Search

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod’s efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( p Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992).

Background: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored. Objective: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging. Methods: Two samples of early MS patients ( n = 185 and n = 55; ⩽5 years diagnosed) and healthy controls ( n = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined. Results: Word-finding difficulty was the most common cognitive complaint of MS patients and the only complaint reported more by patients than healthy controls. Only RAN performance discriminated MS patients with subjective word-finding deficits from those without subjective complaints and from healthy controls. Thinner left parietal cortical gray matter independently predicted impaired RAN performance, driven primarily by the left precuneus. Conclusion: Three levels of evidence (patient-report, objective behavior, regional gray matter) support word-finding difficulty as a prevalent, measurable, disease-related deficit in early MS linked to left parietal cortical thinning.

Objective: To investigate the performance of deep learning (DL) based on fully convolutional neural network (FCNN) in segmenting brain tissues in a large cohort of multiple sclerosis (MS) patients. Methods: We developed a FCNN model to segment brain tissues, including T2-hyperintense MS lesions. The training, validation, and testing of FCNN were based on ~1000 magnetic resonance imaging (MRI) datasets acquired on relapsing–remitting MS patients, as a part of a phase 3 randomized clinical trial. Multimodal MRI data (dual-echo, FLAIR, and T1-weighted images) served as input to the network. Expert validated segmentation was used as the target for training the FCNN. We cross-validated our results using the leave-one-center-out approach. Results: We observed a high average (95% confidence limits) Dice similarity coefficient for all the segmented tissues: 0.95 (0.92–0.98) for white matter, 0.96 (0.93–0.98) for gray matter, 0.99 (0.98–0.99) for cerebrospinal fluid, and 0.82 (0.63–1.0) for T2 lesions. High correlations between the DL segmented tissue volumes and ground truth were observed ( R2 > 0.92 for all tissues). The cross validation showed consistent results across the centers for all tissues. Conclusion: The results from this large-scale study suggest that deep FCNN can automatically segment MS brain tissues, including lesions, with high accuracy.

Background: Psychologically resilient persons persist despite obstacles and bounce back after adversity, leading to better outcomes in non-neurologic populations. It is unknown whether psychological resilience relates to objective functional outcomes in multiple sclerosis (MS). Objective: To determine whether psychological resilience explains differential objective cognitive and motor functioning in persons with early MS. Methods: Psychological resilience was assessed in 185 patients with early MS and 50 matched healthy controls with the Connors-Davidson Resilience Scale (CDRS-10). Subjects completed the MS Functional Composite (MSFC) and a comprehensive neurobehavioral evaluation. Correlations assessed links between CDRS-10 and MSFC, motor indices (Total, Fine Motor, Gross Motor), and cognitive indices (Total, Cognitive Efficiency, Memory). Results: Higher CDRS-10 among patients was linked to better MSFC and motor outcomes (but not cognition), with the most robust relationships for gross motor function (grip strength, gait endurance). Findings were independent of mood and fatigue. CDRS-10 was unrelated to MS disease burden. CDRS-10 was also specifically linked to motor outcomes in healthy controls. Conclusion: Functional outcomes vary across persons with MS, even when disease burden and neurologic disability are low. These findings identify high psychological resilience as a non-disease-specific contributor to motor strength and endurance, which may explain differential outcomes across patients.

Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.

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.

Background. In January 2002 the New York City Chapter of the National Multiple Sclerosis Society convened a panel of experts to review the issue of depressive affective disorders associated with multiple sclerosis (MS). This Consensus Conference was supported by a grant from the Goldman family of New York City. Results. The panel reviewed summaries of current epidemiologic, neurobiologic, and therapeutic studies having to do with depressive disorders among MS patient populations. Depressive disorders occur at high rates among patients with MS, and there is reason to believe that the immunopathology of the disease is involved in the clinical expression of affective disorders. The depressive syndromes of MS have a major, negative impact on quality of life for MS sufferers, but are treatable. At the present time, most MS patients with depression do not receive adequate recognition and treatment. Conclusions. The Goldman Consensus Conference Study Group provides recommendations for improved screening, diagnosis, and clinical management for depressive affective disorders among patients suffering from MS.

Objective: Patients with progressive relapsing (PR) multiple sclerosis (MS) may accrue disability by incomplete recovery from acute exacerbations and by ongoing deterioration. In primary progressive (PP) MS, disability accumulates solely by continuous decline. Because it is the least common form of MS, there is scant information regarding the clinical characteristics of PRMS, but relapses are reportedly uncommon. The purpose of this study is to describe the clinical features of a cohort of patients with PRMS. Methods: A retrospective chart review of 16 patients diagnosed with PRMS at two academic MS centres over a four-year period. Results: Nine men and seven women had PRMS. The mean age at onset was 35.19/11.2 years. The most common presenting symptom was a progressive myelopathy. The mean disease duration was 10.19/8.5 years and the average time to first exacerbation was 4.19/3.7 years. Patients had an average of 2.89/2.3 relapses with an annualized relapse rate of 0.69/0.8. Time to Expanded Disability Status Scale (EDSS) 6.0 was strongly associated with time to first exacerbation. Although there was no correlation between the number of relapses and time to EDSS 6.0, there was a modest inverse relation between time to EDSS 6.0 and annualized relapse rate. Conclusions: Relapses in PRMS may occur more often than previously described and disability may accumulate more rapidly in PRMS than in PPMS. We suggest differentiating between these two forms of MS.

The presence of mitochondrial DNA mutations, including eight of those frequently associated with Leber's hereditary optic neuropathy (LHON), was investigated by sequencing end restriction endonuclease analysis in randomly selected patients with MS. Class I LHON mutations with primary pathogenic significance for blindness were not detected in any of the MS patients studied. A trend was observed for higher frequency of class II LHON mutations with unknown pathogenic significance in the MS patients than in the controls. Specifically, the mutation at position 4216 and its associated simultaneous mutations occurred with a higher frequency. Eleven of the 53 patients (20.8%) were positive for at least two (4216 and 4917 or 13708) or three (4216, 13 708, 15 257) simultaneous class II LHON mutations, white 7 of the 74 controls (9.5%) carried simultaneous mutations (P=0.036). Earlier studies reported the occurrence of either the 11 778 or 3460 LHON type mutations in MS patients with a positive LHON pedigree and/or with a disease course predominantly involving the optic nerves. The mutations we detected did not correlate with the severity of visual loss in either LHON or MS, rather they seemed to be present in randomly selected MS patients. We conclude that the mutations with primary pathogenic significance for blindness are not shared between LHON and randomly selected MS. However, the presence offurther mitochondrial mutations cannot be excluded in MS. The increased incidence of the simultaneous class II LHON mutations in MS patients (and LHON) vs controls may indicate that certain sets of mitochrondrial DNA mutations/variants are associated with and predispose to MS, a possibility which needs to be investigated further. Alternatively, a biological disadvantage may be associated with the coexistence of the mutations detected.