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Background and Purpose: The aim was to evaluate whether magnetic resonance imaging (MRI) phenotypes defined by inflammation and neurodegeneration markers correlate with serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in relapsing-remitting multiple sclerosis (RRMS) patients; and to explore the role of radiological phenotypes and biomarker levels on treatment response and long-term prognostic outcomes., Methods: Magnetic resonance imaging scans from 80 RRMS patients were classified at baseline of interferon-beta (IFNβ) treatment into radiological phenotypes defined by high and low inflammation and high and low neurodegeneration, based on the number of contrast-enhancing lesions, brain parenchymal fraction and the relative volume of non-enhancing black holes on T1-weighted images. Serum levels of NfL and GFAP were measured at baseline with single molecule array (Simoa) assays. MRI phenotypes and serum biomarker levels were investigated for their association with IFNβ response, and times to second-line therapies, secondary-progressive MS (SPMS) conversion and Expanded Disability Status Scale (EDSS) 6.0., Results: Mean (SD) follow-up was 17 (2.9) years. Serum NfL levels and GFAP were higher in the high inflammation (p = 0.04) and high neurodegeneration phenotypes (p = 0.03), respectively. The high inflammation phenotype was associated with poor response to IFNβ treatment (p = 0.04) and with shorter time to second-line therapies (p = 0.04). In contrast, the high neurodegeneration phenotype was associated with shorter time to SPMS (p = 0.006) and a trend towards shorter time to EDSS 6.0 (p = 0.09). High serum NfL levels were associated with poor response to IFNβ treatment (p = 0.004)., Conclusions: Magnetic resonance imaging phenotypes defined by inflammation and neurodegeneration correlate with serum biomarker levels, and both have prognostic implications in treatment response and long-term disease outcomes., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. A polymorphism in the CYP24A1 gene, rs2762943, was recently identified that was associated with an increased MS risk. CYP24A1 encodes a protein involved in the catabolism of the active form of vitamin D. The immunological effects of carrying the rs2762943 risk allele were investigated, as well as its role as genetic modifier., Methods: Serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) were measured in a cohort of 167 MS patients. In a subgroup of patients, expression levels of major histocompatibility complex class II and co-stimulatory molecules were determined by flow cytometry, and serum levels of pro-inflammatory (interferon gamma, granulocyte macrophage colony-stimulating factor, C-X-C motif chemokine ligand 13) and anti-inflammatory (interleukin 10) cytokines and neurofilament light chain were measured by single-molecule array assays. The effect of the rs2762943 polymorphism on disease activity and disability measures was evaluated in 340 MS patients., Results: Compared to non-carriers, carriers of the rs2762943 risk allele were characterized by reduced levels of 1,25(OH) 2 D (p = 0.0001) and elevated levels of interferon gamma (p = 0.03) and granulocyte macrophage colony-stimulating factor (p = 0.008), whereas no significant differences were observed for the other markers. The presence of the rs2762943 risk allele had no significant impact on disease activity and disability outcomes during follow-up. However, risk allele carriers were younger at disease onset (p = 0.04)., Conclusions: These findings suggest that the CYP24A1 rs2762943 polymorphism plays a more important role in MS susceptibility than in disease prognosis and is associated with lower 1,25(OH) 2 D levels and a heightened pro-inflammatory environment in MS patients., (© 2023 European Academy of Neurology.)

Background and Purpose: Non-(acute disseminated encephalomyelitis) (non-ADEM) encephalitis and/or fluid attenuated inversion recovery hyperintense lesions in anti-myelin-oligodendrocyte-glycoprotein-associated encephalitis with seizures (FLAMES) are rarely described in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs). The aim was (i) to describe the clinical features and disease course of children and adults with non-ADEM encephalitis and/or FLAMES associated with MOG Abs and (ii) to describe their association with other central nervous system autoantibodies., Methods: This was a systematic review following the PRISMA guidelines. Patients fulfilled criteria for non-ADEM encephalitis and/or FLAMES, and all were MOG Ab positive., Results: In total, 83 (79%) patients with non-ADEM encephalitis (48 also had FLAMES) and 22 (21%) with isolated FLAMES were included. At the first episode, children (n = 45) had more infections (11/45, 24.4%; p = 0.017) and more of the phenotype consisting of non-ADEM encephalitis (42/45, 93.3%; p = 0.014) than adults (n = 38). Children had more episodes consistent with working memory deficits (25/54, 46.3%; p = 0.014) but fewer psychiatric symptoms (16/54, 29.6%; p = 0.002). Twenty-eight (40.6%) of 69 patients had N-methyl-d-aspartate receptor (NMDAR) Abs in cerebrospinal fluid (CSF), being more frequent in adults (19/29, 65.5%; p < 0.001). Compared to negatives, positive CSF NMDAR Abs had more relapses (14/20, 70%; p = 0.050), required ventilatory support more frequently (8/34, 23.5%; p = 0.009) and had more psychiatric episodes (28/34, 82%; p < 0.001) or abnormal movements (14/34, 41.2%; p = 0.008). Apart from an older age in FLAMES, positive and negative CSF NMDAR Ab groups shared similar features., Conclusion: Non-ADEM encephalitis patients with MOG Abs show specific clinical and radiological features, depending on the age at first episode. The presence of MOG Abs in non-ADEM encephalitis patients should not rule out to test other autoantibodies, especially concomitant NMDAR Abs in patients with suggestive symptoms such as behavioural or movement alterations., (© 2023 European Academy of Neurology.)

Background and Purpose: To evaluate the effect of menopause on disability accumulation in women followed from their clinically isolated syndrome (CIS)., Methods: We examined the longitudinal changes in Expanded Disability Status Scale (EDSS) scores from CIS until the last follow-up in women belonging to the Barcelona CIS prospective cohort, followed through their menopausal transition. The analysis is based on 13,718 EDSS measurements, with an average of 28 EDSS measurements per patient. Differences in EDSS trajectories between menopausal and nonmenopausal women, controlling for age and disease duration, were evaluated. We performed two sensitivity analyses in women with confirmed MS and in those experiencing early menopause., Results: From 764 eligible women, 496 (65%) responded to the questionnaire, and 74 (14.9%) reached menopause over the follow-up. We did not find a significant inflection point in EDSS trajectories around menopause (slope change -0.009; 95% CI -0.066; 0.046). The annual increase in EDSS over the complete course of the disease was significantly higher in menopausal women (0.049; 95% CI, 0.026-0.074) versus nonmenopausal (0.019; 95% CI, 0.008-0.031; interaction p value 0.025). This difference was lost when controlling for age and disease duration (EDSS annual increase of 0.059; 95% CI, 0.025-0.094 vs. 0.038; 95% CI, 0.021-0.057, respectively; interaction p value 0.321). No inflection point was detected when the analysis was restricted to women with confirmed MS or with earlier menopause., Conclusions: Menopause is not associated with an increased risk of disability in a CIS population, considering EDSS trajectories throughout the course of the disease together with age and disease duration., (© 2021 European Academy of Neurology.)

Background and Purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662)., Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase., Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years., Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Comorbidities are common in multiple sclerosis (MS), and have been associated with worse outcomes and increased health care resource usage. We studied the frequency of comorbidities and adverse health behaviors (AHBs) in MS patients in the Mediterranean region of Catalonia., Methods: This population-based, case-control study used primary health care information covering 80% of Catalonia's population. Cases were matched by age/sex with randomly chosen controls (ratio = 1:5). Demographic information, comorbidities, AHBs, annual visits, sick leave days, and medication dispensing were studied. The association of comorbidities with MS and the profile of comorbidities according to sex within MS cases were assessed with multivariate logistic regression models, after adjusting for confounding variables. Health care resource usage was analyzed in MS cases compared to controls, and within MS cases in those with compared to those without comorbidities., Results: Five thousand five hundred forty-eight MS cases and 27,710 controls (70% female, mean age = 48.3 years) were included. Stroke (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.17-1.99), epilepsy (OR = 2.46, 95% CI = 1.94-3.10), bipolar disorder (OR = 1.67, 95% CI = 1.17-2.36), and depression (OR = 1.83, 95% CI = 1.70-1.98) were more frequent in MS. Cases were more prone to smoking but less to alcohol intake. Among cases, psychiatric comorbidities were more frequent in women, whereas cardiovascular diseases and AHBs were more frequent in men. MS patients, particularly with comorbidities, had higher health care resource usage than controls., Conclusions: Psychiatric comorbidities, stroke, epilepsy, and AHBs are more common in MS patients than in the general population in the western Mediterranean region of Catalonia. The presence of comorbidities increases the health care resource usage in MS patients., (© 2021 European Academy of Neurology.)

Background and Purpose: Information regarding multiple sclerosis (MS) patients with the 2019 novel coronavirus disease (COVID-19) is scarce. The study objective was to describe the incidence and characteristics of MS patients with COVID-19, to identify susceptibility and severity risk factors and to assess the proportion of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologies according to disease-modifying treatments., Methods: This was a retrospective study of an MS cohort analysing data collected between February and May 2020. Cases were identified through an email survey and clinical visits. The relationship of demographic and MS characteristics with COVID-19 and of the disease-modifying treatments with SARS-CoV-2 serostatus were examined., Results: Data from 48 suspected cases out of 758 valid respondents and from 45 COVID-19 cases identified through clinical visits were collected. Incidence was 6.3%. Nineteen (20.3%) patients were hospitalized and two (2.2%) died. Multivariable models determined that age (odds ratio [OR] per 10 years 0.53, 95% confidence interval [CI] 0.34-0.85), contact with a confirmed case (OR 197.02, 95% CI 56.36-688.79), residence in Barcelona (OR 2.23, 95% CI 1.03-4.80), MS duration (OR per 5 years 1.41, 95% CI 1.09-1.83) and time on anti-CD20 treatment (OR per 2 years 3.48, 95% CI 1.44-8.45) were independent factors for presenting COVID-19 and age (OR per 10 years 2.71, 95% CI 1.13-6.53) for a severe COVID-19. Out of the 79 (84.9%) with serological test, 45.6% generated antibodies, but only 17.6% of those on anti-CD20 therapies. Lymphopaenia or immunoglobulin levels did not relate to COVID-19., Conclusions: Multiple sclerosis patients present similar incidence, risk factors and outcomes for COVID-19 as the general population. Patients treated with an anti-CD20 therapy for a longer period of time might be at a higher risk of COVID-19 and less than 20% generate an antibody response. Only age was related to severity., (© 2020 European Academy of Neurology.)

Background and Purpose: Both baseline prognostic factors and short-term predictors of treatment response can influence the long-term risk of disability accumulation in patients with relapsing-remitting multiple sclerosis (RRMS). The objective was to develop and validate a scoring system combining baseline prognostic factors and 1-year variables of treatment response into a single numeric score predicting the long-term risk of disability., Methods: We analysed two independent datasets of patients with RRMS who started interferon beta or glatiramer acetate, had an Expanded Disability Status Scale (EDSS) score <4.0 at treatment start and were followed for at least 10 years. The first dataset ('training set') included patients attending three MS centres in Italy and served as a framework to create the so-called RoAD score (Risk of Ambulatory Disability). The second ('validation set') included a cohort of patients followed in Barcelona, Spain, to explore the performance of the RoAD score in predicting the risk of reaching an EDSS score ≥6.0., Results: The RoAD score (ranging from 0 to 8) derived from the training set (n = 1225), was based on demographic (age), clinical baseline prognostic factors (disease duration, EDSS) and 1-year predictors of treatment response (number of relapses, presence of gadolinium enhancement and new T2 lesions). The best cut-off score for discriminating patients at higher risk of reaching the disability milestone was ≥4. When applied to the validation set (n = 296), patients with a RoAD score ≥4 had an approximately 4-fold increased risk for reaching the disability milestone (p < 0.001)., Discussion: The RoAD score is proposed as an useful tool to predict individual prognosis and optimize treatment strategy of patients with RRMS., (© 2021 European Academy of Neurology.)

Background and Purpose: The goal of this study was to assess changes in the resting-state networks (RSNs) of patients with multiple sclerosis (MS) after a cognitive rehabilitation program (CRP), by retrospectively analyzing functional magnetic resonance imaging (fMRI) studies using the classical block design., Methods: Fifteen patients with MS (2 primary progressive, 3 relapsing-remitting, 10 secondary progressive) were scanned before and after the CRP on a 1.5T MRI scanner. In addition, patients underwent pre- and post-CRP neuropsychological assessment using a battery of standardized tests. Five healthy individuals were scanned at the same time points to confirm the test-retest reliability of the imaging technique. For each study, the individual fMRI blocks of rest were merged to produce a "pseudo"-resting-state (pseudo-RS) of 3 minutes duration. RS studies were analyzed with the MELODIC toolbox. A dual regression analysis was applied to estimate the longitudinal changes in RSNs of patients and test controls relative to a set of predefined RSNs used as templates., Results: In healthy individuals, there were no significant differences in RSN results between the two time points studied. In the group of patients with MS, significant differences were found post-CRP in the visual medial, cerebellar, auditory, and frontal-executive RSNs. Furthermore, synchronization increases in the frontal-executive RSN were associated with cognitive improvement on neuropsychological testing., Conclusions: Results obtained using a pseudo-RS approach to analyze data from block-design fMRI studies suggest that a CRP of 5 weeks' duration induces measurable changes in specific RSNs of patients with MS., (Copyright © 2018 by the American Society of Neuroimaging.)

Background and Purpose: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process., Methods: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique., Results: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus., (© 2018 European Academy of Neurology and European Committee of Treatment of Research in Multiple Sclerosis.)

Objective: A pseudoatrophy effect, mostly affecting white matter, can be observed in patients with multiple sclerosis (MS) early on natalizumab therapy. We aimed to investigate whether a similar pattern could be found after interferon-beta treatment onset., Methods: From a prospective, ongoing cohort, 123 patients treated with interferon-beta were included. A brain MRI was performed at baseline (3 months prior) and 12 months after therapy onset in all patients. SPM8 software was used for volumetric analysis. Brain parenchymal, gray and white matter volumes at baseline and follow-up were obtained, allowing calculation of percentage of volume changes (BVc, GMVc, and WMVc, respectively). Descriptive statistics and linear regression models were performed., Results: Eighty-four patients were analyzed (39 patients were excluded mostly due to incomplete MRI protocol or segmentation errors); baseline mean age was 33.6 years (SD 8.7), median disease duration was 2.8 years (.3-14), and median EDSS was 1.5 (0-6). Forty-nine patients (58.3%) had baseline gadolinium-enhancing (Gd+) lesions with a median number of 1 (0-18). The regression analysis (adjusted by the number of Gd+ at follow-up MRI, age, disease duration, and baseline EDSS) showed that a higher baseline number of Gd+ lesions was predictive of larger decreases in BVc and WMVc (P = .013 and P = .003, respectively) but not GMVc (P = .777)., Conclusion: Concurrent inflammation has an impact on brain volume measurements (especially white matter) during the first year of interferon-beta therapy, and should be taken into account when interpreting early brain volume changes on therapy., (Copyright © 2016 by the American Society of Neuroimaging.)

Background and Objectives: Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE., Methods: For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35-55 peptide of myelin oligodendrocyte glycoprotein (MOG35-55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies., Results: Upon immunization with MOG35-55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35-55. Accordingly, resistant mice experienced a rise in regulatory B cells (P=0.001) and, to a lower extent, in regulatory T cells (P=0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35-55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P=0.02) and IL-17 (P=0.009) and higher serum levels of IL-17 (P=0.04) than resistant mice., Conclusions: Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism.

Background and Purpose: Ubiquitin specific peptidase 18 (USP18) is a deubiquitinating enzyme that functions as a negative regulator of the type I interferon (IFN) signalling pathway and is specifically induced by type I IFNs. In the present study, previous observations by our group were expanded suggesting an implication of USP18 in multiple sclerosis (MS) based on the finding of a deficient expression of the gene in peripheral blood mononuclear cells from MS patients compared with healthy controls., Methods: Two polymorphisms, rs2542109 (intronic) and rs9618216 (promoter), were genotyped in a cohort of 691 relapse-onset MS patients and 1028 healthy controls and in 225 MS patients treated with IFNβ and classified into responders and non-responders after 2 years of treatment according to clinical criteria. Correlations between genotypes and expression levels for USP18 and its target ISG15 were performed by real-time polymerase chain reaction., Results: Two USP18 haplotypes were significantly associated with MS, TG and CG. Additional experiments revealed that CG carriers were characterized by lower USP18 gene expression levels in peripheral blood mononuclear cells and higher clinical disease activity. Finally, AA homozygosis for the intronic polymorphism rs2542109 was associated with the responder phenotype; however, USP18 expression levels induced by IFNβ did not differ amongst MS patients carrying different rs2542109 genotypes., Conclusions: Altogether, these results point to a role of USP18 in MS pathogenesis and the therapeutic response to IFNβ., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Background:   Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design., Methods:   A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase., Results:   Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols., Conclusions:   The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Background: The 15-deoxi delta prostaglandin J(2) (15d-PGJ(2)) is a peroxisome proliferator-activated receptor-gamma agonist with potent anti-inflammatory properties. It has been suggested that 15d-PGJ(2) may modulate multiple sclerosis (MS)., Methods: Here, we investigated the plasma levels of 15d-PGJ(2) by enzyme-linked immunoassay in 28 healthy controls and 140 MS patients [30 patients with primary-progressive MS, 28 patients with secondary-progressive MS, and 82 patients with relapsing-remitting MS (28 patients during clinical remission, 25 patients during relapse, and 29 treated with interferon-beta - IFN-beta)]., Results: Levels of 15d-PGJ(2) were similar between healthy controls and untreated MS patients with different clinical courses of the disease. Treatment with IFN-beta had no effect on levels of 15d-PGJ(2)., Conclusions: Although these findings suggest that 15d-PGJ(2) is not involved in the acute or chronic phases of the disease, further studies measuring 15d-PGJ(2) in cerebrospinal fluid samples are needed before excluding a role of 15d-PGJ(2) in MS.

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.)

In some rare cases, demyelinating plaques appear on contrast-enhanced T1-weighted images as pseudotumoral, cyst-like lesions (hypointense, ring enhancing). Serial proton MR spectroscopy, T2 relaxometry and magnetization transfer ratios (MTR) were performed on three pseudotumoral demyelinating lesions to obtain information about their pathological basis. Baseline and 1-month MTR and T2 values were similar to those of cerebrospinal fluid, while spectra showed lactate, lipids and choline. Three-month and 1 year exams showed recovery of MTR, T2 and N-acetylaspartate, approaching the contralateral values, while creatine and choline were normal or surpassed contralateral values. Lipids and lactate gradually disappeared. These results suggest that pseudotumoral, cyst-like, ring-enhancing lesions may be characterized by an accumulation of oedema in the extracellular space with an almost complete absence of cells. Reduction of the oedema allows restoration of the tissue to its original location, indicating that cellular destruction was less important than was expected after the first exam. Thus, the evolution of this kind of lesion should be kept in mind when considering lesion volume from T1-weighted images as a marker of disability or irreversible cellular destruction in MS., (Copyright 2002 John Wiley & Sons, Ltd.)