Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS.

BACKGROUND: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Two Single Nucleotide Polymorphisms in the Purinergic Receptor P2X7 Gene Are Associated with Disease Severity in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) that leads to progressive physical disability. Recent evidence has suggested that P2X7 receptor (P2X7R)-mediated purinergic signalling pathways play a role in MS-associated neuroinflammation, possibly contributing to disease pathogenesis. To evaluate possible associations between P2X7R polymorphisms and MS disease severity, we performed an association study of five non-synonymous SNPs coding variants of the P2X7R gene: rs1718119 Ala348Thr, rs2230911 Thr357Ser, rs2230912 Gln460Arg, rs3751143 Glu496Ala, and rs28360457 Arg307Gln, modulating P2X7R expression in 128 MS patients (relapsing remitting MS, RRMS: n = 94; secondary progressive, SPMS: n = 34). All patients were genotyped, and multiple sclerosis severity score (MSSS) was evaluated in every case; 189 healthy subjects were enrolled as well as controls. Results showed that P2X7R rs1718119(A) 348Thr and rs22390912(G) 464Arg, two SNPs of minor allele frequency (MAF) known to confer gain of function to the P2X7R protein, were associated with significantly higher MSSS in RRMS patients alone (SMRR (p < 0.001, p = 0.01, respectively)). Interestingly, two whole haplotypes resulted in having significant association with MSSS in these same patients. Thus: (1) the P2X7R-4 "ACGAG" haplotype, characterized by the co-presence of the rs1718119-rs2230912 AG MAF alleles, was associated with higher MSSS (Beta: 1.11 p = 0.04), and (2) the P2X7R-1 "GCAAG" complementary haplotype, which contains the rs1718119 and rs2230912 GA wild-type alleles, was more frequently carried by patients with lower MSSS and less severe disease (Beta: −1.54 p < 0.001). Although being preliminary and needing confirmation in an ampler cohort, these results suggest that 348Thr and 464Arg variants have a role as modulators of disease severity in RRMS patients.

Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. OBJECTIVE: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. METHODS: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. RESULTS: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data (p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix (p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. CONCLUSION: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Vitamin D is associated with degree of disability in patients with fully ambulatory relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Vitamin D deficiency is a recognized risk factor for multiple sclerosis (MS) and is associated with increased disease activity. It has also been proposed that the lower the vitamin D levels are, the higher is the handicap. METHODS: To refine the links between vitamin D insufficiency and disability in MS patients, a retrospective cohort analysis was performed including 181 patients prospectively followed without previous vitamin D supplementation, and age, gender, age at MS onset, MS type, MS activity, Expanded Disability Status Scale (EDSS) were analysed in correlation with plasma vitamin D levels. RESULTS: Vitamin D levels were significantly higher in relapsing-remitting MS than in progressive forms of MS in multivariate analyses adjusted for age, ethnicity, gender, disease duration and season (P = 0.0487). Overall, there was a negative correlation between vitamin D level and EDSS score (P = 0.0001, r = -0.33). In relapsing-remitting MS, vitamin D levels were only correlated with disability scores for EDSS < 4 (P = 0.0012). Patients with >20 ng/ml of vitamin D were 2.78 times more likely to have an EDSS < 4 (P = 0.0011, 95% confidence interval 1.49-5.00). CONCLUSION: Data support previous work suggesting that vitamin D deficiency is associated with higher risk of disability in MS. Vitamin D levels also correlated with the degree of disability in fully ambulatory patients with relapsing-remitting MS. These additional results support the pertinence of randomized controlled trials analysing the interest of an early vitamin D supplementation in MS patients to influence evolution of disability.

Antibodies to blood coagulation components are implicated in patients with multiple sclerosis.

BACKGROUND: The strong link between innate immunity and thrombosis/coagulation has recently been investigated in the light of antibodies directed against serine proteases of the coagulation pathway. The antibodies have been proposed as contributing factors to venous thromboembolism development and as key molecules in the initiation of signaling inflammatory pathways in neuroinflammatory diseases. Preliminary studies of Multiple Sclerosis (MS) progression characteristics with the reactivity of antibodies against coagulant components are limited. Considering the development of thrombosis at the early onset of MS, our study aimed to detect antibodies against coagulant components in MS and evaluate their possible association with the clinical profile of the disease. METHOD: A cross-sectional study was carried out to identify antibodies to factor(F)VIIa, thrombin, prothrombin, FXa, FXII, plasmin, and protein C in serum samples from 167 patients with MS and 40 healthy controls using the enzyme-linked immunosorbent assay. Statistical analysis was performed for the evaluation of the data. RESULTS: The analysis revealed a significantly higher prevalence of IgG in MS patients (n = 72, 43%) compared to HCs (n = 8, 20%, p < 0.01). Specifically, elevated anti-FVIIa (n = 19, 11.4%, mean activity p < 0.0001), anti-FXII (n = 12, 7.2%, mean activity p < 0.001) and anti-plasmin (n = 20, 12%, mean activity p < 0.01) levels were observed in patients compared to controls. Additionally, the highest scores of clinical characteristics like the expanded disability status scale and MS severity score were linked with IgG seropositivity against thrombin, whilst anti-FXII levels corresponded with the lowest disease progression. CONCLUSION: The findings of our study illustrate the presence of antibodies against serine proteases of the coagulation cascade in MS and demonstrate the association of antibody activity with disease progression. In particular, thrombin IgG seropositivity was demonstrated to be associated with worse outcomes and a severe disease phenotype. These observations suggest the implication of antibodies in patient monitoring and prognosis, and further evaluation may elucidate inflammatory cascades in which antibodies act as key mediators.

Genetic Markers for Thrombophilia and Cardiovascular Disease Associated with Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with an unknown etiology, although genetic, epigenetic, and environmental factors are thought to play a role. Recently, coagulation components have been shown to provide immunomodulatory and pro-inflammatory effects in the CNS, leading to neuroinflammation and neurodegeneration. The current study aimed to determine whether patients with MS exhibited an overrepresentation of polymorphisms implicated in the coagulation and whether such polymorphisms are associated with advanced disability and disease progression. The cardiovascular disease (CVD) strip assay was applied to 48 MS patients and 25 controls to analyze 11 genetic polymorphisms associated with thrombosis and CVD. According to our results, FXIIIVal34Leu heterozygosity was less frequent (OR: 0.35 (95% CI: 0.12-0.99); p = 0.04), whereas PAI-1 5G/5G homozygosity was more frequent in MS (OR: 6.33 (95% CI: 1.32-30.24); p = 0.016). In addition, carriers of the HPA-1a/1b were likely to have advanced disability (OR: 1.47 (95% CI: 1.03-2.18); p = 0.03) and disease worsening (OR: 1.42 (95% CI: 1.05-2.01); p = 0.02). The results of a sex-based analysis revealed that male HPA-1a/1b carriers were associated with advanced disability (OR: 3.04 (95% CI: 1.22-19.54); p = 0.01), whereas female carriers had an increased likelihood of disease worsening (OR: 1.56 (95% CI: 1.04-2.61); p = 0.03). Our findings suggest that MS may be linked to thrombophilia-related polymorphisms, which warrants further investigation.

Reinforcing the evidence of oligoclonal bands as a prognostic factor in patients with Multiple sclerosis.

The prognostic value of oligoclonal bands in the cerebrospinal fluid of Multiple Sclerosis (MS) patients is controversial. While several studies have demonstrated a worse disease course in OCB positive patients, others did not reproduce these findings. We evaluated the prognostic significance of OCB retrospectively based on clinical records of OCB status upon diagnosis and severity outcomes including the MS Severity Score, Progression Index and regional involvement in Magnetic Resonance Imaging. OCB positive patients had a higher median MSSS and PI, and a greater proportion of spinal cord involvement. These findings provide further evidence of the prognostic importance of OCB in MS patients.

Smoking, cardiovascular risk factors and LRP2 gene variation: Associations with disease severity, cognitive function and brain structure in primary progressive multiple sclerosis.

BACKGROUND: Smoking, cardiovascular risk factors, and genetic factors can have adverse effects in MS. OBJECTIVE: To determine if smoking after disease onset, cardiovascular risk factors, and genetic variants influence primary progressive MS (PPMS). METHOD: In this cross-sectional study, smoking habits, Framingham Risk Score (FRS), genetic variants, including the low-density lipoprotein receptor-related protein 2 (LRP2) SNP rs12988804 and MRI were collected in 60 PPMS trial participants. Disability and cognition were assessed with the Age-Related Multiple Sclerosis Severity (ARMSS) score, the Progressive-Onset MS Multiple Sclerosis Severity Score, and the Brief International Cognitive Assessment for MS. RESULTS: Smoking after PPMS onset was significantly associated with higher ARMSS (95% CI 0.8-2.4, p = 0.00016) statistically significant after Bonferroni correction. Lower magnetization transfer ratio in lesions was also significantly associated with smoking after onset of PPMS after correction (95% CI -0.9--4.4, p = 0.0035). Pack-years in people who smoked after onset was likewise significantly associated with higher ARMSS score (b = 0.06 95% CI 0.02-0.09, p = 0.0021) as well as lower Symbol Digit Modalities Test scores (b = -0.40; 95% CI -0.66--0.13, p = 0.0037), both statistically significant after Bonferroni correction. The LRP2 risk allele was associated with decreased performance on the California Verbal Learning Test 2 after correction (CC vs. CT+TT 95% CI -14.2--3.4, p = 0.0018). CONCLUSION: If validated, these findings suggest that intervention regarding smoking may be beneficial in PPMS. If confirmed, assessment of the LRP2 gene variant may aid in the understanding of underlying pathological mechanisms in PPMS.

Predictors of Multiple Sclerosis Severity Score in Patients with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating autoimmune disorder. Several factors have been shown to associate with MS clinical severity. The influence of different lifestyle factors on MS clinical severity as assessed by the Multiple Sclerosis Severity Score (MSSS) was investigated. METHODS: A questionnaire was administered to 128 Kuwaiti MS patients to assess the association of smoking, nutritional supplement use, food allergy, physical activity (PA), and educational level with MSSS. A multiple linear regression model was used to test for associations. Regression model results were adjusted for sex, history of blood transfusion, age at MS onset, and marital status. RESULTS: Smoking status, passive smoking, and food allergy are not associated with MSSS. Patients with MS with a college education and graduate/professional degrees score, on average, 2.56 lower on the MSSS compared with those with less than a high school education (ß= -2.22, P = .045; and ß = -2.90, P = .048, respectively). Patients who perform PA score, on average, 2.32 lower on the MSSS compared with those with no PA (moderate exercise, P = .003; rigorous exercise, P = .001), and PA correlated significantly with MSSS outcomes (r2 = 0.452, P < .001). CONCLUSIONS: Educational level and PA are significantly associated with reduced MSSS, and both contribute to a less severe MS clinical course. Current MS management protocols should consider lifestyle changes to improve the quality of life of patients with MS.

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Multiple Sclerosis Severity.

Background: The association between lifestyle factors and Multiple Sclerosis (MS) disease severity and progression has been investigated to a lesser extent compared with susceptibility to the disease. Objective: We aimed to assess the impact of lifetime alcohol and cigarette smoking load on MS severity. Methods: Design: a cross-sectional study. Three hundred fifty-one patients consecutively admitted to the Department of Neurology were asked to complete the "Questionnaire of Lifestyle" (part of the European Prospective Investigation into Cancer and Nutrition project). An estimation of the cumulative lifetime cigarette smoking and alcohol load was calculated as the weighted sum of the mean number of cigarettes smoked and standard alcoholic drinks consumed per day at different ages. The measure of exposure was expressed in terms of pack-year and drink-year. Disease severity was estimated by the Multiple Sclerosis Severity Score (MSSS). Logistic regression analyses were performed using MSSS (first tertile vs. third tertile) as the outcome. Results: The median MSSS was higher (3.2 vs. 2.3, p = 0.002) in ever- vs. never-smokers, but we did not find a difference between ever- and never-drinkers (2.7 vs. 2.8, p = ns). Ever-smokers were almost twice as likely to fall in the upper MSSS tertile than never-smokers. Ever-drinkers did not show a statistically significant association between alcohol intake and MS severity. The risk of falling in the worst MSSS tertile for smokers was 10.81 (2.0-58.48; p < 0.01) if they were never-drinkers, whereas it was only 1.65 (0.89-3.03, p = 0.11) if they were also drinkers. On the other side, the risk of falling in the worst MSSS tertile for drinkers did not change as much, whether they also were smokers (0.46; 0.13-1.65; p = 0.23) or not (1.49; 0.55-4.04, p = 0.43). Conclusions: Cigarette smoking, unlike alcohol consumption, is associated with MS severity. Alcohol consumption may attenuate the effect of smoking on disease severity, acting as an effect modifier. The biological background of this effect is unknown. The limitations of our study are mostly due to its cross-sectional design.

The neutrophil-to-lymphocyte ratio is associated with multiple sclerosis.

BACKGROUND: Subtypes of white blood cell counts are known biomarkers of systemic inflammation and a high neutrophil-to-lymphocyte ratio (NLR) has been associated with several autoimmune diseases. Few studies have investigated the NLR in multiple sclerosis (MS). OBJECTIVE: To examine the association between NLR, MS and disability measured by the MS severity score (MSSS). METHODS: Patients were included from the Danish Multiple Sclerosis Biobank. Information on patient NLR was obtained just before their first treatment and clinical information was provided by the Danish Multiple Sclerosis Treatment Register. Information on NLR from controls was collected from the Danish Blood Donor Study. Patients and controls were 1:2 propensity score matched by baseline confounders. RESULTS: Propensity score matching left 740 of 743 MS patients and 1420 of 4691 controls for further analyses. Odds-ratio (OR) was 3.64 (95% confidence interval 2.87-4.60, p < 0.001) for MS disease per unit increase of logarithmically transformed NLR (ln-NLR), corresponding to an OR of 2.68 for each doubling of NLR. Mean NLR was 2.12 for patients and 1.72 for controls (p < 0.001). Ln-NLR correlated weakly with patient MSSS (R 2 = 0.019, p = 0.008). CONCLUSION: Patients with early MS had increased levels of NLR compared to healthy controls and NLR was weakly correlated with MSSS.

The Bayesian risk estimate at onset (BREMSO) correlates with cognitive and physical disability in patients with early multiple sclerosis.

BACKGROUND: Prevention of long-term disability is the goal of therapeutic intervention in Relapsing Remitting MS (RRMS). The Bayesian Risk Estimate for MS at Onset (BREMSO) gives an individual risk score predicting disease evolution into Secondary Progressive MS (SPMS). We investigated whether BREMSO correlates with physical disability, cognitive dysfunction, and regional brain atrophy early in MS. METHODS: One hundred RRMS patients with at least two years of follow-up were enrolled. BREMSO score as well as Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk Test (T25-FW) and 9-Hole Peg Test (9-HPT), were assessed. Intracranial volume (ICV), subcortical gray matter structures and corpus callosum (CC) were automatically segmented on MRI images and their volumes measured. RESULTS: BREMSO score correlated negatively with SDMT at visit1 (ß = -0.33, p = 0.019), visit2 (ß = -0.34, p = 0.017) and visit3 (ß = -0.34, p = 0.014), and positively with MSSS at visit1 (r = 0.38, p = 0.006), visit2 (r = 0.47, p < 0.0001) and visit3 (r = 0.42, p = 0.002), but not with T25-FW and 9-HPT. BREMSO negatively correlated with CC volume at baseline (p < 0.03). No correlations were found with ICV and subcortical gray matter. CONCLUSIONS: BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS.

BDNF and Tau as biomarkers of severity in multiple sclerosis.

AIM: Determine if serum levels of tau and BDNF can be used as severity biomarkers in multiple sclerosis (MS). PATIENTS & METHODS: Subjects with MS, older than 18 and younger than 55 years old were included; 74 patients with a diagnosis of relapsing-remitting MS, 11 with secondary-progressive MS, and 88 controls were included. Total tau and BDNF were measured by Western blot. RESULTS: Increased tau and decreased BDNF in MS patients compared with controls was found. Total-tau has a peak in relapsing-remitting MS, the second decile of the multiple sclerosis severity score, and in the lowest expanded disability status scale and is no different than controls for secondary-progressive MS patients and the most severe cases of MS. CONCLUSION: BDNF is a good biomarker for diagnosis of MS but not for severity or progression. Tau appears to have a more active role in the progression of MS.

Feasibility study for remote assessment of cognitive function in multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published. OBJECTIVE: To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals. METHODS: The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized. RESULTS: 11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007). CONCLUSIONS: Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.

Clinical and demographic factors affecting disease severity in patients with multiple sclerosis.

BACKGROUND: The clinical course of multiple sclerosis (MS) evolves over many years. Its prognosis is highly variable among affected individuals, i.e. while some suffer from early severe disabilities, others remain ambulatory and functional for many years. We used Multiple Sclerosis Severity Score (MSSS) and the new classification for MS severity Herbert et al. introduced in 2006 according to MSSS, to investigate some clinical and demographic factors as potential indicators of disease severity in in MS. METHODS: During a six-month period, patients with definite MS according to the revised McDonald's criteria who referred to three neurology and MS clinics in Tehran (Iran) were included in the study. All patients were interviewed and examined by a neurology resident who had been trained for employing the Expanded Disability Status Scale (EDSS). For each patient, MSSS was determined by using EDSS and disease duration. RESULTS: Overall, 338 (266 female and 72 male) patients were enrolled. Among demographic features, gender, younger age at onset, positive family history, and parental consanguinity were not associated with disease severity. Education was weakly associated with disease severity. Among clinical factors, presenting symptoms such as poly-symptomatic attacks, walking difficulty, and upper and lower extremity dysfunction were associated with more disability while presentation with optic neuritis had better prognosis. Complete recovery after the first attack, longer interval between the first and second attacks, lower number of symptoms at presentation, shorter duration of attacks, and relapsing-remitting course were associated with less disability and better prognosis. These results were noticed in ordinal logistic regression. However when multiple logistic regression was performed, the strongest determinant of disease severity was disease course with odds ratio (OR) = 49.12 for secondary progressive course and OR = 53.25 for primary progressive (± relapse) course. Walking difficulty as the presenting symptom had a borderline association with disease severity (OR = 2.31; P = 0.055). Increased number of onset symptoms was associated (but not significantly) with more severe disease. CONCLUSION: Early prediction of disease severity by demographic and clinical features is currently impossible. We need to determine stronger predictors, possibly a combination of demographic, clinical, biomarkers, and imaging findings.