[Update on Current Care Guideline: Multiple sclerosis]. / Kaypa hoite-suosituksen paivitystiivistelma. MS-tauti.

Treatment for relapsing-remitting multiple sclerosis (RRMS) is initiated upon fulfillment of new McDonald 2010 criteria for RRMS. In addition, lumbar puncture is an essential diagnostic method. Interferon-ß, dimethyl fumarate, glatiramer acetate and teriflunomide are the first-line immunomodulating drugs (IMD) for RRMS. If the disease is active according to clinical or MRI evaluation during the first-line IMD treatment, alemtuzumab, fingolimod or natalizumab may be considered as second-line therapies. IMD treatment is discontinued upon the transition of RRMS to secondary progressive phase. Rehabilitation should be considered at every phase of the disease.

Association between soluble L-selectin and anti-JCV antibodies in natalizumab-treated relapsing-remitting MS patients.

OBJECTIVE: In relapsing-remitting MS (RRMS) patients treated with natalizumab, the low level of L-selectin-expressing CD4+ T cells has been associated with the risk of progressive multifocal leukoencephalopathy (PML). In this study, our aim was to correlate the levels of soluble L-selectin and the anti-JCV antibody index in the sera of RRMS patients treated with natalizumab. METHODS: This study included 99 subjects, including 44 RRMS patients treated with natalizumab, 30 with interferon beta (IFN-ß) and 25 healthy controls. The levels of soluble L-selectin (sL-selectin) in sera were measured by ELISA, and the anti-JC Virus (JCV) antibody index was determined by the second-generation ELISA (STRATIFY JCV™ DxSelect™) assay. RESULTS: A significant correlation was found between the levels of sL-selectin and anti-JCV antibody indices in sera in the natalizumab-treated patients (r=0.402; p=0.007; n=44), but not in those treated with IFN-ß. This correlation became even stronger in JCV seropositive patients treated with natalizumab for longer than 18 months (r=0.529; p=0.043; n=15). CONCLUSION: The results support the hypothesis of sL-selectin being connected to the anti-JCV antibody index values and possibly cellular L-selectin. Measurement of serum sL-selectin should be evaluated further as a potential biomarker for predicting the risk of developing PML.

The use of goal attainment scaling in neuropsychological rehabilitation in multiple sclerosis.

PURPOSE: The overall objective was to apply the goal attainment scaling (GAS) in neuropsychological rehabilitation in multiple sclerosis (MS). The specific aims were to evaluate whether (1) GAS-rated goals are attained; (2) attaining goals is related to standardized rehabilitation outcome measures; and (3) GAS-rated goals can be mapped to the International Classification of Functioning, Disability, and Health (ICF). METHOD: 56 relapsing-remitting MS patients received neuropsychological rehabilitation conducted once a week for 13 consecutive weeks. The attainment of GAS-rated personal goals and the association between achievement of goals and standardized rehabilitation outcome were evaluated. Moreover, GAS-rated goals were mapped to the ICF. RESULTS: Median (interquartile range) GAS attainment T-score was 56.0 (50.0-62.0); 88.8% of personal goals set were fully achieved. The attainment of goals was not significantly associated with the outcome in majority of the standardized measures. Of the 182 meaningful concepts identified in the goals, 181 could be mapped to the ICF. CONCLUSIONS: GAS seems to be an appropriate outcome measure in neuropsychological rehabilitation in MS. GAS-rated personal goals were well achieved, and GAS was found to tap changes not covered with standardized outcome measures. Implications for Rehabilitation GAS seems to be an appropriate outcome measure in neuropsychological rehabilitation in MS. GAS-rated personal goals were well achieved, and GAS was found to tap changes in the areas not covered with standardized outcome measures. GAS seems to offer a possibility to take into account the specific needs of each individual patient. The ICF can be used to classify goals in neuropsychological rehabilitation in MS.

Predictors and impact of the working alliance in the neuropsychological rehabilitation of patients with multiple sclerosis.

BACKGROUND: There is preliminary evidence of positive effects of neuropsychological rehabilitation in multiple sclerosis (MS). However, whether a working alliance affects rehabilitation outcome has not been studied. OBJECTIVE: The aim of this study was to evaluate the effects of the baseline patient-related (cognitive, mood and fatigue symptoms, cognitive status, demographic factors) and illness-related factors (duration and severity of the disease) on the alliance, as well as the effects of the alliance on rehabilitation outcome in neuropsychological rehabilitation among MS patients. METHODS: Fifty-six patients with relapsing-remitting MS received multimodal neuropsychological intervention (attention retraining, learning strategies, psychoeducation, psychological support, homework assignments) conducted once a week in 60-minute sessions for thirteen consecutive weeks. After the intervention, both patients and therapists evaluated the alliance with the short form of the Working Alliance Inventory. RESULTS: None of the baseline factors was related to the alliance. Better patient-evaluated alliance was associated with a more prominent decrease in fatigue symptoms and greater achievement of rehabilitation goals. Better therapist-evaluated alliance was associated with greater benefit from the intervention as evaluated by therapists. CONCLUSION: A positive patient-therapist alliance may relate to positive neuropsychological rehabilitation outcome in MS.

Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-centre trial.

BACKGROUND: There is preliminary evidence on the positive effects of neuropsychological rehabilitation on cognition in multiple sclerosis (MS), but the generalisability of the findings is limited by methodological problems. OBJECTIVE: The aim of the present study was to determine the effects of strategy-oriented neuropsychological rehabilitation on MS. METHODS: A total of 102 relapsing-remitting MS patients with subjective and objective attentional deficits were randomised into an intervention and a control group. Neuropsychological assessments were performed at baseline, at three months immediately after the intervention, and at six months. Patients in the intervention group received neuropsychological rehabilitation once a week in 60-minute sessions for 13 consecutive weeks. The control group received no intervention. RESULTS: Neuropsychological rehabilitation including computer-based attention and working memory retraining, psychoeducation, strategy learning and psychological support did not improve cognitive performance but had a positive effect on perceived cognitive deficits. The intervention group perceived significantly fewer deficits than the control group both immediately after the intervention and at six months. The personal rehabilitation goals were also well achieved. CONCLUSIONS: Strategy-oriented neuropsychological rehabilitation did not improve cognitive performance but reduced perceived cognitive deficits in MS.

Neuropsychological rehabilitation has beneficial effects on perceived cognitive deficits in multiple sclerosis during nine-month follow-up.

BACKGROUND: Systematic reviews have indicated a low level of evidence for the positive effects of neuropsychological and cognitive rehabilitation in multiple sclerosis (MS). How permanent the positive effects are, is unknown. OBJECTIVE: The aim of the present study was to evaluate whether short-term neuropsychological rehabilitation has long-term beneficial effects in a nine-month follow-up. METHODS: 102 relapsing-remitting MS patients with subjective and objective attentional deficits were randomized into intervention and control groups. Altogether 78 out of 102 patients (76%) completed the longitudinal follow-up (intervention group 83%, control group 67%). Intervention group received strategy-oriented neuropsychological rehabilitation conducted once a week in 60-minute sessions during thirteen consecutive weeks. The control group received no intervention. Cognitive deficits, mood, fatigue, impact of disease, and quality of life were evaluated with self-reports at baseline, six months, and one year from baseline. RESULTS: The positive effects of neuropsychological rehabilitation on perceived cognitive deficits were maintained for nine months. Among a subgroup of patients with moderate to severe attentional deficits, positive rehabilitation outcome was even more evident. CONCLUSION: The beneficial effects of strategy-oriented neuropsychological rehabilitation on perceived cognitive deficits in MS may be maintained for at least one year after the beginning of the intervention.

Patient-related factors may affect the outcome of neuropsychological rehabilitation in multiple sclerosis.

OBJECTIVE: The aim of this study was to identify factors associated with neuropsychological rehabilitation outcome in patients with multiple sclerosis (MS). METHODS: Ninety-eight relapsing-remitting MS patients received multimodal neuropsychological intervention (attention retraining, teaching compensatory strategies, psychoeducation, psychological support, and homework assignments) conducted once a week in 60-minute sessions during thirteen consecutive weeks. The evaluated factors included: 1) patient-related (baseline objective and subjective cognitive performance, mood, fatigue, as well as demographic factors); 2) illness-related (duration and severity of the disease); and 3) intervention-related factors (amount of computer-based attention exercises and homework assignments, therapist's evaluation of the benefit, and therapist). RESULTS: Patient-related factors affected rehabilitation outcome, whereas illness- and intervention-related factors did not. The results showed that especially MS patients with male gender and more severe attentional deficits benefitted from the intervention. CONCLUSION: Patient-related factors may affect neuropsychological rehabilitation outcome in MS.

Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene.

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

A follow-up study of chromosome 19q13 in multiple sclerosis susceptibility.

A possible role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility has been suggested. We tested association of sixteen 19q13 markers with MS in 459 families. Nominally significant associations were tested in an independent set of 323 families as well as in the pooled set of 782 families. We were not able to confirm previously suggested associations with APOE, GIPR, ZNF45, ILT6 and D19S585. In the screening dataset nominally significant associations were found with D19S867 and with APOE haplotype (p=0.007 in both), but these were not replicated in the independent dataset nor in the pooled analysis of 757 families. Thus, we were not able to detect any statistically significant allelic associations. Re-sequencing based approaches may be required for elucidating the role chromosome 19q13 with MS.

Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS.

Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.

MYO9B polymorphisms in multiple sclerosis.

Single-nucleotide polymorphisms (SNPs) in the 3' region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS.

No evidence for shared etiology in two demyelinative disorders, MS and PLOSL.

Loss-of-function mutations of DAP12 and TREM2 cause a recessively inherited disease PLOSL, manifesting in brain white matter. The genes of the DAP12-TREM2 signaling receptor are located on 19q13.12 and 6p21.1, to which linkage has been observed also in families affected by another immune-mediated demyelinating disease, MS. We have tested if allelic variation in DAP12 or TREM2 predisposes also to MS by monitoring carrier frequency of the Finnish PLOSL mutation in Finnish MS cases and by studying DAP12 and TREM2 in MS by linkage and association. To conclude, the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of MS.

One-year follow-up study of relapsing-remitting MS patients' cognitive performances: Paced Auditory Serial Addition Test's susceptibility to change.

To evaluate the progression of cognitive decline in multiple sclerosis (MS) patients and the susceptibility of the Multiple Sclerosis Functional Composite (MSFC) Paced Auditory Serial Addition Test (PASAT) to change, we conducted a 1-year follow-up with a comprehensive neuropsychological examination to 19 initially cognitively impaired and 26 cognitively intact relapsing-remitting MS patients, and to 48 healthy controls. The results indicated that the cognitive performance of MS patients remained relatively stable. Healthy controls tended to perform better on most neuropsychological measures at follow-up, the same was not observed in the MS groups. PASAT showed a significant difference between the groups: the cognitively impaired group tended to deteriorate, whereas the control group and the cognitively intact group improved. The change in PASAT could not be explained by the background variables, for example, mood, quality of life, or nervousness. Therefore, the MSFC-PASAT seems to be a sensitive measure to show clinical change in the cognitive status.

PASAT in detecting cognitive impairment in relapsing-remitting MS.

The PASAT, as a part of the Multiple Sclerosis Functional Composite, is used as a sole measure of cognition in multiple sclerosis (MS) clinical trials. In the present study, we evaluated the frequency and characteristics of cognitive impairment among relapsing-remitting MS patients. Using a comprehensive neuropsychological examination as the "golden standard," we assessed PASAT's sensitivity and specificity in MS-related cognitive impairment as well as factors possibly confounding PASAT performance. Forty-five relapsing-remitting MS patients and 48 healthy controls were studied using PASAT and a comprehensive neuropsychological examination. The frequency of cognitive dysfunction among MS patients was 42%. Cognitive impairment in MS was heterogeneous in nature but characterized, especially, by reduced information-processing ability and memory deficits. PASAT's sensitivity for patients' cognitive impairment was 74% and specificity 65%. Misclassification of cognitive impairment seemed to be associated with self-reported nervousness and poor arithmetic skills. Although PASAT offers satisfactory sensitivity in detecting the presence of cognitive impairment, its specificity may be limited by confounding factors.

Association analysis of peroxisome proliferator-activated receptor gamma polymorphisms and late onset Alzheimer's disease in the Finnish population.

Alzheimer's disease (AD), especially late-onset AD (LOAD), is a complex disease. To date, the only established genetic risk factor for LOAD is apolipoprotein E (APOE) epsilon4, which explains partially the risk of the disease and modifies the age of onset. Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates the transcription of BACE1 as well as inflammatory responses in the brain and atherosclerotic risk factors known to be involved also in AD. Based on these findings, the gene encoding PPARgamma can be viewed as an interesting candidate in AD. We examined the effect of the two previously reported variants of PPARgamma polymorphisms, the Pro12Ala and exon 6 C478T, on the risk of LOAD and age of onset in a population-based follow-up sample of aged subjects (125 LOAD patients and 462 non-demented controls). The genetic risk of AD was not significantly associated with the studied polymorphisms, but the PPARgamma Ala12-478T genotype carriers were significantly younger at the onset of dementia than the non-carriers (p = 0.026). These results suggest that the PPARgamma gene may modify the age of onset in LOAD.

PRKCA and multiple sclerosis: association in two independent populations.

Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP)-based association implicated PRKCA (protein kinase C alpha) gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing). Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07-1.68). A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39-1.94). Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian "risk" haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH) individuals of European origin.

Fine mapping of the multiple sclerosis susceptibility locus on 5p14-p12.

Linkage analyses have identified four major MS susceptibility loci in Finns. Here we have fine mapped the region on chromosome 5p in 28 Finnish MS families. Marker D5S416 provided the highest pairwise LOD score, and multipoint and haplotype analyses restrict the critical region to about 5.3 Mb on 5p15 between markers D5S1987 and D5S416. Ascertaining for HLA type and geographical origin indicated that families with and without the HLA DR15 risk haplotype, as well as families within and outside an internal high-risk region, contributed to the linkage to 5p, implying the general significance for this locus in Finnish MS families.

Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24.

Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.