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Idiopathic Parkinson's disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by α-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between α-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of α-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage α-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (

Aim: To compare disease impact on functioning in patients with chronic fatigue syndrome (CFS) and multiple sclerosis (MS).Methods: Fifty-four patients with CFS after giardiasis, 43 patients...

OBJECTIVE: The prevalence of post-stroke fatigue differs widely across studies, and reasons for such divergence are unclear. We aimed to collate individual data on post-stroke fatigue from multiple studies to facilitate high-powered meta-analysis, thus increasing our understanding of this complex phenomenon.METHODS: We conducted an Individual Participant Data (IPD) meta-analysis on post-stroke fatigue and its associated factors. The starting point was our 2016 systematic review and meta-analysis of post-stroke fatigue prevalence, which included 24 studies that used the Fatigue Severity Scale (FSS). Study authors were asked to provide anonymised raw data on the following pre-identified variables: (i) FSS score, (ii) age, (iii) sex, (iv) time post-stroke, (v) depressive symptoms, (vi) stroke severity, (vii) disability, and (viii) stroke type. Linear regression analyses with FSS total score as the dependent variable, clustered by study, were conducted.RESULTS: We obtained data from 14 of the 24 studies, and 12 datasets were suitable for IPD meta-analysis (total n = 2102). Higher levels of fatigue were independently associated with female sex (coeff. = 2.13, 95% CI 0.44-3.82, p = 0.023), depressive symptoms (coeff. = 7.90, 95% CI 1.76-14.04, p = 0.021), longer time since stroke (coeff. = 10.38, 95% CI 4.35-16.41, p = 0.007) and greater disability (coeff. = 4.16, 95% CI 1.52-6.81, p = 0.010). While there was no linear association between fatigue and age, a cubic relationship was identified (p CONCLUSION: Use of IPD meta-analysis gave us the power to identify novel factors associated with fatigue, such as longer time since stroke, as well as a non-linear relationship with age.

To identify MRI biomarkers associated with long-term disability progression in patients with multiple sclerosis (MS), and to define the rate of evolution of global, tissue-specific and regional atrophy in patients with MS over long-term.MRI of the brain and clinical neurological assessment was performed in 81 patients at time of first visit and after 5 and 10 years of follow-up. MRI was acquired on 1.5 T scanners. T1-lesion and T2-lesion volumes (LVs) were calculated. Global and tissue-specific atrophy changes were longitudinally assessed, using a direct measurement approach, by calculating percentage volume changes between different time points. Regional tissue volumes for the subcortical deep grey matter (SDGM) structures were also obtained. Disability progression was defined as an increase in Expanded Disability Status Scale of ≥ 1.0 compared to baseline at 5-year and 10-year follow-up.Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.

Background: The aim was to investigate predictive values of coping styles, clinical and demographic factors on time to unemployment in patients diagnosed with multiple sclerosis (MS) during 1998–2002 in Norway. Method: All patients ( N = 108) diagnosed with MS 1998–2002 in Hordaland and Rogaland counties, Western Norway, were invited to participate in the long-term follow-up study in 2002. Baseline recordings included disability scoring (Expanded Disability Status Scale (EDSS)), fatigue (Fatigue Severity Scale (FSS)), depression (Beck Depression Inventory (BDI)), and questionnaire assessing coping (the Dispositional Coping Styles Scale (COPE)). Logistic regression analysis was used to identify factors associated with unemployed at baseline, and Cox regression analysis to identify factors at baseline associated with time to unemployment during follow-up. Results: In all, 41 (44%) were employed at baseline. After 13 years follow-up in 2015, mean disease duration of 22 years, 16 (17%) were still employed. Median time from baseline to unemployment was 6 years (±5). Older age at diagnosis, female gender, and depression were associated with patients being unemployed at baseline. Female gender, long disease duration, and denial as avoidant coping strategy at baseline predicted shorter time to unemployment. Conclusion: Avoidant coping style, female gender, and longer disease duration were associated with shorter time to unemployment. These factors should be considered when advising patients on MS and future employment.

OBJECTIVES - We report the prevalence and incidence rates of multiple sclerosis (MS) in Oppland County, Norway. METHODS - Records from all patients diagnosed with MS at the two Oppland County hospitals, Gjovik and Lillehammer during 1989-2001 were evaluated. In addition, all general practitioners in Oppland County reported their patients into the study. RESULTS - The age-adjusted prevalence rate of definite MS was 174.4/ 100 000 on the prevalence day 1 January 2002. When the probable cases were included, the prevalence rate rose to 185.6/100 000. The highest prevalence rates were detected in the northern mountain areas, thus corroborating the results from previous local surveys 30-50 years ago. The prevalence of MS was statistically significantly associated with climatic, socioeconomic and geographic variables in the county. The age-adjusted incidence of definite and probable MS in Oppland County was 6.6/100 000 during 1989-1993 increasing to 7.6/100 000 during 1994-1998. DISCUSSION - We found the highest prevalence rates of MS ever reported in Norway. Our findings indicate a possible influence of environmental factors.

Health economic aspects have been increasingly important during introduction of new treatments for multiple sclerosis. As a partial response for Norway, a costof- illness study was carried out to estimate the yearly cost of the illness to society and relate costs and patients’ quality of life to illness severity. Estimated cost to society was Euro 439 million in 2002 exclusive of the cost of reduced quality of life. The cost per patient was close to Euro 65,000. Account taken of methodological differences, the results compare to results for Sweden, Norway’s closest neighboring country. The illness reduced patients’ quality of life with 0.26. More patients were early retired because of their MS in Norway than in any of nine other European countries comprised by a recent European study, illustrating a liberal practice in Norway. The Norwegian cost of unpaid assistance was almost identical to the Swedish cost that was the lowest found across the countries in the European study. When related to illness severity, the cost per patient increased, and the patients’ experienced quality of life decreased with increasing EDSS levels in line with what has been found for other countries. Cost-of-MS studies have been carried out for a number of countries. Together they contribute to our understanding of the economic consequences of multiple sclerosis and, if their results are related to illness severity, also provide valuable information for further economic analyses of treatment and medication. Our study adds to this. publishedVersion

Objective To study employment in benign multiple sclerosis (MS), the frequency of employment was analysed and the effect of early clinical and demographic factors on time to disability pension was evaluated in a population based MS cohort. The frequency of depression, cognitive function, fatigue and pain between benign and non-benign MS patients was compared, and their impact on employment in benign MS was studied. Methods All 188 patients alive, including 60 benign patients with onset of MS during 1976–1986 in Hordaland County, Western Norway, were interviewed and clinically examined in 2003. The Expanded Disability Status Scale (EDSS), depression (Beck Depression Inventory), cognitive function, fatigue, pain, year of disability pension, employment and type of occupation were registered. Benign MS was defined as an EDSS score ≤3.0 at least 10 years after disease onset. Results After a mean disease duration of 22.2 years, 32.4% of the cohort were still employed. A relapsing–remitting course, higher educational level and light physical work were significantly associated with longer time to disability pension in the general MS population. Thirty-nine (65.0%) benign MS patients were employed, independent of light or heavy physical work. Mild depressive symptoms were markedly associated with not being employed in benign MS (OR=7.3). Conclusions A relapsing–remitting course, higher educational level and light physical work significantly predicted longer time to disability pension in the total MS population. Among the benign MS patients, depressive symptoms, although mild, were strongly associated with not being employed.

Objectives - To investigate the impact of different definitions on the frequency of benign multiple sclerosis (MS) in patients with a long follow-up, and to study the presence of non-motor symptoms and employment across the definitions. Materials and methods - All patients alive (n = 188) with disease onset during 1976-1986 in Hordaland County, Norway, were clinically examined including the Expanded Disability Status Scale (EDSS) in 2003. Non-motor symptoms which included depression, cognitive impairment, fatigue and pain, and employment status were also registered. Three definitions of benign MS were used based on the following EDSS cutoff values: 2.0, 3.0 and 4.0. Two additional definitions were added using an EDSS ≤4.0 and incorporating either full-time or full- and part-time employment status. Results - The frequency of benign MS increased from 14.5% for EDSS ≤2.0 to 40.8% for EDSS

Human serum and cerebrospinal fluid (CSF) antibodies against three staphylococcal antigens were measured using the ELISA technique. Antibody levels in sera from patients with multiple sclerosis (MS) were lower than those found in sera from patients with other neurological diseases (OND) and from healthy individuals (N). The CSF antibody mean titres for patients with relapsing remittent MS were about twofold higher than those found for the other groups. Both serum and CSF antibodies were of the IgG class while IgM could only be detected in serum samples. Elevated IgG-indexes, indicating intrathecal immunoglobulin synthesis, were found only among individuals in the MS patient groups. Some of the patients also had elevated indexes of specific antibodies to the staphylococcal antigens used, i.e. lipoteichoic acid (LTA), peptidoglycan (PG) and beta-ribitol teichoic acid (beta-RTA). This indicates that some MS patients have synthesized staphylococcal antibodies intrathecally.

Erythrocytes (E) sensitized with IgG antibodies bound to the fatty streaks in cryostat sections of early human atherosclerotic lesions. E sensitized with IgA or IgM antibodies of F(ab') 2 fragments of IgG did not bind. The binding was inhibited by intact IgG and by Fc fragments but not by F (ab')2 fragments or by albumin, indicating the presence of receptors for the Fc part of IgG (FcR). E sensitized with IgM antibodies and human complement did not bind. The FcR were also studied using soluble immune complexes of horseradish peroxidase (HRP) and rabbit IgG antibodies to HRP. The peroxidase activity was detected histochemically. The bound complexes were localized to most of the lipid cells (foam cells) in the lesions. The cytoplasm of the FcR positive foam cells stained diffusely for acid alpha- naphthyl acetate esterase. Most of the foam cells were stained with monoclonal antibodies against HLA-DR antigens. The data indicate that most foam cells in early atherosclerotic lesions are derived from monocytes.

Antibodies to staphylococcal lipoteichoic acid (LTA) were determined in serum and in cerebrospinal fluid (CSF) from a group of patients with multiple sclerosis (MS) and a group of healthy individuals. Sera from 11 out of 74 MS patients, i.e. 15 per cent, contained precipitating antibodies demonstrated by the double diffusion in agar test, compared to 48 out of 94 control sera, i.e. 51 per cent. By using an indirect haemagglutination test, antibodies to LTA were found in all sera from both patients and controls. On the other hand, LTA antibodies were detected in a higher proportion of the CSF samples from MS patients than from controls. A reduced serum to CSF ration of LTA antibodies compared with the ratio for a reference antibody was demonstrated in 7 out of 10 MS patients, suggesting a local synthesis within the central nervous system. Absorption of seven MS CSF samples with LTA removed one to three of the cathodic oligoclonal IgG bands demonstrated by agarose electrophoresis and reduced the IgG concentration.

Immune complexes of horseradish peroxidase (HRP) and rabbit IgG antibodies to HRP were used to study the Fc gamma receptors in the human central nervous system (CNS). The peroxidase activity was demonstrated with 3,3'-diaminobenzidine tetrahydrochloride and H2O2. The majority of the pia and arachnoid cells of the leptomeninges, the stroma cells of the arachnoid granulations and the adventitial cells in the perivascular spaces of the nervous tissue were stained. The villi of the choroid plexus were also stained. By electron microscopy the reaction products were localized to the plasma membranes of the stroma cells and at the basal aspects of the epithelial cells in the choroid villi. In addition, reaction product was demonstrated on pericytes of some of the brain capillaries. The immune complexes did not bind to the brain parenchyma.

Lipoteichoic acid (LTA) isolated from Staphylococcus aureus Cowan I induced an in vitro blastogenic response in isolated mononuclear cells (MNC). Seventeen of 20 normal donors responded strongly, with peak response after 3 — 5 days of incubation. Significant stimulation was also obtained with human cord blood MNC from 3 donors, further indicating that the stimulation was due to a general mitogenic effect. The mitogenicity of deacylated LTA (dLTA) was similar to that of LTA. Binding of LTA to isolated MNC was demonstrated by an indirect immunofluorescent technique staining with specific rabbit anti-LTA antibodies and by rosette inhibition experiments. Results obtained in cell fraction experiments indicated that LTA had a monocyte dependent mitogenic effect on T lymphocytes.

Ten patients with acute optic neuritis (AON) were examined for T and B lymphocytes in blood and cerebrospinal fluid by means of rosette techniques. The percentage of T lymphocytes in blood was significantly decreased (54+/-3%) compared to controls (66+/-2%). Absolute numbers of T lymphocytes, and relative and absolute B lymphocyte concentrations were not significantly different from controls. The cerebrospinal fluid (CSF) T lymphocyte percentage was significantly increased (88.8% compared to 78.0% in controls). The relative CSF immunoglobulin G concentration was elevated in four patients (40%). On agarose gel electrophoresis, bands in the gamma globulin region were found in two patients (20%).

Absolute and relative numbers of T lymphocytes in peripheral blood were determined in 19 different groups of patients with neurological diseases, using the E-rosette test. A significantly decreased total number of T lymphocytes was found in the following groups: acute Guillain-Barré syndrome (GBS), active multiple sclerosis (MS), and malignant cerebral tumor. A less pronounced and not significant reduction was observed in patients with amyotrophic lateral sclerosis (ALS). In all other groups of patients normal total numbers of T lymphocytes were found, thus indicating that the decrease in T lymphocyte counts in GBS, MS and malignant cerebral tumors is not due to nonspecific injury of nerve tissue.

– In the county of Hordaland, Western Norway, the prevalence of MS has been shown to have increased from 20/100,000 in 1963 to 60/100,000 in 1983. This study shows that the increase in prevalence was caused by a highly significant and marked increase in incidence over a 30-year period. The average annual incidence of about 2 per 100,000 population in 1953–1962 increased to 4 per 100,000 in the period 1968–1977. The rise in incidence was parallel for both sexes until 1970. In the last 10 years, the incidence has continued to increase among females, whereas a decrease has been observed among males.

We have examined the incidence of the Guillain-Barré syndrome (GBS) in the county of Hordaland. We have previously reported a marked increase in the incidence of MS in the same population. 109 GBS-patients were diagnosed in the period 1957-1982 according to the criteria of NINCDS. The annual incidence rates were stable over time with an average incidence of 1.2 per 100,000 population per year. The male/female ratio was 1.7. No statistically significant difference in incidence was found between urban and rural areas. We found an increasing incidence with age, more marked among males than among females. A predilection for GBS to occur in the colder half of the year was also found. 57% of the patients reported an antecedent infection less than 4 weeks prior to the onset of neurological symptoms. The stable incidence rates for GBS over time in contrast to an increase in the incidence of MS in the same population, indicates that different pathogenetic mechanisms are important in the two demyelinating diseases.

– We have previously found an increase in prevalence and incidence of multiple sclerosis (MS) in the county of Hordaland, Western Norway. This study shows that the increase in incidence over a 30-year period is due to an increase of remittent and remittent/progressive MS. The incidence of the chronic progressive form of MS has remained stable during the same period. The two subgroups of MS also vary in symptomatology and age at onset. This suggests that MS has two different forms which behave differently when considered epidemiologically and clinically. The remitting and progressive forms may therefore each have a different etiology.

– A group of 23 professional divers was investigated before and after dives to 300 and 350 metres of sea water. 12 divers were also studied during the actual dive. All divers presented neurological symptoms and signs during compression. Intention tremor, ataxia, motor weakness, sensory symptoms, vertigo, nausea and reduced memory were the most prominent features of the High Pressure Nervous Syndrome (HPNS). There were considerable individual differences. Neuropsychological and neurophysiological investigations performed after one dive showed no significant changes in any of the divers, while there was a clear-cut impairment in a group of 6 divers who had performed 2 dives 3 months apart. These changes indicate that there may be pressure-induced brain dysfunction which persists for a transient post-dive period. Loss of short-term memory is a prominent part of this dysfunction. Transitory neurological signs indicating focal cerebral dysfunction were found immediately post-dive in 4 divers, presumably reflecting the unmasking of pre-existing subclinical minimal CNS lesions.

Introduction - Disease associations may provide useful etiological leads in relation to diseases of unknown cause. Material and methods - We conducted a hospital-based case-control study of 155 MS patients and 200 controls in Hordaland County, Norway to investigate the possible association between MS and autoimmune diseases. Results - The MS patients had a statistically significant more frequent coexistence of rheumatoid arthritis, psoriasis, and goitre when compared to the controls (OR = 2.96 ; 95% CI 1.23-7.66). This difference persisted when analysing the definite MS cases separately (OR = 2.90 ; 95% Cl 1.10-7.96). The familial occurrence of chronic inflammatory diseases was not significantly different in cases and controls. A significant increased risk to develop MS occurred in first degree relatives of MS patients (OR =12.58 ; 95% CI 1.73-552). Conclusion - Acknowledging the low figures, the uncertain estimates with large confidence intervals, and thus the obvious role of chance in this study, the results might indicate that a generalized, genetically controlled problem of the immune system could result in aggregates of the reported diseases, all of which are partly characterized by abberrations of the immune system.

Of 99 consecutive patients with meningococcal disease, 6 died during the acute stage. The 93 survivors were examined one year after hospitalization. 21 (40%) of the adults and 6 (15%) of the children had definite sequelae, and an additional 27% and 11% possible sequelae. 6 adults (12%) and 1 child (2%) had definite neurological sequelae. Electroencephalography (EEG) abnormalities were observed in 7 adults (14%) and 2 children (5%). Epileptogenic activity was present in 3 of these, but none had experienced seizures. 8 adults (19%) and 5 children (14%) had sensorineural hearing loss or impaired vestibular function. Cerebral computerized tomography (CT) scan showed definite and possible abnormalities in 1 (3%) and 6 (18%), respectively, of the 34 patients tested. Neuropsychological tests were performed in 9 patients, 2 of these showed definite impairment. The frequency of neurological abnormalities was higher than in many previous studies, probably reflecting the more comprehensive examinations performed in the present study. However, only 3 patients had serious sequelae. The results suggest that the occurrence of sequelae after meningococcal disease is related to the severity of the acute disease. This may explain the higher rate of sequelae in adults, who have a higher proportion of seriously ill patients. The presence of meningitis is not required for the occurrence of neurological sequelae.

Background Survival time among patients with multiple sclerosis (MS) has varied considerably according to previous reports. Objectives Survival and cause of death were analyzed among all patients with MS (878) with onset of MS in Hordaland County, Western Norway during 1953–2003, of whom 198 were dead at follow-up on January 1, 2005. Methods Standardized mortality ratios (SMRs) and relative mortality ratios (RMRs) were calculated based on observed mortality in MS and expected mortality. Results Median survival from onset was 41 years versus 49 years in the corresponding population, and mortality (SMR) was 2.7-fold increased in MS. The median survival was 43 years among women and 36 years among men, but women had higher relative mortality, when compared with the corresponding population, than men (RMR = 1.40). The median survival time was 45 years among young-onset patients (21–30 years) and 23 years among older-onset patients (51–60 years), but young-onset patients had higher relative mortality than older-onset patients, as shown by a significant reduction by 10-year interval of age at onset (RMR = 0.65). Median survival from onset was longer (43 years) among relapsing–remitting MS than primary progressive MS ([PPMS]; 49 years), and the relative mortality was higher in the PPMS group, (RMR = 1.55). According to death certificates, 57% died from MS. Conclusion Female patients and patients with young onset had longer median time to death but higher relative risk of dying compared with the corresponding population. PPMS had both shorter median time to death from onset and a higher relative risk of dying.

BACKGROUND: Diving is associated with long-term effects on several organ systems. AIM: The objective was to investigate the impact of decompression sickness (DCS) and diving exposure on health-related quality of life (HRQL) in former Norwegian North Sea divers. METHODS: HRQL was recorded by a questionnaire in the cohort of 375 Norwegian North Sea divers registered before 1990. Demographic data, relevant health data and data on diving education, history of DCS and SF-36 were recorded in 230 divers. RESULTS: All SF-36 sub-scores were significantly reduced compared with Norwegian norms. Reduced scores were seen for all scales among divers who reported previous DCS compared to those without DCS. A decreasing trend in scores was seen when comparing no DCS, skin or joint DCS and neurological DCS. There was a decreasing trend in scores related to number of days in saturation and maximal depth. Stratification on DCS showed that the impact of saturation diving was present only in divers with DCS. CONCLUSIONS: HRQL was reduced in this study sample of divers. Having had DCS during the diving career contributed significantly to the reduction in all SF-36 scales, and apparently neurological DCS has the most pronounced impact. Cumulative diving exposure including days in saturation and maximal depth contributed to a reduced HRQL. Language: en

The Norwegian Multiple Sclerosis National Competence Centre was established at the Department of Neurology, Haukeland University Hospital, Bergen in 1996. Promotion of research, supervision and education of doctors and other health care professionals in Norway are the main responsibilities of the Centre. The centre has established national networks for MS care and research and has provided supervision and education of doctors and other health care professionals in Norway. Guidelines for diagnosis and treatment of MS have been established. The National Multiple Sclerosis Registry was established in 1998 and includes by January 2006 50-60% of all MS patients in Norway. Through a national collaboration, the registry aims for inclusion of a biobank unit for collection of cerebrospinal fluid and serum, DNA, and tissue samples.

Background and Purpose—We sought to compare health-related quality of life (HRQoL) in young adults with ischemic stroke on long-term follow-up with controls and to evaluate HRQoL in clinically relevant patient subgroups.Methods—HRQoL was determined with the use of the 8 subscales of the Short-Form General Health Survey (SF-36). Subgroups of patients were defined by sex, age, functional status (modified Rankin Scale), marital status, education, depression (Montgomery-Åsberg Depression Rating Scale), and fatigue (Fatigue Severity Scale). SF-36 scores among patients were compared with SF-36 scores among age- and sex-matched controls and SF-36 scores available from the general Norwegian population.Results—SF-36 scores were obtained after a mean follow-up of 6.0 years among 190 young adults with ischemic stroke during 1988–1997 and among 215 responding controls (55%). The difference in HRQoL between patients, controls, and the general Norwegian population was restricted mainly to the 3 subscales physical functioning, general health, and social functioning (PConclusions—Compared with controls and the general Norwegian population, low level of HRQoL among young adults with ischemic stroke was most pronounced in regard to physical functioning. Early identification and treatment of depression, fatigue, and physical disability may potentially improve HRQoL among stroke patients.

Objective: To explore the range of psychiatric symptoms in patients with multiple sclerosis (MS) and their association with neurological disability. Method: Patients diagnosed with MS during 1998–2000 in Rogaland and Hordaland counties, western Norway, were included. Psychiatric symptoms were assessed by the Neuropsychiatric Inventory (NPI). Patients with systemic lupus erythematosus (SLE) served as controls. Results: Eighty-six of 93 eligible MS patients were included, and 80% showed at least one psychiatric symptom. The most frequent symptoms were depression (59%), sleep disturbance (48%), irritability/emotional lability (42%), and apathy (31%). Depression was associated with higher disability score. MS patients showed significantly higher NPI irritability score (P = 0.002), appetite disturbance score (P

The level of interleukin-10 (IL-10) expression is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 gene, which constitute three haplotypes, GCC, ATA, and ACC. The ATA (a non-GCC) haplotype, which is associated with low IL-10 expression, has been shown to improve interferon (IFN) treatment response in hepatitis C. We analysed the distribution of IL-10 promoter haplotype combinations to determine whether they could influence initial IFN treatment response in 63 patients with relapsing-remitting multiple sclerosis (MS). The patients were grouped into non-GCC or GCC haplotypes, and the clinical and magnetic resonance imaging (MRI) disease activity was compared in the two groups. During the first 6 months of treatment, MS patients with non-GCC haplotypes experienced fewer new MRI T1-contrast enhancing lesions [0.77+/-0.36 (SEM)] than patients with the GCC haplotype (2.45+/-0.57) (P=0.05, Mann-Whitney U test). No differences were detected on clinical disease activity. The results suggest an influence of IL-10 promoter polymorphisms on IFN treatment response in MS.

Objectives – We analysed the long-term outcome of 232 young adults aged 15–49 years with first-ever cerebral infarction in 1988–1997 in western Norway. Material and methods – Mortality, recurrence, epilepsy, functional state as evaluated by modified Rankin scale (mRS), and employment were analysed at follow-up (mean time 5.7 years). Results – Twenty-three (9.9%) patients had died. Recurrence occurred in 9.9%, and post-stroke seizures developed in 10.5%. Recurrence was associated with diabetes mellitus (P = 0.005). Favourable functional outcome (mRS = 2) was found in 77.9%. The functional outcome was better in posterior than anterior circulation infarctions (P = 0.011). Unfavourable functional outcome (mRS > 2) was associated with diabetes mellitus (P = 0.001) and severity of neurological deficits on admission for the index stroke (P

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.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.We found significant concordance of the disease course (kappa = 0.28, P0.001) 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).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.

Multiple sclerosis (MS) patients treated with type I interferon experience reduced disease activity. Because immunoglobulins (Igs), complement and lymphocytes have been given a role in the pathogenesis of MS, we investigated the longitudinal effect of interferon-alpha2a (IFNA) on the variability of these parameters. Patients were treated for 6 months with 4.5 million international units (MIU) IFNA (24 patients), 9.0 MIU IFNA (21 patients) or placebo (23 patients). IFNA induced a significant increase in concentrations of total IgG and IgG subclasses 1, 3 and 4. At 6 months, the mean concentration of IgG had increased by 1.51 g/l (CI: 0.82, 2.21) in the 9.0 MIU IFNA group. There was no significant effect of IFNA treatment on concentrations of IgG2 and IgA, while the effect on IgM was borderline significant. After 6 months, IgM had increased by 0.29 g/l (CI: -0.01, 0.65) in the 9.0 MIU IFNA group. IFNA induced a significant increase in the concentration of C1 inhibitor (INH). At 3 months, the mean concentration of C1 INH had increased by 0.033 g/l (CI: 0.01, 0.05). At 3 months, C4 had increased by 0.05 g/l (CI: 0.01, 0.09) in the 9.0 MIU IFNA group. The effect of IFNA on C4 was inconclusive but indicates an effect during the initial phase of the treatment. C3 showed no significant treatment-mediated change. IFNA induced a significant decrease in lymphocyte concentrations by 0.56 x 106 lymphocytes/ml (CI: -0.81, -0.31) at 3 months. There were no significant associations between changes in immune parameters and changes in clinical and magnetic resonance imaging scores. The results verify that IFNA modulates and activates both the innate and the adaptive arms of the immune system. The observations should be of relevance when evaluating mechanisms of action of IFN treatment in MS.

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers C D3, C D4, C D8, C D45RO, and C D20. The highest density of C D3- positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P B-0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the C D4, C D8, and C D45RO markers. C D20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Objective: To examine the effect of early clinical and demographic factors on occupational outcome, return to work or awarded permanent disability pension in young patients with chronic fatigue syndrome (CFS). Design: Longitudinal cohort study. Intervention: A written self-management programme including a description of active coping strategies for daily life was provided. Setting, participants: Patients with CFS after mononucleosis were evaluated at Department of Neurology, Haukeland University Hospital during 1996–2006 (contact 1). In 2009 self-report questionnaires were sent to all patients (contact 2). Primary and secondary outcome measures: Primary measure was employment status at contact 2. Secondary measures included clinical symptoms, and Fatigue Severity Scale (FSS) scores on both contacts, and Work and Social Adjustment Scale (WSAS) at contact 2. Results: Of 111 patients at contact 1, 92 (83%) patients returned the questionnaire at contact 2. Mean disease duration at contact 1 was 4.7 years and at contact 2 11.4 years. At contact 1, 9 (10%) were part-time or fulltime employed. At contact 2, 49 (55%) were part-time or full-time employed. Logical regression analysis showed that FSS≥5 at contact 2 was associated with depression, arthralgia and long disease duration (all at contact 1). Conclusions: About half of younger patients with CFS with long-term incapacity for work experienced marked improvement including full-time or part-time employment showing better outcomes than expected. Risk factors for transition to permanent disability were depression, arthralgia and disease duration. publishedVersion

Objective: Physical disability explains only part of the reduced quality of life found among multiple sclerosis (MS) patients. Bladder dysfunction and sexual disturbance are frequent and distressing problems for MS patients. We therefore estimated the relationship between the presence and degree of sexual disturbance/bladder dysfunction and the patients' quality of life as measured by the SF-36 Health Survey. Methods: We performed a cross-sectional study of all individuals with the onset of MS between 1976 and 1986 in Hordaland County, Norway. The disease duration at examination was 9-19 years; 194 patients (94%) participated. Results: Fifty-three per cent of the patients with low physical disability (Expanded Disability Status Scale (EDSS)≤44.0) reported disease-related sexual disturbance and 44% had bladder dysfunction according to the Incapacity Status Scale. The corresponding figures for the patients with a high physical disability (EDSS>44.0) were 86 and 81% respectively. The patients with sexual disturbance had markedly and significantly reduced scores on all eight SF-36 scales, this was after adjustment for disease development measured by the EDSS. The patients without sexual disturbance scored 0.5 s.d. lower than a normal population on the social functioning scale, whereas those with marked sexual disturbance scored 1.5 s.d. lower. Similar results were found for the patients with bladder dysfunction. Conclusion: Bladder and sexual problems are associated with a marked reduction in the quality of life, also among patients with otherwise low disability. This underlines the need for identifying and treating these problems.

The T cell specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the control of T cell activation. The gene is located in the 1q21 region, which has been implicated in susceptibility to experimental allergic encephalomyelitis in the mouse. We therefore evaluated whether a polymorphic GA repeat (GA(13)-GA(33)) within the promoter region of the SH2D2A gene shows association to multiple sclerosis (MS). The frequency of the short alleles GA(13-16) was increased among 313 Norwegian MS patients compared to 277 healthy controls (0.332 vs 0.249, OR 1.5, Pc = 0.03). Transmission disequilibrium analysis in 146 Scandinavian families with at least two affected sibs showed increased transmission of GA(16) to MS patients. No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed. After activation of naive CD4(+) T cells, T cells homozygous for MS associated short alleles displayed lower level of TSAd ex vivo than T cells carrying at least one long allele, which were not associated to MS. Since the SH2D2A protein modulates T cell activation, this may be a mechanism for how short SH2D2A alleles confer susceptibility to develop MS.

Objective: To evaluate disability and prognosis in an untreated population-based incidence cohort of multiple sclerosis (MS) patients. Methods: The Expanded Disability Status Scale (EDSS) score was recorded in 220 MS patients. Disease progression was assessed by life table analysis with different endpoints and multivariate Cox regression analysis was performed for evaluation of prognostic factors. Results: The probability of being alive after 15 years was 94.8+1.8% (s.e.), of managing without a wheelchair (EDSS57.0) 75.8+3.2%, of walking without walking assistance (EDSS56.0) 60.3+3.6%, and of not being awarded a disability pension 46.0+3.7%. The probability of still having a relapsing-remitting (RR) course after 15 years was 62.0+4.1%. A RR course and long interval between the initial (onset) and second episode (43 years) predicted favorable outcome. There was also a trend towards favorable outcome in patients with optic neuritis, sensory symptoms and low age at onset, but these factors were associated with the RR course. Motor symptoms and high age at onset indicated unfavorable outcome, but these factors were associated with the primary progressive course. Conclusions: A RR course and long inter-episode intervals in the early phase of the disease were associated with a better outcome. Other onset characteristics indicating a favorable outcome were associated with the RR course while characteristics indicating an unfavorable outcome were associated with the PP course.

Article abstract Sera from patients with MS treated with recombinant interferon (rIFN) α-2a, rIFNβ-1a, or rIFNβ-1b were analyzed for cross-reacting neutralizing antibodies (NAB). Because cross-reactivity was not found, switching treatment from rIFNβ-1a or rIFNβ-1b to rIFNα-2a might provide a secondary treatment response in patients with NAB to rIFNβ-1a or rIFNβ-1b. A positive treatment response also might be achieved by switching NAB rIFNα-2a–positive patients to rIFNβ-1a or rIFNβ-1b.–1571

Objective - To investigate whether supplementation with fish oil given together with dietary advice and vitamin supplementation influenced the clinical outcome in newly diagnosed multiple sclerosis (MS) patients. Material and methods - Sixteen consecutive, newly diagnosed patients with multiple sclerosis were recruited to an open intervention study. They were given dietary advice and supplemented with 0.9 g/day of long-chain marine fatty acids and vitamins. The patients were followed for 2 years with respect to dietary habits, blood parameters and neurological assessment including exacerbation rate. Results - There was a significant reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale (EDSS) as compared to pre-study values. The plasma total phospholipid n-3 fatty acids increased and n-6 fatty acids decreased significantly. Conclusions - The results suggest that fish oil supplementation given together with vitamins and dietary advice can improve clinical outcome in patients with newly diagnosed MS.

Objective: To investigate the predictive value of quality of life on changes in disability measured by the Expanded Disability Status Scale (EDSS).Background: There are few good prognostic factors for disease development in MS. Quality of life and self-rated health have been shown to be highly predictive of morbidity and disease development in heart disease and cancer.Methods: Data on quality of life (SF-36 Health Survey) were ascertained at baseline for 97 relapsing-remitting patients with MS participating in a short-term clinical trial on interferon α-2a. These scores were correlated with change in EDSS scores 1 year later, 6 months after treatment ended.Results: Low scores on the SF-36 mental health scale were correlated with increased (worsened) EDSS scores 1 year later (r = −0.29, p = 0.006). The results were not altered by adjusting for disease activity at baseline, which was measured by the number gadolinium-enhanced MRI lesions, relapse rate for the preceding 2 years, and baseline EDSS score. Similar results were found for self-rated health (according to the first question of the SF-36).Conclusions: These findings reinforce the importance of incorporating the patients’ evaluation of their quality of life during treatment. Further, assessing such measures is important in evaluating effects in treatment trials in MS.

OBJECTIVES To evaluate the treatment effect of recombinant interferon-alpha2a (rIFN-alpha2a) on complement activation and regulation in MS patients. MATERIAL AND METHODS Plasma levels of the complement activation products C3bc and terminal complement complex (TCC) and serum levels of the complement regulatory proteins, complement receptor 1, CR1 (CD35) and the membrane inhibitor of reactive lysis, protectin (CD59), were determined by enzyme-linked immunosorbent assay (ELISA) in MS patients treated with IFN-alpha2a (14 patients) or placebo (7 patients). RESULTS The level of soluble CD35 decreased while the level of TCC and to a lesser degree C3bc increased in the IFN-alpha2a treated patients during the initial part of the treatment. There was also a concomitant reduction of leukocytes in the same patients. CONCLUSIONS The results indicate that complement is activated during the initial phase of rIFN-alpha2a treatment. This could partly be due to a concomitant reduction in soluble CD35.

Increased levels of anti-peripheral nerve myelin (anti-PNM) antibodies were demonstrated by ELISA in serum from 4 of 7 patients with Guillain-Barré syndrome (GBS). Treatment with plasma exchange (PE) was performed and 6 of the 7 patients showed clinical improvement with marked increase in muscular strength. One patient, however, continued to deteriorate during the treatment. No correlation between clinical improvement and levels of anti-PNM antibodies was observed. Whether the antibodies are of pathogenetic importance in GBS is therefore still unknown.

OBJECTIVE—The prevalence of anti-EBV antibodies was studied in a group of 144 patients with multiple sclerosis and 170 age, sex, and area matched controls from the county of Hordaland, western Norway. The prevalence of three other herpesviruses, herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV), were also included. METHODS—Antibodies to various virus antigens were determined by enzyme linked immunosorbent assay (ELISA) and indirect immunfluorescence (IIF) in serum samples from 144 patients with multiple sclerosis and 170controls. RESULTS—All of the 144 patients with multiple sclerosis had IgG antibodies to EBV compared with 162 of 170 controls (p=0.008). The frequency of IgG antibodies to EBV capsid antigen (VCA), nuclear antigen (EBNA), and early antigen (EA) was significantly higher in patients with multiple sclerosis compared with the controls (p

The developing nervous system is vulnerable to heavy metal exposure, which can cause alterations in neuronal and glial cells in the brain. Thus, heavy metals such as mercury and lead reduce myelin galactocerebroside (GalC) synthesis, and increase the ratio of non-hydroxylated fatty acids to hydroxylated fatty acids (GalC-N:GalC-OH) in the GalC molecules in newborn rats. This study investigated the effect of lead on the expression of myelin components by the myelin-forming oligodendroglial cells (OG) in vitro. Primary cultures of mixed glial cells from brains of newborn rats were continuously exposed to triethyllead (TEL; 1nM, 10nM, 50nM and 100nM) for 3 weeks, one week after seeding. The first morphological alteration observed was an increased proliferation of OG in cultures exposed to 10nM TEL. Biochemical analyses showed up-regulation of the enzymes, 2'3’-cyclic nucleotide 3’-phosphodiesterase and 5’-nucleotidase. GalC synthesis was also stimulated, and the ratio GalC-N:GalC-OH was reduced. The results indicate that TEL stimulates the differentiation and maturation of OG in cultures, which suggests that the alterations induced by heavy metals in newborn rats are not due to interference with the OG maturation.

Fifty-two patients with Guillain-Barré syndrome (GBS) were re-examined 1-14 years (median 7 years) after the initial onset of symptoms. At the follow-up 38 patients (73%) reported being completely symptom-free. Neurological examination revealed that 11 patients (21%) had motor and 16 patients (31%) had sensory signs, mainly distal in the lower limbs. One patient (2%) had cranial nerve signs. Fifteen patients (29%) had areflexia, generally of the ankle jerks. Severe pareses (high maximal disability grade), long duration of maximal symptoms and recovery were significantly associated with persistent disability. Age, sex, preceding infection, latency between infection and the onset of disease, weakness as an initial symptom, autonomic dysfunction, speed of progression, electro-physiological signs of axonal degeneration, cerebrospinal-fluid protein concentration and treatment with plasma exchange did not significantly influence the disability grade at follow-up.

After a mean of 6 years, the frequencies of later vascular events (recurrent ischemic stroke or myocardial infarction) in 232 young ischemic stroke patients (younger than 50 years) with none to five traditional risk factors were 2.1%, 6%, 19%, 26%, 30%, and 67% (p< 0.001). Long-term secondary preventive medication may not be indicated in young ischemic stroke patients with no risk factor.