A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis.

OBJECTIVE: To investigate the HLA-DR associations in relapsing-remitting/secondary progressive multiple sclerosis (RR/SPMS) and primary progressive MS (PPMS). The HLA-DR2 allele (or its split, HLA-DRB1*15) is felt to be a risk factor for MS, rather than a genetic marker for the population of origin. Some studies have indicated a different HLA-DR antigen profile in PPMS patients compared with those having an initially relapsing-remitting course, only those with relapsing disease showing an increase in HLA-DR2. Association of PPMS with DR4 has been suggested. Several DR alleles have also been felt to influence the prognosis in MS. METHODS: Genomic DNA was prepared from peripheral blood of 202 RR/SPMS patients identified in a population-based prevalence study, 102 PPMS patients identified throughout Northern Ireland and 398 normal controls (Nor) matched for the postcode areas of those identified in the prevalence study. Samples were typed for the HLA-DR antigens using polymerase chain reaction (PCR) technology and sequence specific oligonucleotide probes (SSOP). RESULTS: A high incidence of HLA-DRB1*15 was found in each MS group - PPMS (63.73%), RR/SPMS (66.83%) - compared with normals (32.41%), (PPMS vs. Nor, P<0.0001: RR/SPMS vs. Nor, P<0.0001). HLA-DRB1*04 occurred at a lower incidence in both MS groups compared with controls - RR/SPMS (22%), PPMS (30%), Nor (35%). Overall, highly significant differences existed across the full HLA-DR allele distribution (RR/SPMS vs. Nor, P<0.0001, df=12: PPMS vs. Nor, P=0.0007, df=12). No significant differences existed between PPMS and RR/SPMS (P=0.47, df=12), and the allele distributions in benign and aggressive MS were similar. CONCLUSIONS: These data suggest that in this population, HLA-DRB1*15 is indeed associated with PPMS and that PPMS has a HLA-DR profile distinct from the normal population but not from those with an initially relapsing-remitting course. No single allele is associated with either a good or poor prognosis.     

Lack of association of transforming growth factor (TGF)-beta 1 and beta 2 gene polymorphisms with multiple sclerosis (MS) in Northern Ireland.

OBJECTIVE: To examine the influence of TGF-beta genes on MS susceptibility. BACKGROUND: TGF-beta, of which three homologous isoforms exist (1, 2 and 3), is a strongly immunosuppressive cytokine-inhibiting expression of pro-inflammatory cytokines and blocking cytokine induction of adhesion molecules. TGF-beta delays onset of EAE and TGF-beta 1 gene knockout mice develop fatal multifocal inflammatory disease. High TGF-beta levels exist during MS remission whilst E-selectin, whose expression is inhibited by TGF-beta, is found at higher levels in primary progressive disease (PPMS) and it is postulated that the unremitting course of PPMS may be due to low levels of TGF-beta. METHODS: Gene association studies using separate polymorphic microsatellite markers for TGF-beta 1 and TGF-beta 2 were performed, incorporating 151 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 104 PPMS patients and 159 normal controls (Nor). Forward primers were 5' end-labelled with 6-Fam, PCR products were analysed on an Applied Biosystems 373A fluorescent fragment analyser and Genescan 672 software was used for allele sizing. RESULTS: No significant differences existed in allele frequencies between either MS group and controls regarding the TGF-beta 1 marker: RR/SPMS vs Nor (P = 0.48, df = 8); PPMS vs Nor (P = 0.34, df = 8). Similarly there were no associations demonstrated with the TGF-beta 2 marker: RR/SPMS vs Nor (P = 0.24, df = 2); PPMS vs Nor (P = 0.53, df = 2). CONCLUSION: These data indicate that TGF-beta 1 and beta 2 genes are not loci influencing MS susceptibility, either RR/SPMS or PPMS, in this population.     

Genetic association studies of tumour necrosis factor α and β and tumour necrosis factor receptor 1 and 2 polymorphisms across the clinical spectrum of multiple sclerosis

Allelic association studies with microsatellite markers around the tumour-necrosis factor (TNF) genes have demonstrated significantly different allele distributions of TNF markers (a and b) between relapsing-remitting/secondary progressive multiple sclerosis (MS) (RR/SPMS) patients and normal controls. Considering the suspected genetic and immunological heterogeneity in MS, we tested this association in primary progressive MS (PPMS) patients. Elevated levels of serum soluble TNF receptors (sTNF-R) are reported in patients with gadolinium enhancing lesions, and animal models suggest a possible therapeutic role of sTNF-RI in MS. Thus we performed similar association studies using markers for the TNF-R genes. Gene association studies were carried out on 199–216 normal controls, 174 RR/SPMS patients and 102 PPMS patients using polymorphic dinucleotide repeat TNF markers (a, b and d), and separate markers for TNF-RI and TNF-RII. Forward primers were fluorescently labelled, polymerase chain reaction (PCR) products were analysed on a fluorescent fragment analyser, and Genescan 672 software was used for allele sizing. Samples were typed for HLA-DR antigens using PCR technology and sequence-specific oligonucleotide probes. TNFa marker allele distributions differed significantly between PPMS patients and controls (P = 0.028), largely attributable to an increase in the 118-bp TNFa allele in PPMS patients (P = 0.00024). Allele distributions were similar in PPMS and RR/SPMS patients (P = 0.91). Logistic regression analysis, however, indicated that these associations were not independent of that with HLA-DRB1*15. For the TNFb marker, the 127-bp allele showed association with both patient categories (PPMS vs. controls, P = 0.010; RR/SPMS vs. controls, P = 0.027), whilst the 128-bp allele occurred more frequently in controls (PPMS vs. controls, P = 0.036: RR/SPMS vs. controls, P = 0.0009). As with the TNFa 118 bp allele, the association with TNFb was not independent of the HLA association. No association occurred with the TNFd marker, and there were also no significant differences in allele frequencies between MS groups and controls regarding the marker for TNF-RI or TNF-RII. In Northern Irish patients the TNF contribution to MS genetic susceptibility is therefore similar across the clinical spectrum of the disease but is not independent of the association with HLA-DRB1*15. Received: 3 December 1999 Received in revised form: 30 April 1999 Accepted: 14 May 1999     

Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions.In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score.In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.     

An evaluation of interleukin genes fails to identify clear susceptibility loci for multiple sclerosis

Differential expression of interleukins may influence susceptibility to inflammatory diseases such as MS. IL-1a production is increased in MS patients during acute relapse, IL-2 receptor (IL-2R) secretion correlates with disease activity in several inflammatory disorders and is variable in MS. Both IL-4 and IL-10 expression vary significantly with relapse/remission in MS and IL-9 is postulated to inhibit steroid-induced apoptosis. To examine the influence of interleukin (IL) genes on MS susceptibility and clinical course, gene association studies using separate polymorphic microsatellite markers for il-1 alpha, il-2, il-2r beta, il-4 il-9 and il-10 were performed, incorporating 150-177 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 100-110 primary progressive (PPMS) patients and 152-210 controls. No significant differences existed in allele frequencies between either MS group and controls for any of the interleukin microsatellite markers studied, nor were statistically significant differences observed in PPMS vs. RR/SPMS for any marker. These data indicate that the IL-1 alpha, IL-2, IL-2R beta, IL-4, IL-9 and IL-10 genes are unlikely to be susceptibility loci for MS in this population.     

Expression of chemokine receptors in the different clinical forms of multiple sclerosis

Chemokines and their receptors are important in the trafficking of peripheral leukocytes into the central nervous system, a major event in the pathogenesis of multiple sderosis (MS). Evidence based on clinical, pathological and magnetic resonance imaging grounds supports some divergence between forms of MS with relapses [relapsing-remitting (RR) and secondary progressive (SP)] and the primary progressive (PP) form. To elucidate whether different pathogenic mechanisms are involved in PPMS, we compared membrane expression of a group of CC and CXC chemokine receptors (CCR1, CCR5, CXCR3, CXCR4) in peripheral blood of 68 MS patients (25 PPMS, 23 SPMS and 20 RRMS) and 26 healthy controls. We found a significant increase in surface expression of CCR5 in CD4+, CD8+, CD19+ and CD14+ cells as well as an increased percentage of CXCR3 and CXCR4 in CD14+ cells in MS patients compared to controls. Increased levels of CXCL10 (IP-10) and CCL5 (RANTES) in cerebrospinal fluid were also observed in a subgroup of MS patients. These results support that chemokines and their receptors are involved in the pathogenesis of MS However, a pattem of chemokine-chemokine receptor expression characteristic of each clinical form of the disease failed to be observed.     

Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRB1*1501, CCR5 deletion mutation,apolipoprotein E)

As the understanding of the autoimmune inflammatory response in multiple sclerosis (MS) expands, polymorphic genes involved in this process become possible candidates that may determine the severity of disease. Therefore, three candidate genes DRB1*1501, CCR5 and apolipoprotein E (APOE) were examined in a population-based patient sample (n = 70) to assess an association between disease progression measured by clinical disability and MRI parameters. The total lesion area (TLA) on T2-weighted images was measured with a semi-automated threshold technique. Patients with the CCR5delta32 allele showed a non-significant trend towards a smaller lesion burden (TLA/years duration), but were not associated to a milder EDSS/years duration. Our data support previous assumptions of a modulation of severity in MS by the CCR5delta32 genotype, which may convey less inflammation and tissue destruction. Carriers of the DRB1*1501 and APOE-epsilon4 allels did not reveal more severe disease progression, neither by the EDSS/years of duration nor by the TLA/years duration. This study was performed on a population-based sample in a genetically homogeneous Danish population but, due to the limited number of patients examined, weak associations between candidate genes and disease variables cannot be excluded.     

Treatment of progressive multiple sclerosis with cyclophosphamide

Intravenous (IV) cyclophosphamide is currently used in secondary progressive (SP) and Primary progressive (PP) Multiple Sclerosis (MS) but its efficacy remains uncertain. Furthermore, it is necessary to determine which MS should be successfully treated with IV cyclophosphamide. We retrospectively investigated 111 consecutive patients with progressive MS (21 PPMS and 90 SPMS) treated in an open label fashion with IV cyclophosphamide. We analysed clinical data (gender, age, duration of progression, primary versus secondary MS). The treatment response was assessed by EDSS change after 6 months and 1 year of treatment. The annual relapse average decreased from 1.92 before treatment to 0.39 during the treatment. Age and gender did not influence response to therapy. We did not find any difference of response between PPMS and SPMS. Duration of the progressive phase in SPMS was not a predictive factor of efficacy. A better response was noted in SPMS patients with surimposed relapses than in patients without relapses during the year before treatment (p<0.05). Furthermore, the better response in SPMS patients with relapses before treatment suggests that it is necessary to treat when MS is still in an inflammatory stage.     

Clinical, MRI, CSF and electrophysiological findings in different stages of multiple sclerosis

Effective therapy in the earliest stages of multiple sclerosis (MS) demands early correct diagnosis. Retrospective analysis included 130 patients (90 women) with a median age of 35.5 years, median duration of the disease of 2 years and median EDSS score of 3.0. Twenty-seven patients had clinically isolated syndrome (CIS) suggestive of MS, 66 relapsing-remitting (RR) MS, 19 secondary progressive (SP) MS and 18 primary progressive (PP) MS. The predominant symptoms were sensory in 52% of the patients with CIS compared to 27% in patients with RRMS, whereas they were more often motor in patients with PPMS. Patients with CIS had higher CSF cell counts than patients diagnosed in later stages of the disease and oligoclonal bands were found in 89% of all patients without statistically significant differences between the subgroups. Prolonged latencies of visual evoked potentials (VEP) were found in only 29% of patients with CIS compared to 66% in RRMS, 75% in SPMS and 65% of PPMS patients. Fifty-six percent of patients with CIS, 88% with RRMS, 74% with SPMS and 78% of patients with PPMS fulfilled modified the Barkhof et al. MRI criteria at the time of diagnosis. Patients in early MS often present with sensory symptoms. Brain MRI can be inconclusive in over 40% of patients with CIS but the elevated CSF cell count and positive oligoclonal bands are helpful in establishing the diagnosis of CIS suggestive of MS. In later stages of the disease the combination of clinical features, MRI, prolonged VEP latencies and positive CSF oligoclonal bands secures the correct diagnosis.     

Chemokine receptor CCR5 in interferon-treated multiple sclerosis

OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were analyzed in 109 patients with relapsing-remitting MS treated with IFN-beta who were followed clinically for 1 year. Cellular CCR5 expression was measured by flow cytometry. RESULTS: Patients with MS had a higher percentage of CCR5-positive monocytes than healthy controls. Increased monocyte expression of CCR5 correlated weakly with an increased short-term relapse risk but there was no relationship between CCR5 Delta32 allele and CCR5 promoter polymorphism genotypes and relapse risk. CONCLUSIONS: The results do not support a major role of CCR5 in the pathogenesis of relapses in MS patients treated with IFN-beta, but it is possible that monocyte CCR5 expression may be used as a marker of disease activity.     

Natural history of secondary-progressive multiple sclerosis

OBJECTIVE: To examine prognosis and risk factors for progression to and from secondary-progressive multiple sclerosis (SPMS). METHODS: Patients with definite relapsing-remitting MS (RRMS), onset before July 1988, attending a British-Columbian MS clinic before July 1998, and at least one Expanded Disability Status Scale (EDSS) scores were selected from the population-based database. Time to SPMS (from onset and birth) and the subsequent time to EDSS 8 were examined, as were potential risk factors. RESULTS: In all, 2484/2837 (87.6%) were relapsing-remitting (RR) at onset, with 1445/2484 (58.2%) reaching SPMS, taking a median 18.9 years (95% CI: 18.2-19.7). Those younger at onset took longer to reach SPMS (P < 0.0005), but did so at a younger age (P < 0.0005). Males reached SPMS more rapidly from onset and at a younger age (P < 0.0005), but were around the same age as females at EDSS 8 (P = 0.975). Characteristics at SPMS onset associated with a longer time from SPMS to EDSS 8 and an older age at EDSS 8 were: longer disease duration (P < 0.02), older age (P < 0.01) and lower EDSS (P < 0.0005). Onset symptoms had little influence on time to SPMS or subsequent progression. CONCLUSIONS: The RR phase lasted on average almost two decades, being shorter for males and those older at onset of MS. However, neither were necessarily unfavorable predictors as those older at onset were typically older at SPMS and eventually males and females reached EDSS 8 at around the same age. A longer RR phase was a favorable predictor of disease progression in SPMS. Furthermore, reaching SPMS at an older age or lower EDSS did not necessarily confer a worse outcome.     

Analysis of interleukin-4 receptor alpha chain variants in multiple sclerosis

A recent candidate gene study employing microsatellite markers suggested a possible linkage of multiple sclerosis (MS) with the interleukin-4 receptor (IL4R) gene. Consequently, we investigated the association of different IL4R variants with MS in 341 German MS patients and 305 healthy controls. Analysis of the first 100 MS patients for six IL4R variants showed an increased frequency of the R551 variant in MS patients versus healthy controls and carriage of the same IL4R variant was weakly associated with myelin oligodendrocyte glycoprotein (MOG) autoantibody production. However, further analysis of all 341 MS patients did not confirm the finding that this IL4R variant represents a general genetic risk factor for MS but revealed an increased frequency of the R551 variant in MS patients with primary progressive MS (PPMS, n=48) as compared to patients with relapsing remitting MS or secondary progressive MS (RR/SPMS n=284; P=0.005 for genotype differences) and to 305 healthy controls (P=0.001 for genotype differences). This association was statistically independent of the presence of the well-known MS susceptibility allele HLA-DRB1*15. After correction for multiple comparisons only the genotype differences between PPMS patients and healthy controls remained statistically significant. These results indicate, that the IL4R variant R551 may influence the genetic predisposition for PPMS but does not represent a general genetic risk factor for MS.     

No association of CCR5delta32 gene mutation with multiple sclerosis in Croatian and Slovenian patients

Several studies investigating the role of the CCR5delta32 mutation in multiple sclerosis (MS) have reported varied, often contradictory results. Therefore in the present study we have analysed whether the CCR5delta32 mutation is associated with the risk of/or disease process in Croatian and Slovene MS patients. Three hundred and twenty-five MS patients and 356 healthy controls were genotyped by the polymerase chain reaction method. Our results showed no significant differences in the distribution of CCR5delta32 mutations between MS and control subjects, indicating that this mutation does not influence susceptibility to MS. Furthermore, we did not observe that CCR5delta32 carrier-status could modulate age of disease onset or progression of the disease. It is therefore our conclusion that the present study indicates that the CCR5delta32 mutation is neither protective of, nor a risk factor, for MS development.     

High-Dose Cyclophosphamide in the Treatment of Multiple Sclerosis

High dose cyclophosphamide (HDC) has been successfully used for the treatment of a variety of autoimmune diseases. In this study, we sought to determine whether the use of high dose cyclophosphamide provided stabilization of relapsing remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The parameters evaluated were EDSS scores, lesion load and brain volumes by MRI and frequency of relapses. Twenty-three patients underwent immunoablative therapy with HDC and were followed for 3.5 years. Nine were relapsing remitting (RRMS), 11 secondary progressive (SPMS), and 3 primary progressive (PPMS). Four of 9 RRMS have had no clinical progression up to 3.5 years following treatment. Three of 9 patients maintained a normal neurologic examination with improved EDSS scores. Seven of the nine RRMS patients had reduction in flare frequency which was maintained for 3.5 years following treatment or no immunomodulating agents. Subgroup analysis in the RRMS patients of lesion load and brain parenchymal volume revealed a favorable trend in these parameters which did not reach statistical significance. The treatment was generally ineffective for SPMS and failed in the 2 PPMS patients. HDC was well tolerated, demonstrated a good safety profile and had minimal adverse effects. These results along with previous reports suggest that early use of HDC therapy in RRMS is promising.     

Cognitive impairment in primary and secondary progressive multiple sclerosis

The aim of this study was to use neuropsychological data to characterize two subtypes of multiple sclerosis (MS) patients in a large patient sample. We studied patients with primary-progressive MS (PPMS) and secondary-progressive MS (SPMS). A group of 121 MS patients (36 PPS, 85 SPMS) and 40 healthy controls were administered a brief battery of cognitive tests. Executive functioning, memory and attention were studied. Results demonstrate that PPMS patients exhibited slightly more impairment than patients with SPMS, although this difference is not significant (50% vs 37%). However, PPMS patients revealed a significantly poorer performance in verbal learning (p < 0.05) and in verbal fluency (p < 0.05). Whereas PPMS patients had significantly shorter disease durations (p < 0.05), there was no statistical difference in disability between both groups. We conclude from our study that cognitive deficits in progressive MS are frequent. Patients with PPMS tend to be more frequently and severely affected than SPMS patients. Our findings of high prevalence of cognitive involvement in PPMS have not been reported previously     

C-C chemokine receptor 2 gene polymorphism in Japanese patients with multiple sclerosis

C-C chemokine receptor 2 (CCR2) is a receptor for chemoattractant protein-1 (MCP-1) and associated with infiltrating lymphocytes in chronic active multiple sclerosis (MS) lesions. To study the role of CCR2 gene in the development of MS, we investigated the CCR2-64I polymorphism in 122 MS patients and 112 healthy controls in a Japanese population. We also analysed the influence of CCR2-64I polymorphism on the clinical course, age at disease onset, and severity. The distribution of the CCR2-64I allele was significantly different between patients and controls (p=0.0187), and the 64I/64I homozygote was significantly less common in MS than in control. Logistic analysis, adjusted for HLA-DRB1*1501-positivity, revealed negative association between the CCR2-64I and MS (p=0.0204). There were no significant associations between CCR2 polymorphism and the clinical features of MS. Our results indicate that the presence of CCR2-64I allele seems to provide protection against the development of MS.     

Cell surface adhesion molecules and cytokine profiles in primary progressive multiple sclerosis

OBJECTIVE: We evaluated the utility of adhesion molecule (AM) and cytokine/chemokine expressions in blood and cerebrospinal fluid (CSF) as markers of disease activity in primary progressive multiple sclerosis (PPMS). METHODS: The expressions of AMs and the levels of 17 cytokines in patients with PPMS (n = 25) were compared with those in secondary progressive MS (SPMS) (n = 18) and controls (n =11) and correlated with the volumes of focal and atrophic changes on MRI. RESULTS: The expressions of very late activation antigen 4 (VLA-4), lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) in blood and CSF were higher in PPMS than in controls. Comparison between PPMS and SPMS showed higher levels of ICAM-1 in blood and CSF in PPMS, while the level of the vascular adhesion molecule (VCAM-1) was higher only in blood. There was no difference in the levels of cytokines in serum or CSF between PPMS and SPMS or controls, but evidence suggesting intrathecal synthesis of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) was found in PPMS. The expressions of CSF VLA-4 in PPMS correlated with the total volume of cerebral lesions and the number of diffuse brain lesions in MRI, while the amount of LFA-1 in CSF correlated with the number of spinal T2 lesions. The level of serum MIP-1beta correlated with the T2 lesion load and EDSS score in PPMS. CONCLUSIONS: The upregulated expressions of AMs in blood and CSF and evidence for intrathecal synthesis of MCP-1 and IL-8 in PPMS indicate the importance of inflammatory changes in the pathogenesis of PPMS.     

Longitudinal patterns of cortical thinning in multiple sclerosis

In multiple sclerosis (MS), cortical atrophy is correlated with clinical and neuropsychological measures. We aimed to examine the differences in the temporospatial evolution of cortical thickness (CTh) between MS‐subtypes and to study the association of CTh with T2‐weighted white matter lesions (T2LV) and clinical progression. Two hundred and forty‐three MS patients (180 relapsing–remitting [RRMS], 51 secondary‐progressive [SPMS], and 12 primary‐progressive [PPMS]) underwent annual clinical (incl. expanded disability status scale [EDSS]) and MRI‐examinations over 6 years. T2LV and CTh were measured. CTh did not differ between MS‐subgroups. Higher total T2LV was associated with extended bilateral CTh‐reduction on average, but did not correlate with CTh‐changes over time. In RRMS, CTh‐ and EDSS‐changes over time were negatively correlated in large bilateral prefrontal, frontal, parietal, temporal, and occipital areas. In SPMS, CTh was not associated with the EDSS. In PPMS, CTh‐ and EDSS‐changes over time were correlated in small clusters predominantly in left parietal areas. Increase of brain lesion load does not lead to an immediate CTh‐reduction. Although CTh did not differ between MS‐subtypes, a dissociation in the correlation between CTh‐ and EDSS‐changes over time between RRMS and progressive‐MS was shown, possibly underlining the contribution of subcortical pathology to clinical progression in progressive‐MS.     

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.