BCG vaccination and multiple sclerosis risk: A Norwegian cohort study.

INTRODUCTION: Bacillus Calmette-Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS). OBJECTIVE: The objective is to examine if BCG given in early adulthood decreases MS risk. METHODS: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk. RESULTS: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80-1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66-1.13). CONCLUSION: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk.

Predictors of hospitalization due to infection in rituximab-treated MS patients.

BACKGROUND: Rituximab is extensively used off-label to treat multiple sclerosis (MS), and long-term vigilance for adverse events is needed. This study was conducted to determine frequencies and predictors of hematological adverse events, including hypogammaglobulinemia, severe lymphopenia, neutropenia, and infections leading to hospitalization. METHODS: This retrospective cohort study included all patients with MS initiating rituximab treatment at Haukeland University Hospital between January 1st, 2017, and July 1st, 2021. Patients were followed by clinical monitoring and repeated blood sampling every six months. Clinical outcomes and laboratory results were retrieved from the Norwegian MS Registry and Biobank and the patient administrative system at Haukeland University Hospital. RESULTS: Five hundred and fifty-six patients were included, 515 with relapsing-remitting MS (RRMS) and 41 with progressive MS. Overall, 33 patients (5.9%) experienced 56 episodes of infections requiring hospital admission. Sixty patients (10.8%) had confirmed hypogammaglobulinemia, 17 (3.1%) had confirmed severe lymphopenia, and 10 (1.8%) had confirmed severe neutropenia. Predictors of infection requiring hospital admission were progressive MS (adjusted OR (aOR): 4.81; 95%CI: 1.25-18.48), duration of treatment with rituximab (aOR: 1.52; 95%CI: 1.11-2.09) and confirmed severe lymphopenia (aOR: 13.58; 95%CI: 3.41-54.06) and neutropenia (aOR: 13.40; 95%CI: 2.93-61.25). Of the hematological abnormalities, only hypogammaglobulinemia was associated with treatment duration (aOR: 1.35; 95%CI: 1.09-1.69). CONCLUSION: The risk of hospitalization due to infection is associated with time on rituximab treatment, in patients with lympho- or neutropenia, and in patients with primary progressive MS. We observed a time-dependent decline in IgG values, in contrast to neutrophil and lymphocyte count, suggesting a cumulative dose-dependent response. These predictors can assist clinicians in assessing and monitoring MS patients receiving rituximab.

High incidence and prevalence of MS in Møre and Romsdal County, Norway, 1950-2018.

OBJECTIVE: To determine prevalence and longitudinal trends in incidence of MS in Møre and Romsdal County, Western Norway, from 1950 to 2018. METHODS: Retrospective longitudinal population-based observational study. All patients diagnosed, or living, with MS in Møre and Romsdal were identified as incident or prevalent cases from local, regional, and national sources. We compiled the data in the Norwegian Multiple Sclerosis Registry and Biobank and used the aggregated data set to calculate incidence and prevalence rates using population measures obtained from Statistics Norway. RESULTS: On January 1, 2018, the estimated prevalence was 335.8 (95% CI, 314.1-358.5) per 100,000 inhabitants, with a female:male ratio of 2.3. From 1950 through 2017, we observed a considerable (p < 0.001) increase in average annual incidence rates from 2.1 (95% CI, 1.3-3.3) to 14.4 (95% CI, 11.9-17.3) per 100,000. From 2005 through 2017, the incidence among women increased from 17.1 (95% CI, 14.0-20.7) to 23.2 (95% CI, 18.7-28.5) per 100,000, whereas the incidence among men declined from 10.3 (95% CI, 7.9-13.2) to 5.9 (95% CI, 3.4-8.8) per 100,000. CONCLUSION: Møre and Romsdal County in Western Norway has the highest prevalence of MS reported in Norway. The incidence has steadily increased since 1950, and during the latest 15 years, we observed opposing trends in sex-specific incidence rates.

Antiepileptic and psychiatric medication in a nationwide cohort of patients with glioma WHO grade II-IV.

INTRODUCTION: Glioma is the most common intracranial primary brain tumor. Patients with glioma often suffer from epilepsy, anxiety and depression. Aims of this study were to identify risk factors for drug-treated anxiety and depression, and to determine the use of psychiatric medication in a national glioma cohort. METHODS: Data from the Cancer Registry of Norway on all persons diagnosed with glioma WHO grade II-IV 2004-2010 were linked with data from the Norwegian Prescription Database. Cox regression analysis was used to assess risk factors for drug-treated anxiety and depression. Standardized incidence ratios were calculated for psychiatric medication dispensed to glioma patients and compared to the general population. RESULTS: The glioma cohort consisted of 1056 males and 772 females. Of the 1828 patients, 565 had glioma grade II-III, and 1263 had grade IV. The patients with glioma grade II-III who were treated with levetiracetam had an increased risk for drug-treated anxiety compared to patients without levetiracetam; hazard ratio 2.8 (95% confidence interval 1.7-4.9). Female gender increased the risk for drug-treated anxiety compared to males in patients with glioma grade IV; hazard ratio 1.5 (95% confidence interval 1.2-2.0). Antidepressants were less frequently dispensed to patients with glioma grade II-III and epilepsy than to the general population. CONCLUSIONS: Patients with glioma grade II-III on levetiracetam had an increased risk for drug-treated anxiety. The subgroup of patients with glioma grade II-III and epilepsy received less antidepressants than the general population.

Increased levels of cell-free mitochondrial DNA in the cerebrospinal fluid of patients with multiple sclerosis.

Mitochondrial DNA (mtDNA) can act as damage-associated molecular pattern molecule (DAMP) and initiate an inflammatory response. We hypothesized that the concentration of mtDNA might reflect inflammatory activity in multiple sclerosis and investigated therefore levels of cell-free mitochondrial DNA in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. Significantly higher levels of mtDNA were found in patients compared to controls and there was an inverse correlation between disease duration and mtDNA concentration. Our study suggests that mitochondria can be involved early in multiple sclerosis, but whether this is as an initiator of the inflammatory response or part of its maintenance is unclear. Further, our study suggests that changes in mtDNA may provide a novel marker for early disease activity.

The influence of coping styles on long-term employment in multiple sclerosis: A prospective study.

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.

Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway.

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71 °N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.

Month of birth as a latitude-dependent risk factor for multiple sclerosis in Norway.

OBJECTIVE: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient. METHODS: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose. RESULTS: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98-1.24), in Middle Norway 1.11 (0.97-1.27) and in Northern Norway 1.28 (1.0-1.63) compared with the other months. CONCLUSIONS: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

Risk of MS is not associated with exposure to crude oil, but increases with low level of education.

BACKGROUND: Offshore workers in the Norwegian upstream petroleum industry are exposed to a number of chemicals such as organic solvents, mineral oils and other hydrocarbons, possibly contributing to an increased risk of multiple sclerosis (MS). OBJECTIVE: To estimate the risk of MS in this population compared with the general working population in Norway, adjusting for education. METHODS: Using the Norwegian Registry of Employers and Employees we included all 27,900 offshore workers registered from 1981 to 2003 and 366,805 referents from the general working population matched by gender, age and community of residence. The cohort was linked to the Norwegian MS Registry and the Norwegian Education Registry. RESULTS: There was no increased risk of MS among the offshore workers. We found a marked and linear inverse relationship between level of education and the risk of MS in the total study population, with a rate ratio of 0.48 (95% CI, 0.53 to 0.88) for workers with a graduate degree compared to workers with elementary school only. CONCLUSIONS: These findings do not support a major aetiological role of petroleum-based products, but rather point to smoking and other lifestyle factors related to the level of education as being important for the risk of MS.

How long can you keep working with benign multiple sclerosis?

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.

Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.

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, Gjøvik 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.

Incidence, clinical features, treatment and outcome of primary central nervous system lymphoma in Norway.

The incidence of primary central nervous system lymphoma (PCNSL) has been reported to increase in some parts of the world, while being stable in other regions. In an attempt to characterize the incidence rate, clinical features, treatment, outcome, and prognostic factors of PCNSL in Norway, we report our experience in a large unselected series of patients. Clinical features, histological diagnosis, radiological findings, treatment, and outcome of all patients diagnosed with PCNSL in Norway in the years 1989-1998 were registered. During the 10-year period 58 new cases of histologically verified PCNSL were registered in Norway. The annual incidence rate of PCNSL was on average 1.34 cases per million people with a non-significant increasing trend (p=0.069). For patients diagnosed before death (n=45) the estimated survival following histological diagnosis was 55%, 47%, and 23% at 1, 2, and 5 years, respectively. In Cox-regression analysis age, WHO performance status and treatment had independent prognostic impact on survival. In the studied decade, there was a non-significant trend towards increased incidence of PCNSL, perhaps due to increased availability of diagnostic imaging, especially magnetic resonance imaging.