These data confirm substantial neocortical volume loss in MS patients and suggest that neocortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to neurologic impairment. Although a proportion of this neocortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent neurodegenerative process also is active.

ObjectiveTo assess whether it is feasible to establish specific cut-off values able to discriminate ‘physiological’ or ‘pathological’ brain volume rates in patients with multiple sclerosis (MS).MethodsThe study was based on the analysis of longitudinal MRI data sets of patients with MS (n=206, 87% relapsing–remitting, 7% secondary progressive and 6% primary progressive) and healthy controls (HC; n=35). Brain atrophy rates were computed over a mean follow-up of 7.5 years (range 1–12) for patients with MS and 6.3 years (range 1–12.5) for HC with the SIENA software and expressed as annualised per cent brain volume change (PBVC/y). A weighted (on the follow-up length) receiver operating characteristic analysis and the area under the curve (AUC) were used for statistics.ResultsThe weighted PBVC/y was −0.51±0.27% in patients with MS and −0.27±0.15% in HC (p<0.0001). There was a significant age-related difference in PBVC/y between HC older and younger than 35 years of age (p=0.02), but not in patients with MS (p=0.8). The cut-off of PBVC/y, as measured by SIENA that could maximise the accuracy in discriminating patients with MS from HC, was −0.37%, with 67% sensitivity and 80% specificity. According to the observed distribution, values of PBVC/y as measured by SIENA that could define a pathological range were above −0.52% with 95% specificity, above −0.46% with 90% specificity and above −0.40% with 80% specificity.ConclusionsOur evidence-based criteria provide values able to discriminate the presence or absence of ‘pathological’ brain volume loss in MS with high specificity. Such results could be of great value in a clinical setting, particularly in assessing treatment efficacy in MS.

Cortical atrophy was found only in cognitively impaired patients and was significantly correlated with a poorer performance on tests of verbal memory, attention/concentration, and verbal fluency. Gray matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

Background : We previously reported selective decreases of neocortical volumes in patients with early relapsing-remitting (RR) multiple sclerosis (MS) with mild cognitive impairment, with a good correlation between cortical volumes and cognitive measures.Objective: To assess the relevance of gray matter changes over time to changes in cognition in RRMS.Design: A longitudinal survey after 2.5 years. Each patient underwent a magnetic resonance imaging (MRI) protocol identical to that performed at baseline; cognitive performance was reassessed with the Rao Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. Setting: Two university MS clinics.Patients: Of 41 patients with RRMS who participated in the original cross-sectional study, 28 were available for the follow-up evaluation (18 women; mean±SD age, 37.1±8.9 years; mean±SD MS duration, 7.3±2.9 years; mean±SD Expanded Disability Status Scale score, 1.8±1.5). Main Outcome Measures:We measured the percentage of brain volume changes, normalized cortical volume (NCV) changes, and normalized deep gray matter volume changes on conventional T1-weighted MRIs and changes in lesion load on T2-weighted MRIs. The number of tests failed on the Rao Brief Repeatable Battery were used to classify the patients as cognitively deteriorating or stable or improving.Results: We identified 12 of 28 cognitively deteriorating and 16 of 28 stable or improving patients. These subgroups did not differ in the mean±SD percentage of brain volume changes (−2.1%±1.2% vs −1.3%±1.3%; P=.11), normalized deep gray matter volume changes (−2.1±2.8 mL vs −0.6±3.1 mL; P=.60), and changes in lesion load on T2-weighted MRIs (1.9±2.6 mL vs 1.6±2.3 mL; P=.73). However, NCV changes were significantly higher in deteriorating than in stable or improving patients (−43.0±18.9 mL vs −17.8 ± 26.6 mL; P = .007). In deteriorating patients, NCV changes were correlated with performance in a verbal fluency test (r=0.73; PϽ.001). In a regression model, only NCV changes were significantly associated with deteriorating cognitive performance (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). Conclusion:Progressive neocortical gray matter loss is relevant to MS-associated cognitive impairment and may represent a sensitive marker of deteriorating cognitive performance in RRMS.

Information from patients who are unable to continue their visits to a study centre may be of major importance for the interpretation of results in multiple sclerosis (MS) clinical trials. To validate a questionnaire based on the Expanded Disability Status Scale (EDSS), patients in five different European centres were assessed independently by pairs of trained EDSS raters, first by telephone interview and a few days later by standardized neurological examination. Seventy women and 40 men with an average age of 43.7 years (range 19-74 years) were included in the study. Mean EDSS score at the last visit was 4.5 (0-9). EDSS assessment by telephone was highly correlated with the EDSS determined by physical examination (Pearson's correlation coefficient = 0.95). An intraclass correlation coefficient (ICC) of 94.8% was found for the total sample; 77.6% and 86%, respectively, for patients with EDSS < 4.5 (n = 46) and > 4.5 (n = 64). Kappa values for full agreement were 0.48; for variation by +0.5 steps and +1.0 steps, 0.79 and 0.90, respectively. Best agreement could be found in higher EDSS scores, where assessment by telephone interview might be needed most. The telephone questionnaire is a valid tool to assess EDSS score in cases where the patient is unable to continue visiting a study centre or in long-term follow-up of trial participants.

These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.

Cerebral NAA/Cr and MTr values are diffusely decreased in MS patients with early disease, low demyelinating lesion load, and no significant disability. This suggests that axonal and/or tissue injury begins very early in the course of MS and might be at least partially independent of cerebral demyelination.

Our findings show an increased risk of postpartum relapses and disability accrual in women with higher disease activity before and during pregnancy. Since it may reduce the risk of postpartum relapses, early DMD resumption should be encouraged, particularly in patients with more active disease.