International consensus statement on the use of disease-modifying agents in multiple sclerosis

OBJECTIVE: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. METHODS: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. RESULTS: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. CONCLUSIONS: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.     

A randomized,double-blind,dose-comparison study of weekly interferon beta-1a in relapsing MS

BACKGROUND: Interferon beta-1a (IFNbeta-1a; Avonex) is effective for the treatment of relapsing MS; however, the optimal dose of IFNbeta-1a is not known. OBJECTIVE: To determine whether IFNbeta-1a 60 micro g IM once weekly is more effective than IFNbeta-1a 30 micro g IM once weekly in reducing disability progression in relapsing MS. METHODS: In a double-blind, parallel-group, dose-comparison study, 802 patients with relapsing MS from 38 centers in Europe were randomized to IFNbeta-1a 30 micro g (n = 402) or 60 micro g (n = 400) IM once weekly for >/=36 months. The primary endpoint was disability progression, defined as time to a sustained increase of >/=1.0 point on the Expanded Disability Status Scale (EDSS) persisting for 6 months. Additional endpoints included relapses, MRI, safety, immunogenicity, and subgroup analyses of disability progression. RESULTS: Both groups showed equal rates of disability progression (hazard ratio, 0.96; 95% CI, 0.77 to 1.20; p = 0.73). In both groups the proportion of subjects with progression of disability by 36 months estimated from Kaplan-Meier curves was 37%. No dose effects were observed on any of the secondary clinical endpoints. Only one MRI measure at one time point, number of new or enlarging T2 lesions at month 36 compared with month 24, showed a difference favoring the 60- micro g dose. Both doses were well tolerated; however, slightly higher incidences of flulike symptoms and muscle weakness were observed in the 60- micro g group. The incidences of neutralizing antibodies (titers >/= 20) were 2.3% in the 30- micro g group and 5.8% in the 60- micro g group. CONCLUSION: There was no difference between IFNbeta-1a 30 micro g and 60 micro g IM in clinical or MRI measures.     

A long-term prospective study of optic neuritis: evaluation of risk factors

Eighty-six patients with monosymptomatic optic neuritis of unknown cause were followed prospectively for a median period of 12.9 years. At onset, cerebrospinal fluid (CSF) pleocytosis was present in 46 patients (53%) but oligoclonal immunoglobulin in only 40 (47%) of the patients. The human leukocyte antigen (HLA)-DR2 was present in 45 (52%). Clinically definite multiple sclerosis (MS) was established in 33 patients. Actuarial analysis showed that the cumulative probability of developing MS within 15 years was 45%. Three risk factors were identified: low age and abnormal CSF at onset, and early recurrence of optic neuritis. Female gender, onset in the winter season, and the presence of HLA-DR2 antigen increased the risk for MS, but not significantly. Magnetic resonance imaging detected bilateral discrete white matter lesions, similar to those in MS, in 11 of 25 patients, 7 to 18 years after the isolated attack of optic neuritis. Nine were among the 13 with abnormal CSF and only 2 belonged to the group of 12 with normal CSF (p = 0.01). Normal CSF at the onset of optic neuritis conferred better prognosis but did not preclude the development of MS.     

Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria"

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.     

Analysis of peripheral blood lymphocyte phenotype and function during dexamethazone treatment of progressive multiple sclerosis

Five patients with chronic progressive multiple sclerosis (MS) and three control patients with lumbar disc herniation were treated with dexamethazone during 14 days. The effect on peripheral blood T-cell subsets and on the proliferative response of peripheral blood mononuclear cells (PBMC) to pokeweed mitogen (PWM) and anti-mu antibody was analyzed. Before treatment, the proportion of CD3+ and CD4+ PBMC was similar in MS and control patients, but the proportion of CD8+ and DR+ PBMC was lower and the PBMC were less responsive to anti-mu stimulation in MS patients compared to controls. Steroid treatment induced reversible granulocytosis and lymphocytosis. CD3+ and CD4+ cells increased and DR+ cells decreased in MS patients but not in controls. Proliferation of anti-mu stimulated PBMC increased in MS-patients during the two weeks of treatment, but decreased in controls. The enhancement in the MS patients of pre-existing immune abnormalities suggests that a cautious attitude is warranted in the use of steroid treatment in chronic progressive MS.     

Tumor necrosis factor alpha gene polymorphism in multiple sclerosis and optic neuritis

The NcoI tumor necrosis factor (TNF alpha) polymorphism was studied in relapsing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the NcoI marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were observed in the disease groups when compared with controls.     

In vitro synthesis of IgG by cells from the cerebrospinal fluid in a patient with multiple sclerosis

Mononuclear cells of the cerebrospinal fluid from a patient with multiple sclerosis were maintained in vitro for 5 days. Synthesis of IgG occurred and was significantly higher during a relapse of the disease than during remissions. The electrophoretic IgG species that were found in the cerebrospinal fluid of the patient were also synthesized in vitro.