Background and objectivesDiagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis.MethodsUsing available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases.ResultsWe present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system.ConclusionsDifferential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.
We were unable to validate the finding that serum IL-17F is a predictor of PR in a large independent cohort of subjects with RRMS. Differences in patient populations and methodology might explain the failure to validate the results from the Stanford study.
The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.
AnalysisGroup. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology. 1996;47:889-894. 44. Malucchi S, Sala A, Gilli F, et al. Neutralizing antibodies reduce the efficacy of betaIFN during treat-ment of multiple sclerosis.
In a phase III, double-blind, placebo-controlled, 2-year clinical trial, interferon beta-1a (IFN-β-1a, Avonex) treatment significantly delayed disability progression, decreased exacerbations, and reduced brain lesions on magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS). In this open-label, safety-extension study, we evaluated the longer-term safety and antigenicity of IFN-β-1a. An open-label, safety-extension study of IFN-β-1a, administered at a dose of 30 μg intramuscular (IM) per week in patients with MS, was initiated in May 1995. Subjects enrolled in this study included interferon-naive patients and patients who had prior treatment with either IFN-β-1a in the phase III trial, IFN-β-1b (Betaseron), or both. Safety was evaluated by assessment of adverse events, tolerability by treatment discontinuations, and antigenicity by measurements of neutralizing antibody (NAB) titers. The number of intravenous (IV) steroid courses required per patient per year was determined as a surrogate measure of clinical relapses. There were 382 patients enrolled, with a median duration of treatment, including the phase III trial, of 2.5 years. Twenty-eight percent of participants have been on treatment for at least 3 years. The adverse event profile was similar to that observed in the phase III trial. Injection site reactions were rare and injection site necrosis was not observed. The incidence of NAB to IFN-β over 30 months of treatment was approximately 5%. IFN-β-1a was well tolerated in subjects who had switched from IFN-β-1b. Seventy-seven percent of the patients with NAB to IFN-β-1b at study entry had lost their NAB by month 24 on IFN-β-1a treatment. There was a 47% reduction in IV steroid use in the safety-extension study in those who had previously received placebo in the phase III trial. Long-term treatment of MS patients with IFN-β-1a continues to have a favorable safety profile, with low NAB titers and continuing clinical benefit.
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