone alone at a dose of 1 mg/kg per day, without prior treatment with IV methylprednisolone (1 g per day for 3 days), may increase the risk for recurrent optic neuritis, and should be avoided.

Optic neuritis and multiple sclerosis.

Review of the association between optic neuritis (ON) and multiple sclerosis (MS). MS often presents as acute unilateral ON. While it is clear that many patients with ON suffer from a generalized disease of the central nervous system that will go on to clinically definite MS (CDMS), it is also clear that others do not. With more and more well-informed patients and the emerging pharmacotheraphy for MS, the distinction between those patients with ON who have MS and those who do not, has become more important than ever before. Recently, a large randomized clinical trial on patients with ON or other clinically isolated syndromes suggestive of MS and evidence of prior subclinical demyelination on magnetic resonance imaging of the brain, found that treatment with recombinant interferon-beta-1a is beneficial by reducing the development of CDMS. Ophthalmologists should refer their patients with acute ON to a neurologist for MS-directed investigations and decisions regarding early institution of disease modifying therapy.

Systemic disease and neuro-ophthalmology: annual update 2000 (Part I).

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system (1–86), with substantial long-term neurologic consequences (1,4,9,25,34, 52,54,55,57,60,63,65). After 10 years with MS, 50% of patients are unable to perform household and occupational responsibilities; after 15 to 20 years, 50% are unable to walk without assistance; after 25 years, 50% are unable to ambulate. The average annual cost of MS in the United States is greater than 6.8 billion dollars (1). There are three main subtypes of the disease: relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP). This update reviews the current status of MS therapy (1–86). We have chosen to focus on the new and emerging immunomodulatory therapies for disease relapses and the treatments to prevent disease progression. We do not review the treatments for common MS-related sensory and motor symptoms, fatigue, or depression (35).

Conversión a esclerosis múltiple clínicamente definida tras un síndrome medular aislado: valor de la resonancia magnética craneal y medular

Isolated spinal cord syndrome might be due to a first episode of multiple sclerosis. The aim of the study was to determine the clinical usefulness and paraclinical characteristics and of spinal and brain MR imaging predicting conversion to clinically definite multiple sclerosis (CDMS) in patients with an isolated spinal cord syndrome. We have evaluate thirty-eight patients with isolated spinal cord syndrome. A clinical protocol, lumbar puncture, evoked potential and brain-spinal cord MRI were performed. Twenty two percent of the patients fulfilling brain MRI Paty criteria (p < 0.01), 54.5% Fazekas (p = 0.007) and 80% of patients fulfilling Barkhof criteria (p = 0.009) presented CDMS. The spinal MR imaging from CDMS patients was always abnormal, showing cervical and marginal location with a diameter < 2 cm. Brain MRI is strongly predictive of the risk of developing CDMS and spinal cord MRI may increase the sensitivity to detect conversion to CDMS.

The prognosis of idiopathic optic neuritis.

We evaluated the risk of developing clinically definite multiple sclerosis (CDMS) after acute isolated optic neuritis in 102 patients in a follow-up study (duration 6.5 +/- 2.0 years). The probability of CDMS was 13% after 2 years, 30% after 4 years, 38% after 6 years, and 49% after 8 and 10 years. CDMS occurred in 42 (59%) of 71 patients with brain lesions detected with magnetic resonance imaging (MRI). No patient with normal MRI exam developed the disease. Patients with 3 or more MRI-detected lesions presented a shorter first interattack interval and a higher relapse rate compared to subjects with only 1 or 2 lesions. The predictive value of CSF examination and of evoked potentials was poor.

Intrathecal IgG synthesis and autoantibody-secreting cells in multiple sclerosis

We studied intrathecal IgG synthesis and autoantibody-secreting cells in 148 patients with possible onset symptoms of MS (POSMS) or clinically definite MS (CDMS). In POSMS intrathecal synthesis of IgG oligoclonal bands and abnormalities on T2-weighted magnetic resonance imaging were associated but the former were more prevalent. The cerebrospinal fluid (CSF) leukocyte count and the number of anti-protelipid protein antibody-secreting cells in cerebrospinal fluid (CSF) correlated with disease activity in POSMS. Intrathecal IgG synthesis levels and the number of anti-myelin basic protein antibody-secreting cells in CSF correlated with disease activity in CDMS. Our results support recent reports of pathogenetic heterogeneity and a pathogenetic role of the antibody response in MS.

Bimonthly cranial MRI activity following an isolated monosymptomatic demyelinating syndrome: potential outcome measures for future multiple sclerosis 'prevention' trials.

Patients with characteristic white matter lesions on MR imaging are at increased risk for the subsequent development of clinically definite MS (CDMS) following an isolated, monosymptomatic demyelinating syndrome (IMDS). These MR positive first-onset patients are thus candidates for MS prevention trials. Seven consecutive patients with IMDS and two or more periventricular and/or oval lesions on MR imaging were enrolled into a prospective trial based on serial T2-weighted and enhanced MR imaging at two month intervals for 12 - 15 months. Forty-seven new enhancing lesions were detected with triple dose MR contrast compared to 31 lesions using the standard dose. Four of the seven patients accounted for 98% of all enhancing lesions in this study, while the remaining three patients showed little MRI or clinical disease activity. New T2 lesion counts correlated strongly with enhanced lesion counts (r=0.82 - 0.98). We detected 49 new T2-hyperintense (T2) lesions based on short-interval (2 monthly) follow-up, and 31 new T2-lesions comparing exit and entry examinations. These results suggest several potential MR-based strategies for evaluating first onset patients in a phase III MS prevention trial. Since these patients have a small average T2-lesion load, it is quite easy to visually detect new T2 lesions. As a result, at a bimonthly study interval, T2-weighted lesion analysis is an effective measure of cumulative disease activity, provided high-resolution T2-weighted imaging studies are acquired to quantitate new T2-lesions. Enhanced lesion activity remains an important measure of blood - brain - barrier breakdown and may predict short term MRI and clinical disease activity in IMDS patients.

Acute Optic Neuritis.

In acute monosymptomatic optic neuritis, treatment with oral prednisone alone should be avoided. Therapy with intravenous methylprednisolone (1 g/day for 3 days) followed by 11 days of oral prednisone (1 mg/kg with a short taper) should be considered instead. This is particularly true if a patient considers accelerated visual recovery to be particularly urgent or if magnetic resonance imaging (MRI) demonstrates three or more signal abnormalities consistent with demyelination. In patients without a diagnosis of clinically definite multiple sclerosis (CDMS), an MRI should be considered to assess the prognosis for developing multiple sclerosis (MS) and to eliminate other causes of optic neuropathy. Foregoing an MRI or steroid treatment is an acceptable option. Chest x-ray, blood tests, and lumbar puncture are not necessary in evaluating patients with typical clinical features of optic neuritis. These tests may be appropriate, however, for patients who are about to undergo corticosteroid therapy, which could complicate or mask an unrecognized condition.

Quantitative MRI in patients with clinically isolated syndromes suggestive of demyelination.

To assess the long-term predictive value of quantitative lesion load measurement on brain MRIs in patients after a 10-year follow-up who presented initially with a clinically isolated syndrome of the optic nerve, brainstem, or spinal cord. Quantitative MRI measurement is being used in treatment trials as a surrogate marker in MS, but there is a lack of long-term MRI follow-up data in assessing the natural course of the disease from the earliest stages. Using a semiautomated threshold technique, the total lesion volume (TLV), the course of the disease, and disability were assessed in 58 patients at onset and after 5 and 10 years. The TLV at presentation correlated significantly (r = 0.81, p = 0.0001) with the TLV and also with the Expanded Disability Status Scale (EDSS) score (r = 0.45, p = 0.001) at 10-year follow-up. In contrast there was no correlation of the TLV at 5 years with subsequent change in EDSS score over the next 5 years (r = 0.18, p = 0.12). The change in TLV over the first 5 years in patients who developed clinically definite MS (CDMS) differed significantly according to the type of disease course (relapsing-remitting with disability, secondary progressive, or benign) manifesting at 10-year follow-up. Quantification of changes detected by T2-weighted brain MRI at the earliest clinical stages is strongly predictive of the subsequent development of CDMS as well as the clinical course and level of disability 10 years later.