The NAIMS cooperative pilot project: Design, implementation and future directions.

The North American Imaging in Multiple Sclerosis (NAIMS) Cooperative represents a network of 27 academic centers focused on accelerating the pace of magnetic resonance imaging (MRI) research in multiple sclerosis (MS) through idea exchange and collaboration. Recently, NAIMS completed its first project evaluating the feasibility of implementation and reproducibility of quantitative MRI measures derived from scanning a single MS patient using a high-resolution 3T protocol at seven sites. The results showed the feasibility of utilizing advanced quantitative MRI measures in multicenter studies and demonstrated the importance of careful standardization of scanning protocols, central image processing, and strategies to account for inter-site variability.

International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

MRI outcomes in the diagnosis and disease course of multiple sclerosis.

Despite major advances in MRI, including practical implementations of multiple quantitative MRI methods, the conventional measures of focal, macroscopic disease remain the core MRI outcome measures in clinical trials. MRI enhancing lesion counts are used to assess inflammation, and new T2-lesions provide an index of (interval) activity between scans. These simple MRI measures also have immediate significance for early diagnosis as components of the 2010 revised dissemination in space and time criteria, and they provide a mechanism to monitor the subclinical disease in patients, including after treatment is initiated. The focal macroscopic injury, which includes demyelination and axonal damage, is at least partially linked to the diffuse injury through pathophysiologic mechanisms, such as secondary degeneration, but the diffuse diseases is largely independent. Quantitative measures of the more widespread pathology of the normal appearing white and gray matter currently remain applicable to populations of patients rather than individuals. Gray matter pathology, including focal lesions of the cortical gray matter and diffuse changes in the deep and cortical gray has emerged as both early and clinically relevant, as has atrophy. Major technical improvements in MRI hardware and pulse sequence design allow more specific and potentially more sensitive treatment metrics required for targeting outcomes most relevant to neuronal degeneration, remyelination and repair.

Predictors of long-term outcome in multiple sclerosis patients treated with interferon ß.

OBJECTIVE: To identify early predictors of long-term outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with intramuscular (IM) interferon beta-1a (IFNß-1a). METHODS: A multicenter, observational, 15-year follow-up study of patients who completed ≥2 years in the pivotal trial of IM IFNß-1a for RRMS was conducted. One hundred thirty-six patients participated in the 15-year follow-up (69 originally randomized to IM IFNß-1a and 67 to placebo). After the 2-year clinical trial, treatment was not regulated by study protocol. Disease activity during the 2-year trial was defined as: ≥2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 magnetic resonance imaging (MRI); ≥3 new T2 lesions on year 2 MRI compared to baseline; and ≥2 relapses over 2 years. Odds ratios were calculated for early disease activity predicting severe Expanded Disability Status Scale (EDSS) worsening (worst quartile of change, ≥4.5 EDSS points) during the 15-year interval. RESULTS: The proportion of patients experiencing early disease activity was lower in patients on IM IFNß-1a than placebo for all disease activity markers (range, 23.5-29.0% vs 41.0-45.5%). In the IM IFNß-1a group, persistent disease activity predicted severe EDSS worsening: gadolinium-enhancing lesions (odds ratio [OR], 8.96; p < 0.001); relapses (OR, 4.44; p = 0.010); and new T2 lesions (OR, 2.90; p = 0.080). In placebo patients, early disease activity was not as strongly associated with long-term outcomes (OR range, 1.53-2.62; p = 0.069-0.408). INTERPRETATION: Disease activity despite treatment with IFNß is associated with unfavorable long-term outcomes. Particular attention should be paid to gadolinium-enhancing lesions on IFNß therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNß-treated patients with MRI, and for changing therapy in patients with active disease.

Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance.

OBJECTIVE: To determine whether immediate initiation of treatment at the time of a clinically isolated syndrome in patients at high risk for clinically definite multiple sclerosis alters disease course over 10 years. DESIGN: Prospective follow-up study. SETTING: Twenty-four Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) sites in the United States and Canada. PARTICIPANTS: A total of 81 patients originally randomly assigned to receive intramuscular interferon beta-1a (the immediate-treatment group) and 74 patients originally randomly assigned to receive placebo (the delayed-treatment group). All patients were from CHAMPS. INTERVENTION: For the immediate-treatment group, treatment was initiated within a month after the onset of a clinically isolated syndrome, and for the delayed-treatment group, treatment was initiated a median of 30 months (interquartile range, 24-35 months) after CHAMPS randomization. MAIN OUTCOME MEASURES: Rate of developing clinically definite multiple sclerosis, annualized relapse rate, disease course classification, disability measures, and magnetic resonance imaging measures. RESULTS: The immediate-treatment group showed a lower 10-year rate of clinically definite multiple sclerosis (unadjusted hazard ratio, 0.64 [95% CI, 0.48-0.87]; P = .004) and a lower annualized relapse rate between years 5 and 10 (P = .03). There was no differential effect on disability, magnetic resonance imaging T2-weighted lesions, or the proportion of patients developing progressive disease at 10 years. Few patients reached the Expanded Disability Status Scale milestone scores of 4.0 or greater (9% of patients) or 6.0 or greater (6% of patients). CONCLUSIONS: Immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome in high-risk patients reduces relapse rates over 10 years but does not improve disability outcomes compared with a control group that also initiated therapy relatively early in the disease course. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00179478.

MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials.

Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI--and patient--resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.

Variants of multiple sclerosis.

The classic multiple sclerosis variants including Devic's neuromyelitis optica (NMO), Balo's concentric Sclerosis, Schilder's disease, and Marburg MS are both interesting and instructive from a disease pathophysiology perspective. Although rare, the variants are important as they often arise in the differential diagnosis for severe, acute demyelinating disease, including MS and acute disseminated encephalomyelitis. In the case of NMO, an originally unsuspected and entirely new pathophysiology based on water channels has been described, only after the recent original description of the more specific diagnostic test for NMO based on serum immunoglobulin.

Fast multislice mapping of the myelin water fraction using multicompartment analysis of T2* decay at 3T: a preliminary postmortem study.

Quantitative mapping of the myelin water content can provide significant insight into the pathophysiology of several white matter diseases, such as multiple sclerosis and leukoencephalopathies, and can potentially become a useful clinical tool for early diagnosis of these diseases. In this study, multicompartment analysis of T(2)(*) decay (MCAT(2)(*)) was used for the quantitative mapping of myelin water fraction (MWF). T(2)(*) decay of each voxel at multiple slice locations was acquired in fixed human brains using a multigradient-echo (MGRE) pulse sequence with alternating readout gradient polarities. Compared to prior techniques using Carr-Purcell-Meiboom-Gill (CPMG) acquisition, the MGRE acquisition approach has: 1) a very short first echo time ( approximately 2 ms) and echo-spacing ( approximately 1 ms), which allows for the acquisition of multiple sampling points during the fast decay of the myelin water signal; 2) a low RF duty cycle, which is especially important for achieving acceptable specific absorption rate (SAR) levels at high field strengths. Multicompartment analysis was then applied to the T(2)(*) decay in each pixel using a 3-pool model of white matter to detect the signal arising from the myelin water, myelinated axonal water, and mixed water compartments.

Identification of fibers at risk for degeneration by diffusion tractography in patients at high risk for MS after a clinically isolated syndrome.

PURPOSE: Focal inflammatory/demyelinating lesions are thought to be the source of Wallerian degeneration or other injury to local, transiting fiber tracts in the brain or spinal cord in multiple sclerosis (MS). A methodology is established to isolate connections between focal demyelinating lesions and intersecting fibers to permit explicit analyses of the pathology of secondary fiber injury distant from the focal lesion. MATERIALS AND METHODS: A strategy is described and feasibility demonstrated in three patients with a clinically isolated syndrome and positive MRI (at high risk for MS). The strategy utilizes streamtube diffusion tractography to identify neuronal fibers that intersect a focal lesion and pass through a region of interest, in this case the corpus callosum, where distal (to focal lesion) interrogation can be accomplished. RESULTS: A sizeable fraction of the normal appearing white matter (NAWM) in the early stages of disease can be defined in the corpus callosum, which is distinctive in that this tissue connects to distant demyelinating lesions. CONCLUSION: The new class of tissue called fibers-at-risk for degeneration (FAR) can be identified and interrogated by a variety of quantitative MRI methodologies to better understand neuronal degeneration in MS.

MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation".

Although the diagnosis of multiple sclerosis relies on the demonstration of disease dissemination in space and time, the exclusion of other neurological disorders is also essential. The limited specificity of abnormalities disclosed by MRI may increase the likelihood of diagnosis of multiple sclerosis in patients affected by other disorders. The available criteria for diagnosis of multiple sclerosis have not taken advantage of the potential of MRI to detect features "not suggestive" of multiple sclerosis. Recognition of such features in the work-up of patients suspected of having multiple sclerosis may reduce the likelihood of a false positive diagnosis of the disorder in some, while suggesting the correct alternative diagnosis in other patients. On the basis of this, a workshop of the European MAGNIMS (Magnetic Resonance Network in Multiple Sclerosis) was held to define a series of MRI red flags in the setting of clinically suspected multiple sclerosis that is derived from evidence-based findings and educated guesses. The presence of such red flags should alert clinicians to reconsider the differential diagnosis more extensively. In this review we will report on the conclusions of this international consensus, which should represent a first step beyond the concept of "no better explanation", and inform future diagnostic criteria for multiple sclerosis.

Update on multiple sclerosis.

In this article the basic features of the focal MR imaging lesions and the underlying pathology are reviewed. Next, the diffuse pathology in the normal-appearing white and gray matter as revealed by conventional and quantitative MR imaging techniques is discussed, including reference to how the focal and diffuse pathology may be in part linked through axonal-neuronal degeneration. The MR imaging criteria incorporated for the first time into formal clinical diagnostic criteria for multiple sclerosis are next discussed. Finally, a discussion is provided as to how MR imaging is used in monitoring subclinical disease either before or subsequent to initiation of treatment, in identifying aggressive subclinical disease, and in monitoring treatment.

Update on multiple sclerosis.

In this article the basic features of the focal MR imaging lesions and the underlying pathology are reviewed. Next, the diffuse pathology in the normal-appearing white and gray matter as revealed by conventional and quantitative MR imaging techniques is discussed, including reference to how the focal and diffuse pathology may be in part linked through axonal-neuronal degeneration. The MR imaging criteria incorporated for the first time into formal clinical diagnostic criteria for multiple sclerosis are next discussed. Finally, a discussion is provided as to how MR imaging is used in monitoring subclinical disease either before or subsequent to initiation of treatment, in identifying aggressive subclinical disease, and treatment of nonresponders.

Cognition, MRS neurometabolites, and MRI volumetrics in non-neuropsychiatric systemic lupus erythematosus: preliminary data.

OBJECTIVE: To correlate cognitive dysfunction with structural and neurometabolic brain findings in patients with non-neuropsychiatric systemic lupus erythematosus (non-NPSLE). BACKGROUND: Over 25% of non-NPSLE patients have cognitive dysfunction, but the cerebral basis of this observation is not well understood. METHOD: Seven patients with non-NPSLE and seven control subjects were given a series of neuropsychological tests and neuroimaging with magnetic resonance imaging and magnetic resonance spectroscopy. Analyses of cognitive function and structural and neurometabolic measures of the brain were performed. RESULTS: Compared with controls, the non-NPSLE patients were significantly impaired on a global cognitive impairment index (CII). No significant differences between the groups were found in choline/creatine (Ch/Cr), N-acetylaspartic acid/Cr, or hippocampal volumes. Ch/Cr was highly associated with CII across the sample. CONCLUSIONS: This is the first study to correlate cognitive impairment with an increase in Ch/Cr ratio among patients with SLE. These results, although preliminary, suggest that changes in cerebral white matter may be important in determining the subtle cognitive impairment that may occur in patients with SLE, even in the absence of neuropsychiatric symptoms.

MRI in multiple sclerosis.

MRI provides multiple uses and applications in multiple sclerosis(MS). The basic features of the MRI-detected lesions, including the underlying pathology, are discussed. MRI allows assessment of the normal-appearing white and gray matter, and neuronal tract and functional system disturbances. An overview of the clinical significance of these MRI measures is included, as a basis for understanding their role as outcome measures in clinical trials. MRI recently assumed greater importance in its role in establishing an earlier diagnosis of MS after a first clinical event, and in monitoring subclinical disease before or subsequent to the formal diagnosis. The background to these applications and practical issues are discussed.

Magnetic resonance techniques for the in vivo assessment of multiple sclerosis pathology: consensus report of the white matter study group.

On October 9-11, 2003, the third meeting of the White Matter Study Group of the International Society for Magnetic Resonance in Medicine was held in Venice, Italy. This article is the report of the meeting on how to use MRI in the diagnostic workup of multiple sclerosis (MS) and allied white matter disorders, and to define the nature and the extent of MS pathology in vivo. Both of these steps are central to the design of future treatment strategies aimed at limiting the functional consequences of the most disabling aspects of this disease.

Multiple sclerosis pathology in the normal and abnormal appearing white matter of the corpus callosum by diffusion tensor imaging.

Lesions in the corpus callosum in multiple sclerosis (MS) include those that are hyperintense on T2-weighted images, which can be either focal (isolated) or connected, but there is evidence that the corpus callosum, similar to other white matter regions, contains normal appearing white matter (NAWM) which is abnormal based on quantitative MR methodologies. In this pilot study, diffusion tensor based measures were determined in corpus callosum from 10 patients with MS and 12 age and gender matched controls. T2-hyperintense lesions were carefully segmented out from normal appearing corpus callosum to minimize contamination of the NAWM fraction with these lesions. The orientationally averaged diffusion coefficient was increased and the fractional anisotropy reduced in the NAWM fraction of the MS patients. These results confirm prior studies which suggest that pathology in the NAWM occurs independent of focal MS lesions, and are not likely the result of sample contamination through or across slices. This injury to the NAWM may be the result of focal, microscopic T2-invisible lesions and/or secondary degeneration related to distant lesions whose related fibres cross the corpus callosum.

Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis.

The association between regional measures of cortical atrophy and neuropsychological (NP) dysfunction was studied in 35 multiple sclerosis (MS) patients. Patients underwent neurological examination, MRI, and NP testing. Blind quantitative MRI analysis yielded total T(2) lesion area (TLA) and third ventricle width (3VW). Cortical atrophy, rated by blind visual inspection, was more extensive in superior frontal and parietal cortices than in other regions. No MRI measures were correlated with depression scores. TLA and 3VW were significantly correlated with each NP test. Cortical atrophy measures for bilateral superior frontal cortex were retained in regression models predicting impairments in verbal learning, spatial learning, attention, and conceptual reasoning. The authors conclude that cerebral atrophy predicts NP impairment while accounting for the influence of TLA or 3VW. Regions of cortex most susceptible to atrophic and cognitive changes in MS are the right and left superior frontal lobes.

Interferon beta-1a for early multiple sclerosis: CHAMPS trial subgroup analyses.

The objective of this work was to assess the effect of interferon beta-1a (Avonex) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30 microg interferon beta-1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem-cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon beta-1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem-cerebellar syndromes, and spinal cord syndromes.