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Melinda Magyari,1,3 Nils Koch-Henriksen,1,2 Per Soelberg Sørensen3 1Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen, 2Department of Clinical Epidemiology, Clinical Institute, University of Aarhus, Aarhus, 3Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Aim of the database: The Danish Multiple Sclerosis Treatment Register (DMSTR) serves as a clinical quality register, enabling the health authorities to monitor the quality of the disease-modifying treatment, and it is an important data source for epidemiological research. Study population: The DMSTR includes all patients with multiple sclerosis who had been treated with disease-modifying drugs since 1996. At present, more than 8,400 patients have been registered in this database. Data are continuously entered online into a central database from all sites in Denmark at start and at regular visits. Main variables: Include age, sex, onset year and year of the diagnosis, basic clinical information, and information about treatment, side effects, and relapses. Descriptive data: Notification is done at treatment start, and thereafter at every scheduled clinical visit 3 months after treatment start, and thereafter every 6 months. The longitudinally collected information about the disease activity and side effects made it possible to investigate the clinical efficacy and adverse events of different disease-modifying therapies. Conclusion: The database contributed to a certain harmonization of treatment procedures in Denmark and will continue to be a major factor in terms of quality in clinical praxis, research and monitoring of adverse events, and plays an important role in research. Keywords: multiple sclerosis, epidemiology, immunomodulatory treatment, neutralizing antibodies, observational studies, registry research, disease modifying therapy

Background and purpose: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria. Methods: A retrospective population‐based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re‐evaluation from multiple sources. Crude and sex‐ and serostatus‐specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person‐years) from 2006 to 2015 were estimated and age‐adjusted rates were determined. Results: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52–2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person‐years provided an incidence rate of 1.32 (95% CI 1.08–1.61) per 1 000 000 person‐years. Age‐adjusted prevalence was 1.87 (95% CI 1.56–2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98–1.46) per 1 000 000 person‐years. Conclusions: In this first report of a large population‐based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations. [ABSTRACT FROM AUTHOR]

Background: Subtypes of white blood cell counts are known biomarkers of systemic inflammation and a high neutrophil-to-lymphocyte ratio (NLR) has been associated with several autoimmune diseases. Few studies have investigated the NLR in multiple sclerosis (MS). Objective: To examine the association between NLR, MS and disability measured by the MS severity score (MSSS). Methods: Patients were included from the Danish Multiple Sclerosis Biobank. Information on patient NLR was obtained just before their first treatment and clinical information was provided by the Danish Multiple Sclerosis Treatment Register. Information on NLR from controls was collected from the Danish Blood Donor Study. Patients and controls were 1:2 propensity score matched by baseline confounders. Results: Propensity score matching left 740 of 743 MS patients and 1420 of 4691 controls for further analyses. Odds-ratio (OR) was 3.64 (95% confidence interval 2.87-4.60, p<0.001) for MS disease per unit increase of logarithmically transformed NLR (ln-NLR), corresponding to an OR of 2.68 for each doubling of NLR. Mean NLR was 2.12 for patients and 1.72 for controls (p<0.001). Ln-NLR correlated weakly with patient MSSS (R²=0.019, p = 0.008). Conclusion: Patients with early MS had increased levels of NLR compared to healthy controls and NLR was weakly correlated with MSSS. [ABSTRACT FROM AUTHOR]

Background and purpose: To assess long‐term treatment effectiveness of disease‐modifying therapy (DMT) initiated early in disease course versus later treatment start. Methods: We included all Danish patients with multiple sclerosis (MS) treated with DMT through two nationwide population‐based MS registries. Patients were categorized as early treated if treatment started within 2 years after the first MS symptom (n = 2316) and later treated if treatment started between 2 and 8 years after clinical onset (n = 1479). We compared time from treatment start to progression to an Expanded Disability Status Scale (EDSS) score of 6 and mortality between cohorts as hazard ratio (HR) using a Cox proportional hazards model with adjustment for stabilized inverse probability of treatment weights. Several sensitivity analyses were conducted. Results: The median follow‐up time of 3795 patients was 7.0 (range 0.6–19.5) years for the EDSS score of 6 outcome and 10.4 (range 1.2–20.1) years for the mortality outcome. Patients with later treatment start showed a 42% increased hazard rate of reaching an EDSS score of 6 compared with the early‐treated patients [HR, 1.42; 95% confidence interval (CI), 1.18–1.70; P < 0.001]. When stratified by sex, the increased hazard among later‐treated women persisted (HR, 1.53; 95% CI, 1.22–1.93; P < 0.001), whereas the HR was lower in men (1.25; 95% CI, 0.93–1.69; P = 0.15). Mortality was increased by 38% in later starters (HR, 1.38; 95% CI, 0.96–1.99; P = 0.08). Conclusions: Patients who started treatment with DMT later reached an EDSS score of 6 more quickly compared with patients who started early and the delay showed a tendency to shorten time to death. Our results support the use of early treatment. [ABSTRACT FROM AUTHOR]

Background and purpose The social and economic consequences of comorbidity in multiple sclerosis ( MS) are largely unexplored. Differences were investigated in income and in the rate of broken relationships between cases of MS with and without chronic comorbidity. Methods We conducted a nationwide cohort study including all incident cases of MS in Denmark with clinical MS onset between 1980 and 2005. The difference in income was investigated at MS onset and 5 and 10 years after MS onset. The difference in the rate of broken relationships was investigated in subjects who were in a relationship at MS onset or who entered a relationship after MS onset. We used logistic, multiple linear and Poisson regression analyses. Results Cases of MS with somatic comorbidity had increased odds of low incomes both 5 years {odds ratio ( OR), 1.41 [95% confidence interval ( CI), 1.19-1.67; P < 0.0005]} and 10 years [OR, 1.37 (95% CI, 1.17-1.60); P < 0.0005] after MS onset. The odds of a low income with psychiatric comorbidity was increased 10 years after MS onset [OR, 3.06 (95% CI, 1.47-6.37); P = 0.003]. The rate of broken relationships was increased in cases of MS with any somatic comorbidity [incidence rate ratio, 1.46 (95% CI, 1.32-1.61); P < 0.0005]. Conclusions Our results underscore the burden of comorbidity in MS on patients, their partners and society. [ABSTRACT FROM AUTHOR]

Background Initiation of fingolimod treatment is associated with a transient decrease of heart rate, and atrioventricular ( AV) conduction block may occur. Objective To evaluate the therapeutic effect and safety of fingolimod treatment in MS patients in Denmark with focus on cardiac and pulmonary side effects at treatment onset. Materials & methods We analysed data from the first 496 fingolimod-treated Danish patients, observed for at least 3 months. In a subset of 204 patients, we monitored cardiac and pulmonary adverse effects following treatment initiation. Results The overall annualized relapse rate ( ARR) was 0.37 (95% CI 0.31-0.44); 0.22 (95% CI 0.03-0.81) in de novo-treated patients, 0.29 (95% CI; 0.23-0.37) in patients switching from IFN-beta or GA and 0.46 (9 5% CI 0.34-0.60) after natalizumab. In the subset of 204 patients, 8 (3.9%) required prolonged cardiac monitoring due to bradycardia and/or second-degree AV block type I. All patients recovered spontaneously. Two patients discontinued fingolimod. Eleven (5.4%) patients reported respiratory complaints and two of these patients discontinued treatment. Conclusions Fingolimod appears to be safe and effective in MS patients in a clinical setting. Mild cardiac adverse effects occurred at a similar rate as in clinical trials. [ABSTRACT FROM AUTHOR]

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]

Objective The chemokine receptor CCR5 may be important for the recruitment of pathogenic T cells to the CNS in multiple sclerosis ( MS). We hypothesized that this chemokine receptor might still be important for T-cell migration during treatment with anti-very late antigen ( VLA)-4 antibody. We therefore analysed whether natalizumab-treated MS patients carrying the CCR5 Δ32 deletion allele, which results in reduced expression of CCR5 on the cell surface, had lower disease activity. Methods CCR5 Δ32 was analysed in 212 natalizumab-treated MS patients. Results CCR5 Δ32 status had no significant impact on the frequency of relapses 1 year prior to natalizumab treatment or during the first 48 weeks of treatment. The multiple sclerosis severity score ( MSSS) was significantly lower at baseline in patients carrying CCR5 Δ32 ( P = 0.031). Conclusions CCR5 Δ32 is not associated with lower disease activity in MS patients treated with natalizumab. We found lower MSSS scores in patients carrying CCR5 Δ32 compared with the remaining patients, which is consistent with previous studies reporting an association with a more favourable disease course. Further studies are, however, needed before the relationship between CCR5 Δ32 and disease activity in MS can be definitely established. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To establish whether the clinical effect of neutralizing antibodies (NAbs) against interferon-beta (IFNβ) depends on the type of IFNβ (1a or 1b) used for treatment of patients with relapsing-remitting multiple sclerosis (MS). Introduction NAbs against IFNβ-1b appear faster and may be more evenly distributed on IgG subclasses, whereas NAbs against IFNβ-1a develop more slowly and may be devoid of IgG3. This might cause different clinical responses to NAbs. Design/patients All Danish MS-patients who had started first-time treatment with IFNβ-1a 22 μg s.c tiw (Rebif22) or IFNβ-1b 250 μg s.c. qod (Betaferon) before January 1st 2003 were included. Relapses were recorded at bi-annual visit. Methods We measured NAbs every 12 months using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. We used a mixed logistic regression analysis in which NAb-status (three levels), IFNβ-preparation, and time since treatment started were included as explanatory variables, and relapse rate as response variable. Results In 1,309 patients, who were observed for 21,958 months, 32.3% were classified as NAb-positive. The odds-ratio (OR) for relapses in NAb-positive months compared with NAb-negative months was 1.25; P = 0.02. The risk of relapses was higher with Betaferon than with Rebif22 (OR 1.26; P < 0.01). The effect of NAb-level on relapses was independent of whether the patients were treated with Betaferon or Rebif22 (P = 0.89) and of time (P = 0.80). Conclusion NAbs caused by IFNβ-1a s.c. do not differ from NAbs caused by IFNβ-1b in their detrimental clinical effect. [ABSTRACT FROM AUTHOR]

Background Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting as infectious mononucleosis (IM) are recognized as risk factors for multiple sclerosis (MS). However, their combined effect and possible interaction on MS risk is not known. Objective To assess the association between HLA-DRB1*15 and risk of MS in persons with and without IM. Methods We compared the prevalence of DRB1*15 in MS patients with (n = 76) and without (n = 1,836) IM with the corresponding distributions in blood donors with (n = 62) and without (n = 484) IM histories. This allowed us to estimate the relative risk of MS associated with DRB1*15 in the presence and absence, respectively, of previous IM. We then estimated the interaction between DRB1*15 and IM as the ratio of the two individual odds ratios. Results In IM-naïve individuals, DRB1*15 carried a 2.4-fold (95% confidence interval [CI], 2.0-3.0) increased MS risk. In contrast, among persons with IM history, DRB1*15 was associated with a 7.0-fold (95% CI, 3.3-15.4) increased MS risk. Thus, the MS risk conferred by HLA-DRB1*15 was 2.9 (95% CI, 1.3-6.5)-fold stronger in the presence than in the absence of IM. Combined with previous results, this result indicates that DRB1*15-positive persons with a history of IM may be at a 10.0-fold (95% CI, 6.0-17.9) increased risk of MS compared with persons who are DRB1*15 and IM-naïve. Conclusion DRB1*15 and IM may act in synergy causing MS. [ABSTRACT FROM AUTHOR]

Background The idea of physical trauma being involved in the causation of multiple sclerosis (MS) had been discussed since the earliest description of the illness. Despite the ongoing debate, the proposed association between physical and especially head trauma and MS failed to be proved or to be refuted conclusively. Objective To determine whether head trauma is associated with an increased risk of developing MS. Method A cohort of 150,868 subjects, 95,111 men, and 55,757 women registered in the National Danish Patient Registry with hospital admission for cerebral concussion, contusion, or skull fracture between 1977 and 1992, aged under 55, was selected. This trauma cohort was linked with the Danish MS Registry and followed up to the end of 1999 to retrieve subjects who had onset of MS after the year of the head trauma. We calculated the expected number of subjects, who, under a null-hypothesis, would subsequently develop MS, by using population age-, year-, and sex-specific MS-incidence densities from the Danish MS Registry. Results For men and women combined, the observed to expected number of MS cases (possible cases included) with onset after the head injury was 182/193.6 (standardized incidence ratio [SIR], 0.94; 95% CI, 0.81-1.09) and for possible MS excluded, 171/164.7 (SIR, 1.04; 95% CI, 0.89-1.21). In an analysis of a sub-cohort of 16,425 subjects with severe trauma (contusion, traumatic cerebral hemorrhage, and base or skull fracture), the observed to expected numbers, including possible MS, were 15/15.3 (SIR, 0.98; 95% CI, 0.55-1.62) and with possible MS excluded, 13/12.9 (SIR, 1.01; 95% CI, 0.53-1.73). As for the total group and for any of the subgroups and for men and women separately, none of the SIRs differed statistically significantly from unity. Neither were there any trends, which could be missed by type II errors. Conclusion Head injury of any severity does not affect the risk of acquiring MS later in life. [ABSTRACT FROM AUTHOR]

Objective To establish whether multiple sclerosis (MS) patients, who have lost the therapeutic effect of interferon-beta (IFN-β) owing to neutralizing antibodies (NAbs) and subsequently revert from a NAb-positive to a NAb-negative state under continued IFN-β-1b therapy, regain clinical effect after reversion. Background Several studies have shown that a significant proportion of patients treated with IFN-β develop NAbs that hamper or abolish the therapeutic effect of IFN-β. However, some patients, who become NAb-positive under treatment with IFN-β-1b, may revert to a NAb-negative state under continuous treatment. Methods We identified 40 patients from the Danish IFN protocol, who fulfilled the criteria: NAbpositive status for at least 12 months followed by reversion to NAb-negative state for at least 12 months. For comparison, we included 64 matching cases that had remained NAb-negative during an observation time of at least 36 months. The two groups were clinically and demographically alike. We measured NAb-neutralizing capacity using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. A patient was defined as NAb-positive after two consecutive blood tests separated by at least 6 months. Reversion to a NAb-negative state required at least two consecutive negative tests. To allow for the confounding effect of time we employed a mixed Poisson model. Results Patients who had been NAb-positive and reverted to a NAb-negative state regained treatment effect with the relapse rate as before the NAb-positive period adjusting for the effect of time, and the relapse rate was the same as in the permanently NAb-negative patients in corresponding time periods. The relapse rate ratio comparing the NAb-positive with the NAb-negative periods was 1.98 (95% confidence interval: 1.32-2.97). Conclusion Under NAb-positive periods, the clinical effect of IFN-β was abolished. When NAbs disappeared spontaneously under continued treatment, patients regained the full effect of INF-β-1b therapy with no negative carry-over effect from the previous NAb-positive period. [ABSTRACT FROM AUTHOR]

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 firstdegree 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 periodspecific 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). Conclusion Patients with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Neutralising antibodies (NAbs) against interferon (IFN)-β reduce the treatment effect in multiple sclerosis (MS). However, data from pivotal trials of IFN-β 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-β 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-β 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-β therapy, though neutralising in vitro in sensitive assays increase the half-life of IFN-β in vivo and, thereby, enhance the therapeutic effect. With affinity maturation, NAbs effectively prevent IFN-β binding to its receptors also in vivo and, hence, abolish the treatment effect. [ABSTRACT FROM AUTHOR]

Administration of interferons (IFNs) may induce antibodies that interfere with therapeutic efficacy. We have optimized and validated methods for large-scale economic screening. Sera from patients with relapsing–remitting multiple sclerosis (MS) were investigated for binding antibody (BAb) by protein-G affinity-chromatography radioimmunoassay and a commercially available enzyme immunoassay (EIA). Neutralizing antibody (NAb) was investigated by cytopathic effect assays (CEA) using both fixed amount and serially diluted sera. BAb correlated with log10-transformed titres obtained by EIA (r=0.70, P<0.0001); the latter, however, failed to demonstrate low-level BAb. Comparison of clinical significance of NAb-positivity measured by biological assays with different sensitivities demonstrated an optimal odds ratio for relapse rate using 10 laboratory units (LU)/mL. Purification of IgG prior to CEA removed toxicity from toxic sera. The neutralizing capacity data correlated linearly with log10-transformed titres obtained by a Kawade 10-to-1 LU/mL CEA (r=0.77, P<0.0001). In conclusion, neutralizing capacity CEA utilizing a fixed amount of serum predicts differences in relapse rates in IFNβ-treated MS patients and correlates with NAb titres of the 10-to-1 LU/mL CEA. Neutralizing capacity CEA is less laborious and more economical than titre-based NAb assays and suitable for large-scale screenings of MS patients. [ABSTRACT FROM AUTHOR]

Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-β-treated patients, we found that the hazard ratio for developing an attack was 2.8 in patients with CD26+CD4+ T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-β antibodies. CD26+CD4+ T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-β. [ABSTRACT FROM AUTHOR]

After approval by the European Union in 1996 of interferon-beta for treatment of relapsing-remitting multiple sclerosis (RRMS), 862 patients in Denmark have received treatment (by April 1999), and 304 of those were enrolled into an open labelled randomised trial to compare the efficacy and tolerability of treatment with interferon-beta-1b (Betaferon) 8 MIU subcutaneous every other day and interferon-beta-1a (Rebif) 6 MIU subcutaneous once a week. Primary and secondary end-points included: (1) the relapse rate, (2) tolerability, (3) neutralizing antibody formation using the same specialised laboratory and validated assay, (4) time to first relapse, (5) time to sustained progression, and (6) number of gadolinium-enhancing lesions in T1-weighted MRI and the total lesion load in T2-weighted MRI. All the records are kept in a nationwide clinical database connected with the Danish Multiple Sclerosis Registry. The randomised trial will be completed by the end of 1999, and the results are not yet available. The annual relapse rate in all treated patients until April 1999 was 0.73, the annual rate of steroid treated relapses was 0.21. By 1 April 1999 8.8% of the patients had discontinued treatment and 10.4% had changed to another interferon-beta preparation. It has been planned to extend the follow-up of all patients treated according to the Danish National Protocol for a period of several years. The continuous and nation-wide registration of the course of the disease in interferon-beta treated RRMS patients may provide valuable knowledge of the treatment-modified long-term course of the disease in a cohort of patients, selected on the basis of well-defined criteria. Multiple Sclerosis (2000) 6, 172–175. [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]

Objectives: To determine the underlying causes of death in a large population based register series of patients with multiple sclerosis.Methods: The Danish Multiple Sclerosis Registry, which contains virtually all diagnosed cases of multiple sclerosis in Denmark who were alive in 1949 plus cases with onset of multiple sclerosis in the period 1949-93, who have been diagnosed and notified by 1 January 1994, was linked with the Danish Registry of Causes of Death, in which ICD codes for causes of death from the death certificate are stored for all Danish citizens.Results: 6068 register cases of multiple sclerosis, who had died in the period 1951-93, were included. Multiple sclerosis was noted on the death certificate as the underlying cause of death in 55.4%; cardiac or vascular diseases in 17.6%; cancers in 8.6%; respiratory or infectious diseases in 5.1%; other natural causes in 9.5%; accident or suicide in 3.8%. The distribution varied with age at death. Standardised mortality ratios (SMRs) were computed on the basis of the 8142 incident cases, who had onset of multiple sclerosis within the period 1951-93; the SMRs for causes of death other than multiple sclerosis were highest for infectious or pulmonary diseases: 2.46 (95% confidence interval (95% CI) 2.04-2.94); suicide: 1.62 (95% CI 1.29-2.01); cardiac or vascular diseases: 1.34 (95% CI 1.22-1.48); accidents 1.34 (95% CI 1.02-1.71); and significantly lower than unity for cancers: 0.79 (95% CI 0.70-0.90), lower for men than for women.Conclusions: More than half of the patients with multiple sclerosis die from multiple sclerosis or complications of the disease. Among other causes, patients with multiple sclerosis have an increased risk of dying from heart or vascular diseases but a reduced risk of dying from cancer. An increased risk of death from suicide and accidents can be indirectly attributed to multiple sclerosis. The diminished risk of dying from cancer may be a result of incomplete ascertainment of cancers in disabled patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

In a nationwide investigation the risk of death by suicide for patients with multiple sclerosis (MS) was assessed using records kept at the Danish Multiple Sclerosis Registry (DMSR) and the Danish National Register of Cause of Death. The investigation covers all MS patients registered with DSMR with an onset of the disease within the period 1953-85, or for whom MS was diagnosed in the same period. Fifty three of the 5525 cases in the onset cohort group committed suicide. Using the figures from the population death statistics by adjustment to number of subjects, duration of observation, sex, age, and calendar year at the start of observation, the expected number of suicides was calculated to be nearly 29. The cumulative lifetime risk of suicide from onset of MS, using an actuarial method of calculation, was 1.95%. The standard mortality ratio (SMR) of suicide in MS was 1.83. It was highest for males and for patients with onset of MS before the age of 30 years and those diagnosed before the age of 40. The SMR was highest within the first five years after diagnosis. [ABSTRACT FROM AUTHOR]

Presents letters related to medicine published in the 'British Medical Journal.' Relevance of antithyroid drugs to the treatment of Graves' disease; Role of deformity of the nasal septum; Success of the seat belt campaign.