Central motor conduction time in progressive multiple sclerosis. Correlations with MRI and disease activity.

We investigated various magnetic resonance MRI parameters for both brain and spinal cord to see if any improved the clinicoradiological correlation in multiple sclerosis. Ninety-one multiple sclerosis patients (28 relapsing-remitting, 32 secondary progressive and 31 primary progressive) were imaged using conventional T1, proton density- and T2-weighted MRI of the brain and spinal cord. Focal brain and spinal cord lesion load was scored, as were diffuse signal abnormalities, brain ventricular volume and spinal cord cross-sectional area. Clinical measures included the expanded disability status scale (EDSS), the functional systems score and a dedicated urology complaint questionnaire. Secondary progressive patients differed from relapsing-remitting and primary progressive patients by a larger number of hypointense T1 lesions in the brain, ventricular enlargement and spinal cord atrophy. Primary progressive patients more often had diffuse abnormalities in the brain and/or spinal cord than did relapsing-remitting and secondary progressive patients. In the entire study population, EDSS correlated with both brain and spinal cord MRI parameters, which were independent. The urological complaint score correlated only with spinal cord MRI parameters. In relapsing-remitting and secondary progressive multiple sclerosis, the correlation between MRI and clinical parameters was better than in the entire population. In this subgroup EDSS variance could be explained best by T1 brain lesion load, ventricle volume and spinal cord cross-sectional area. In the primary progressive subgroup the clinicoradiological correlation was weak for brain parameters but was present between spinal cord symptoms and spinal cord MRI parameters. In conclusion, the different brain and spinal cord MRI parameters currently available revealed considerable heterogeneity between clinical subtypes of multiple sclerosis. In relapsing-remitting and secondary progressive multiple sclerosis both brain and spinal cord MRI may provide a tool for monitoring patients, while in primary progressive multiple sclerosis the clinicoradiological correlation is weak for brain imaging.

The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more demyelination in total and higher brain loads of active demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active demyelination was highest in secondary progressive multiple sclerosis and remained ~18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number (P<0.05). Conversely, the proportion of remyelinated shadow plaques (P<0.05) and the overall remyelination capacity (P<0.01) per brain were higher in primary, compared with secondary, progressive multiple sclerosis. By contrast, there were no group differences in the brain load or frequency of low-grade inflammatory plaques with slowly expanding demyelination. Spinal cord lesion loads and remyelination capacity were also comparable in the two patient groups. Remyelinated areas were more vulnerable than the normal-appearing white matter to new demyelination, including active demyelination in secondary progressive multiple sclerosis. 'Recurrent' slowly expanding demyelination, affecting remyelinated areas, and the load of slowly expanding demyelination correlated with incomplete remyelination in both groups. In turn, incomplete remyelination in the spinal cord correlated with higher disease-related disability (determined retrospectively; r = -0.53; P<0.05 for remyelination capacity versus disease severity). By contrast, such a correlation was not observed in the brain. We propose that regulatory and reparative properties could protect the white matter of the brain in patients with primary progressive multiple sclerosis. These patients may, thereby, be spared symptoms until the spinal cord is affected. By contrast, recurrent active demyelination of repaired myelin could explain why similar symptoms often develop in consecutive relapses in relapsing-remitting/secondary progressive multiple sclerosis. Our data also indicate that slowly expanding demyelination may irreparably destroy normal and repaired myelin, supporting the concept of slowly expanding demyelination as an important pathological correlate of clinical progression.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

ObjectivesTo evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability.MethodsIn this cross-sectional study, 270...

Neurophysiological evaluation of motor corticospinal pathways by TMS in idiopathic early-onset Parkinson’s disease

In this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS). T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord. Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = -0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001), and PPMS (r = -0.27, p = 0.01). Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials.

Vitamin B6 status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial.

Multiple sclerosis (MS) is a multifocal demyelinating disease with progressive neurodegeneration caused by an increased auto immune response to self-antigens. Based on the ability of remyelination, MS is characterized into 4 subtypes: Relapsing Remitting MS (RRMS) (most commonly found ∼87%), Primary Progressive MS (PPMS), Secondary Progressive MS (SPMS), and Progressive Relapsing MS (PRMS). MS is termed as T cell-mediated autoimmune disorder with a predominant expression of CD8+ cells, (involved (MHC-I) activation), CD4+ T cells and microglia/macrophages. The pathophysiology of MS involves focal demyelination (myelin sheath destruction), oligodendrocyte destruction and astrocyte proliferation. Majority of people experience symptoms like muscle spasms, constipation, weakness, urinary problems and alterative sessions of relapses and remissions between the ages of 20 and 40. Currently, Disease Modifying Therapies (DMTs) were known to decrease the frequency and severity of relapses, exacerbations and development of new lesions. To date, U.S FDA approved drug for the treatment of PPMS is Ocrelizumab. Nevertheless, many drugs exhibited success in the preclinical phases and successfully reached clinical trials.

Background: Multiple sclerosis (MS) is a disease which has a variable clinical presentation followed by a variable clinical course. Therefore, accuracy of clinical rating scales to measure disability at initial clinical presentation and during follow-up visits is essential to accurately capture the variability inherent in this disease. This is particularly vital when attempting to identify the efficacy of interventions. Objective: This observational study in veterans with MS compared the Kurtkze Expanded Disability Status Scale (EDSS) and the Total Functional Independence Measure (TFIM) scale as measures of MS-related disability. Methods: We retrospectively reviewed the electronic charts of 76 veterans with MS who are regularly followed in our VA MS clinic. Local Institutional Review Board approval was obtained for the protocol. Data were analyzed using SAS (SAS System for Windows, version 9.2, SAS Institute Inc., Cary, NC, USA). Chi-square and Fisher exact tests were used to assess categorical variables. Kruskal–Wallis tests evaluated the relationships between MS types [relapsing–remitting MS (RR), secondary progressive MS (SP), primary progressive MS (PP) and clinical isolated syndrome (CIS)] and the initial TFIM, EDSS and Impairment Index (II) scores. Results: The EDSS score accurately measured MS-related impairment at initial evaluation and follow-up relative to an II. However, the EDSS score did not change over time, compared to the TFIM suggesting reduced sensitivity of the EDSS for detecting change in MS-related disability over time. Conclusions: This suggests TFIM scale is a more sensitive measure of MS-related disability than EDSS for use in future MS clinical trials.Implications for RehabilitationThis study highlights that given the paucity of scales to which EDSS has been compared, TFIM is a valuable adjunct to EDSS in measuring MS-related disability.TFIM is able to accurately measure the severity of MS-related disability and help provide for services patients with MS-related disability would need.TFIM is an easy to administer and a sensitive scale to measure the change in MS-related disability following interventions.

Clinical predictors of disease progression in a cohort of Tunisian progressive Multiple Sclerosis

Dysphagia is one of the most common symptoms in multiple sclerosis (MS) patients. It can reduce the quality of life and increase the risk of mortality by developing complications such as aspiration pneumonia. The present study was conducted to estimate the prevalence of dysphagia in MS patients and investigate the associations between dysphagia and disease characteristics. The Persian version of the DYMUS questionnaire was used to assess dysphagia in 865 patients with MS, including 738 (85.3%) relapsing-remitting MS (RRMS), 106 (12.3%) secondary progressive MS (SPMS), and 21 (2.4%) primary progressive MS (PPMS). Also, demographic and clinical data, including age, sex, smoking status, Expanded Disability Status Scale (EDSS) score, disease duration, disease-modifying therapies exposure, initial symptoms of MS, were recorded. The mean (SD) age was 37.95(9.25) years, and 83.1% of the participants were female. The prevalence of dysphagia was estimated to be 25.4% among all patients. According to the DYMUS questionnaire results, the prevalence of dysphagia in RRMS, SPMS, and PPMS patients was 22.2%, 44.3%, and 42.9%, respectively. After multivariate analysis the current EDSS score (OR = 1.197, CI: 1.062, 1.350, p = 0.003), cerebellar impairment (OR = 1.335, CI: 1.450, 4.716, p = 0.004) and motor dysfunction (OR = 1.651, CI: 1.004, 2.715, p = 0.048) emerged as the risk factors for dysphagia. Since dysphagia, as previously mentioned, is a common symptom in multiple sclerosis, particularly in SPMS and PPMS courses, active screening for this condition is recommended in all patients, particularly those with identified risk factors.

To define the value of electrically elicited motor evoked potentials (MEP), obtained during the initial phase of the coma, for correct prediction of the post-coma motor status. Fifty-two patients were investigated by MEP within 72 hours after onset of the coma. It was the aim to correlate the MEP findings to the motor function two months after coma onset. Three patients with normal MEP showed no post-coma motor deficit. In 21 patients, a bilateral, symmetric prolongation of the central motor conduction time (CMCT) was registered. Eighteen of these 21 patients (86%) showed a normal post-coma motor status. In 28 patients, unilaterally absent evoked potential, or unilaterally prolonged CMCT, or bilaterally prolonged CMCT with significant difference in each hemisphere were observed. A post-coma contralateral paresis was found in 25 of these 28 patients (89%). That paresis was functionally important in 15 patients (54%) and functionally unimportant in 13 patients (46%). We identified certain MEP patterns (unilateral extinction of the evoked potential, unilateral, bilateral prolongation of the CMCT with significant "side" difference), which indicated a pyramidal tract lesion and a post-coma motor deficit with an accuracy of 89%. This refers to the motor results, which may not be the final post-coma motor results which are usually assessed six months after the coma onset. The MEP changes did not allow one to predict the severity of the paresis. The accuracy of prediction of a motor deficit increased from the MEP finding of unilaterally prolonged CMCT to the MEP finding of unilateral extinction of the potential. The most common finding, bilateral central motor slowing without significant "side" difference, did not indicate a post-coma paresis in 86%, leading to the assumption, that bilateral, symmetrical prolongation of the CMCT was not caused by lesions of the descending motor pathways, but by the drugs administered for treating the comatose patient. In conclusion, MEP allows one to predict the presence of a post-coma motor deficit with a high degree of accuracy already in the initial phase of coma, but MEP fails to predict the severity of that deficit.

A cross-sectional comparison of performance, neurophysiological and MRI outcomes of responders and non-responders to fampridine treatment in multiple sclerosis – An explorative study

BackgroundMultiple sclerosis (MS) is a disease with profound heterogeneity in clinical course.ObjectiveTo analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS).MethodsA total of 6890 MS patients aged 21−64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients.ResultsRRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively).ConclusionOur findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS.

Background: In multiple sclerosis (MS), microRNA (miRNA) dysregulation is mostly reported in different immune cells, but less information is available on circulating miRNAs that exert strong biomarker potential due to their exceptional stability in body fluids. Objective: The aim of this study was to profile expression of circulating miRNAs in primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) and assess their association with neurological worsening. Methods: The expressions of 84 different miRNAs were profiled in serum of 83 subjects (62 MS and 21 controls) using miScript miRNA techniques. First, they were screened on 18 PPMS and 10 controls; thereafter, 10 most aberrantly expressed miRNAs were validated on a larger cohort. Results: In comparison with controls, upregulation of miR-191-5p was found in both progressive MS subtypes, while miR-376c-3p was overexpressed only in PPMS. Additionally, upregulation of miR-128-3p and miR-24-3p was detected in PPMS when compared to controls and SPMS. Progression index correlated with miR-128-3p in PPMS and miR-375 in SPMS. Conclusion: We detected overexpression of four miRNAs that have not been previously associated with progressive forms of MS. The increased expression of circulating miR-191-5p seems to be associated with progressive forms of MS, while miR-128-3p seems to be associated mostly with PPMS.