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There are two nationwide population-based registers for multiple sclerosis ( MS) in Denmark. The oldest register is The Danish Multiple Sclerosis Registry ( DMSR), which is an epidemiological register for estimation of prevalence and incidence of MS and survival, and for identifying exposures earlier in life that may affect the risk of MS. This register has no systematic follow-up data except for survival. The DMSR has over the years published nationwide incidence- and prevalence data from Denmark and has been involved in a number of 'historical prospective' studies to elucidate the association between a number of different environmental exposures in the past and the subsequent risk of MS. Some of these studies have been able to exonerate suspected risk factors. The other register, the nationwide Danish Multiple Sclerosis Treatment Register, is a follow-up register for all patients who have received disease-modifying treatments since 1996. It has, in particular, contributed to the knowledge of the role of antibodies against the biological drugs used for the treatment of MS. [ABSTRACT FROM AUTHOR]

Mason K, Thygesen LC, Stenager E, Brønnum-Hansen H, Koch-Henriksen N. Evaluating the use and limitations of the Danish National Patient Register in register-based research using an example of multiple sclerosis. Acta Neurol Scand: 2012: 125: 213-217. © 2011 John Wiley & Sons A/S. Background - The Danish National Patient Register, Landspatientregistret (LPR), is a register of all hospital discharges and outpatient treatments in Denmark. Aims - It is increasingly used in research so it is important to understand to what extent this can be used as an accurate source of information. Virtually all patients in Denmark with multiple sclerosis (MS) are reported to the Combined MS Registry (DMSR), so this was used as the standard which the LPR was compared against. Methods - All residents of Denmark are assigned a unique Civil Register (CPR) number; this was used to compare data between registers. The LPR completeness was estimated by the proportion of cases from the DMSR that could be retrieved from the LPR. The LPR validity was estimated by the proportion of cases, listed in the LPR and DMSR, in whom the MS diagnosis could be confirmed as definite/probable/possible by the DMSR. Results - We found that 86.9% of those who were DMSR listed with an approved MS diagnosis were also listed in the LPR with a MS diagnosis. The diagnosis was valid in 96.3% of patients listed in the LPR when compared against the DMSR. Conclusions - The low completeness reduces the usefulness of the LPR in epidemiological MS research, in particular incidence studies. The study also found that the completeness of the LPR could be increased to 92.8% by including LPR records from other departments in addition, but this reduced the validity of the LPR to 95.1%. However, these results cannot uncritically be applied to registration of other diseases in the LPR. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies of natalizumab (Tysabri®) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity. Patients and Methods: We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy. Results: During a median observation time of 11.3 months (range 3.0–21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with ≥2 relapses or sustained increase in EDSS of ≥2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab. Conclusions: Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment. [ABSTRACT FROM AUTHOR]

The Danish Multiple Sclerosis Registry was established in 1948 in continuation with a nationwide survey of the prevalence of Multiple Sclerosis (MS) in Denmark. The register has since collected information on MS patients from all Danish departments of neurology, practising neurologists, MS rehabilitation centres, the National Patient Registry, the Danish MS Society, and departments of neuropathology. The registry is linked with the Danish Central Population Registry. The completeness has been estimated at more than 90%. All cases are reclassified by two neurologists as to diagnosis and year of onset. 12 070 cases with a confirmed diagnosis of MS are kept in the databases. They were prevalent in 1949 or have had onset in the period 1948 – 1993. The registry is continuously updated with new information on registered cases and new cases. The crude average annual incidence rate 1980 – 89 was 4.99/10[sup 5]; the prevalence rate was 112/10[sup 5] by 1 January 1990. Cross-linking with other registers have enabled analytical prospective epidemiological studies, and the registry has provided population based unbiassed samples of patients for a number of clinical studies. [ABSTRACT FROM AUTHOR]

Examines the relation between chronic headache and nasal stenosis on nasal septum deformity in Denmark. Differences of treatment between the operative and control group; Decrease of headache manifested in the operative group; Difficulty of detecting effects of various treatments of chronic headaches.

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P. S. Sørensen has received personal compensation for consultations, serving on scientific advisory boards, steering committees, independent data-monitoring committees or have received honoraria as speaker from Merck, Novartis and TEVA. S. Bramow has received personal compensations from Biogen Denmark, Merck Denmark and Novartis Denmark for educational activities and received congress travel support from Novartis Denmark. M. Magyari has served in the scientific advisory board for Sanofi, Novartis and Merck and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme and Bristol Myers Squibb. L. Werdelin has nothing to declare. N. Koch-Henriksen has nothing to declare. P. Vermersch has received honoraria and congress travel support from Biogen, Sanofi Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science, Janssen and BMS-Celgene and research supports from Novartis, Sanofi Genzyme and Merck. F. Sellebjerg has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme.

Background: The course of multiple sclerosis (MS) appears to be milder in recent decades., Objective: To investigate how time from onset to disability milestones and how demographic and clinical characteristics have changed through subsequent onset cohorts of patients with MS., Methods: In the nationwide Danish Multiple Sclerosis Registry, we have registered all 13,562 Danish patients with onset of MS or clinically isolated syndrome from 1996 through 2020. For the analyses of prognosis, we used all cases with relapsing onset ( N  = 11,669). After stratification into 5-year onset cohorts, we computed the hazard ratios for disability endpoints for all cohorts having at least 10 years of follow-up and the oldest 1996-2000 onset cohort as reference., Results: Patients in more recent MS onset cohorts have a shorter diagnostic delay and more of them start disease-modifying treatment within 1 year since diagnosis. The prognosis was better for later onset cohorts. For the 2001-2005 cohort, the hazard ratio for confirmed Expanded Disability Status Scale (EDSS) 4 was 0.85 (95% confidence interval (CI), 0.76-0.95) and for confirmed EDSS 6: 0.76 (95% CI, 0.65-0.88). For the more recent 2006-2010 cohort, the corresponding hazard ratios were 0.70 (95% CI, 0.62-0.79) and 0.60 (95% CI, 0.50-0.71)., Conclusion: We observed a considerable improvement of the prognosis in recent onset cohorts of relapsing-onset MS.

Background: Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas., Methods: Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007-2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO)., Results: Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria., Conclusions: This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD., Competing Interests: Declaration of Competing Interest Dr. Papp has received support for scientific meetings from Merck and Sanofi Genzyme and honoraria for lecturing from Alexion. K. Trones has no conflict of interest. Dr. Magyari has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. Dr. Koch-Henriksen has received support for participation in congresses and symposia by Biogen, Merck, Novartis, Sanofi Genzyme, and Teva, and has received fee for lecturing by Novartis. Dr. Iljicsov has received support for congress participation and speaker honoraria from Biogen, Human Bioplazma, Merck, Novartis, Sanofi Genzyme and Teva. Dr. Rajda: congress invitation from Roche and Biogen; honoraria for lecturing from Teva. Dr. Nielsen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi-Genzyme, Biogen Denmark, Novartis, Merck. Dr. Lovas has no conflict of interest. Dr. Rozsa Dr has no conflict of interest. Kristiansen has no conflict of interest. Dr. Stenager has no conflict of interest. Dr. Frederiksen has received no funding to support the presented work. She has served on scientific advisory boards for and received funding, honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis and Almirall. Dr. Komoly has received honoraria for talks and payment for occasional consultancy or research funding from TEVA, Bayer-Schering, Merck, Biogen. Dr. Sellebjerg has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva. Dr. Petersen: research support to the MS clinic at Aarhus University Hospital from Merck, Alexion, Roche, Biogen, Novartis, Sanofi. Dr. Illes has served on scientific advisory boards, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, Merck, Roche, Sanofi Genzyme, and was a member of clinical endpoint committees in clinical trials of NMOSD but it has no conflict of interest with the current study., (Copyright © 2021. Published by Elsevier B.V.)

Background: The importance of environmental risk factors in the onset of multiple sclerosis (MS) has been studied extensively. Similarly, a growing number of studies address the importance of environmental factors, including seasonality, for ongoing activity of established disease. Specifically, past research demonstrates higher rates of relapse activity in summer months among individuals with MS. Our study adds to the existing literature on seasonality of disease relapse by analysing a large population-based and virtually complete cohort of patient with relapsing and remitting MS (RRMS) in an area of temperate climate., Methods: The Danish Multiple Sclerosis Registry includes follow-up for all patients receiving disease modifying treatment from 1996-2020, with near-complete registration of all relapses and their dates. We compared the observed and expected numbers of relapses for each calendar month and calculated month-specific annualized relapse rates (ARR) using Poisson regression. In addition, we analysed seasonal variation in disability as measured by the Expanded Disability Status Scale (EDSS)., Results: From 1996 to 2020 we followed 13,575 MS patients treated with disease modifying therapy (4165 men and 9410 women) for a total of 82,187 person years and 134,593 control visits. The mean age at entry was 41.1 years with standard deviation 10.9 years. We recorded 16,083 relapses throughout the observation period, and for 15,728 of the relapses the date of onset was known. Relapses were unevenly distributed by calendar month (p < 0.00001). The most prominent deviation was a paucity of relapses in July in which the ARR was 0.166 compared with mean of 0.191 for the whole year. Otherwise, the ARR formed a plateau slightly above mean during the spring months. Mean EDSS was slightly higher in autumn (2.78) than in spring (2.74), but there was no difference between winter and summer; p < 0.0001., Conclusion: In contrast with previous studies, we observed a nadir of relapses in July among Danish patients with RRMS. This finding may be related to increased exposure to sunlight in the summer, particularly during vacation when outdoor recreational activities are more frequent and potential exposure to infections is decreased. Confirmation of this in future studies is warranted., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: The Danish Multiple Sclerosis Registry is the oldest operative and nationwide MS registry. We present The Danish Multiple Sclerosis Registry with its history, data collection, scientific contribution, and national and international research collaboration., Materials and Methods: Detailed description of data collection, completeness, quality optimizing procedures, funding, and legal, ethical and data protection issues are provided., Results: The total number of registered cases with clinical isolated syndrome and multiple sclerosis since 1956 was by start of May 2020 30,023 of whom 16,515 cases were alive and residing in Denmark, giving a prevalence rate of about 284 per 100,000 population. The mean annual number of new cases receiving an MS diagnosis was 649 per year in the period 2010 to 2019. In total, 7,945 patients (48.1%) are receiving disease modifying therapy at the start of May 2020., Conclusions: Multiple Sclerosis registers are becoming increasingly important, not only for epidemiological research but also by quantifying the burden of the disease for the patients and society and helping health care providers and regulators in their decisions. The Danish Multiple Sclerosis Registry has served as data source for a number of scientific publications including epidemiological studies on changes in incidence and mortality, cohort studies investigating risk factors for developing MS, comorbidities and socioeconomic outcomes in the MS population, and observational studies on effectiveness of disease modifying treatments outside the narrow realms of randomized clinical trials., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: In multiple sclerosis (MS) the quantitative role of relapses in Expanded Disability Status Scale (EDSS) worsening beyond the recovery phase is not well known. Most studies have examined the predictive role of early relapses in more distant endpoints. Relapses and worsening may be associated because they could be independent effects of the same underlying disease characteristics without causal relationship. With the design of the present study we aim to estimate the direct effect on disability of relapses., Methods: We used data from the obligatory bi-annually registration in the Danish Multiple Sclerosis Registry of relapses and EDSS for all patients treated with disease modifying drugs for relapsing/remitting MS from 1996 to 2015 with exclusion of patients in whom no relapses had ever been recorded during treatment. We paired two consecutive control periods into study intervals which were the actual study units. Study intervals were qualified and included if they were at length 12-24 months, with EDSS ≤ 5.5 at start, and if a preceding relapse had been no closer than nine months to the EDSS assessment at the start or end of the study interval to eliminate relapse-related temporary EDSS worsening. We compared EDSS worsening in study intervals with and without relapses. The same patients could contribute with study intervals with and without relapses. For statistical analyses we used Generalized Estimating Equations to account for intra-patient correlations., Results: We analysed 5187 study intervals from 2015 MS patients. The mean of EDSS increase was 0.205 units in qualifying study intervals with relapses and 0.065 without relapses when adjusted for length of study interval, sex, and EDSS at start of interval; p < 0.0001. However, the effect of relapses on EDSS was absent in male patients (p = 0.521), and when EDSS was ≥ 4.0 at start of the study interval (p = 0.726)., Conclusion: Relapses play an independent and significant role for worsening of MS in patients under disease-modifying therapy (DMT) and eliminating relapses would not only free the patients from the temporary perils of relapses but would also reduce the worsening of the disease., (Copyright © 2019. Published by Elsevier B.V.)

Multiple sclerosis is a disease with a highly variable incidence worldwide. While knowledge about multiple sclerosis risk factors has grown over the years, the aetiology of multiple sclerosis has still not been fully established. We examined multiple sclerosis incidence rates among first-generation immigrants in Denmark, a high-incidence country, and their Danish-born children (second-generation immigrants), to evaluate the importance and timing of exposure to environmental factors in the aetiology of multiple sclerosis. By means of the Danish Civil Registration System we identified 9 121 187 individuals living in Denmark between 1968 and 2015, including 1 176 419 first-generation and 184 282 second-generation immigrants. Study participants were followed for multiple sclerosis in the Danish Multiple Sclerosis Registry from 1968 to 2015. The relative risk (RR) of multiple sclerosis according to immigration status was estimated by means of multiple sclerosis incidence rate ratios obtained in log-linear Poisson regression analysis. Altogether, 16 905 cases of multiple sclerosis were identified in the study cohort, 578 among first-generation and 106 among second-generation immigrants. Multiple sclerosis risk among first-generation immigrants whose parents were born in low, intermediate and high multiple sclerosis risk areas were 21% (RR = 0.21; 95% CI: 0.16-0.28), 43% (RR = 0.43; 95% CI: 0.36-0.50) and 75% (RR = 0.75; 95% CI: 0.67-0.83), respectively, of that among ethnic Danes (test for trend P < 0.0001). First-generation immigrants arriving in Denmark before age 15 years had a multiple sclerosis risk higher than that in their country of birth but lower than that in Denmark, reaching on average 69% of the multiple sclerosis risk among ethnic Danes (RR = 0.69; 95% CI: 0.55-0.87). Multiple sclerosis risk among individuals who came to Denmark at a later age remained closer to that of their country of birth, corresponding to 45% of the multiple sclerosis risk among ethnic Danes (RR = 0.45; 95% CI: 0.41-0.49). Our study supports the idea that environmental factors exerting their role in childhood or adolescence may be of aetiological relevance in multiple sclerosis., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Infections are suspected environmental triggers for multiple sclerosis (MS). The relationship between the timing and cumulative number of childhood infections regarding pediatric MS risk is uninvestigated., Objectives: To investigate whether childhood infections contribute to pediatric MS., Methods: A nationwide nested case-control study with detailed MS case ascertainment including chart review was undertaken. For each MS case, we selected five control children using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data with the cumulative number of childhood infections as exposure and MS as outcome. Hazard ratios (HRs) including 95% confidence intervals (CIs) were estimated using Cox regression., Results: We identified 212 children with MS and 1,060 controls. Median age at MS onset was 15.3 years (range: 7.6-17.8 years); 72% were girls. Each infection during the preceding 3 years increased the hazard for MS by 11% (95% CI = 1.01-1.22, p = 0.04); having 5+ infections compared with 0-4 infections in the preceding 3 years doubled the hazard for MS (HR: 2.18; 95% CI = 1.12-4.30, p = 0.02)., Conclusion: Children with MS appeared to have more infections in the 3 years preceding MS clinical onset; accordingly, immune response to infections may influence MS pathogenesis.

Objectives: To estimate the nationwide population-based incidence, prevalence, and geographical distribution of neuromyelitis optica (NMO) spectrum disorder (NMOSD) in Denmark based on the 2015 International Panel for NMO Diagnosis (IPND) criteria., Methods: We conducted a multicentre, historically prospective study. Data were sourced from the Danish National Patient Registry, the Danish Multiple Sclerosis Registry, departments of neurology, and laboratories providing aquaporin-4 antibody test. Cases were selected based on the 2006 Wingerchuk and the 2015 IPND criteria and were individually validated by an expert panel., Results: We confirmed NMO in 30 cases (2006 criteria) and NMOSD in 56 cases (2015 IPND criteria) between 2007 and 2014. Defined by the 2006 criteria, the incidence of NMO was 0.029 per 100,000 person-years (95% confidence interval [CI] 0.014-0.051), and the prevalence (aged 16 years and older) was 0.566 per 100,000 (95% CI 0.370-0.830). Based on the 2015 IPND criteria, the incidence of NMOSD was 0.070 per 100,000 person-years (95% CI 0.046-0.102), and the prevalence (aged 16 years and older) was 1.09 per 100,000 (95% CI 0.808-1.440), without regional differences., Conclusions: Our estimates of incidence and prevalence are similar to other Caucasian population-based studies using the 2015 IPND criteria. We found no geographical clustering in Denmark., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Aim: The International Paediatric Multiple Sclerosis Study Group (IPMSSG) has proposed criteria for acute disseminated encephalomyelitis (ADEM) not evaluated in clinical practice. Our objective was to assess epidemiological implications of the IPMSSG criteria for ADEM in a cohort study using prospectively collected data., Method: We identified all diagnosed cases of ADEM in Denmark between 2008 and 2015 from the Danish National Patient Register by International Classification of Diseases 10 codes assigned to acute demyelinating episodes, and we reviewed all medical records to validate ADEM., Results: We found 52 children up to the age of 18 years with a verified clinical diagnosis of ADEM (incidence rate 0.54/100 000 person-years; all had abnormal brain magnetic resonance imaging). Only 18 (35%) fulfilled the IPMSSG criteria regarding encephalopathy and polyfocal neurological deficits. Among all 52 children with ADEM, 33 per cent had clinical sequelae after a median follow-up of 4 years 6 months (range: 10mo-8y 3mo). Surprisingly, none progressed to multiphasic ADEM or multiple sclerosis, but median age at end of follow-up was only 10 years 9 months (range: 2y-24y 3mo)., Interpretation: Among 52 children with ADEM, none converted to multiphasic ADEM or multiple sclerosis (median follow-up: 4y 6mo; range: 10mo-8y 3mo). Applying the IPMSSG criteria to all children with a diagnosis of ADEM leaves 65 per cent of the cases without a diagnosis and lowers the incidence rate of paediatric ADEM., What This Paper Adds: The incidence of paediatric acute disseminated encephalomyelitis (ADEM) was 0.54 per 100 000 person-years in children younger than 18 years. Only 35 per cent of children with ADEM fulfilled the International Paediatric Study Group consensus criteria. ADEM in clinical practice was primarily based on magnetic resonance imaging findings. Paediatric neurologists diagnosed ADEM in the absence of encephalopathy. None of the children with ADEM progressed to multiple sclerosis/multiphasic ADEM during follow-up., (© 2018 Mac Keith Press.)

Background: The incidence of acquired demyelinating syndromes (ADS) including multiple sclerosis (MS) has never been investigated in a Danish pediatric population., Objectives: We estimated the nationwide age- and sex-specific incidence of pediatric ADS including MS., Methods: Data were sourced from the Danish Multiple Sclerosis Registry, providing cases of pediatric MS for 1977-2015, and the National Patient Register, providing cases of ADS during 2008-2015. All medical records were reviewed to validate the register-based diagnoses., Results: We identified 364 cases of pediatric MS occurring during 1977-2015 (incidence rate = 0.79 per 100,000 person-years). MS was exceptionally rare before puberty, but the incidence rose considerably from 9 years in girls and 11 years in boys. The female-to-male ratio was 2.5; the median age at onset was 16 years (range = 7-17 years). The MS incidence rate was relatively stable through the study period. During 2008-2015, we identified 219 ADS cases. The incidence was 2.29 per 100,000 person-years with considerable differences in the age peaks for the separate ADS., Conclusion: The incidence rates of MS and other ADS in Denmark were higher than those reported for some other European countries. Referral bias and classification differences may account for this disparity, in particular the age-intervals and the definition of onset.

Objective: To describe the pattern of development of incidence of multiple sclerosis (MS) over 60 years in Denmark with age-period-cohort analyses and seasonality of birth., Methods: Data on virtually all patients with onset of MS have since 1950 been prospectively recorded and kept in the Danish Multiple Sclerosis Registry with multiple sources of notification. Annualized incidence rates per 100,000 were directly standardized to the European Standard Population., Results: We have registered 19,536 cases with clinical onset of confirmed MS in Denmark from 1950 to 2009. From the 1950-1959 to the 2000-2009 onset period, incidence more than doubled in women, with an increase from 5.91 (95% confidence interval [CI]: 5.60-6.24) to 12.33 (95% CI: 11.91-12.75) per 100,000 per year compared with a modest 24% increase in men from 4.52 (95% CI: 4.24-4.81) to 6.08 (95% CI: 5.79-6.38). With age at onset of 50 years and older, incidence increased with a factor 4.30 in women and 2.72 in men. The female/male sex ratio increased over time and with year of birth. Age-period-cohort analysis revealed a significant birth cohort effect in addition to the age and period effect. We found no statistically significant seasonality of births., Conclusion: The incidence of MS has doubled in women, most pronounced with late onset, and has only modestly increased in men. Lifestyle changes in the female population that could include fewer childbirths, increased occurrence of obesity, and increased cigarette consumption may have a role., (© 2018 American Academy of Neurology.)

Background: Animal studies have suggested that drugs inhibiting the enzyme histone deacetylase might have a beneficial effect on multiple sclerosis (MS). Valproic acid (VPA), an anti-epileptic drug, is the only widely used human drug with a histone deacetylase inhibitory effect., Objective: The objective of this paper is to examine if VPA use is associated with a reduced risk of MS., Methods: We conducted a propensity score-matched cohort study in the period 1997-2011 linking nationwide register data on filled VPA prescriptions, MS cases, and several covariates. The VPA users were matched on propensity scores in a 1:4 ratio with non-users of VPA. Incidence rates of MS were compared among VPA users and non-users of VPA using Cox regression to estimate hazard ratios (HRs)., Results: Among 16 028 ever-users of VPA and 54 172 non-users, 18 and 26 cases of MS were identified, respectively. Neither current VPA users nor recent users of VPA, who had ceased VPA treatment within the last year, were at a reduced risk of MS compared with non-users of VPA (HR = 1.30 (95% confidence interval, 0.44-3.80), n = 4, and HR = 1.22 (0.28-5.32), n = 2, respectively). Similarly, in an intention-to-treat analysis, ever-users of VPA were not at reduced risk of MS (HR = 2.41 (1.32-4.43), n = 18)., Conclusion: In the first human study addressing a possible beneficial effect of VPA use on the risk of MS, we found no support for a protective effect. However, given the wide confidence intervals, only large effects can be ruled out with sufficient certainty., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Current knowledge concerning the association between exposure to stressful life-events (SFLEs) in childhood and later risk of multiple sclerosis (MS) is sparse., Objectives: We studied the associations between SFLEs in childhood and subsequent risk of MS in a nationwide cohort of 2.9 million Danes born from 1968 to 2011., Methods: A SFLE in childhood was defined as exposure before age 18 years to parental divorce, parental death, or death of a sibling, using information from the Danish Civil Registration System. MS cases in the cohort were identified in the Danish Multiple Sclerosis Registry. Associations of SFLE with MS risk were evaluated by incidence rate ratios (RR) of MS obtained in log-linear Poisson regression models., Results: Persons exposed to any SFLE in childhood were at 11% elevated risk of MS (RR = 1.11; 95% confidence interval: 1.03-1.20), compared to non-exposed persons. Stratification by subtype of SFLE showed that parental death and death of a sibling were not associated with MS risk. However, persons exposed to parental divorce were at 13% increased risk of developing MS compared to non-exposed (RR = 1.13; 1.04-1.23)., Conclusions: Associations of SFLEs in childhood with risk of MS are weak. However, parental divorce is somehow associated with modestly increased risk of MS., (© The Author(s), 2014.)

Objective: It is unclear whether psychological stress is associated with increased risk of multiple sclerosis (MS). We studied the association between major stressful life events and MS in a nationwide cohort study using death of a child or a spouse or marital dissolution as indicators of severe stress., Methods: We created two study cohorts based on all Danish men and women born 1950-1992. One cohort consisted of all persons who became parents between 1968 and 2010, and another cohort consisted of all persons who married between 1968 and 2010. Members of both cohorts were followed for MS between 1982 and 2010 using data from the National Multiple Sclerosis Registry. Associations between major stressful life events and risk of MS were evaluated by means of MS incidence rate ratios (RR) with 95% confidence interval (CI) obtained in Poisson regression analyses., Results: During approximately 30 million person-years of follow-up, bereaved parents experienced no unusual risk of MS compared with parents who did not lose a child (RR=1.12 (95% CI 0.89 to 1.38)). Likewise, neither divorced (RR=0.98 (95% CI 0.89 to 1.06)) nor widowed (RR=0.98 (95% CI 0.71 to 1.32) persons were at any unusual risk of MS compared with married persons of the same sex., Conclusions: Our national cohort study provides little evidence for a causal association between major stressful life events (as exemplified by divorce or the loss of a child or a spouse) and subsequent MS risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The incidence of multiple sclerosis (MS) in Denmark has doubled in women since 1970, whereas it has been almost unchanged in men. The rapid epidemiological changes suggest that environmental factors may modify the risk of MS., Objectives: To investigate whether occupational, physical, or social environmental influence the risk of MS differently in women than in men., Methods: The cohort consists of all 1403 patients (939 women, 464 men) identified through Danish Multiple Sclerosis Registry aged 1-55 of years at clinical onset between 2000 and 2004, and up to 25 control persons for each case, matched by sex, year of birth and residential municipality. The same cohort was previously used to investigate the influence of the reproductive factors on the risk of MS., Results: By linkage to Danish population registers we found a slight albeit statistically significant excess for 6 female MS patients who had been employed in agriculture: OR 3.52; 95% CI 1.38-9.00, p=0.008 (0.046 when corrected for multiple significance) and a trend for exposure to outdoor work in 12 : OR 1.94, 95% CI 1.06-3.55, p=0.03 (0.09 when corrected for multiple significance), but the numbers of cases were small, and the effects were not found in men. Educational level, housing conditions in youth, or the presence of children unrelated by blood in the household did not influence the risk of MS., Conclusions: Our study did not reveal any additional factors beyond the previously published childbirths which could explain the extent of the MS incidence increase in women., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3-12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval [CI] 0.88-1.00), 0.47 (95 % CI 0.43-0.52) during natalizumab therapy, 0.63 (95 % CI 0.51-0.76) 1-6 months after natalizumab and 0.55 (95 % CI 0.42-0.70) 7-12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.

Background and Purpose: Case reports have observed a co-occurrence of multiple sclerosis (MS) and Parkinson's disease (PD) and it has been hypothesized that MS lesions could affect dopaminergic pathways causing parkinsonism. Our aim was to examine the association between MS and PD in a historically prospective cohort study using Danish nationwide register data., Methods: Multiple sclerosis patients identified in the Multiple Sclerosis Registry were followed for PD from 1977 to 2011 in the National Patient Register. As measures of relative risk, ratios of observed to expected incidence rates of first hospitalization for PD amongst persons with MS were used, i.e. standardized incidence ratios (SIRs) with 95% confidence intervals (CIs)., Results: Amongst 15,557 MS patients 26 cases of PD were observed versus 26.51 expected, reflecting no overall increased risk of PD (SIR 0.98, 95% CI 0.67-1.44). Similar estimates were seen for female (SIR 0.99, 95% CI 0.58-1.67) and male MS patients (SIR 0.97, 95% CI 0.55-1.72). Likewise, no increased risk of PD amongst MS patients was observed in a robustness analysis backdating the date of diagnosis of PD by 5 years to account for the time lag between disease onset and first hospital contact with PD (SIR 0.57, 95% CI 0.32-1.00)., Conclusion: Our data do not suggest an increased risk of PD amongst patients with MS., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Background: The incidence of multiple sclerosis (MS) in Denmark has doubled in women since 1970, whereas it has been almost unchanged in men., Objectives: To investigate whether age at first childbirth and number of births have an effect on the risk of developing MS., Methods: The cohort consisted of 1403 patients with MS of both sexes, identified through the Danish Multiple Sclerosis Registry, with clinical onset between 2000 and 2004. For each case, 25 control persons were drawn by random from the Danish Civil Registration System matched by sex, year of birth, and residential municipality., Results: More female cases than controls had no childbirths or fewer births before clinical onset (p=0.018) but only in the last five years preceding onset (p<0.0001). Childbirths within five years before clinical onset reduced the risk of MS onset in women: OR=0.54 (95% CI 0.41-0.70, p<0.0001) for one child and OR=0.68 (95% CI 0.53-0.87, p=0.002) for more than one child. Parental age at first childbirth had no effect on the risk of MS., Conclusions: The data did not suggest reversed causality between childbirth and MS.

Background: Apart from a recent study reporting a 2- to 3-fold increased risk of multiple sclerosis (MS) among women and men who were delivered by Cesarean section (C-section), little attention has been given to the possible association between mode of delivery and the risk of MS., Objectives: We studied the association between C-section and risk of MS, in a cohort of 1.7 million Danes born from 1973 to 2005., Methods: Information on C-section and MS was obtained from the Danish Medical Birth Register and the Danish MS Register, respectively. The association between C-section and MS was evaluated by means of MS incidence rate ratios (RR) with 95% confidence intervals (CI) obtained in log-linear Poisson regression analyses., Results: There were 930 cases of MS in the study cohort, of whom 80 (9%) were delivered by C-section. Overall, we found there was no significant association between C-section and risk of MS (RR = 1.17; 0.92-1.46). Analyses stratified by sex revealed no unusual risk of MS for women (RR = 1.08: 0.80-1.42) nor men (RR = 1.37: 0.91-1.98). A supplementary sibling-matched Cox regression analysis likewise suggested there was no excess risk of MS in persons delivered by C-section (HR = 1.03; 0.63-1.69)., Conclusions: Mode of delivery appears to be unimportant in relation to MS development in the offspring.

In a national cohort comprising 1.5 million Danes born from 1966 to 1992, we studied the association between childhood socioeconomic status (SES) and the risk of multiple sclerosis (MS) from 1981 to 2007 using information about household income and parental educational levels at the person's 15th birthday. The association between childhood SES and MS was evaluated using MS incidence rate ratios with 95% confidence intervals obtained in log-linear Poisson regression analyses. We found no strong association between childhood SES and MS but did observe a tendency toward a reduced risk of MS among children from households with more highly educated parents, particularly mothers. Children whose mothers had a secondary (rate ratio = 0.95, 95% confidence interval: 0.86, 1.04) or higher (rate ratio = 0.86, 95% confidence interval: 0.76, 0.97) education had reduced risks of MS (5% and 14%, respectively) compared with children of mothers with a basic education (P for trend = 0.02). Results were practically unchanged in an analysis restricted to persons aged 15-29 years, among whom the possible effect of own SES on MS risk is considered limited. Overall, SES in childhood seems of no major importance for the subsequent risk of MS; however, offspring of well-educated mothers may be at a slightly reduced risk of MS.

Background: Patients with multiple sclerosis (MS) are potentially at high risk of fracture due to falls and osteoporosis., Objective: To estimate incidence rates of fractures in MS patients, stratified by fracture type, sex and age, and to compare these rates with controls., Methods: The case population consisted of all patients with an accepted diagnosis of MS in the Danish MS Registry (1949-2007). Data were linked to the National Hospital Discharge Register (1977-2007). Patients with MS (n = 11,157) were 1:6 matched by year of birth, gender, calendar time and region to persons without MS (controls). Incidence rates of fracture were estimated as the number of fractures per 1000 person-years. Incidence rate ratios (IRRs) were calculated by dividing fracture rates in MS patients by fracture rates in controls., Results: Among patients with MS, the incidence rate of any fracture yielded 22.8 per 1000 person-years. The IRR of any fracture between MS patients and controls was 1.40 (95% CI 1.33-1.46). In particular, IRRs of tibia fracture (3.36 [2.75-4.11]), femur fracture (6.66 [5.06-8.76]) and hip fracture (3.20 [2.83-3.62]) were elevated in MS patients versus controls., Conclusion: Fractures occurred more often in patients with MS, especially fractures of the tibia, hip and femur.

Introduction: The claim of detection of several environmental risk factors for multiple sclerosis (MS), some of them new, makes the research of population-based MS registers for critical review or confirmation of alleged associations more relevant than ever before., Aims: To present examples of the use and important contributions from the Danish MS Registry (DMSR) over decades., Methods: The DMSR has through more than six decades registered virtually all patients with MS in Denmark, using multiple sources of notification and has been used for descriptive epidemiology, follow-up studies, studies of comorbidity and 'historical prospective' studies of proposed risk factors for MS., Results: Based on research from DMSR, we have found that female incidence of multiple sclerosis in Denmark has increased considerably; that patients with MS loose their working ability and their spouses/partners at a much higher rate than the background population; that patients with MS have a considerable excess mortality which seem to have decreased over several centuries decades - not centuries, also before the era of disease modifying treatment; that fewer patients with MS than expected from the population get diagnosed with or die from cancer; that infectious mononucleosis increases the risk of MS; that head trauma and a number of occupational exposures, for example, nurses, utility workers, exposure to solvents do not carry an enhanced risk of MS., Conclusion: The DMSR has, as an example of long-lasting population-based registers, proven to be an effective tool for studying MS epidemiology. In future, the need for this kind of registers will continue, as biology or immunology cannot stand alone., (© 2012 John Wiley & Sons A/S.)

A 2006 study from the United Kingdom found that penicillin use may decrease the risk of multiple sclerosis (MS). To confirm this finding, the authors conducted a nationwide case-control study in Denmark, using the Danish Multiple Sclerosis Registry to identify 3,259 patients with MS onset from 1996 to 2008, and selected 10 population controls per case (n = 32,590), matched on sex and age. Through the National Prescription Database, prescriptions for antibiotics redeemed from 1995 to 2008 and before the date of first MS symptom/index date were identified. Conditional logistic regression analysis was used to compute odds ratios associating antibiotic use with MS occurrence. In total, 1,922 patients (59%) redeemed penicillin prescriptions before the index date and 2,292 (70%) redeemed any type of antibiotic prescription. Penicillin use was associated with an increased risk of MS (odds ratio = 1.21, 95% confidence interval: 1.10, 1.27). Use of any type of antibiotic was similarly associated with an increased risk of MS (odds ratio = 1.41, 95% confidence interval: 1.29, 1.53). The odds ratios for different types of antibiotics ranged between 1.08 and 1.83. Thus, this study found that penicillin use and use of other antibiotics were similarly associated with increased risk of MS, suggesting that the underlying infections may be causally associated with MS.

Introduction: The Danish Multiple Sclerosis (MS) Registry was established in 1956., Content: The register comprises data on all Danes who had MS in 1949 or who have been diagnosed since. Data on new cases and updated information on persons with an MS diagnosis already notified are continuously collected and classified according to standardized diagnostic criteria., Validity and Coverage: The completeness and validity is high (91% and 94%, respectively)., Conclusion: In January 2005 the register included data on 20,652 persons with a valid MS diagnosis, of whom 9,377 were alive. The register is the only existing nationwide MS register and covers a period of more than 50 years.

Introduction: This paper reviews the most important articles using data from the Danish Multiple Sclerosis Registry (DMSR) published in the past 25 years., Research Topics: These articles include: descriptive epidemiological studies, indicating that the female incidence of multiple sclerosis (MS) in Denmark has increased considerably; follow-up studies on social events, showing that patients at a high rate lose their working ability and their spouses/partners; mortality studies, demonstrating a considerable excess mortality; cause-of-death studies; comorbidity studies; and, most importantly, historical prospective studies identifying some risk factors (e.g. infectious mononucleosis) and refuting others (head trauma and a number of occupational exposures e.g. nurses, utility workers, people exposed to solvents). The most important results are briefly presented., Conclusion: The Danish MS register has proven to be a valuable tool for MS epidemiology and has provided knowledge that could not otherwise be achieved.

Background: Time to disability pension is one of the endpoints to be used to determine the prognosis of multiple sclerosis (MS) in prospective studies., Objective:   To assess the time to cessation of work and receiving disability pension in MS, and how it may depend on gender, type of work and age and symptom at onset., Method: A total of 2240 Danes with onset of definite/probable MS 1980-1989, identified from the Danish MS-Registry, were included. Information on social endpoints was retrieved from Statistics Denmark. Cox regression analyses were used with onset as starting point., Results: Afferent onset symptoms [hazard ratio (HR 0.57)] and non-physical type of work (HR 0.70) were favourable prognostic factors compared with high age at onset, physical work and efferent symptoms at onset. The mean time to disability pension was 13 years for patients with afferent/brainstem onset symptom but 8.7 years for those with efferent onset symptoms (P < 0.0001). The effect of onset symptom was reduced and the effect of sex became significant when all covariates and age at onset were included in multivariate Cox regression., Conclusions: Onset age, type of onset symptom and work are robust predictors of disability pension in MS. Disability pension proves to be a reliable milestone in estimation of the prognosis of MS., (© 2010 The Author(s). Journal compilation © 2010 EFNS.)

Background: There is a need for follow-up studies of the familial situation of multiple sclerosis (MS) patients., Objectives: To evaluate the probability of MS patients to remain in marriage or relationship with the same partner after onset of MS in comparison with the population., Patients and Methods: All 2538 Danes with onset of MS 1980-1989, retrieved from the Danish MS-Registry, and 50,760 matched and randomly drawn control persons were included. Information on family status was retrieved from Statistics Denmark. Cox analyses were used with onset as starting point., Results: Five years after onset, the cumulative probability of remaining in the same relationship was 86% in patients vs. 89% in controls. The probabilities continued to deviate, and at 24 years, the probability was 33% in patients vs. 53% in the control persons (p < 0.001). Among patients with young onset (< 36 years of age), those with no children had a higher risk of divorce than those having children less than 7 years (Hazard Ratio 1.51; p < 0.0001), and men had a higher risk of divorce than women (Hazard Ratio 1.33; p < 0.01)., Conclusion: MS significantly affects the probability of remaining in the same relationship compared with the background population.

Multiple sclerosis is an inflammatory disease of the central nervous system of unknown aetiology. Its prevalence varies by ethnicity and place: persons of northern European descent are at increased risk while persons living at lower latitudes appear to be protected against the disease. The Danish Multiple Sclerosis Registry is a national registry established in 1956 after a population-based survey which receives information from numerous sources. It is considered to be more than 90% complete, with a validity of 94%. Using data from the Registry, we calculated prevalences per 100,000 inhabitants. The standardized prevalence of multiple sclerosis increased from 58.8 (95% confidence interval: 54.9-62.7) in 1950 to 154.5 per 100,000 (95% confidence interval: 148.8-160.2) in 2005, and the female to male ratio increased from 1.31 in 1950 to 2.02 in 2005. The increase in prevalence is due to both increased survival of multiple sclerosis patients and an increased incidence rate. The rise in prevalence in the past 50 years is probably due more to environmental factors than to genetic changes in the Danish population. Among women, environmental changes could include older age at first birth, use of oral contraceptives, or changes in sun behaviour and/or vitamin D status.

Multiple sclerosis affects young and middle-aged people and often leads to physical and cognitive handicaps. There is a need for detailed knowledge of the social consequences of the disease. We aim here to describe the course of the working life and career of multiple sclerosis patients at the time of onset and thereafter, in terms of probability of early pension and income development. All 2538 patients with multiple sclerosis in Denmark with disease onset between 1980 and 1989, identified through the Danish MS-Registry, were included in this study. Twenty matched control persons per patient were randomly drawn from the civil registration system. Information on economic status was retrieved from Statistics Denmark. A survival analysis technique was used with onset as the starting point. We found that the probability of remaining without early pension was at 5 years 70% for patients and 97% for controls, and at 20 years 22% for patients and 86% for controls. Due to lower rates for early pension, gross income with time was lower in patients than controls. We conclude that multiple sclerosis seriously affects the economic life of multiple sclerosis patients, even within a few years of onset.

Background: Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study., Methods: Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs., Results: Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4-2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7-27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4-0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3-0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn's disease (RR = 1.4 (CI: 1.04-1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99-1.7), n = 51), Addison's disease (RR = 3.4 (CI: 1.3-9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4-10.0), n = 4)., Patients: with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

Neutralising antibodies (NAbs) against interferon (IFN)-beta reduce the treatment effect in multiple sclerosis (MS). However, data from pivotal trials of IFN-beta in MS suggest that NAb-positive patients may have a reduced relapse rate during the first six to 12 months of therapy. We collected clinical data and plasma samples for NAb measurements prospectively, every six months, in 468 patients treated with the same IFN-beta preparation for at least 24 months. NAbs were measured blindly with a cytopathic effect (CPE) assay. During treatment months 0-6, patients who became NAb-positive had significantly fewer relapses compared to patients who maintained the NAb-negative status, whereas the opposite was observed after month 6. This is in accordance with observations in randomised studies of the three different IFN-beta preparations, showing that patients who become NAb-positive have lower relapse rates during the first six or 12 months of therapy. We hypothesise that low affinity NAbs, present early after the start of IFN-beta therapy, though neutralising in vitro in sensitive assays increase the half-life of IFN-beta in vivo and, thereby, enhance the therapeutic effect. With affinity maturation, NAbs effectively prevent IFN-beta binding to its receptors also in vivo and, hence, abolish the treatment effect.

Background: Infectious mononucleosis caused by the Epstein-Barr virus has been associated with increased risk of multiple sclerosis. However, little is known about the characteristics of this association., Objective: To assess the significance of sex, age at and time since infectious mononucleosis, and attained age to the risk of developing multiple sclerosis after infectious mononucleosis., Design: Cohort study using persons tested serologically for infectious mononucleosis at Statens Serum Institut, the Danish Civil Registration System, the Danish National Hospital Discharge Register, and the Danish Multiple Sclerosis Registry., Setting: Statens Serum Institut., Patients: A cohort of 25 234 Danish patients with mononucleosis was followed up for the occurrence of multiple sclerosis beginning on April 1, 1968, or January 1 of the year after the diagnosis of mononucleosis or after a negative Paul-Bunnell test result, respectively, whichever came later and ending on the date of multiple sclerosis diagnosis, death, emigration, or December 31, 1996, whichever came first., Main Outcome Measure: The ratio of observed to expected multiple sclerosis cases in the cohort (standardized incidence ratio)., Results: A total of 104 cases of multiple sclerosis were observed during 556,703 person-years of follow-up, corresponding to a standardized incidence ratio of 2.27 (95% confidence interval, 1.87-2.75). The risk of multiple sclerosis was persistently increased for more than 30 years after infectious mononucleosis and uniformly distributed across all investigated strata of sex and age. The relative risk of multiple sclerosis did not vary by presumed severity of infectious mononucleosis., Conclusions: The risk of multiple sclerosis is increased in persons with prior infectious mononucleosis, regardless of sex, age, and time since infectious mononucleosis or severity of infection. The risk of multiple sclerosis may be increased soon after infectious mononucleosis and persists for at least 30 years after the infection.

Background: Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported., Objective: To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS., Design, Setting, and Participants: Two population-based disease registers, the Danish Hospital Discharge Register and the Danish Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil Registration System., Main Outcome Measure: Patients with T1D and first-degree relatives of patients with MS were followed up for occurrence of MS and T1D, respectively, and the relative risks were expressed as standardized incidence ratios, that is, ratios of observed to expected numbers of outcomes based on national age, sex, and period-specific MS and T1D incidence rates., Results: Patients with T1D were at more than 3-fold increased risk for development of MS (relative risk, 3.26; 95% confidence interval, 1.80-5.88; n = 11). First-degree relatives of patients with MS were at 63% increased risk (relative risk, 1.63; 95% confidence interval, 1.26-2.12; n = 56) for development of T1D. However, adjusting for familial relationship to patients with T1D reduced the excess risk to 44% (relative risk, 1.44; 95% confidence interval, 1.11-1.88; n = 56)., Conclusion: The present nationwide cohort study demonstrates an intraindividual and, to a lesser degree, an intrafamilial co-occurrence of MS and T1D.

It has been hypothesized that age at infection with a common microbial agent may be associated with the risk of multiple sclerosis (MS). The authors addressed this hypothesis by using number of older siblings and other sibship characteristics as an approximation of age at exposure to common infections. Data on family characteristics and vital status from the Danish Civil Registration System were used to establish a cohort of all Danes whose mothers had been born in Denmark since 1935. Persons diagnosed with MS during the period 1968-1998 were identified through linkage with the Danish Multiple Sclerosis Register. The cohort of 1.9 million Danes was followed for 28.1 million person-years; during that time, 1,036 persons developed MS. Overall, there was no association between number of older siblings, number of younger siblings, total number of siblings, age distance from the nearest younger sibling, or exposure to younger siblings under 2 years of age and risk of MS later in life. There was no association of MS risk with multiple birth (vs. singleton birth) or with the age of the mother or father at birth. These results do not lend support to the hypothesis that number of older siblings or any of the other sibship characteristics studied is associated with risk of MS.

We compared the rate of fatal accidents among Danes with multiple sclerosis (MS) with that of the general population. The study was based on linkage of the Danish Multiple Sclerosis Registry to the Cause of Death Registry and covered all 10174 persons in whom MS was diagnosed during the period 1953-1996. The end of follow-up was 1 January 1999. We calculated standardized mortality ratios (SMRs) for various types of fatal accidents. A total of 76 persons (48 men and 28 women) died from accidents, whereas the expected number of fatalities from such causes was 55.7 (31.4 men and 24.3 women). Thus, the risk for death from accidents among persons with MS was 37% higher than that of the general population (SMR = 1.37). We found no significant excess risk for fatal road accidents (SMR = 0.80). The risk for falls was elevated (SMR = 1.29) but not statistically significantly so. The risks were particularly high for deaths from burns (SMR = 8.90) and suffocation (SMR = 5.57). We conclude that persons with MS are more prone to fatal accidents than the general population. The excess risk is due not to traffic accidents but to burns and suffocation.

Objective: The aim of the present study was to provide data on the use of immunomodulatory therapies in a population comprising all treated patients with relapsing-remitting multiple sclerosis (RRMS) in Denmark., Patients and Methods: From the introduction of immunomodulatory therapy in Denmark in 1996 through 2003, all patients that started immunomodulatory therapy were followed prospectively with neurological examination and standard laboratory tests every six months, and clinical data were reported to the MS Treatment Register, including relapses, Expanded Disability Status Scale scores and side effects., Results: From 1996 through 2003 in all 2393 patients had started immunomodulatory therapy for RRMS, of whom 1252 (52.3%) were still on therapy with the same product at follow-up on 1 January 2005, whereas 1141 patients had discontinued or changed immunomodulatory therapy. Multiple Cox regression analysis of the risk of suffering a relapse showed a hazard ratio of 1.48 in patients with three or more relapses in the 24 months prior to onset compared with patients with two relapses or less; the hazard ratio was 0.84 in patients with age 238 years at treatment start compared with patients of age <38, and 1.17 for females compared with males. For disease progression the hazard ratio was 1.24 for age =38 years compared with age 2 37 years. Significant differences were observed in the hazard ratios between the different preparations, probably due to selection bias., Conclusion: The response to immunomodulatory therapy can be predicted to some extent from demographic variables. Differences between preparations can mainly be ascribed to selection bias, and open studies are not suited for comparison of efficacy between different preparations.

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population-based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population-based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live-born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person-years of follow-up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89-1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94-1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05-1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.

Objective: To compare the suicide risk among Danish citizens with multiple sclerosis with that of the general population, and to evaluate changes over 45 years., Methods: The study was based on linkage of the Danish Multiple Sclerosis Registry to the Cause of Death Registry. It comprised all 10,174 persons in whom multiple sclerosis was diagnosed in the period 1953 to 1996. The end of follow up was 1 January 1999. Standardised mortality ratios (SMRs) were calculated for various times after diagnosis and for age and calendar period of diagnosis., Results: In all, 115 persons (63 men, 52 women) had taken their own lives, whereas the expected number of suicides was 54.2 (29.1 men, 25.1 women). Thus the suicide risk among persons with multiple sclerosis was more than twice that of the general population (SMR = 2.12). The increased risk was particularly high during the first year after diagnosis (SMR = 3.15)., Conclusions: The risk of suicide in multiple sclerosis was almost twice as high as expected more than 20 years after diagnosis. The excess suicide risk has not declined since 1953.