Multiple Sclerosis: Celius EG

Midgard R, Beiske AG, Celius EG, Jensen D, Hovdal H, Mellgren SI, Myhr KM. · Molde sjukehus/Haukeland Universitetssykehus 6407 Molde. · Tidsskr Nor Laegeforen. · Pubmed #12806674 No free full text.

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Myhr KM, Riise T, Green Lilleås FE, Beiske TG, Celius EG, Edland A, Jensen D, Larsen JP, Nilsen R, Nortvedt MW, Smievoll AI, Vedeler C, Nyland HI. · Department of Neurology, Haukeland University Hospital, University of Bergen, Norway. · Neurology. · Pubmed #10102427 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of interferon-alpha2a (IFN-alpha2a) in relapsing-remitting MS (RRMS). BACKGROUND: Several immune-modulating therapy regimens of IFN-alpha have shown varying results in MS. A recent pilot study suggested benefits from IFN-alpha2a. METHODS: Ninety-seven patients were randomized to receive subcutaneous injections of placebo (33 patients) or 4.5 million international units (mIU) (32 patients) or 9.0 mIU (32 patients) of IFN-alpha2a three times weekly for 6 months, with a further 6 months of follow-up. Monthly gadodiamide-enhanced MRI was the primary method of evaluating efficacy. RESULTS: IFN-alpha2a treatment resulted in fewer new MRI lesions during the treatment period (p < 0.003). The probability of no new lesions during treatment was >2.5 times higher with 9.0 mIU IFN-alpha2a than with placebo (p < 0.005). The median number of lesions at the end of treatment was lower with IFN-alpha2a treatment than with placebo (p = 0.0004), but the difference disappeared during follow-up. The total number of lesions (mean) increased by 4.78 with placebo, 0.86 with 4.5 mIU IFN-alpha2a, and 0.28 with 9.0 mIU IFN-alpha2a during treatment (p = 0.030). No treatment effect on exacerbation rate, progression of disability, or quality of life was detected. Nine patients discontinued treatment, five because of adverse events. CONCLUSIONS: IFN-alpha2a treatment significantly reduced disease activity as measured by MRI, but the efficacy disappeared within 6 months after discontinuation of treatment. A long-term study of more patients using disability as a primary outcome measure is needed to evaluate the clinical impact.

Celius EG, Smestad C. · Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway. · Acta Neurol Scand Suppl. · Pubmed #19566494 No free full text.

Abstract: OBJECTIVES: To study changes in sex ratio, disease course, time from onset to diagnosis and age at diagnosis by year of birth in a well-defined population of multiple sclerosis (MS) patients. MATERIALS AND METHODS: Based on the Oslo MS Registry patients born from 1910 to 1980 with residence in Oslo at time of diagnosis were studied. Data were analyzed by 10-year intervals based on year of birth. RESULTS: The female to male ratio increased significantly from 1.48 to 2.30 through seven decades. Also, the ratio of initial relapsing-remitting (RR-MS) to primary progressive (PP-MS) disease course increased significantly from 1.93 to 16.00. The time from onset to diagnosis and the mean age at diagnosis declined significantly during the same period. CONCLUSIONS: This study shows that there has been a change in MS sex ratio, disease course and age at diagnosis through a period of seven decades, suggesting an environmental factor mainly affecting women at a younger age and causing a RR-MS disease course.

Kemppinen A, Suvela M, Tienari PJ, Elovaara I, Koivisto K, Pirttilä T, Reunanen M, Rautakorpi I, Hillert J, Lundmark F, Oturai A, Ryder L, Harbo HF, Celius EG, Palotie A, Daly M, Peltonen L, Saarela J. · Department of Molecular Medicine, National Public Health Institute and Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland. · Eur J Hum Genet. · Pubmed #19142207 No free full text.

Abstract: 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.

Lerdal A, Celius EG, Moum T. · Department of Health Sciences, Buskerud University College, Drammen, Norway. · J Adv Nurs. · Pubmed #19032506 No free full text.

Abstract: AIM: This paper is a report of a study to examine the degree to which socio-demographic variables, clinical variables and health-related quality of life are related to perceptions of disease severity and changes in disease severity in patients with multiple sclerosis. BACKGROUND: Studies have shown that patients with multiple sclerosis report lower quality of life than the general population. METHOD: Questionnaires measuring health-related quality of life and perceived multiple sclerosis severity were mailed twice, 1 year apart, in May/June of 2000 and 2001, (t1 and t2), to patients with confirmed multiple sclerosis in Oslo, Norway (n=502). Clinical data about disease onset and course were retrieved from the Oslo City Multiple Sclerosis Registry. FINDINGS: Among the 313 (62.4%) people who responded at both times, those with primary progressive disease course reported higher perceived multiple sclerosis severity (P<0.001), more mental health problems (P=0.004) and lower physical functioning (P<0.001) than those with a relapsing remitting/secondary progressive disease course. Patients with primary progressive disease course reported higher mean scores for multiple sclerosis severity at t2 than at t1. Multivariate regression analysis showed that social functioning was the only factor with statistically significant relationships to perceived multiple sclerosis severity among all sub-domains of health-related quality of life or personal factors. However, physical impairment was also independently related to patients' ratings of changes in multiple sclerosis severity during the year and illness severity 1 year later. CONCLUSION: In addition to patients' physical impairment, healthcare workers should pay special attention to issues related to their social functioning.

Lorentzen AR, Smestad C, Lie BA, Oturai AB, Akesson E, Saarela J, Myhr KM, Vartdal F, Celius EG, Sørensen PS, Hillert J, Spurkland A, Harbo HF. · Department of Neurology, University of Oslo, Oslo, Norway; Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. · J Neuroimmunol. · Pubmed #18554728 No free full text.

Abstract: We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid position 52 in TSAd. The GA(16)-rs926103()A haplotype was associated with MS in Norwegians (OR 1.4, P=0.04). A similar trend was observed among Danes. In the independent Norwegian, Danish and Swedish sample sets the GA(16) allele showed a combined OR of 1.13, P=0.05. Thus, the present study shows that the SH2D2A gene may contribute to susceptibility to MS.

Smestad C, Sandvik L, Holmoy T, Harbo HF, Celius EG. · Department of Neurology, Ullevål University Hospital, 0407, Oslo, Norway. · J Neurol. · Pubmed #18080855 No free full text.

Abstract: OBJECTIVES : Oslo, the capital of Norway, has a high prevalence of multiple sclerosis (MS). In recent decades there has been substantial immigration to Oslo from Asia, the Middle East and Africa. The aim of the study was to estimate the prevalence of MS among non-Western immigrants living in Oslo, adjusted for duration of residence. METHODS : Data were obtained from the MS registry at Ullevål University Hospital. The prevalence of MS was adjusted for ethnicity, age and duration of residence in Norway. RESULTS : A total of 786 definite MS patients were alive and resident in Oslo on 31 December 2005, yielding a crude prevalence of 148/10(5). Twenty-seven patients were of non-Western origin: Middle East 14, Asia 9, Africa 4. The non-Western patients' mean age at migration was 20. The crude prevalence (95 % CI) of MS patients was 170/10(5) (159-182) for the Norwegian/Western, 85/10(5) (50-143) for the Middle East, 21/10(5) (11-41) for the Asian, and 20/10(5) (7-53) for the African cohorts. The high MS prevalence in the Middle East cohort and the low prevalence among Asian/African immigrants were also pronounced after adjustment for age and duration of residence. CONCLUSIONS : The Middle East immigrants had a markedly higher prevalence of MS despite a shorter duration of residence than other non-Western patients. These findings suggest that people from the Middle East have a greater genetic disposition for MS. Furthermore, the high age at migration among the non-Western immigrants indicates that possible environmental factors affecting MS risk may also act on adults.

Knudsen GP, Harbo HF, Smestad C, Celius EG, Akesson E, Oturai A, Ryder LP, Spurkland A, Ørstavik KH. · Department of Medical Genetics, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway. · Eur J Neurol. · Pubmed #17970735 No free full text.

Abstract: The aetiology of multiple sclerosis (MS) is unknown. Autoimmune mechanisms are most probably involved. Loss of immunological tolerance to self-antigens is a common feature of autoimmune disorders. Response to X-linked self-antigens could be influenced by X-chromosome inactivation, and contribute to the gender bias observed in autoimmune disorders. Previous studies have indicated an association between skewed X inactivation and autoimmune thyroid disease and scleroderma. To investigate a potential role of X inactivation in MS, we compared the X-inactivation pattern in 568 female MS patients with controls. We found no difference in degree of skewing between patients (median 64%) and controls (median 65%) (P = 0.474). The X-inactivation pattern did thus not explain the female predominance of MS patients in general. As the aetiology of different subgroups of MS may differ, patients were grouped according to disease course: relapsing-remitting (RR-MS), secondary progressive (SP-MS) and primary progressive (PP-MS). A comparison of the X-inactivation pattern between subgroups indicated a possible difference in degree of skewing between patients with a progressive versus a relapsing course (P = 0.05).

Lerdal A, Celius EG, Krupp L, Dahl AA. · Department of Health, Buskerud University College, Drammen, Norway. · Eur J Neurol. · Pubmed #17903208 No free full text.

Abstract: We sought to identify clinical characteristics and socio-demographic variables associated with longitudinal patterns of fatigue in multiple sclerosis (MS) patients. A questionnaire including the Fatigue Severity Scale (FSS) was mailed to a community sample of 502 MS patients three times 1 year apart. Three patterns of fatigue were defined: persistent fatigue (PF) (mean FSS score > or = 5 at all time-points), sporadic fatigue (SF) (mean FSS score > or = 5 at one or two time-points) and no fatigue (mean FSS score < 5 at all time-points). Among the 267 (53%) patients who responded at all time-points, 101 [38%, 95% confidence intervals (CI) 32-44] had persistent, 98 (37%, 95% CI 31-43) sporadic and 68 (25%, 95% CI 20-31) no fatigue. Persistent and sporadic fatigue were more common in patients with, increased neurological impairment (P < 0.001), primary progressive MS (P = 0.01), insomnia (P < 0.001), heat sensitivity (P < 0.001), sudden-onset fatigue (P < 0.001) or mood disturbance (P < 0.001) compared with patients without fatigue. Multivariable analysis showed that depression (PF P = 0.02, SF P < 0.001), heat sensitivity (PF P = 0.04, SF P = 0.02) and physical impairment (PF P = 0.004, SF P = 0.01) were associated with both sporadic and persistent fatigue. About 75% of the patients had persistent or sporadic fatigue over a 2 years observation period. Multivariable analyses confirmed a significant association between levels of depression, physical impairment and persistent fatigue.

Holmøy T, Celius EG. · Nevrologisk avdeling Ullevål universitetssykehus. · Tidsskr Nor Laegeforen. · Pubmed #17700745 links to  free full text

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Smestad C, Brynedal B, Jonasdottir G, Lorentzen AR, Masterman T, Akesson E, Spurkland A, Lie BA, Palmgren J, Celius EG, Hillert J, Harbo HF. · Department of Neurology, Ullevål University Hospital, Oslo, Norway. · Eur J Neurol. · Pubmed #17662002 No free full text.

Abstract: The human leucocyte antigen (HLA) class II haplotype DRB1*15-DQB1*06 (DR15-DQ6) is associated with susceptibility to multiple sclerosis (MS), and HLA class I associations in MS have also been reported. However, the influence of HLA class I and II alleles on clinical phenotypes in MS has not yet been completely studied. This study aimed at evaluating the impact of HLA-A and -DRB1 alleles on clinical variables in Scandinavian MS patients. The correlation between HLA-A or -DRB1 alleles and age at onset, disease course and Multiple Sclerosis Severity Score (MSSS) were studied in 1457 Norwegian and Swedish MS patients by regression analyses and Kruskal-Wallis rank sum test. Presence of HLA-DRB1*15 was correlated with younger age at onset of disease (corrected P = 0.009). No correlation was found between HLA-A and the variables studied. This study analysed the effect of HLA-A on clinical variables in a large Scandinavian sample set, but could not identify any significant contribution from HLA-A on the clinical phenotype in MS. However, associations between HLA-DRB1*15 and age at onset of MS were reproduced in this extended Scandinavian MS cohort.

Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J. · Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden. · Nat Genet. · Pubmed #17660816 No free full text.

Abstract: Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.

Datta P, Harbo HF, Ryder LP, Akesson E, Benedikz J, Celius EG, Andersen O, Myhr KM, Sandberg-Wollheim M, Hillert J, Svejgaard A, Sorensen PS, Spurkland A, Oturai A. · Danish Multiple Sclerosis Research Centre, Copenhagen, Denmark. · Mult Scler. · Pubmed #17548436 No free full text.

Abstract: In this study, the results from three Nordic linkage disequilibrium screens in multiple sclerosis (MS) were investigated, in a new sample set of 314 Nordic MS trios from Denmark, Norway, Sweden and Iceland. Among 30 non-HLA and two HLA microsatellite markers individually genotyped, eight markers displayed distorted transmission with uncorrected P-value<0.05, ranked in this order: D6S2443 (6p21.32, HLA class II) (P corrected=0.01), D2S2201 (2p24), D19S552 (19q13), D3S3584 (3q21), D17S975 (17q11), D1S2627 (1p22), D6S273 (6p21.33, HLA class III) and D12S1051 (12q23). These non-HLA regions need further investigation as possible MS candidate gene regions in our population.

Harbo HF, Utsi E, Lorentzen AR, Kampman MT, Celius EG, Myhr KM, Lie BA, Mellgren SI, Thorsby E. · Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway. · Tissue Antigens. · Pubmed #17389012 No free full text.

Abstract: This study confirms a low frequency of multiple sclerosis (MS) among Sami. Only 12 Sami with a diagnosis of MS were identified in the Norwegian Sami population, which represents a significantly lower prevalence of MS in Sami (30/10(5)) compared with other Norwegians (73-164/10(5)). The clinical characteristics as well as the results of human leukocyte antigen (HLA)-DRB1 and -DQB1 typing of the Sami MS patients are reported, showing that three (27%) of the Sami MS patients carried the MS-associated HLA-DRB1*15-DQB1*06 haplotype. Interestingly, the DRB1*15-DQB1*06 haplotype had a significantly reduced frequency among Sami controls (0.086) compared with non-Sami Norwegian controls (0.163) (P(corrected) = 0.015). The low frequency of the disease-associated DRB1*15-DQB1*06 haplotype in the Sami population may contribute to the low prevalence of MS in Sami, in addition to other yet unidentified genetic and environmental factors.

Hensiek AE, Seaman SR, Barcellos LF, Oturai A, Eraksoi M, Cocco E, Vecsei L, Stewart G, Dubois B, Bellman-Strobl J, Leone M, Andersen O, Bencsik K, Booth D, Celius EG, Harbo HF, Hauser SL, Heard R, Hillert J, Myhr KM, Marrosu MG, Oksenberg JR, Rajda C, Sawcer SJ, Sørensen PS, Zipp F, Compston DA. · Department of Clinical Neuroscience, University of Cambridge Clinical School, Addenbrooke's Hospital, Box 165, Cambridge CB2 2QQ, UK. · Neurology. · Pubmed #17261686 No free full text.

Abstract: BACKGROUND: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. METHOD: We evaluated 1,083 families with > or =2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. RESULTS: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa -0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs and no evidence for anticipation or effects of genetic loading. CONCLUSION: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.

Lundmark F, Harbo HF, Celius EG, Saarela J, Datta P, Oturai A, Lindgren CM, Masterman T, Salter H, Hillert J. · Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden. · J Neuroimmunol. · Pubmed #17020785 No free full text.

Abstract: We have investigated the genetic involvement of the CD4 and the LAG3 genes, two appealing candidates for MS due to their suggested role in MS pathology. We genotyped a Swedish case-control material consisting of 920 MS patients and 778 controls in an initial study of CD4, three SNPs showed a significant association with MS. An independent material consisting of 1720 Nordic MS patients and 1416 controls were used for confirmation of associated markers in CD4 and to do a confirmative study of the LAG3 gene from previous findings. The result, including a total of 2640 MS patients and 2194 controls shows no significant association with CD4 and LAG3 and MS. We conclude that these genes are of minor importance in regard of genetic predisposition to the MS.

Harbo HF, Ekstrøm PO, Lorentzen AR, Sundvold-Gjerstad V, Celius EG, Sawcer S, Spurkland A. · Institute of Immunology, University of Oslo, Oslo, Norway. · J Neuroimmunol. · Pubmed #16764945 No free full text.

Abstract: We systematically assessed 53 genes involved in T cell signaling, among which 72 SNPs in 32 genes were reported in databases as causing non-synonymous amino acid substitutions. Screening of 41 of these SNPs in DNA pools from 4000 Norwegian controls showed that only 12 SNPs (29%) were polymorphic. These were tested for association to MS in DNA pools from 364 Norwegian MS patients. To eliminate sources of variance introduced by DNA pooling, the SNPs in the best-ranked PLCG1 as well as the PTPN22 gene were thereafter genotyped in individual MS and control samples, however, without finding evidence for association to MS.

Lorentzen AR, Celius EG, Ekstrøm PO, Wiencke K, Lie BA, Myhr KM, Ling V, Thorsby E, Vartdal F, Spurkland A, Harbo HF. · Institute of Immunology, University of Oslo and Rikshospitalet University Hospital, 00207 Oslo, Norway. · J Neuroimmunol. · Pubmed #16005527 No free full text.

Abstract: Chromosome region 2q33 encodes several regulators of the immune system, among these the CD28, CTLA4, and ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the CD28/CTLA4/ICOS gene region.

Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sørensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sá M, Salemi G, Savettieri G, Hillert J, Compston DA. · Neurology Department, Cambridge University, UK. · Neurology. · Pubmed #15824338 No free full text.

Abstract: BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Harbo HF, Lie BA, Sawcer S, Celius EG, Dai KZ, Oturai A, Hillert J, Lorentzen AR, Laaksonen M, Myhr KM, Ryder LP, Fredrikson S, Nyland H, Sørensen PS, Sandberg-Wollheim M, Andersen O, Svejgaard A, Edland A, Mellgren SI, Compston A, Vartdal F, Spurkland A. · Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway. · Tissue Antigens. · Pubmed #14989713 No free full text.

Abstract: In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS.

Oturai AB, Ryder LP, Fredrikson S, Myhr KM, Celius EG, Harbo HF, Andersen O, Akesson E, Hillert J, Madsen HO, Nyland H, Spurkland A, Datta P, Svejgaard A, Sorensen PS. · Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Mult Scler. · Pubmed #14760946 No free full text.

Abstract: BACKGROUND: Investigation of coaffected sib pairs is one method to determine the genetic influence on the clinical presentation of many complex diseases, such as multiple sclerosis (MS). Investigation of the clinical concordance in coaffected sib pairs may be a prerequisite to identify genes that modify the clinical outcome. The aim of this study was to investigate a possible genetic influence on selected demographic and clinical variables among familial Scandinavian MS cases. MATERIAL AND METHODS: We identified 136 Caucasian Scandinavian families with MS coaffected sib pairs from Denmark, Norway and Sweden. Cohen's kappa coefficient and the intraclass correlation coefficient were used to assess concordances in sib pairs. Furthermore, clinical features and HLA-DR2 carrier status were compared among the probands of sib pairs. RESULTS: We found significant concordance of the disease course (kappa = 0.28, P < 0.001) and adjusted age of onset (r = 0.23, P = 0.028). Among probands of sib pairs, HLA-DR2 carrier patients had a younger age of onset (P = 0.024). CONCLUSION: Analyses of Scandinavian coaffected sib pairs suggest that disease course and age of onset are partly under genetic control. Furthermore, HLA-DR2 in probands of sib pairs suggests importance for age of onset.

Landrø NI, Celius EG, Sletvold H. · Department of Psychology, University of Oslo, Box 1094, Blindern, N-00317, Oslo, Norway. · J Neurol Sci. · Pubmed #14706226 No free full text.

Abstract: Depressive symptoms may influence neuropsychological functioning negatively. A substantial proportion of multiple sclerosis (MS) patients exhibit neuropsychological impairments and depressive symptomatology is more common in MS as compared to healthy controls and to other neurological diseases. The objectives of the present study were to assess information processing speed, working memory and executive functions in early phase MS and to investigate whether severity of depressive symptoms account for these aspects of cognition in MS. The patients show slowed information processing speed and impaired working memory, whereas executive functioning, as measured with the Wisconsin Card Sorting Test, is unaffected. Depressive symptoms account for slowed information processing speed, but not for impaired working memory.

Landrø NI, Sletvold H, Celius EG. · Department of Psychology, University of Oslo, Oslo, Norway. · Arch Clin Neuropsychol. · Pubmed #14590566 No free full text.

Abstract: Memory functioning and emotional changes were evaluated in 26 early phase multiple sclerosis (MS) patients, as compared with 24 healthy controls. There were no significant differences between the groups with respect to age, education, verbal intelligence, or general visual information processing abilities. The MS group performed significantly below controls on the recognition of nonsense visual stimuli. On most verbal memory test indicators, the MS group did not perform deficiently, but there emerged a between-group difference at trend level on a measure reflecting sensitivity to proactive inhibition. The MS patients reported emotional changes and increased levels of psychological symptoms in several areas. Memory task performance was not significantly correlated with subjective complaints of memory impairment, depressive symptoms, or degree of physical disability. However, subjective complaints of memory impairment were related to depression.

Lerdal A, Celius EG, Moum T. · Faculty of Health, Buskerud University College, Drammen, Norway. · Mult Scler. · Pubmed #14582778 No free full text.

Abstract: OBJECTIVE: To explore the relationship between fatigue, sociodemographic and clinical variables in a population of patients with multiple sclerosis (MS). RATIONALE: There is a need to identify empirical relationships with possible antecedents of fatigue among patients with MS. METHODS: A mailed questionnaire designed to survey sociodemographic variables and the Fatigue Severity Scale (FSS) was mailed to 502 individuals from the population of patients with definite MS in the city of Oslo. A total of 368 (73%) responded. Clinical data were collected from the Oslo City MS-Registry. RESULTS: The prevalence of fatigue in this population was 60.1%. The FSS score showed a negative correlation with education (r = -0.15, P < 0.01) and a positive correlation with age (r = 0.20, P < 0.001) and time since disease onset (r = 0.11, P < 0.05). When controlled for gender, level of education and time since disease onset, the data showed a positive relationship between fatigue and age (P < 0.001) among patients with primary progressive (PP) disease. This relationship between age and fatigue was not found among patients with relapsing-remitting/secondary progressive (RR/SP) disease. CONCLUSION: The negative relationship between level of formal education (FE) and fatigue among individuals with RR/SP disease suggests that behavioral factors may be among the antecedents of fatigue in this patient group. In contrast to normative data from the general population, our findings revealed no differences in fatigue related to gender Thus, this study supports the hypothesis that there are disease-specific antecedents of fatigue among patients with MS.

Harbo HF, Datta P, Oturai A, Ryder LP, Sawcer S, Setakis E, Akesson E, Celius EG, Modin H, Sandberg-Wollheim M, Myhr KM, Andersen O, Hillert J, Sorensen PS, Svejgaard A, Compston A, Vartdal F, Spurkland A. · Institute of Immunology, Rikshospitalet University Hospital, 0027 Oslo, Norway. · J Neuroimmunol. · Pubmed #14575924 No free full text.

Abstract: We report the first two genome-wide screens for linkage disequilibrium between putative multiple sclerosis (MS) susceptibility genes and genetic markers performed in the genetically homogenous Scandinavian population, using 6000 microsatellite markers and DNA pools of approximately 200 MS cases and 200 controls in each screen. Usable data were achieved from the same 3331 markers in both screens. Nine markers from eight genomic regions (1p33, 3q13, 6p21, 6q14, 7p22, 9p21, 9q21 and Xq22) were identified as potentially associated with MS in both screens.