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Background and Objectives: Diagnosis 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., Methods: Using 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., Results: We 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., Conclusions: Differential 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.

Background: Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes., Objective: The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS., Methods: We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database., Results: Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses., Conclusions: Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.

Due to past success in testing and gaining regulatory approval for a variety of therapies in multiple sclerosis (MS), the conduct of future clinical trials has become increasingly problematic. An international workshop has met to discuss the issues facing the MS clinical trial community and to examine possible new strategies for the design of trials. Particular focus has been placed on trials that either avoid the use of a placebo because of ethical considerations or on designs that allow new therapies to be studied more rapidly or with fewer patients than needed in a conventional placebo-controlled trial. The discussions resulting from the workshop should provide a basis for the examination and implementation of innovative clinical trial designs in MS.

Interferon-beta (IFNbeta) reduces the number and load of new contrast-enhancing lesions (CELs) in patients with multiple sclerosis (MS). However, the ability of IFNbeta to reduce lesion sizes and re-enhancements of pre-existing CELs has not been examined extensively. Activity of contrast re-enhancing lesions (Re-CELs) and contrast single-enhancing lesions (S-CELs) were monitored in ten patients with relapsing-remitting (RR) MS. These patients underwent monthly post-contrast magnetic resonance imaging (MRIs) for an 18-month natural history phase and an 18-month therapy phase with subcutaneous IFNbeta-1b, totaling 37 images per patient. The activity was analysed using the first image as a baseline and registering subsequent active monthly images to the baseline. There was a 76.4% reduction in the number of CELs with IFNbeta therapy. The decrease was greater (P = 0.003) for S-CELs (82.3%) than for Re-CELs (57.4%). S-CELs showed no changes in durations of enhancement and maximal lesion sizes with treatment. Exclusively for Re-CELs, IFNbeta-1b significantly decreased maximal lesion sizes, total number of enhancement periods and total months of enhancement. Thus, IFNbeta appears to be effective in reducing the degree of severity of inflammation among Re-CELs, as reflected by their reduced maximal lesion sizes and durations of enhancement.

T1 black holes (BH) have been found to represent focal areas of substantial central nervous system tissue damage in multiple sclerosis (MS) patients. We examined the development of T1 BH over a three-year period of treatment with interferon (IFN)beta-1b in a group of 20 patients with relapsing-remitting MS. The number of contrast-enhancing lesions (CEL) after one year of treatment predicted a change in the T1 BH volume in the following two years. In patients without CEL, the T1 BH volume remained stable, whereas it increased in patients with CEL. The occurrence of CEL in patients treated with IFNbeta may indicate a heightened risk of accumulating T1 BH.

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.

Correlations between conventional MRI measures of disease activity and clinical disability in multiple sclerosis (MS) have been disappointing. Because ring-enhancing lesions may reflect a more destructive pathology, we tested their potential association with disease severity. We evaluated active lesions with regard to their enhancement pattern on serial magnetic resonance images in a cohort of 28 patients with relapsing-remitting MS. The percentage of ring-enhancing lesions correlated with EDSS, T2 lesion load and duration of disease and predicted the occurrence of relapses during the baseline period of observation as well as after 3 years of follow-up in multiple logistic regression analysis. The findings suggest that the pathological process reflected by ring-enhancing lesions may contribute to more severe clinical disease.

Objective: To determine whether lesion evolution in relapsing-remitting multiple sclerosis (RRMS) patients is altered by treatment with interferonbeta1b (IFNbeta-1b) or by intravenous methylprednisolone (IVMP) as measured by magnetization transfer imaging., Methods: Magnetization transfer ratios (MTR) of 225 contrast enhancing lesions (CEL), in four RRMS patients were serially determined for 12 months before and 12-18 months after contrast enhancement in a baseline vs treatment trial with IFNbeta-1b. During the baseline period, 185 new CEL were identified: 76 were treated with IVMP (1 g/day x 5 days) and designated steroid CEL (S-CEL); the remaining 109 were considered baseline lesions (BCEL). During IFNbeta-1b treatment, 40 CEL (IFN-CEL) were identified. After image co-registration, regions of interest (ROIs) defining new CEL were transferred to the MTR image set to determine the mean lesion MTR on each monthly exam. The lesion MTR was compared to MTR of normal appearing white matter (NAWM) on the same exam., Results: As early as 12 months prior to enhancement, the MTR of CEL was reduced compared to NAWM (mean 9.43 +/- 3.2%; P<0.001). The further reduction in MTR (28% +/- 4.0) at the time of contrast enhancement was not significantly different for BCEL, S-CEL or IFN-CEL Following enhancement, lesion recovery for IFN-CEL (P=0.02) and S-CEL (P=0.002) was significantly higher than BCEL CONCLUSION: IFNbeta-1b and IVMP reduce tissue damage and promote lesion recovery in RRMS patients. The additional benefit of IVMP compared to IFNbeta-1b may be related to its inhibitory effect on demyelination.

Monthly MRI activity and clinical disability were evaluated in two relapsing-remitting multiple sclerosis (RRMS) patients for 4 years during a cross-over treatment trial with IFNbeta-1b, and for a mean of 21 months after terminating treatment with IFNbeta-1b. Post-treatment MRI activity was compared to baseline activity in these patients. Although contrast enhancing lesions (CEL) and the bulk white matter lesion load (BWMLL) on T2-weighted images eventually returned to baseline values, there was a refractory period of 6 - 10 months after terminating treatment, before baseline MRI activity was restored. Although the mechanism for a sustained effect of IFNbeta-1b is unclear at this time, these results have important implications for enrollment of such patients into new treatment protocols that rely on contrast enhancing lesion frequency as an outcome measure.

The use of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has increased in our understanding of the natural history of the disease course and has provided and important tool for the analysis of new experimental therapies. Studies using MRI as well as pathological studies of MS indicate that the first event in the development of a new MS lesion as seen on T2 weighted images is disruption of the blood brain barrier (BBBD) which can be demonstrated by areas of increased signal on T1 weighted images done after the administration of gadolinium DTPA. When GdDTPA enhanced MRIs are used to monitor disease activity in patients with mild relapsing remitting MS, a considerable degree of disease activity is observed in clinically stable patients. These findings indicate that MS is an active and progressive disease in most patients even during the earliest phases of the disease and before significant clinical disability has occurred. MRI is also an important tool in evaluating new therapies. Using simple baseline vs treatment designs evidence for an effect of a new treatment on MRI parameters such as Gd-DTPA enhanced measure of BBBD can be achieved using a small study cohort and over a short duration. Together these advances should lead to more rapid progress in the understanding of MS and in identifying new treatments.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system in which autoimmune T lymphocytes reacting with myelin antigens are believed to play a pathogenic role. Since HLA binding is involved in the selection of T cell responses, we have examined PLP peptide binding to HLA DR2, an HLA allele frequently found in MS patients. Both PLP 40-60 and PLP 89-106 show significant, high affinity binding to HLA DR2. We then tested whether responses to PLP peptides 40-60 and 89-106 are elevated in multiple sclerosis patients compared to matched controls. We also analysed T cell responses to MBP 87-106, which is considered to be the immunodominant region of MBP in humans. Here we demonstrate heterogenous T cell responses to PLP 40-60, PLP 89-106 and MBP 87-106 in both MS patients and controls. The overall number of TCL and the HLA restriction of those TCL did not vary significantly in the two groups. PLP 40-60 specific cytolytic TCL were increased in MS patients, whereas healthy controls had increased percentages of cytolytic TCL responding to PLP 89-106 and MBP 87-106. Although the data presented here shows heterogenous responses in T cell numbers, differences in numbers and specificity of cytolytic cells could be involved in the pathogenesis of autoimmune demyelinating disease.