Vitamin D, HLA-DRB1 and Epstein-Barr virus antibody levels in a prospective cohort of multiple sclerosis patients.

BACKGROUND AND PURPOSE: Our objective was to study the association between serum levels of anti Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody and 25-hydroxyvitamin D (25(OH)D) in a prospective cohort of patients with relapsing-remitting multiple sclerosis. METHOD: The study comprised 90 patients with relapsing-remitting multiple sclerosis, all participants in a randomized clinical trial of ω-3 fatty acids (the OFAMS study). Repeated, paired measurements of serum 25(OH)D and serum EBNA-1 immunoglobulin G (IgG) levels were obtained at baseline and every 6 months for 24 months. The association between serum EBNA-1 IgG and serum 25(OH)D levels was analysed using generalized linear models for hierarchical data. RESULTS: There was a significant variation in EBNA-1 IgG antibody level between sampling months (Fdf 11 = 1.8, P = 0.043, one-way anova). There was a negative association between EBNA-1 IgG and 25(OH)D [B = -0.230, 95% confidence interval (CI) (-0.440, -0.023), P = 0.030] and a positive association between EBNA-1 IgG and HLA-DRB1*15 positive status [B = 94.7, 95% CI (2.423, 186.9), P = 0.044]. The association between 25(OH)D and EBNA-1 IgG remained significant after adjusting for the patient's age, gender, HLA-DRB1*15, retinol levels and interferon ß-1a treatment. CONCLUSION: Our study demonstrates monthly differences in EBNA-1 IgG levels and an association between EBNA-1 IgG, 25(OH)D levels and HLA-DRB1*15. These results indicate that EBNA-1 IgG serum levels are affected by genetic and environmental factors that also modulate multiple sclerosis risk.

Does low socioeconomic status in early life protect against multiple sclerosis? A multinational, case-control study.

BACKGROUND AND PURPOSE: The findings from existing research on the association between socioeconomic status (SES) and multiple sclerosis (MS) are inconsistent. Most previous studies are limited to one country and do not adequately adjust for other risk factors for the disease. METHODS: The association between SES and MS was examined using data from the multinational Environmental Risk Factors in Multiple Sclerosis (EnvIMS) case-control study, comprising 2144 cases and 3859 controls from Norway, Canada and Italy. Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals for the association between early life SES, measured by parental educational level, and MS. Analyses were adjusted for age, sex, sunlight exposure, history of infectious mononucleosis, smoking, obesity and family size. RESULTS: Relative to those whose parents had primary school education or below, the adjusted odds ratio (95% confidence interval) for MS amongst individuals with university-educated parents, and the P value for trend across education levels, were 1.45 (1.03-2.05) in Canada (P for trend 0.030), 1.09 (0.85-1.39) in Norway (P for trend 0.395) and 0.65 (0.39-1.07) in Italy (P for trend 0.158). CONCLUSION: There is no consistent association between parental SES and MS risk in Norway, Canada and Italy, with a protective effect of low SES only found in Canada.

Risk of depression in diabetes is highest for young persons using oral anti-diabetic agents.

AIMS: Previous studies report an increased risk of depression in patients with diabetes, but there is little knowledge about if or how the risk varies according to sex, groups of age and different type of treatments for the diabetes. We therefore aimed to investigate the risk of depression in different types of treatment for diabetes and in subgroups of age and sex. METHODS: Data on the Norwegian population from 20 years of age being prescribed antidepressants (n = 253 668) and anti-diabetic agents (n = 121 392) in 2006 was obtained from the National Register of Prescriptions and analysed in a cross-sectional design. RESULTS: Individuals using insulin in monotherapy (n = 29 611) had an age- and sex-adjusted odds ratio of 1.47 (95% CI 1.42-1.53) for receiving antidepressants. Corresponding odds ratios for individuals receiving oral anti-diabetic agents in monotherapy (n = 76 387) and for those who received both insulin and oral anti-diabetic agents (n = 15 394) were 1.44 (95% CI 1.41-1.47) and 1.82 (95% CI 1.80-1.97), respectively. No major differences in risk according to age were found for persons receiving insulin in monotherapy, while a marked and inverse association between age and risk of receiving antidepressants was found for those receiving oral anti-diabetic agents. Highest risk of antidepressant treatment [odds ratio 4.15 (95% CI 3.12-5.52)] was found for patients receiving both oral anti-diabetic agents and insulin at 30-39 years. The risk was equally increased among men and women. CONCLUSIONS: The risk of depression among patients with diabetes varies strongly according to age and type of treatment for diabetes.

Health-related quality of life and disease-modifying treatment behaviour in relapsing-remitting multiple sclerosis--a multicentre cohort study.

OBJECTIVES: To assess the overall health-related quality of life (HRQoL) in a population-based cohort of patients recently diagnosed with multiple sclerosis (MS) compared with the general Norwegian population, to compare HRQoL among MS patients continuing, switching, stopping or not starting disease-modifying treatment (DMT) and to assess the motivation for DMT according to HRQoL. MATERIALS AND METHODS: A multicentre retrospective survey completed by patients recently diagnosed with relapsing-remitting MS (relapsing-remitting multiple sclerosis, RRMS) during 2001-2007 at four university clinics in Norway was performed. HRQoL was measured by the SF-36 version 2 Health Survey and standardized according to the general population with a mean of 50 and a standard deviation of 10. Motivation for DMT was assessed using Visual Analogue Scale (VAS). RESULTS: The mean age at diagnosis was 37 years. Patients had reduced mean scores for all eight dimensions of the SF-36 with lowest scores on social functioning (mean = 31.1), mental health (mean = 32.7), general health (mean = 39.7) and vitality (mean = 40.9) compared with the general population. Continuers scored higher on mental summary scale (mean = 37.9) and lower on physical summary scale (mean = 43.8) compared with non-starters. Non-starters scored highest on physical summary scale (mean = 45.2, P = 0.007) and lowest on mental summary scale (36.1, P = 0.01) compared with continuers, stoppers and switchers. Patients with high SF-36 physical health summary score and low SF-36 mental health summary score were less motivated for using DMT. CONCLUSION: The association of HRQoL and motivation to DMT emphasizes the need for health care personnel to inform and motivate patients to DMT, especially among patients with low mental health and otherwise high physical health and functioning.

A questionnaire for multinational case-control studies of environmental risk factors in multiple sclerosis (EnvIMS-Q).

OBJECTIVES: The increasing incidence of multiple sclerosis (MS) worldwide, especially in women, points to the crucial role of environmental and lifestyle risk factors in determining the disease occurrence. An international multicentre case-control study of Environmental Risk Factors In Multiple Sclerosis (EnvIMS) has been launched in Norway, Sweden, Italy, Serbia and Canada, aimed to examine MS environmental risk factors in a large study population and disclose reciprocal interactions. To ensure equivalent methodology in detecting age-related past exposures in individuals with and without MS across the study sites, a new questionnaire (EnvIMS-Q) is presented. MATERIALS AND METHODS: EnvIMS-Q builds on previously developed guidelines for epidemiological studies in MS and is a 6-page self-administered postal questionnaire. Participants are de-identified through the use of a numerical code. Its content is identical for cases and controls including 'core' and population-specific questions as proxies for vitamin D exposure (sun exposure, dietary habits and supplementation), childhood infections (including infectious mononucleosis) and cigarette smoking. Information on possible confounders or effect modifiers is also obtained. EnvIMS-Q was initially drafted in English and subsequently translated into Italian, Serbian, Norwegian, Swedish and French-Canadian. EnvIMS-Q has been tested for acceptability, feasibility and reliability. RESULTS AND CONCLUSIONS: EnvIMS-Q has shown cross-cultural feasibility, acceptability and reliability in both patients with MS and healthy subjects from all sites. EnvIMS-Q is an efficient tool to ensure proper assessment of age-specific exposure to environmental factors in large multinational population-based case-control studies of MS risk factors.

Stress and the risk of multiple sclerosis.

OBJECTIVE: Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of multiple sclerosis (MS) exacerbations. We wanted to study prospectively whether stress can increase the risk of developing the disease itself. METHODS: We studied 2 cohorts of female nurses: the Nurses' Health Study (NHS) (n = 121,700) followed from 1976 and the Nurses' Health Study II (NHS II) (n = 116,671) followed from 1989. The risk of MS after self-report on general stress at home and at work in the NHS in 1982 was studied prospectively using Cox regression. Logistic regression was used to retrospectively estimate the effects of physical and sexual abuse in childhood and adolescence collected in the NHS II 2001. We identified 77 cases of MS in the NHS by 2005 and 292 in the NHS II by 2004. All analyses were adjusted for age, ethnicity, latitude of birth, body mass index at age 18, and smoking. RESULTS: We found no increased risk of MS associated with severe stress at home in the NHS (hazard ratio 0.85 [95% confidence interval (CI)] 0.32-2.26). No significantly increased risk of MS was found among those who reported severe physical abuse during childhood (odds ratio [OR] 0.68, 95% CI 0.41-1.14) or adolescence (OR 0.77, 95% CI 0.46-1.28) or those having been repeatedly forced into sexual activity in childhood (OR 1.47, 95% CI 0.87-2.48) or adolescence (OR 1.21, 95% CI 0.68-2.17). CONCLUSIONS: These results do not support a major role of stress in the development of the disease, but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS.

Benign multiple sclerosis: a need for a consensus.

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 cut-off values: 2.0, 3.0 and 4.0. Two additional definitions were added using an EDSS

Long-term follow-up of benign multiple sclerosis in Hordaland County, Western Norway.

OBJECTIVE: To study the frequency of benign multiple sclerosis (MS) after 20 years disease duration and identify early clinical and demographic prognostic factors of a benign course. METHODS: A population-based cohort including all 230 MS patients with clinical disease onset during 1976-1986 in Hordaland County, Western Norway was followed up with clinical examination in 1995 and 2003. Benign MS was defined as an Expanded Disability Status Scale (EDSS) score

Environmental risk factors in multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation. RESULTS: Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein-Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns. CONCLUSIONS: Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed.

Neurological symptoms among dental assistants: a cross-sectional study.

BACKGROUND: Dental assistants help the dentist in preparing material for filling teeth. Amalgam was the filling material mostly commonly used in Norway before 1980, and declined to about 5% of all fillings in 2005. Amalgam is usually an alloy of silver, copper, tin and mercury. Copper amalgam, giving particularly high exposure to mercury was used in Norway until 1994. Metallic mercury is neurotoxic. Few studies of the health of dental assistants exist, despite their exposure to mercury. There are questions about the existence of possible chronic neurological symptoms today within this working group, due to this exposure. The aim of this study was to compare the occurrence of neurological symptoms among dental assistants likely to be exposed to mercury from work with dental filling material, compared to similar health personnel with no such exposure. METHODS: All dental assistants still at work and born before 1970 registered in the archives of a trade union in Hordaland county of Norway were invited to participate (response rate 68%, n = 41), as well as a similar number of randomly selected assistant nurses (response rate 87%, n = 64) in the same age group. The participants completed a self-administered, mailed questionnaire, with questions about demographic variables, life-style factors, musculoskeletal, neurological and psychosomatic symptoms (Euroquest). RESULTS: The dental assistants reported significant higher occurrence of neurological symptoms; psychosomatic symptoms, problems with memory, concentration, fatigue and sleep disturbance, but not for mood. This was found by analyses of variance, adjusting for age, education, alcohol consumption, smoking and personality traits. For each specific neurological symptom, adjusted logistic regression analyses were performed, showing that these symptoms were mainly from arms, hands, legs and balance organs. CONCLUSION: There is a possibility that the higher occurrence of neurological symptoms among the dental assistants may be related to their previous work exposure to mercury amalgam fillings. This should be studied further to assess the clinical importance of the reported symptoms.

Self-rated physical health predicts change in disability in multiple sclerosis.

OBJECTIVE: To examine whether self-rated physical health, as measured by the Physical Functioning Scale (PF) and the Role-physical Scale (RF) of the SF-36 Health Survey, could predict change in disability measured by the Expanded Disability Status Scale (EDSS) in patients with multiple sclerosis (MS) over a follow-up period of 3 years. METHODS: A group of 156 clinically definite MS patients (Poser criteria), who had never been treated with disease-modifying therapies, were recruited consecutively from an outpatient clinic setting at the Institute of Neurology, Belgrade. The self-rated physical health was measured by using PF and RF of the SF-36. RESULTS: At follow-up, 33 out of 156 patients (21%) had dropped out. The mean EDSS score had increased from 3.7 to 4.5. Multiple regression analyses using change in EDSS as the dependent variable and baseline scores of EDSS and RF as independent variables showed a significant effect for RF (standardized beta= -0.21). A similar but non-significant effect was found for PF. Dichotomizing change in disability according to clinically meaningful deterioration and using logistic regression, an odds ratio of 1.27 (95% confidence interval 1.01-1.62) was found for the smallest unit of change in the self-rated scale. This means that patients who rated their own physical health as poor had a higher increase in disability compared with patients with the same level of disability at baseline who rated their physical health better. CONCLUSIONS: MS patients' perception of their health comprises information predictive for disease development not included in the more objective measure of disability status.

Prevalence of bladder, bowel and sexual problems among multiple sclerosis patients two to five years after diagnosis.

Most multiple sclerosis (MS) patients experience some sexual, bladder and/or bowel dysfunction during the course of the disease--one of MS most disabling features. This study estimated the frequency of these problems among patients, two to five years after diagnosis, and investigated how these problems are associated with health-related quality of life (using the Multiple Sclerosis Quality of Life-54 questionnaire). The study population comprised a cohort of patients (n = 56), diagnosed in a three-year period, in Hordaland County, Norway. The patients were examined clinically, including scoring of the Expanded Disability Status Scale (EDSS), and completed questionnaires related to bowel and bladder dysfunction, sexual problems and health-related quality of life. More than half the patients had bladder and sexual problems. The frequency of self-reported bladder problems corresponded to the relatively high levels of residual urine found. The presence of these problems was associated with lower scores on the quality of life scales. Further, the bowel problems reported were markedly associated with the quality of life scores. Since treatments and preventive strategies can manage many of these problems, we suggest increasing the focus on these aspects of the disease when consulting patients, including at early stages.

Acute suppression of serum IgM and IgA in tank workers exposed to benzene.

We investigated associations between benzene exposure and alterations of proteins and cells of the immune system among workers maintaining cargo tanks containing crude oil residues. Individual exposure to benzene, benzene in blood and urine, peripheral blood lymphocytes (total lymphocytes, lymphocytes in subpopulations CD3, CD4, CD8, CD19, CD56 and CD4/CD8 ratio), complement factors C3 and C4 and serum concentration of immunoglobulins (IgG, IgA, IgM and IgE) were analysed among 13 tank workers and nine unexposed referents (catering section). Benzene exposure was measured during three consecutive 12-h work days. Blood and urine samples were collected pre-shift on the first day (baseline), post-shift on the third day, and pre-next shift on the following morning. The time spent in the cargo tank was logged. The individual geometric mean benzene exposure in the breathing zone of tank workers over 3 days was 0.15 p.p.m. (range 0.01-0.62 p.p.m.) (n = 26). The geometric mean benzene concentration in blood post-shift was 12.3 nmol/l among tank workers versus 0.7 nmol/l among the referents. Tank workers showed a decline (versus referents) in IgM from baseline to post-shift (t-test, P = 0.04) and IgA from baseline to pre-next shift (t-test, P = 0.01). They also showed a decline in CD4 T cells from baseline to post-shift (t-test, P = 0.04). Suppression correlated with benzene exposure, benzene concentrations in blood and urine and time spent in the tank. The groups did not differ significantly in the change in other immune parameters. The clinical significance is unknown and warrants further studies.

The epidemiology of multiple sclerosis in Europe.

Multiple sclerosis (MS) is a chronic and potentially highly disabling disorder with considerable social impact and economic consequences. It is the major cause of non-traumatic disability in young adults. The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multidisciplinary health care. Available MS epidemiological estimates are aimed at providing a measure of the disease burden in Europe. The total estimated prevalence rate of MS for the past three decades is 83 per 100,000 with higher rates in northern countries and a female:male ratio around 2.0. Prevalence rates are higher for women for all countries considered. The highest prevalence rates have been estimated for the age group 35-64 years for both sexes and for all countries. The estimated European mean annual MS incidence rate is 4.3 cases per 100,000. The mean distribution by disease course and by disability is also reported. Despite the wealth of epidemiological data on MS, comparing epidemiological indices among European countries is a hard task and often leads only to approximate estimates. This represents a major methodological concern when evaluating the MS burden in Europe and when implementing specific cost-of-illness studies.

A higher risk of congenital anomalies in the offspring of personnel who served aboard a Norwegian missile torpedo boat.

BACKGROUND: In the 1990s, congenital anomalies were reported among children whose fathers had served aboard a Norwegian missile torpedo boat (MTB). The Royal Norwegian Navy asked the University of Bergen to look into this problem as one part of a general health and work environment surveillance. AIMS: To estimate any increased risk of having children with congenital anomalies and having stillborn children among the offspring of workers that had served aboard the MTB and to investigate possible differences in exposure and other risk factors between these groups. METHODS: Data from a cross-sectional study among all current employees of the Norwegian Navy (n = 2265, response rate 58%) were analysed. RESULTS: The prevalence ratio of having a child with congenital malformations associated with working on the ship was 4.0 (95% CI 1.9 to 8.6). The prevalence ratio of having a child who was stillborn or died within one week was 4.1 (95% CI 1.7 to 9.9). CONCLUSION: Service aboard the MTB was associated with an increased risk of having children with congenital birth defects and having children that were stillborn. The causes of these findings are unknown.

Benzene exposure on a crude oil production vessel.

OBJECTIVES: The aim was to describe the personal exposure to benzene on a typical crude oil production vessel and to identify factors influencing the exposure level. METHODS: The study population included process operators, deck workers, mechanics and contractors on a production vessel in the Norwegian sector of the North Sea. The personal exposure to benzene during ordinary activity, during a short shutdown and during tank work was monitored using organic vapour passive dosimeter badges (3M 3500). Information on the tasks performed on the day of sampling was recorded. Exposure was assessed by grouping the measurements according to job category, mode of operation and the tasks performed on the sampling day. Univariate analysis of variance was used to test the differences between the groups. RESULTS: Forty-two workers participated in the exposure assessment, comprising a total of 139 measurements. The arithmetic and geometric mean of benzene exposure for all measurements was 0.43 and 0.02 p.p.m., respectively. Twenty-five measurements (18%) were below the limit of detection (0.001 p.p.m.), while ten samples (7%) exceeded the occupational exposure limit of 0.6 p.p.m. The geometric mean exposure was 0.004 p.p.m. (95% CI 0.003-0.006) during ordinary activity, 0.01 p.p.m. (95% CI 0.005-0.02) during shutdown and 0.28 p.p.m. (95% CI 0.16-0.49) during tank work. Workers performing annual cleaning and maintenance of tanks containing crude oil or residues of crude oil had higher levels of exposure than workers performing other tasks, including work near open hydrocarbon-transport systems (all P < 0.001). However, because of the mandatory use of respirators, the actual personal benzene exposure was lower. The job categories explained only 5% of the variance in exposure, whereas grouping by mode of operation explained 54% of the variance and grouping by task 68%. CONCLUSION: The results show that, although benzene exposure during ordinary and high activity seems to be low in the processing area on the production vessel, cleaning of tanks and performing maintenance work in a cleaned tank have a potential for high exposure.

Further considerations on the distribution of multiple sclerosis in Sweden.

OBJECTIVES: The geographic distribution of multiple sclerosis (MS) in Sweden over time was compared in order to analyze homogeneity. METHODS: The distribution of MS was compared among three nationwide resources: 1301 hospital cases 1925-1934; 5425 deaths 1952-1992; and 11,371 disability pension recipients 1971-1994. RESULTS: Distributions by county (lan) were markedly non-homogenous, with greatest variations in the early prevalence series (16-232% of the national mean), less within the death data (75-170%), and least for the disability series (87-128%). Maximal rates for MS in the early prevalence series were found for the cluster of seven counties surrounding the two major lakes of south central Sweden, as well as for one region on the northern shore of the Bay of Bothnia, and another also off the Bay north of Stockholm. CONCLUSION: Though the epidemiologic sources are quite different, they are internally consistent and thus provide three consecutive cross-sectional views of the distribution over time. When considered together the data may be compatible with a thesis of the origin and spread of MS within Sweden from the south-central inland lake regions of the country. Such spread within a half century is too rapid for a genetic cause, including HLA patterns.

Multiple sclerosis and lifestyle factors: the Hordaland Health Study.

This study compared multiple sclerosis (MS) patients (n=87) with the general population and with people reporting angina pectoris (n=109), asthma (n=1,353) and diabetes (n=219) regarding health-related quality of life (SF-12), working status and lifestyle factors including smoking, alcohol consumption, body mass index (BMI) and leisure physical activity. The study was cross-sectional and included the birth cohorts from 1950 to 1957 living in Hordaland County, Norway in 1997. A total of 22,312 people participated, yielding a response rate of 65%. The MS patients had a high rate of smoking and a low mean BMI, despite lower leisure physical activity compared with the rest of the study population. This suggests that it may be advisable to increase the focus on smoking, physical activity and the balance between energy intake and use.

The use of quality of life measures in multiple sclerosis research.

Quality of life research contributes knowledge essential to the health and healthcare of multiple sclerosis (MS) patients. This article reviews 83 MS studies in English that have presented data on quality of life. The studies may be classified into three categories, according to the application and the main focus: 1) evaluating the development and validity of quality of life questionnaires and clinical scales (n = 27); 2) evaluating factors that might influence the quality of life or comparing the quality of life among various groups (n = 37); and 3) using quality of life questionnaires as outcome measures in medical trials and other interventions (n = 19). The studies have shown that quality of life questionnaires more broadly measure the impact of MS than do the most frequently used measures of disease activity and effects. Using quality of life measures provides additional information in evaluating the effects of treatment and in studying the development of the disease. Such information is crucial in planning interventions for MS patients. A challenge in this field is to improve the study designs, including reaching some agreement on how to measure the quality of life.