Manganese-Enhanced MRI in Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cellular uptake of the manganese ion, when administered as a contrast agent for MR imaging, can noninvasively highlight cellular activity and disease processes in both animals and humans. The purpose of this study was to explore the enhancement profile of manganese in patients with multiple sclerosis. MATERIALS AND METHODS: Mangafodipir is a manganese chelate that was clinically approved for MR imaging of liver lesions. We present a case series of 6 adults with multiple sclerosis who were scanned at baseline with gadolinium, then injected with mangafodipir, and followed at variable time points thereafter. RESULTS: Fourteen new lesions formed during or shortly before the study, of which 10 demonstrated manganese enhancement of varying intensity, timing, and spatial pattern. One gadolinium-enhancing extra-axial mass, presumably a meningioma, also demonstrated enhancement with manganese. Most interesting, manganese enhancement was detected in lesions that formed in the days after mangafodipir injection, and this enhancement persisted for several weeks, consistent with contrast coming from intracellular uptake of manganese. Some lesions demonstrated a diffuse pattern of manganese enhancement in an area larger than that of both gadolinium enhancement and T2-FLAIR signal abnormality. CONCLUSIONS: This work demonstrates the first use of a manganese-based contrast agent to enhance MS lesions on MR imaging. Multiple sclerosis lesions were enhanced with a temporal and spatial profile distinct from that of gadolinium. Further experiments are necessary to uncover the mechanism of manganese contrast enhancement as well as cell-specific uptake.

Intrathecal effects of daclizumab treatment of multiple sclerosis.

OBJECTIVES: We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon-ß and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system. METHODS: Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF. RESULTS: The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56(bright) NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. CONCLUSIONS: Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment. CLASSIFICATION OF EVIDENCE: The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period.

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.

The role of radiotracer imaging in Parkinson disease.

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials.

BACKGROUND: A European (EU) and a North American (NA) placebo-controlled study with interferon beta-1b (IFNB-1b) in secondary progressive multiple sclerosis (SPMS) showed divergent results with regard to their primary outcome of sustained Expanded Disability Status Scale (EDSS) progression, while effects were similar on relapse and MRI-related endpoints. Reasons for this discrepancy were explored in the combined dataset. METHODS: Baseline characteristics and variability in EDSS assessments were compared. Retrospective combined analyses for time to confirmed progression were performed to assess treatment effects overall and in subgroups defined by pre-study disease activity criteria and other key baseline variables. RESULTS: The variance of EDSS measurements was 6.5% higher in the NA-SPMS study. The EU study included patients in an earlier phase of SPMS and with more active disease both pre-study (relapses, MRI) as well as on study (EDSS, relapses, and MRI variables as assessed in the placebo groups). The pooled analysis showed an overall risk reduction by about 20% in patients treated with 8 MIU (250 mcg) IFNB-1b for EDSS progression confirmed at 6 months (p = 0.008). Risk reduction by 30% to 40% was found for patients with at least one relapse or change in EDSS by >1 in the 2 years prior to study entry. No other consistent across-studies relation of clinical and MRI variables at baseline to potential treatment response was found. CONCLUSIONS: Although post hoc, this combined analysis of the two large studies with IFNB-1b in secondary progressive multiple sclerosis suggests that both pronounced disability progression and continuing relapse activity might help in identifying those patients in the secondary progressive phase of the disease who are more likely to benefit from treatment.

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.