Ring and nodular multiple sclerosis lesions: a retrospective natural history study.

BACKGROUND: In patients with multiple sclerosis (MS), contrast-enhancing lesions (CELs) on postcontrast MRI are considered markers of the inflammatory responses associated with blood-brain barrier breakdown. Based upon shape, CELs may be defined as nodular (nCEL) or ring (rCEL) lesions. Several short-term studies pointed towards the assumption that rCELs represent areas of a more aggressive inflammatory process. METHODS: In the present long-term (i.e., 2 years) retrospective natural history study, we used monthly imaging to follow rCEL and nCELs evolution in 16 patients with MS during the natural history. New CELs were identified monthly on month 4-9 MRIs, using month 1-3 MRIs to ensure that all CELs were not previously enhancing. Chronic black holes (cBHs) were counted monthly upon CEL disappearance up to the 24th MRI. Generalized estimating equation methods investigated within-patient differences between rCELs and nCELs in volume and likelihood to convert into cBHs. Kaplan-Meier survival curves estimated differences in the length of persistence between cBHs originating from nCELs and cBHs deriving from rCELs. RESULTS: Fifty-two new rCELs and 281 nCELs were identified. rCELs had larger mean (z = 5.06, p < or = 0.0001) volumes than nCELs. The proportion of cBHs from rCELs was similar (z = 1.81, p = 0.0710) to the proportion of cBHs from nCELs. Likewise, the length of persistence of cBHs deriving from rCELs was similar (chi(1)(2) = 2.339, p = 0.1262) to the duration of cBHs from nCELs. CONCLUSIONS: Our data suggest that worse radiologic characteristics associated with the acute phase of ring contrast-enhancing lesions and nodular contrast-enhancing lesions do not necessarily reflect a poorer lesion outcome over time.

Thalamic involvement and its impact on clinical disability in patients with multiple sclerosis: a diffusion tensor imaging study at 3T.

BACKGROUND AND PURPOSE: Several studies suggest that grey matter involvement may play a role in multiple sclerosis (MS) pathology. Diffusion tensor imaging (DTI) at 3T was used to investigate the presence of damage to the normal-appearing thalamus in MS and its relationship with disability. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting (RR, n = 13, age = 41.7 +/- 6.1, Expanded Disability Status Scale [EDSS] score = 2.2 +/- 1.2) and secondary-progressive (n = 11, age = 46.9 +/- 9.6, EDSS = 5.9 +/- 1.0) MS and 24 age- and sex-matched healthy volunteers were studied. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in regions of interest of normal-appearing thalamus. We examined group differences in MD and FA and correlations between DTI-derived metrics and clinical or imaging measures of disease. RESULTS: Patients with MS had higher thalamic FA (P < .0001) and MD (P = .035) than volunteers. MD values correlated with the Paced Auditory Serial Addition Task (r = -0.43, P = .034) and motor EDSS (r = 0.47, P = .021) scores. In patients with RRMS, MD values correlated with global EDSS (r = 0.75, P = .003) and motor EDSS (r = 0.68, P = .010). Correlations were found between MD values and T1 and T2 lesion load (r = 0.58, P < .05) and brain parenchymal fraction (r = -0.46, P < .05). CONCLUSIONS: DTI was able to detect abnormalities in normal-appearing thalamus of patients with MS. The strength of association between thalamic DTI measures and functional impairment was in the same range as those seen with standard MR imaging disease measures. The assessment of the integrity of the thalamus with DTI is a promising metric as a marker of disease for future studies.

Differential diagnosis of suspected multiple sclerosis: a consensus approach.

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.

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses.

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.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

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.

A case study on the effect of neutralizing antibodies to interferon beta 1b in multiple sclerosis patients followed for 3 years with monthly imaging.

Interferon beta (IFN-beta) is among the first-line treatment options for patients with multiple sclerosis (MS). A potential caveat of therapy, however, is the development of neutralizing antibodies (NAb) and/or neutralizing activity (NA) non-antibody mediated, although debate is still ongoing as to whether NAb significantly hampers the efficacy of the drug or rather represents an immunologically irrelevant epiphenomenon. In the present study, we describe the effect of NAb on IFN-beta-1b through clinical and magnetic resonance imaging (MRI) outcome measures of five relapsing-remitting multiple sclerosis (RRMS) patients who were treated with 250 mug of subcutaneously administered IFN-beta-1b every other day and developed NAb at varying titres and times during the course of therapy. Despite the small number of NAb(+) patients, heterogeneity in MRI/clinical response to IFN-beta-1b was identified. Response to IFN-beta-1b therapy was observed in the absence or presence of NAb. Also observed was failure to IFN-beta-1b coincident with high and sustained NAb titres, but also before NAb development or in the presence of low NAb titres. Multiple MRI and NAb measurements performed within the same individual allow for a better description of the complex heterogeneous response to IFN-beta-1b with respect to NAb occurrence.

In vivo detection of cortical plaques by MR imaging in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: In vivo detection of cortical lesions in patients with multiple sclerosis (MS) by MR imaging is hampered by several factors. Among them is the low contrast between small cortical lesions and surrounding cortical gray matter offered by present techniques. METHODS: T1-weighted 3D spoiled gradient-recalled-echo (SPGR) volumes and 2D fluid-attenuated inversion recovery (FLAIR) sequences of 22 patients with MS who had 12 monthly brain MR imaging examinations at 1.5T, using a quadrature head coil, were retrospectively analyzed. These serial studies were coregistered and averaged to generate a single high signal-to-noise ratio (SNR) mean image, which was used to identify cortical lesions. The means of 12 FLAIRs and SPGRs from 14 age- and sex-matched healthy volunteers were analyzed as well. RESULTS: No cortical lesions were found on images of healthy subjects. Eighty-six cortical lesions were identified in 13 (59.1%) patients, predominantly in the frontal lobe (73.3%); 23.3% of cortical lesions lay entirely in the cortex, whereas the remaining lesions invaded the white matter underneath. CONCLUSION: Averaging multiple SPGRs created a single high SNR volume, allowing identification of cortical lesions. Because data were obtained monthly for 1 year, the average image does not account for transient lesion activity. However, for cortical lesions that remained stable during this time, the findings are valid in demonstrating the importance of high SNR images for detecting cortical brain abnormalities in MS.

Relationship between inflammatory lesions and cerebral atrophy in multiple sclerosis.

OBJECTIVE: To investigate the temporal relationship between inflammation and cerebral atrophy in a longitudinal study of 19 patients with relapsing-remitting multiple sclerosis (RRMS) using serial monthly contrast enhanced MRI examinations and monthly measurements of brain fractional volume (BFV) for an average of 4 (range 2.4 to 10) years. METHODS: In this retrospective study, all patients had an active MRI scan at entry with a minimum of two new contrast enhancing lesions (CEL) on baseline MRI examinations. Patients were followed for a minimum of 3 months during a baseline (pretreatment) phase and subsequently followed during treatment with recombinant interferon beta (IFN) and various other immunomodulatory agents. Pre- and post contrast axial images were obtained using 3-mm slice thickness and a gadolinium contrast dose of 0.1 mmol/kg. Monthly CEL were sequentially numbered on hardcopy films and monthly BFV was determined on precontrast T1W images using a semiautomated program. For BFV measurements, all T1W scans were registered to the entry examination, which served as a mask image. Cerebral atrophy was measured as percent brain fractional volume change (PBVC) compared to the entry baseline scan. RESULTS: The results demonstrate that cerebral atrophy paralleled that of contrast enhancing lesion accumulation. The correlation between cumulative CEL and PBVC ranged from R2 = 0.47 to 0.81. Immunomodulatory agents that effectively reduced CEL accumulation also slowed the rate of atrophy. CONCLUSIONS: The correlation between contrast enhancing lesions (CEL) and atrophy suggests that patients who are not responding to therapy with a decrease in CEL may also be at risk for developing increased atrophy.

Interferon-beta-1b effects on re-enhancing lesions in patients with multiple sclerosis.

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.

The future of multiple sclerosis therapies: redesigning multiple sclerosis clinical trials in a new therapeutic era.

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.

MRI as a marker for disease heterogeneity in multiple sclerosis.

BACKGROUND: Whereas recent data from imaging studies challenge the prevailing notion that multiple sclerosis (MS) is purely an inflammatory disease, pathologic studies suggest differences in the disease processes between individual patients with MS. The ability to dissect the pathophysiologic disease heterogeneity, if it indeed exists, by methodologies that can be applied in vivo is important both for the development of new therapeutics and for the ability to identify the optimal therapy for an individual patient. OBJECTIVE: To design a stratification algorithm for patients with MS based on accepted MRI measurements reflective of inflammation and axonal damage/tissue loss and to assess if such MS subgroups retain their intergroup differences long term. METHODS: Mathematical modeling was used to select three discriminatory MRI measures for clinical outcome based on the cross-sectional analysis of 71 patients with untreated MS and tested general applicability of the stratification scheme on the independent longitudinal cohort of 71 MS patients. RESULTS: By consecutive employment of MRI measures reflective of inflammation and tissue loss, the authors were able to separate MS patients into four clinically meaningful subgroups. The analysis of the longitudinal confirmatory cohort demonstrated persistence of the intergroup differences in selected MRI measures for 8 years. CONCLUSIONS: The inflammatory activity and destructiveness of the multiple sclerosis process are to some degree independent of each other, and the successive evaluation of both of these variables can strengthen prediction of clinical outcome in individual patients.

Contrast-enhanced MRI lesions during treatment with interferonbeta-1b predict increase in T1 black hole volume in patients with relapsing-remitting multiple sclerosis.

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.

Interferon-beta-1b slows progression of atrophy in RRMS: Three-year follow-up in NAb- and NAb+ patients.

OBJECTIVE: To determine the effect of interferon-beta-1b (IFNbeta-1b) treatment on total contrast-enhancing lesions (CEL), white matter lesion load (WMLL), and cerebral atrophy (CA) in patients with relapsing-remitting multiple sclerosis (RRMS) using serial monthly MRI. METHODS: An open-label baseline-vs-treatment crossover trial was conducted with 30 RRMS patients monitored during a 6-month baseline and up to 36 months on treatment with IFNbeta-1b. Monthly MRI exams and neurologic exams using the Expanded Disability Status Scale (EDSS) were performed. RESULTS: The percentage changes from baseline for years 1, 2, and 3 on IFNbeta-1b were as follows: brain volume (BV) = -1.35, -1.48, and -1.68%; CEL = -76.5, -60.1, and -54.7%; WMLL = -12.2, -9.8, and -10.4%. There was no difference in the BV, CEL, or WMLL for between-year comparisons, and the decrease in BV from year 1 to years 2 and 3 was less than the change from baseline to year 1. EDSS did increase (p < 0.001) when comparing the last 3 months of baseline (2.8 +/- 2.1) and the last 3 months on IFNbeta-1b (3.6 +/- 2.1). Eleven patients developed neutralizing antibody (NAb) during the study. The effect of IFNbeta-1b on CEL and WMLL was significantly reduced in NAb+ patients compared with NAb- patients (p < 0.003). CONCLUSION: IFNbeta-1b decreases contrast-enhancing lesions and white matter lesion load over 3 years on therapy and slows the progression in cerebral atrophy during years 2 and 3.

Longitudinal MRI study: the effects of azathioprine in MS patients refractory to interferon beta-1b.

An open-label study was performed to assess the effectiveness of oral azathioprine (AZA) on augmenting the response to interferon beta-1b (IFNbeta-1b) in patients with treatment-refractory relapsing-remitting MS. Six IFNbeta-1b-treated MS patients with continued disease activity were studied on IFNbeta-1b and AZA therapy for a median period of 15 months. A 69% reduction in the number of contrast-enhancing lesions was observed during the combination therapy (p = 0.002).

Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis.

Autoimmune diseases such as multiple sclerosis are characterized by complex genetic traits and pathomechanisms that translate into clinical heterogeneity. This wide heterogeneity of multiple sclerosis as well as different biological responses to immunomodulatory drugs can be expected to contribute to differential treatment responses. Strategies that dissect the relationship between the treatment response and the biological characteristics in individual patients are valuable not only as a clinical tool, but also in leading to a better understanding of the disease. Here we address the in vitro and ex vivo RNA expression profile under one approved therapy of multiple sclerosis, interferon-beta (IFN-beta, Betaseron), by cDNA microarrays and demonstrate that non-responder and responder phenotypes to IFN-beta as assessed by longitudinal gadolinium-enhanced MRI scans and clinical disease activity differ in their ex vivo gene expression profile. These findings will help to better elucidate the mechanism of action of IFN-beta in relation to different disease patterns and eventually lead to optimized therapy.

Impaired renal function in progressive multiple sclerosis.

The authors analyzed renal function in 25 patients with progressive MS. The mean glomerular filtration rate (GFR) was 92 mL/min/1.73 m(2), compared to the predicted GFR of 110 (p < 0.001). Nine of the 25 (36%) patients had abnormally low GFR (<90). The mean serum creatinine for patients with MS was lower than predicted normal values and poorly estimated GFR using standard equations. These data document impaired renal function in patients with progressive MS and have implications for treatment of these patients with potentially nephrotoxic drugs.

T cell response to 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in multiple sclerosis patients.

T cell responses targeting myelin antigens are possibly involved in the pathogenesis of demyelinating diseases, such as multiple sclerosis (MS). Little is known about human T cell responses to 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), the third most abundant myelin protein. We examined the primary peripheral T cell response to CNPase and characterized CNPase-specific CD4+ long-term T cell lines (TCL) from MS patients and healthy donors. The strongest primary responses were found in two MS patients with very active disease and were directed against CNP(343-373). We identified immunodominant epitope clusters in the regions CNP(343-373) and (356-388) that were recognized in the context of MS-associated HLA-DR2 and DR4 molecules. These data provide the immunological basis for further investigation of CNPase as a potential target self-antigen in MS.

Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFNbeta-1b.

OBJECTIVE: To determine the effect of IV methylprednisolone (IVMP) on brain fraction volume (BFV), contrast-enhancing (CE) lesions, and white matter lesion load (WMLL) in patients with relapsing-remitting MS treated for acute exacerbations. BACKGROUND: MRI metrics of MS disease activity are being used as outcome measures in early phase treatment trials, however the short-term effects of IVMP treatment on cerebral atrophy are unknown. METHODS: Serial monthly MRI were performed in 26 patients enrolled in a baseline vs treatment trial with interferon beta-1b (IFNbeta-1b) who were followed for 3 months before and after IVMP. All 26 patients were evaluated while receiving IFNbeta-1b, and 12 patients were also studied during the baseline stage of the trial (NHx). Acute exacerbations were treated with IVMP (1 g/d) for 3 to 5 days. Precontrast and postcontrast T1-weighted and proton density T2-weighted fast spin-echo images were analyzed. RESULTS: Fifty-six acute exacerbations were evaluated. For the 3 months before IVMP, there was no difference in WMLL or BFV compared to month IVMP was administered. There was a significant decrease in BFV at month 1 after IVMP in the IFNbeta-1b and NHx groups. Compared to the month IVMP was administered, there was a difference in the CE lesions for months -3 and -1 prior (p < 0.039) in NHx patients. Following IVMP, CE lesions decreased (p < 0.0004) for months 1, 2, and 3 in both groups, but there was no effect on WMLL. CONCLUSIONS: BFV and CE lesions were significantly decreased for 1 month (BFV) and 3 months (CE lesions) following IVMP. Therefore, MRI studies should be delayed by probably at least 2 months following IVMP to avoid a possible confounding steroid effect in a clinical trial.

Role of magnetic resonance imaging in the diagnosis and monitoring of multiple sclerosis: consensus report of the White Matter Study Group.

On June 24-26, 2001, the first meeting of the White Matter Study Group (WMSG) of the International Society for Magnetic Resonance in Medicine (ISMRM) was held in Bordeaux, France. This paper is the report of the consensus reached among the delegates of the meeting on how to use magnetic resonance imaging (MRI) to make an early diagnosis of multiple sclerosis (MS), to measure MS activity accurately and reliably, and to monitor the effect of treatment on disease evolution.

The role of MRI as a surrogate outcome measure in multiple sclerosis.

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.