Evaluating Magnetic Resonance Diffusion Properties Together with Brain Volumetry May Predict Progression to Multiple Sclerosis.

RATIONALE AND OBJECTIVES: Although the gold standard in predicting future progression from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) consists in the McDonald criteria, efforts are being made to employ various advanced MRI techniques for predicting clinical progression. This study's main aim was to evaluate the predictive power of diffusion tensor imaging (DTI) of the brain and brain volumetry to distinguish between patients having CIS with future progression to CDMS from those without progression during the following 2 years and to compare those parameters with conventional MRI evaluation. MATERIALS AND METHODS: All participants underwent an MRI scan of the brain. DTI and volumetric data were processed and various parameters were compared between the study groups. RESULTS: We found significant differences between the subgroups of patients differing by future progression to CDMS in most of those DTI and volumetric parameters measured. Fractional anisotropy of water diffusion proved to be the strongest predictor of clinical conversion among all parameters evaluated, demonstrating also higher specificity compared to evaluation of conventional MRI images according to McDonald criteria. CONCLUSION: Conclusion: Our results provide evidence that the evaluation of DTI parameters together with brain volumetry in patients with early-stage CIS may be useful in predicting conversion to CDMS within the following 2 years of the disease course.

MR Diffusion Properties of Cervical Spinal Cord as a Predictor of Progression to Multiple Sclerosis in Patients with Clinically Isolated Syndrome.

BACKGROUND AND PURPOSE: This study's aim was to investigate diffusion properties of the cervical spinal cord in patients with clinically isolated syndrome (CIS) through analysis of diffusion tensor imaging (DTI) data and thereby to assess the capacity of this technique for predicting the progression of CIS to clinically definite multiple sclerosis (CDMS). METHODS: The study groups were comprised of 47 patients with CIS (15 of them with progression to CDMS within 2 years of follow-up) and 57 asymptomatic controls. All patients and controls had undergone magnetic resonance imaging (MRI) of the cervical spine including DTI and brain MRI. Methodological approaches included histogram analysis of the cervical cord's diffusion parameters and evaluation of T2 hyperintense lesions of the spinal cord and brain. All parameters were compared between the study groups. Sensitivity and specificity calculations were then performed with a view to predicting conversion to CDMS. RESULTS: The patient subgroups defined by progression to CDMS differed significantly in values of fractional anisotropy (FA) kurtosis measured within white matter (WM) and normal-appearing WM (NAWM). The same parameters also differed significantly when patients with progression to CDMS were compared to healthy controls. Receiver operating characteristic (ROC) analysis revealed sensitivity and specificity of FA kurtosis of WM and NAWM of 93% and 72%, respectively, in terms of predicting CIS to CDMS progression. CONCLUSION: This study presents evidence that histogram analysis of diffusion parameters of the cervical spinal cord in patients with CIS may be helpful in predicting conversion to CDMS.

Conversion of clinically isolated syndrome to multiple sclerosis: a prospective study.

BACKGROUND: Multiple sclerosis (MS) begins with an acute clinical attack (clinically isolated syndrome) in approximately 85% of patients. The conversion rate from clinically isolated syndrome to multiple sclerosis has been documented at 30% to 82% in previous studies. When an individual presents for evaluation after a single episode of inflammation of the CNS, several decisions regarding follow-up in subsequent years need to be made, including that of whether or not to start a therapy. There is, therefore, an emerging need to identify the predictive factors that anticipate conversion from CIS to MS. METHODS: This paper presents a single-center prospective longitudinal study aimed at identification of the most powerful independent predictors for conversion from CIS to MS, utilizing the 2010 McDonald MS criteria and focusing on selected demographic, clinical, radiographical (magnetic resonance imaging - MRI), cerebrospinal fluid (predominantly oligoclonal bands - OCB) and electrophysiological parameters (multimodal sensory and motor-evoked potentials - EP). Two independent outcomes meeting MS criteria are evaluated: development of second clinical relapse (clinically definite multiple sclerosis) and progression in magnetic resonance imaging (based on new MRI T2 brain and/or spinal cord lesions). CIS patients were followed clinically and MRI was repeated at one and two years within the course of a follow-up period of at least 24 months (median 27, range 24-36 months). RESULTS: Of the 64 CIS patients enrolled who completed at least a 2-year follow-up period (42 women and 22 men, median age 36.5, range 22-66 years), 45 (70.3%) (29 women and 16 men, median age 38; range 22-66 years) fulfilled the 2010 McDonald criteria for MS by dissemination in space (DIS) and time (DIT) over the follow-up period. Twenty-nine CIS patients converted to MS through a clinically symptomatic attack, and 16 CIS patients developed new T2 lesions on MRI, while 19 patients without progression remained stable as CIS. Confirmed among potential predictors for the conversion of CIS patients to MS were increased (>10) baseline MRI T2-hyperintense lesions (odds ratio (OR) 3.107, p = 0.046), OCB positivity (OR 5.958, p = 0.003) and subclinical EP abnormality (OR 14.400, p = 0.003). Multivariate statistical models (logistic regression and Cox proportional hazards regression models) confirmed these parameters as independent predictors of high sensitivity (84%) and acceptable specificity (63%). CONCLUSION: In addition to accepted predictors for the conversion of CIS to MS (i.e. baseline MRI T2 lesion load and OCB positivity), already implemented in current diagnostic criteria for MS, this study demonstrates, in addition, the high predictive value of subclinical multimodal evoked potential abnormalities.

The value of anti-JCV antibody index assessment in multiple sclerosis patients treated with natalizumab with respect to demographic, clinical and radiological findings.

BACKGROUND: Natalizumab-related progressive multifocal leukoencephalopathy (PML) is associated with the presence of anti-John Cunningham virus (JCV) antibodies. The aim of this investigation was to evaluate the long-term stability of anti-JCV antibody serum levels and their relation to various demographic, clinical and radiological characteristics in patients suffering from multiple sclerosis (MS). METHODS: Seventy-eight relapsing-remitting MS patients treated with natalizumab and evaluated for the presence of serum anti-JCV antibodies over a time period of 1-6 years (3-11 samples) were included in the study. Anti-JCV antibody levels and their changes were correlated with various demographic, clinical and radiological findings. RESULTS: Median follow-up time was 43.5 months, with a median of 5.3 samples available per patient. At baseline, 46 (59%) of the patients were seropositive. During follow-up, anti-JCV antibody status changed from negative to positive or vice versa in 23% of patients. Baseline anti-JCV antibody index correlated positively with age (p = 0.03). PATIENTS: with stable positive anti-JCV antibody index had more T2 hyperintensities (20.2 vs. 13.1; p < 0.007) on cerebral magnetic resonance imaging (MRI) and were also older than the stable negative anti-JCV antibody index group of patients (45.2.vs. 40.3 years; p < 0.01). No significant increase in T2 hyperintensities after seroconversion was revealed. Average duration from beginning of natalizumab therapy to seroconversion (n = 13) was 33 months. Annual seroconversion rate of anti-JCV antibody status was 6.5%. A baseline anti-JCV antibody index of >0.90 (n = 33) predicted stable seropositivity (100%), while baseline anti-JCV antibody index <0.20 did not predicted stable seronegativity (59%). PML was not diagnosed in any of the patients studied during the follow-up. CONCLUSIONS: A positive baseline anti-JCV antibody index of >0.90 predicts stable positive JCV serostatus, in contrast with a baseline anti-JCV antibody index of <0.20, which remained negative in 59% of cases. Stable positive anti-JCV index patients have more MRI T2 hyperintensities and are older compared with stable negative anti-JCV index patients.

Matrix metalloproteinase-9 and matrix metalloproteinase-2 gene polymorphisms in multiple sclerosis.

We investigated the association of matrix metalloproteinase-9 (-1562C/T, +279R/Q) and matrix metalloproteinase-2 (-1575G/A, -1306C/T) gene polymorphisms with multiple sclerosis (MS) susceptibility, gender differences and disability in 244 patients and 132 healthy subjects. A significant decrease of the -1562T allele carriers in MS patients compared to controls (Pa=0.01, Pacorr=0.05) in -1562C/T MMP-9 gene polymorphism was found, (odds ratio (OR) -0.58, 95% confidence interval (CI):0.38-0.89). Significant differences were also demonstrated between female patients and healthy females (Pa=0.01, Pacorr=0.05), (OR-0.53, 95% CI:0.32-0.86). Other polymorphisms were not associated either with MS susceptibility or with phenotype of the disease. No association with disability was found.

Association of interleukin 6, interleukin 7 receptor alpha, and interleukin 12B gene polymorphisms with multiple sclerosis.

Pro-inflammatory and anti-inflammatory cytokines have been shown to play a crucial role in the pathophysiology of multiple sclerosis (MS). We investigated the association between interleukin (IL) IL6-174 G/C (rs1800795), IL7RA C/T (rs6897932), and IL-12B A1188C (rs3212227) gene polymorphisms (SNPs) and MS. The study consisted of 297 unrelated MS patients and 135 healthy individuals. In IL6-174G/C (rs1800795), a significant association between the C allele and MS risk [OR 1.41, 95% CI (1.05-1.92); P = 0.025] was found. Carriage of genotypes CC and CG were more common in MS patients [OR 1.58, 95% CI (1.04-2.39); P = 0.031] and also in female MS patients [OR 1.68, 95% CI (1.02-2.79); P = 0.043]. However, after applying Bonferroni's correction the differences did not remain significant. No significant association between the IL7RA C/T (rs6897932) and IL12B A1188C (rs3212227) gene polymorphisms and MS susceptibility was observed. Regarding IL-12B A1188C (rs3212227), a significant association between the CC genotype and MS progression, expressed as MSSS, was demonstrated in the female MS group. Our results indicate that the distribution of IL6-174G/C (rs1800795) SNP was marginally associated with MS susceptibility. We also showed that IL-12B A1188C (rs3212227) can contribute to the progression of the disease in the Czech population.

The Impact of Five VDR Polymorphisms on Multiple Sclerosis Risk and Progression: a Case-Control and Genotype-Phenotype Study.

Vitamin D receptor polymorphisms have been the target of many studies focusing on multiple sclerosis. However, previously reported results have been inconclusive. The objective of this study was to investigate the association between five vitamin D receptor polymorphisms (EcoRV, FokI, ApaI, TaqI, and BsmI) and multiple sclerosis susceptibility and its course. The study was carried out as a case-control and genotype-phenotype study, consisted of 296 Czech multiple sclerosis patients and 135 healthy controls. Genotyping was carried out using polymerase chain reaction and restriction analysis. In multiple sclerosis men, allele and/or genotype distributions differed in EcoRV, TaqI, BsmI, and ApaI polymorphisms as compared to controls (EcoRV, pa = 0.02; Taq, pg = 0.02, pa = 0.02; BsmI, pg = 0.02, pa = 0.04; ApaI, pg = 0.008, pa = 0.005). In multiple sclerosis women, differences in the frequency of alleles and genotypes were found to be significant in ApaI (controls vs multiple sclerosis women: pg = 0.01, pa = 0.05). Conclusive results were observed between multiple sclerosis women in the case of EcoRV [differences in Expanded Disability Status Scale (p = 0.05); CT genotype was found to increase the risk of primary progressive multiple sclerosis 5.5 times (CT vs CC+TT pcorr = 0.01, sensitivity 0.833, specificity 0.525, power test 0.823)] and FokI [borderline difference in Multiple Sclerosis Severity Score (p = 0.05)]. Our results indicate that the distribution of investigated vitamin D receptor polymorphisms is a risk factor for multiple sclerosis susceptibility and progression in the Czech population. The association between disease risk and polymorphisms was found to be stronger in men. The association of disease progression with polymorphisms was observed only in women.

Cognition and fatigue in patients with relapsing multiple sclerosis treated by subcutaneous interferon ß-1a: an observational study SKORE.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, which often causes progressive neurological disability. In addition to motor and sensory dysfunction, cognitive decline and fatigue are frequent manifestations of the disease. Fatigue is probably the most common symptom, with up to 90% of MS individuals reporting fatigue at some point. Cognitive impairment affects about 50% of patients and may be present at all MS stages. The aim of this observational study was to evaluate changes in cognition, fatigue, and disability status in 300 relapsing-remitting MS (RRMS) patients, treated with subcutaneous (sc) interferon (IFN) ß-1a over 2 years. METHODS: The study was designed as an observational, multicentre, prospective, single-arm, phase IV study carried out in 13 MS centres in the Czech Republic. Cognition status was assessed using the Paced Auditory Serial Addition Task (PASAT), fatigue using the Fatigue Descriptive Scale (FDS), and disability using the Expanded Disability Status Scale (EDSS), at baseline, and after 6, 12 and 24 months. The percentage of patients with changed versus stable cognition, fatigue status and disability was calculated at each time point and the changes in these scores were evaluated. RESULTS: The proportion of patients with cognitive improvement was higher compared with those with a stable or decreased PASAT scores at all time points, and the average cognitive performance improved during the follow-up period. Also the proportion of patients with stable or improved fatigue and EDSS scores was higher compared with those in which FDS or EDSS scores declined, this was found at all time points of the analysed sample. However, the direct effect of IFN ß-1a on cognition and fatigue cannot be concluded from this study. CONCLUSIONS: The results of this observational study have demonstrated a stable or improved cognitive performance, fatigue status, and disability level in the majority of RRMS patients treated with sc IFN ß-1a over a two-year follow-up period, in a real life setting, in the Czech Republic.

Association of HLA-DRB1*1501 tagging rs3135388 gene polymorphism with multiple sclerosis.

We investigated the HLA-DRB1*1501 tagging rs3135388 gene polymorphism and its association with multiple sclerosis (MS) susceptibility, disability and gender differences. The study group consisted of 306 MS patients and 137 healthy individuals. A significant difference in genotype distribution (Pg=3.06×10(-9)) and allele frequency (Pa=6.08×10(-10)) between MS patients and controls was demonstrated. The homozygotes AA and heterozygotes GA were more frequent in MS patients (OR=4.27, 95% CI: 2.64-6.92). A significant difference between female MS patients and female controls in genotype distribution (Pg=1.3×10(-8)) and allele frequency (Pa=2.82×10(-9)); (OR=5.11, 95% CI: 2.86-9.15) was also proved. Our results indicate that the distribution of the rs3135388 gene polymorphism is a risk factor for MS susceptibility in the Czech female population.

Two frequent polymorphisms of angiotensinogen and their association with multiple sclerosis progression rate.

A total of 195 patients with multiple sclerosis (MS) and 126 controls were investigated for angiotensinogen/(-6)A/G, M235T/and angiotensin converting enzyme I/D gene polymorphisms to test their association with MS susceptibility and/or disease progression using Global Multiple Sclerosis Severity Score (MSSS). We demonstrated a significant association of M235T polymorphism with MSSS. The MM homozygotes had the lowest (3.8), heterozygotes MT higher (5.2) and homozygotes TT the highest (5.4) mean MSSS values (P=0.02). For polymorphisms (-6)A/G of ATG, only a trend was observed (P=0.06), where the homozygotes GG carried lower MSSS values than heterozygotes and homozygotes AA. No significant association with susceptibility was observed. For ACE I/D polymorphism, neither significant differences in the genotype-phenotype study nor in the case-control study were observed.