Definition, prevalence and predictive factors of benign multiple sclerosis

Background: Multiple sclerosis (MS) is characterized by a great inter-individual variability in disease course and severity. Some patients experience a rather mild course, controversially called ‘benign MS’ (BMS). The usefulness of this entity in clinical practice remains unclear. Methods: We performed a literature search in PubMed, Web of Science and Cochrane Library databases from November 1980 to December 2015, using the following key words: benign multiple sclerosis, diagnosis, imaging, prognosis, predictive, natural history and predefined inclusion criteria. Results: Our search yielded 26 publications. Most definitions were based on the Expanded Disease Status Scale (EDSS), which is heavily weighted towards physical disability. Between 30 and 80% of relapsing-remitting MS patients have EDSS <3 or 4 at 10 years after onset. Having only one relapse in the first 5 years and EDSS ≤2 at 5 years or EDSS ≤3 at 10 years appears to be predictive for a prolonged benign disease course, without protecting against disease progression at a later stage. Evidence on the predictive value of MRI parameters remains limited. Conclusions: Current BMS definitions have some predictive value for future physical disability, but do not take into account the age at EDSS and the potentially disrupting effects of non-EDSS symptoms and cognitive impairment. It appears to correspond to mild RRMS in the first decades and its prevalence varies. Since early and accurate prediction of BMS is not yet possible, the clinical relevance is limited. Research approaches are suggested

Correlations of health status indicators with perceived neuropsychological impairment and cognitive processing speed in multiple sclerosis

Background: Comorbidity and health behaviours may explain heterogeneity regarding cognitive performance in multiple sclerosis. Patient-reported cognitive difficulties have impact but do not consistently correlate with objective cognitive performance. Our study aims to investigate whether health status indicators including comorbidities, body mass index, physical activity, smoking, sleeping behaviour and consumption patterns for fish, alcohol and caffeinated drinks are associated with measures of subjective and objective cognitive performance. Methods: Survey data on self-reported cognitive performance, assessed with the MS Neuropsychological Screening Questionnaire (MSNQ), were related to the presence of arterial hypertension, diabetes mellitus, cardiovascular and chronic renal diseases, hypercholesterolemia, depression based on 2-question screening tool, health and consumption behaviors. We included the Symbol Digit Modalities Test when available within 6 months as an objective, performance-based metric of cognitive processing speed. We investigated the interrelation between all variables with a Spearman correlation matrix and corrected for multiple testing. Regression models were built and controlled for age, sex and phenotype. Results: We used available data from 751 patients with definite MS, including 290 SDMT scores within a time window of 6 months, to study relations between variables. MSNQ and SDMT scores were not significantly correlated. Correlation patterns for subjective and objective performance differed. Age, disease duration and physical disability correlated with SDMT scores only. Regression analyses could be performed for MSNQ scores in 595/751 (79.2%) and for SDMT scores in 234/751 (31.2%) participants. After restricting variables to avoid collinearity and adjusting for the number of variables, regression models explained 15% of the variance for subjective and 14% of the variance for objective cognitive performance. A higher number of physical comorbidities, reporting depressive symptoms, sleeping 9 h or more and daily use of sleeping medication were associated with lower subjective cognitive performance, whereas increasing age was associated with reduced processing speed. These associations persisted after correction for multiple testing. Conclusion: Increasing age is associated with reduced cognitive processing speed whereas comorbidities and sleep behaviors contribute to subjective cognitive performance

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Associations of alcohol consumption with clinical and MRI measures in multiple sclerosis

Evaluation of: Foster M, Zivadinov R, Weinstock-Guttman B et al. Associations of alcohol consumption with clinical and MRI measures in multiple sclerosis. J. Neuroimmunol. 243(1-2), 61-68 (2012). While the harmful effects of alcohol abuse are well documented, experimental and clinical data support a potential benefit of light to moderate alcohol consumption. Cross-sectional studies have suggested an association between alcohol consumption and multiple sclerosis (MS) disability. In the absence of prospective, longitudinal studies, the causal nature of this relationship cannot be established. It remains possible that patients with increased disability progression reduce their alcohol intake. Even though there is substantial evidence for anti-inflammatory effects of low-to-moderate doses of alcohol, the associations need to be interpreted very cautiously. This study discusses the current state of knowledge about MS and alcohol consumption, and the limitations in conducting research with retrospective data in patients with MS

Reduced information processing speed as primum movens for cognitive decline in MS

Background: Cognitive impairment affects half of the multiple sclerosis (MS) patient population and is an important contributor to patients' daily activities. Most cognitive impairment studies in MS are, however, cross-sectional or/and focused on the early disease stages. Objective: We aim to assess the time course of decline of different cognitive domains. Methods: We collected neuropsychological data on 514 MS patients to construct Kaplan-Meier survival curves of the tests included in the Neuropsychological Screening Battery for MS (NSBMS) and the Symbol Digit Modalities Test (SDMT). Cox-proportional hazard models were constructed to examine the influence of MS onset type, age at onset, gender, depression and level of education on the time course, expressed as age or disease. Results: Survival curves of tests focusing on information processing speed (IPS) declined significantly faster than tests with less specific demands of IPS. Median age for pathological decline was 56.2 years (95% CI: 54.4-58.2) on the SDMT and 63.9 years (95% CI: 60-66.9) on the CLTR, a memory task. Conclusion: In conclusion, IPS is the cognitive domain not only most widely affected by MS but it is also the first cognitive deficit to emerge in MS

Cerebral hypoperfusion: a new pathophysiologic concept in multiple sclerosis?

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS

A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis.

A double-blind clinical trial of mitoxantrone versus methylprednisolone was performed in 49 patients with relapsing, secondary multiple sclerosis. Patients were randomized to receive 13 infusions of mitoxantrone 12 mg/m2 (n = 28), or 13 infusions of 1 g of methylprednisolone (n = 21), over 32 months. Twenty-four patients completed the trial. There were no statistical differences between the two groups of patients at study entry. A significant improvement in the Expanded Disability Scale Score (EDSS) was observed in the mitoxantrone group after one year of treatment (p < 0.0022). The total number of relapses, the mean number of relapses/patient/year, and the total number of gadolinium-enhanced lesions on bi-annual MRI scans were significantly decreased in the mitoxantrone group throughout the study period. Nausea, vomiting, and alopecia were more frequent in the mitoxantrone-treated patients. Mitoxantrone has a role in the treatment of MS patients with frequent exacerbations and rapid disease progression

The Arm Function in Multiple Sclerosis Questionnaire (AMSQ): Development and validation of a new tool using IRT methods

Purpose: We developed the Arm Function in Multiple Sclerosis Questionnaire (AMSQ) to measure arm and hand function in MS, based on existing scales. We aimed at developing a unidimensional scale containing enough items to be used as an itembank. In this study, we investigated reliability and differential item functioning of the Dutch version. Method: Patients were recruited from two MS Centers and a Dutch website for MS patients. We performed item factor analysis on the polychoric correlation matrix, using multiple fit-indices to investigate model fit. The graded response model, an item response theory model, was used to investigate item goodness-of-fit, reliability of the estimated trait levels (θ), differential item functioning, and total information. Differential item functioning was investigated for type of MS, gender, administration version, and test length. Results: Factor analysis results suggested one factor. All items showed p-values of the item goodness-of-fit statistic above 0.0016. The reliability was 0.95, and no items showed differential item functioning on any of the investigated variables. Conclusion: AMSQ is a unidimensional 31-item questionnaire for measuring arm function in MS. Because of a well fit in a graded response model, it is suitable for further development as a computer adaptive test. ▸ Implications for Rehabilitation • A new questionnaire for arm and hand function recommended in people with multiple sclerosis (AMSQ). • Scale characteristics make the questionnaire suitable for use in clinical practice and research. • Good reliability. • Further development as a computer adaptive test to reduce burden of (repetitive) testing in patients is feasible