The Rao's Brief Repeatable Battery in the study of cognition in different multiple sclerosis phenotypes: application of normative data in a Serbian population.

Cognitive impairment is prevalent in multiple sclerosis (MS) occurring in 43-72 % of patients with all MS phenotypes. The aim of our study was to assess cognitive performance in different MS subtypes in Serbian population. Rao's Brief Repeatable Battery of neuropsychological tests (BRB-N) was administered to 168 MS patients [37 patients with clinically isolated syndrome (CIS) suggestive of MS, 65 with relapsing-remitting MS (RRMS), 31 with secondary progressive MS (SPMS) and 35 patients with primary progressive MS (PPMS)]. The percentage of cognitively impaired patients in our total MS cohort was 58.9 %. Prevalence of cognitive dysfunction was 40.5 % in CIS group, 36.9 % in RRMS, 96.8 % in SPMS, and 85.7 % in PPMS group. Patients in CIS and RRMS groups performed consistently better all tests of the Rao's battery than patients in SPMS and PPMS cohort. CIS and RRMS groups performed consistently better in all tests of the Rao's battery than SPMS and PPMS cohort. Additionally, difference in the performance of any of the BRB-N tests was not found between CIS and RRMS. However, there was a significant difference between SPMS and PPMS patients in the performance on five tests of Rao's battery. Statistical significance (p < 0.05) in favor of PPMS patients was demonstrated for the following tasks: SRT_lts, SRT_cltr, SDMT, SRT_D, SPART_D. Our study demonstrates that cognitive impairment is frequent in all MS phenotypes. Furthermore, we have found that cognitive deficit is most severe and most frequent in SPMS patients, followed by PPMS subjects and then CIS and RRMS patients.

Sexual dysfunction in multiple sclerosis: A 6-year follow-up study.

PURPOSE: Sexual dysfunction (SD) is a common but often overlooked and undertreated symptom in multiple sclerosis (MS). The purpose of our longitudinal study was to explore the changes in the level of sexual functioning in MS cohort after a period of 3 and 6 years of follow-up, as well as to investigate the predictors of changes in SD during the period of observation. METHODS: The study population comprise a cohort of 93 patients with MS (McDonald's criteria, 2001) who were assessed at three time points during the study (baseline, and at the 3- and 6-year follow-up). The presence and severity of SD was quantified by Szasz sexual functioning scale. Independent predictors of the ordinal-scaled measure of sexual problems were identified using a generalized linear mixed regression models. RESULTS: The number of reported SD symptoms increased markedly for both genders during the whole period of observation. Duration of follow-up, age, level of physical disability, depression and fatigue were identified as independent prognostic factors for deterioration of sexual functioning in patients with MS during the 6-year follow-up. CONCLUSION: Our study provides insight into dynamics of change in sexual function among patients with MS and predictors of change, over the period of 6 years.

Change in quality of life and predictors of change among patients with multiple sclerosis: a prospective cohort study.

PURPOSE: The aim of this study was to determine the changes in the health-related quality of life (HRQoL) and predictors of change among patients with multiple sclerosis (MS) at 3 and 6 years during the follow-up period. METHODS: A group of 109 consecutive MS patients (McDonald's criteria) referred to the Clinic of Neurology, Belgrade, were enrolled in the study. At three time points during the study (baseline, and at 3 and 6 years during the follow-up period), the HRQoL (measured by MSQoL-54), Expanded Disability Status Scale, and Hamilton Rating Scale for Depression and Fatigue Severity Scale were assessed. RESULTS: During the study period, 93 patients provided both follow-up assessments. Statistically significant deterioration in the HRQoL at each subsequent time point was detected for all scales of the MSQoL-54 except for the pain and change in health scales. A higher level of education was a significant prognostic factor for a better HRQoL on the cognitive function scale throughout the entire period of observation, while marital status (single, including divorced and widowed) and increased age at the onset of MS had significant predictive values of poorer quality-of-life scores on the overall quality-of-life scale at 6-year follow-up. Higher levels of physical disability and depression at baseline were statistically significant prognostic markers for deterioration in HRQoL for the majority of MSQoL-54 scales during the entire follow-up period. CONCLUSIONS: Our study suggests that baseline demographic and clinical characteristics could be applied as prognostic markers of the HRQOL for patients diagnosed with MS.

Interferon-beta and disability progression in relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess the impact of interferon (IFN)-beta treatment on the progression of unremitting disability in IFN-beta treated and untreated relapsing-remitting (RR) patients with multiple sclerosis (MS) using prospective cohort study. METHODS: A cohort of 419 RRMS (236 IFN-beta-treated and 183 untreated) patients was followed for up to 7 years. Cox proportional hazards regression models adjusted for the number of relapses in the last year before first visit was used to assess the differences between the two groups for the three end points: secondary progression (SP), and sustained Expanded Disability Status Scale (EDSS) score 4 and 6. Time from disease onset was used as survival time variable. RESULTS: The IFN-beta-treated group showed a highly significant reduction (hazard ratio [HR], 0.34, 95% confidence interval [CI] 0.19-0.61, p<0.001) in the risk of SP when compared with untreated patients. There were significant differences in favor of the IFN-beta-treated group for the end point EDSS score of 4 (HR=0.45, 95%CI 0.28-0.73, p=0.001) and EDSS score of 6 (HR=0.34, 95%CI 0.16-0.75, p=0.007). CONCLUSION: This observational study further supports the notion that IFN-beta could have potential beneficial effect on disease progression in RRMS.

Predictive value of health-related quality of life in progression of disability and depression in persons with multiple sclerosis: a 3-year study.

In our study, we examined whether health-related quality of life (HRQoL) could predict changes in disability, depression, and fatigue in patients with multiple sclerosis (MS) over a 3-year follow-up period. A group of 109 consecutive MS patients (McDonald's criteria) referring to the Institute of Neurology, Belgrade were enrolled in the study. At two time points during the study (baseline, and after a 3-year period) an HRQoL (measured by MSQoL-54), EDSS, Hamilton Rating Scale for Depression (HDRS) and Fatigue Severity Scale (FSS) were assessed. At the end of a 3-year follow-up, 12 out of 109 patients (11%) had dropped out. Multiple linear regression analysis showed that Physical Health scale of MSQoL-54 is significant independent predictor of change in EDSS after 3 years (p = 0.035). Mental health composite score of MSQoL-54 was predictor of change in HDRS score (p = 0.049). In separate regression analysis, only social function was independent predictor of the development of depression (p = 0.041). None of the HRQoL domains had predictive effect on the change of FSS. Our study suggests that baseline HRQoL scores, measured by MSQoL-54, could be applied as a prognostic marker for progression of both, disability, and severity of depressive symptoms in MS.

Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are associated with anti-aquaporin-4 autoantibodies (AQP4-IgG). Limited data is available on longitudinal cerebrospinal fluid (CSF) AQP4-IgG and their relation to disease activity and inflammatory parameters. AQP4-IgG titers were measured in matched longitudinal serum and CSF samples of 12 patients with NMOSD by an immunofluorescence assay and correlated with clinical parameters. CSF AQP4-IgG were present in patients with high serum titers and correlated with spinal MRI lesion length and CSF parameters. Clinical improvement was associated with a decrease in CSF, but not serum, AQP4-IgG titers. Thus, CSF AQP4-IgG were associated with clinical activity and neuroinflammation.

Expression of Th1 and Th17 cytokines and transcription factors in multiple sclerosis patients: does baseline T-bet mRNA predict the response to interferon-beta treatment?

We studied the effect of one-year interferon (IFN)-beta treatment on the in vivo mRNA expression of IFN-gamma, interleukin (IL)-17, T-bet and RoR-gammat, on peripheral blood mononuclear cells (PBMC) from 36 multiple sclerosis (MS) patients. In the total MS group, IFN-beta induced decrease in mRNA levels of IFN-gamma and T-bet (p<0.0001), while the levels of IL-17 and RoR-gammat remained similar. In both responders and non-responders, IFN-beta induced significant decrease of IFN-gamma (p<0.0001 and p=0.011, respectively), while decrease in T-bet was detected only in responders (p<0.0001). Higher pre-treatment T-bet allowed prediction of the clinical response in the first year (beta=0.601, p=0.036). Our preliminary findings suggest that T-bet expression might be a potential prognostic marker of treatment response to IFN-beta in MS.

The analysis of IL-1 beta and its naturally occurring inhibitors in multiple sclerosis: The elevation of IL-1 receptor antagonist and IL-1 receptor type II after steroid therapy.

The aim of our investigation was to analyze the pattern of interleukin-1 (IL-1) family compounds: IL-1 beta, IL-1 receptor accessory protein (Acp), IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type II (IL-1RII) in the serum and cerebrospinal fluid (CSF) from 67 multiple sclerosis (MS) patients and 31 controls. We found significantly elevated CSF levels of IL-1 beta, IL-1Ra and Acp in MS patients compared to controls (p=0.001), while IL-1 beta and Acp were significantly elevated in MS sera (p=0.001). IL-1Ra and/or IL-1 RII increased in sera of all 10 investigated patients after the steroid treatment for relapse. Our findings suggest the important beneficial role of the induction of IL-1 RII and IL-1Ra in MS.

Lifestyle factors and multiple sclerosis: A case-control study in Belgrade.

The aim of this case-control study was to assess the risk of developing multiple sclerosis (MS) associated with certain lifestyle factors (cigarette smoking and coffee and alcohol consumption). The study groups consisted of 210 cases with clinically proven and/or laboratory-confirmed MS (Poser's criteria) and an identical number of sex- and age-matched hospital controls. In the MS patients, cigarette smoking was significantly more frequent than in the controls (OR = 1.6, p = 0.021). A dose-response relationship between the risk of MS and both duration (years) of smoking (p = 0.027) and number of cigarettes smoked daily (p = 0.021) was observed. Coffee consumption was significantly more frequent in the MS group (OR = 1.7, p = 0.047), with dose-response relationships. The analysis of alcohol drinking showed a significant association between consumption of hard liquor per day and risk of MS (OR = 6.7, p = 0.026). In multivariate logistic regression analysis, smoking was detected to be a significant independent risk factor for MS (OR = 2.4, p = 0.004).

[Evaluation of the long term effect of mitoxantrone on neurological disability in patients with active multiple sclerosis]. / Procena dugotrajnog efekta mitoksantrona na stepen neuroloskog ostecenja kod bolesnika s aktivnom multiple sklerozom.

Several in vivo and in vitro studies showed that mitoxantrone (MTX), a novel anthracendione antineoplastic agent, had an immunomodulatory effect that suppressed humoral immunity, reduced T-cell numbers, lessened helper activity, enhanced suppressor function and had some positive effect on acute and chronic experimental allergic encephalomyelitis in rats. Up to now, several trials of therapy with MTX have been performed in patients with multiple sclerosis (MS). MTX has been recently shown to reduce disease activity, as expressed by reducing relapse rate and decreasing new, active MRI lesions, in a selected group of patients with active relapsing-remitting (RR) MS. Furthermore, more recently, it has been demonstrated that MTX reduce neurological disability in secondary progressive MS. We designed the open-label clinical trial involving 35 MS patients with active disease in order to evaluate the long-term clinical effects of 6-months MTX treatment during a follow-up period of 20-46 months (mean, 30 months). The study comprised 35 patients, who met the Poser criteria for clinically definite MS. All patients were clinically treated at the Institute of Neurology, Clinical Centre of Serbia, Belgrade, during the period from March 1996 to August 2000. The neurological disability state was evaluated at the entry, every month until completion of the therapy and every six months until August 2000, by means of Kurtzke Expanded Disability Status Scale (EDSS) score. All patients had active MS. The criteria for disease activity were: 1) at least 2 relapses within the previous 2 years, or 2) progression of at least 1.0 point on EDSS scale during the same period. The included patients did not receive immunosuppressive therapy six months prior to the entry. The patients were assigned to receive MTX 20 mg intravenously (iv) per month and methylprednisolone 1g iv per month, over six months. The clinical characteristics and demographic data of patients included in the study were shown in table 1. The parameters monitored during the trial were shown in table 2. Clinical assessment showed a significant improvement of the final mean EDSS score after 6 months of the therapy as compared to the value at entry in the total MS group (p=0.00001). Although EDSS value showed an increasing tendency during the follow-up period (20-46 months), the mean EDSS value was still significantly lower at the end of the follow-up comparing to the value at entry (p=0.013) (Figure 1). Overall, MTX was well tolerated and only minor side effects occurred. Cardiotoxicity was not registered. Our findings further support the notion that mitoxantrone reduces neurological disability in active relapsing and secondary progressive multiple sclerosis patients. However, follow-up suggests that this effect slowly subsides after discontinuation of therapy, implying the need for prolongation of such treatment (up to 120 mg/m2) for a period as long as possible.

Decreased frequency of the tumor necrosis factor alpha -308 allele in Serbian patients with multiple sclerosis.

Tumor necrosis factor (TNF) alpha has been considered the prototypic cytopathogenic cytokine in multiple sclerosis (MS), but recently this cytokine has been shown to possess significant anti-inflammatory and neuroprotective effects in demyelinating diseases. It has been reported that the TNFalpha -308 polymorphism influences levels of TNFalpha production, and that the rare allele, TNF2, is associated with high TNFalpha production. We investigated the TNFalpha -308 polymorphism in 143 unrelated Serbian patients with MS and 123 ethnically matched, healthy individuals using the allele-specific restriction fragment length polymorphism polymerase chain reaction technique. The frequency of the TNF2 allele was significantly decreased in MS patients (14%) in comparison with controls (24%; p = 0.044). The TNF2 allele had no influence on disease behavior, since it was not associated with the course and severity of MS in this group of patients. The result suggests that in the Serbian population polymorphism at position -308 of TNFalpha or at an adjacent locus might have a role in MS susceptibility.

Antibodies against myelin oligodendrocyte glycoprotein in the cerebrospinal fluid of multiple sclerosis patients.

Antibodies against myelin oligodendrocyte glycoprotein (MOG) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) in different animal species and are implicated in the immunopathogenesis of multiple sclerosis (MS). In order to evaluate the anti-MOG response, we have analyzed the cerebrospinal fluids (CSFs) from 44 MS patients and 51 controls, 11 with other inflammatory neurological disorders (OIND) and 40 with non-inflammatory neurological disorders (NIND). The frequency of anti-MOG antibodies positive patients in the MS group (30%) was significantly higher compared to the NIND (8%, p=0.02), but not compared to the OIND group (55%, p=0.228). Interestingly, all six patients with neurosarcoidosis had MOG-specific antibodies in their CSF. Frequency of anti-MOG antibodies was similar in patients with clinically active and stable MS (32% and 26%, respectively; p=0.921). However, in clinically active MS patients, antibody titers were higher in comparison with patients with stable disease, although the difference did not reach the level of statistical significance (p=0.06). These results further support the potential role of anti-MOG antibodies in the immunopathology of MS in the subset of patients with this disease. Furthermore, our findings suggest for the first time that anti-MOG antibodies could be an accessory diagnostic tool in neurosarcoidosis.

Survival of multiple sclerosis patients in the Belgrade population.

The aim of this study was to estimate survival rates of multiple sclerosis (MS) patients in the Belgrade population, Yugoslavia, and furthermore, to determine the prognostic value of some demographic and clinical variables for survival. The cumulative survival probability was calculated by the Kaplan-Meier method. The prognostic value of different variables was assessed by univariate and multivariate analyses using the Cox regression model. In the Belgrade population, the cumulative 25-year survival probability of MS patients and the mean survival time from MS onset were 73.2% and 38 years, respectively. The univariate analysis showed that survival was significantly related to sex, age at onset, course of disease and monoregional initial symptoms. A multivariate model demonstrated that a relapsing-remitting course of MS and monoregional onset were predictors of a better prognosis. The presence of motor symptoms at the onset was found to be an independent predictor of a poorer outcome of MS.