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Objective: To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS)., Methods: The percent brain volume change (PBVC) was computed on existing longitudinal (2 time points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68)., Results: There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease., Conclusions: This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.

The International Panel on the Diagnosis of Multiple Sclerosis (MS) incorporated the Barkhof/Tintoré (B/T) magnetic resonance criteria into their diagnostic scheme to provide evidence of dissemination in space of central nervous system lesions, a prerequisite for diagnosing MS in patients who present with clinically isolated syndromes (CIS). Although specific for MS, the B/T criteria were criticised for their low sensitivity and relative complexity in clinical use. We used lesion characteristics at onset from 349 CIS patients in logistic regression and recursive partitioning modelling in a search for simpler and more sensitive criteria, while maintaining current specificity. The resulting models, all based on the presence of periventricular and deep white matter lesions, performed roughly in agreement with the B/T criteria, but were unable to provide higher diagnostic accuracy based on information from a single scan. Apparently, findings from contrast-enhanced and follow-up magnetic resonance scans are needed to improve the diagnostic algorithm.

In this multicenter study, we used dynamic causal modeling to characterize the abnormalities of effective connectivity of the sensorimotor network in 61 patients with multiple sclerosis (MS) compared with 74 age-matched healthy subjects. We also investigated the correlation of such abnormalities with findings derived from structural MRI. In a subgroup of subjects, diffusion tensor (DT) MRI metrics of the corpus callosum and the left corticospinal tract (CST) were also assessed. MS patients showed increased effective connectivity relative to controls between: (a) the left primary SMC and the left dorsal premotor cortex (PMd), (b) the left PMd and the supplementary motor areas (SMA), (c) the left secondary sensorimotor cortex (SII) and the SMA, (d) the right SII and the SMA, (e) the left SII and the right SII, and (f) the right SMC and the SMA. MS patients had relatively reduced effective connectivity between the left SMC and the right cerebellum. No interaction was found between disease group and center. Coefficients of altered connectivity were weakly correlated with brain T2 LV, but moderately correlated with DT MRI-measured damage of the left CST. In conclusion, large multicenter fMRI studies of effective connectivity changes in diseased people are feasible and can facilitate studies with sample size large enough for robust outcomes. Increased effective connectivity in the patients for the simple motor task suggests local network modulation contributing to enhanced long-distance effective connectivity in MS patients. This extends and generalizes previous evidence that enhancement of effective connectivity may provide an important compensatory mechanism in MS., ((c) 2008 Wiley-Liss, Inc.)

Short-term adaptation indicates the attenuation of the functional MRI (fMRI) response during repeated task execution. It is considered to be a physiological process, but it is unknown whether short-term adaptation changes significantly in patients with brain disorders, such as multiple sclerosis (MS). In order to investigate short-term adaptation during a repeated right-hand tapping task in both controls and in patients with MS, we analyzed the fMRI data collected in a large cohort of controls and MS patients who were recruited into a multi-centre European fMRI study. Four fMRI runs were acquired for each of the 55 controls and 56 MS patients at baseline and 33 controls and 26 MS patients at 1-year follow-up. The externally cued (1 Hz) right hand tapping movement was limited to 3 cm amplitude by using at all sites (7 at baseline and 6 at follow-up) identically manufactured wooden frames. No significant differences in cerebral activation were found between sites. Furthermore, our results showed linear response adaptation (i.e. reduced activation) from run 1 to run 4 (over a 25 minute period) in the primary motor area (contralateral more than ipsilateral), in the supplementary motor area and in the primary sensory cortex, sensory-motor cortex and cerebellum, bilaterally. This linear activation decay was the same in both control and patient groups, did not change between baseline and 1-year follow-up and was not influenced by the modest disease progression observed over 1 year. These findings confirm that the short-term adaptation to a simple motor task is a physiological process which is preserved in MS.

Purpose: To investigate whether multiple sclerosis (MS) atrophy can be assessed by SIENA and SIENAX software using other image types from MS research protocols than T1-weighted images without contrast agent, which are not always available., Materials and Methods: We selected 46 MS patients with identical magnetic resonance imaging (MRI) protocols at two timepoints. We calculated normalized brain volume (NBV) using SIENAX, and percentage brain volume change (PBVC) using SIENA, from T1-weighted images with and without contrast agent, T2-weighted images, and (calculated) pseudo-T1-weighted images. Relative agreement of the results was assessed using variance component estimation., Results: Relative agreement with T1-weighted images without contrast agent was good for T1-weighted images with contrast agent (ICC=0.86 for NBV, ICC=0.77 for PBVC), and reasonably good for pseudo-T1 and T2-weighted images (T2: ICC=0.72 for NBV, 0.58 for PBVC; pseudo-T1: ICC=0.68 for NBV, 0.83 for PBVC)., Conclusion: Brain atrophy can be studied using SIENA and SIENAX if T1-weighted images without contrast agent are not available. T1-weighted images with contrast agent should be used if available. Otherwise, pseudo-T1 and T2-weighted images seem acceptable and accessible alternatives. The use of these other images will greatly improve research possibilities, especially regarding older datasets., (Copyright (c) 2008 Wiley-Liss, Inc.)

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1.5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

Objectives: To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS., Methods: Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM)., Results: During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00-2.77) as an independent predictor of evolution to definite MS., Conclusions: Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.

Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.

We performed a prospective multi-centre study using functional magnetic resonance imaging (fMRI) to better characterize the relationships between clinical expression and brain function in patients with multiple sclerosis (MS) at eight European sites (56 MS patients and 60 age-matched, healthy controls). Patients showed greater task-related activation bilaterally in brain regions including the pre- and post-central, inferior and superior frontal, cingulate and superior temporal gyri and insula (P < 0.05, all statistics corrected for multiple comparisons). Both patients and healthy controls showed greater brain activation with increasing age in the ipsilateral pre-central and inferior frontal gyri (P < 0.05). Patients, but not controls, showed greater brain activation in the anterior cingulate gyrus and the bilateral ventral striatum (P < 0.05) with less hand dexterity. An interaction between functional activation changes in MS and age was found. This large fMRI study over a broadly selected MS patient population confirms that movement for patients demands significantly greater cognitive 'resource allocation' and suggests age-related differences in brain responses to the disease. These observations add to evidence that brain functional responses (including potentially adaptive brain plasticity) contribute to modulation of clinical expression of MS pathology and demonstrate the feasibility of a multi-site functional MRI study of MS.

Purpose: To investigate intercenter agreement of brain volume (change) measurement in multiple sclerosis (MS) using structural image evaluation using normalization of atrophy (SIENA) and the cross-sectional version of SIENA (SIENAX) with additional manual editing to correct for inadequate brain extraction., Materials and Methods: Baseline and follow-up T1-weighted MR images of 20 MS patients were dispatched to five centers. Each center performed fully-automated and manually-edited analyses for SIENAX, yielding normalized brain volume (NBV), and SIENA, yielding percentage brain volume change (PBVC). Intercenter agreement was assessed with the concordance correlation coefficient (CCC)., Results: Intercenter agreement was perfect for fully automated NBV and PBVC (both CCC = 1.0), and remained substantial upon manual editing (CCC = 0.94 for NBV, CCC = 0.95 for PBVC). Mean NBV values for each center decreased significantly after manual editing (overall mean NBV = 1605.3 cm(3) vs. 1651.1 cm(3) without manual editing; t = -4.58, P < 0.001). Total variance in PBVC decreased significantly by a factor of 1.8 after manual editing (sigma(2) = 2.82 before, and sigma(2) = 1.54 after manual editing, P < 0.05)., Conclusion: Substantial intercenter agreement was found for manually-edited SIENAX and SIENA, suggesting that measurements from multiple centers may be pooled. Manual editing reduces overestimation of NBV, and is likely to increase statistical power for PBVC., ((c) 2007 Wiley-Liss, Inc.)

Previous diagnostic guidelines for MS relied largely on clinical evidence and cerebrospinal fluid analysis. In 2001, guidelines were published that allowed partial substitution of the required clinical evidence by magnetic resonance imaging findings and defined primary progressive multiple sclerosis (PPMS). Recently, revised guidelines on MS diagnosis were published, mainly to improve definitions of dissemination in space (using spinal cord imaging) and in time (using T2 lesions), enabling a faster and more accurate MS diagnosis. Criteria for PPMS were also revised. Current research is concentrating on the definition of uniform clinical terms, to allow a more standardized diagnosis, and aims to simplify the criteria while improving diagnostic accuracy.

We assessed the interobserver agreement on the radiological part of the International Panel (IP) criteria for the diagnosis of multiple sclerosis (MS), comprising the assessment of dissemination in space (DIS) and time (DIT) based exclusively on MRI. Four radiologists trained and four radiologists naive in the application of the IP criteria scored the fulfillment for DIS (i.e., > or =3 periventricular, > or =1 infratentorial, > or =1 juxtacortical, > or = 1 enhancing lesion or a total of > or =9 T2-weighted lesions) and DIT (presence of new or enhancing lesions at follow-up) in baseline and two follow-up scans from 20 patients suspected for having MS. The IP-trained radiologists agreed at least moderately on all assessments (kappa>0.40), whereas the IP-naive radiologists showed fair agreement (kappa<0.40) on five of 16 assessments. In the final conclusion on DIS and DIT, the IP-trained radiologists agreed substantially on both items (kappa=0.62 and kappa=0.60, respectively) compared with a fair agreement on DIS (kappa=0.29) and moderate agreement on DIT (kappa=0.52) among the IP-naive radiologists. Given the poor interobserver agreement among IP-naive observers, the new IP criteria for MS require additional training and should perhaps be simplified.

Background: The McDonald International Panel accepted the Barkhof/Tintoré criteria for providing MRI evidence of dissemination in space to allow a diagnosis of multiple sclerosis in patients with clinically isolated syndromes (CIS). We applied these criteria in a large cohort of patients with CIS, representative of those seen in a general diagnostic setting, to assess their accuracy in predicting conversion to definite multiple sclerosis and to identify factors that affect this risk., Methods: In a collaborative study of seven centres, baseline MRI and clinical follow-up data for 532 patients with CIS were studied, with the development of a second clinical event used as the main outcome. All scans were scored for lesion counts and spatial lesion distribution to assess the fulfilment--ie, at least three out of four--of the Barkhof/Tintoré criteria. We used survival analysis and 2x2 tables to assess the test characteristics of the criteria at baseline., Findings: Overall conversion rate was 32.5% with a median survival time of 85.3 months. Fulfilment of the criteria at baseline showed, after a survival time of 2 years, a conversion rate of about 45% (95% CI 37-53) versus about 10% (6-16) in those with no asymptomatic lesions at baseline (p<0.0001). For patients with a follow-up of at least 2 years, the fulfilment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion and an increase in risk of nearly four times for conversion compared with those not fulfilling the criteria (odds ratio 3.7, 95% CI 2.3-5.9; p<0.0001). Cox proportional hazards regression analysis accorded with this increased risk. No effects were recorded on the performance of the criteria by sex, presenting symptoms, or centre. Age at baseline did have a small but significant effect as predictor (hazard ratio 0.97, 0.95-0.99; p=0.002), but did not affect the prognostic value of the MRI criteria., Interpretation: MRI abnormalities have important prognostic value. The cut-off, based on the Barkhof/Tintoré criteria, as incorporated in the McDonald diagnostic scheme yields acceptable specificity, but could have lower sensitivity than previously reported.

Retrospectively, we assessed the specificity of two proposed magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in patients suspected to have MS but who ultimately receive another diagnosis. Brain MRIs of 28 patients mixed with 28 MRIs of MS patients from the same cohort of 377 consecutively referred patients were scored by a neuroradiologist masked to the final diagnosis. The criteria for dissemination in space incorporated in the McDonald International Panel showed good specificity (89%). However, the more sensitive criteria proposed by a Subcommittee of the American Academy of Neurology resulted in a lower specificity (29%), indicating an increased risk of a false-positive diagnosis.

New diagnostic criteria for multiple sclerosis (MS) have been proposed by Swanton and co authors, but were not yet evaluated in patients suspected of MS, but diagnosed with another disease. The dissemination in space (DIS) criterion of these Swanton criteria was investigated in such a patient group and compared with the present McDonald criteria. We found that with the Swanton criteria for DIS, simplicity can be combined with some gain in sensitivity, without major loss of specificity. [ABSTRACT FROM AUTHOR]