Multiple Sclerosis: Mellgren SI

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.

This publication has no abstract.

Andersen O, Elovaara I, Färkkilä M, Hansen HJ, Mellgren SI, Myhr KM, Sandberg-Wollheim M, Soelberg Sørensen P. · Institute of Clinical Neuroscience, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden. · J Neurol Neurosurg Psychiatry. · Pubmed #15090564 links to  free full text

Abstract: OBJECTIVE: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. METHODS: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. RESULTS: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. CONCLUSIONS: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

Myhr KM, Mellgren SI. · Norwegian Multiple Sclerosis National Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway. · Acta Neurol Scand Suppl. · Pubmed #19566504 No free full text.

Abstract: BACKGROUND: Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS) that usually is clinically characterized by repeated subacute relapses followed by remissions. Therapeutic strategies include corticosteroid treatment of relapses and immunomodulatory- or immunosuppressive treatment to prevent new relapses and progression of disability. OBJECTIVES: To review the evidences for the use of corticosteroids in the treatment of relapses in MS as well as its possible disease modifying potential. MATERIALS & METHODS: Available literature from PubMed search and personal experiences on corticosteroid treatment in multiple sclerosis were reviewed. RESULTS: High dose short-term oral or intravenous methylprednisolone for 3-5 days speed up recovery from relapses, but the treatment has no influence on the occurrence of new relapses or long-term disability. There is also some evidence that pulsed treatment with methylprednisolone have beneficial long-term effects in multiple sclerosis. CONCLUSION: Relapses with moderate to serious disability should be treated with high dose intravenous or oral methylprednisolone. More data is needed to determine long-term disease modifying effects of corticosteroids.

Sorensen PS, Mellgren SI, Svenningsson A, Elovaara I, Frederiksen JL, Beiske AG, Myhr KM, Søgaard LV, Olsen IC, Sandberg-Wollheim M. · Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Lancet Neurol. · Pubmed #19409854 No free full text.

Abstract: BACKGROUND: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis. METHODS: NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527. FINDINGS: 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks. INTERPRETATION: Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts.

Beiske AG, Naess H, Aarseth JH, Andersen O, Elovaara I, Farkkila M, Hansen HJ, Mellgren SI, Sandberg-Wollheim M, Sorensen PS, Myhr KM, Anonymous00298. · Department of Neurology, University Hospital of Akershus, Lørenskog, Norway. · Mult Scler. · Pubmed #17439908 No free full text.

Abstract: Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta1a (IFN-beta1a), 22 mug subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS.

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.

Kampman MT, Wilsgaard T, Mellgren SI. · Department of Neurology, University Hospital of North Norway, P.O. Box 33, 9038 Tromsø, Norway. · J Neurol. · Pubmed #17377831 No free full text.

Abstract: BACKGROUND: A relationship between the latitude related distribution of multiple sclerosis (MS) and exposure to sunlight has long been considered. Higher sun exposure during early life has been associated with decreased risk of MS. OBJECTIVE: Since Norway is an exception to the latitude gradient of MS prevalence, we tested here whether sunlight exposure or vitamin D-related dietary factors in childhood and adolescence are associated with the risk of MS. METHODS: Retrospective recall questionnaire data from 152 MS patients and 402 population controls born at and living at latitudes 66-71 degrees N were analysed by means of conditional logistic regression analysis accounting for the matching variables age, sex, and place of birth. RESULTS: Increased outdoor activities during summer in early life were associated with a decreased risk of MS, most pronounced at ages 16-20 years (odds ratio (OR) 0.55, 95% CI 0.39-0.78, p = 0.001, adjusted for intake of fish and cod-liver oil). A protective effect of supplementation with cod-liver oil was suggested in the subgroup that reported low summer outdoor activities (OR 0.57, 95% CI 0.31-1.05, p = 0.072). Consumption of fish three or more times a week was also associated with reduced risk of MS (OR 0.55, 95% CI 0.33-0.93, p = 0.024). CONCLUSION: Summer outdoor activities in childhood and adolescence are associated with a reduced risk of MS even north of the Arctic Circle. Supplemental cod-liver oil may be protective when sun exposure is less, suggesting that both climate and diet may interact to influence MS risk at a population level.

Torkildsen O, Utsi E, Harbo HF, Mellgren SI, Vedeler CA, Myhr KM. · The Multiple Sclerosis National Competence Centre, Department of Clinical Medicine, Section for Neurology, University of Bergen, Haukeland University Hospital, Bergen, Norway. · Scand J Immunol. · Pubmed #16091126 No free full text.

Abstract: Interleukin-10 (IL-10) production is genetically determined and influenced by different polymorphisms in the promoter region of IL-10. These polymorphisms may contribute to the risk and clinical outcome of various infectious and immunological-related diseases. The Samis are the aboriginal inhabitants of Norway and Fennoscandinavia and are ethnically different from the Norwegians. Different distribution of various immune-related diseases among the Samis compared with Norwegians have been reported. This is the first study to evaluate the distribution of IL-10 polymorphisms in the Sami population. Two hundred healthy Samis were genotyped for polymorphisms in the promoter region of IL-10 at region -1082 (G/A), -819 (T/C) and -592 (A/C). The allele frequencies, genotypes and haplotypes were compared with 187 healthy Norwegians. A significantly higher number of the Samis than the Norwegians had the ATA/ATA genotype, whereas the Norwegians displayed a higher frequency of the GCC/GCC genotype (P=0.0057). There was a significant difference in haplotypes in the two populations with a P=0.0024. These findings may be important for the distribution and clinical outcome of various infectious and immune-related disorders in the two populations.

Torkildsen O, Utsi E, Mellgren SI, Harbo HF, Vedeler CA, Myhr KM. · The Multiple Sclerosis National Competence Centre, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway. · Immunology. · Pubmed #15946259 links to  free full text

Abstract: Receptors for the Fc domain of IgG (Fc gammaR) play a critical role in linking cellular and humoral immunity. The various Fc gammaR genotypes may contribute to differences in infectious and immune-related diseases in various ethnic populations. The Samis are the aboriginal inhabitants of Norway and Fennoscandinavia and differ ethnically from the Norwegians. The distribution of various immune-related diseases has been reported to differ between Sami and Norwegians. This is the first study to evaluate the distribution of Fc gammaR polymorphisms in a Sami population. Two hundred Samis were genotyped for polymorphisms in the Fc gammaRIIA, Fc gammaRIIIA and Fc gammaRIIIB genes. The genotype and allele frequencies were compared with those of 272 healthy Norwegians. The Sami and Norwegian Fc gammaRIIA, Fc gammaRIIIA and Fc gammaRIIIB genotypes differed significantly. The Samis had higher frequencies of the Fc gammaRIIa-H/H131, Fc gammaRIIIa-F/F158 and Fc gammaRIIIb-NA1/NA1 genotypes. The Fc gammaR genotypes were non-randomly distributed in both populations. These findings may be important for the prevalence of autoimmune and infectious diseases in the two populations.

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.

Grønlie SA, Myrvoll E, Hansen G, Grønning M, Mellgren SI. · Department of Neurology, University Hospital, Tromsø, Norway. · J Neurol. · Pubmed #10751116 No free full text.

Abstract: This study was performed to determine the prevalence of multiple sclerosis (MS) in 1993 and annual incidence rates 1983-1992, and to examine whether the disease occurs among the Sami people. According to earlier reports the two northernmost counties of Norway, Troms and Finnmark with 225,000 inhabitants, have a relatively low prevalence of MS: 20.6 per 100,000 in 1973 and 31.5 in 1983. Also no person who is of pure Sami heritage (i.e., with both parents speaking Sami natively) has been found with the disease. Except for the introduction of magnetic resonance imaging as a diagnostic tool, there has been no significant change in the neurological service in the area during the past 20 years. Files of patients with the diagnosis of MS were reviewed, and questionnaires were sent to all patients alive on the prevalence day of 1 January 1993. The prevalence in 1993 was 73.0 per 100,000. The mean crude annual incidence rate was 3.5 per 100,000 during the period 1983-1992 compared with 3.0 during 1974-1982. In 1983 there were no pure Sami among the MS patients, but one had a Sami father. On 1 January 1993 there were three patients with both Sami parents and three with only one Sami parent, which is a rate that is still lower than would be expected if the prevalence of MS among the Sami were similar to that in the rest of the Norwegian population. The study shows that the incidence of MS in Troms and Finnmark has been increasing over the past 10 years, but is still lower than on the western coast and in the eastern part of Norway. The lowest incidence is found in Finnmark, where the Sami population is highest. During the past 10 years MS has also been diagnosed among the Sami population.

Midgard R, Seland JH, Hovdal H, Celius EG, Eriksen K, Jensen D, Heger H, Mellgren SI, Wexler A, Beiske AG, Myhr KM. · Nevrologisk avdeling, Molde sjukehus, 6407 Molde. · Tidsskr Nor Laegeforen. · Pubmed #15742012 links to  free full text

Abstract: A national group of neurologists and ophthalmologists have evaluated guidelines and recommendations for diagnosis, treatment and follow up of optic neuritis based on clinical experience and a review of relevant literature. Optic neuritis is a common, well characterised condition that appears as an isolated syndrome or as a manifestation of multiple sclerosis. Several other diseases must be considered for a differential diagnosis. Corticosteroid treatment of optic neuritis has been investigated in a number of trials, which show that corticosteroid treatment speeds up the recovery of vision without affecting the final visual outcome. The diagnostic procedure and the treatment options have changed over the last few years. Some aspects of investigation, treatment and follow up are still controversial.