Multiple sclerosis in the Faroe Islands. 7. Results of a case control questionnaire with multiple controls.

Detailed questionnaires were completed in 1978-79 by 23 of the 28 then known resident Faroese multiple sclerosis (MS) patients and 127 controls. These controls were divided into 69 Group A (patient sibs and other relatives), 37 Group B (matched neighbor controls, their spouses and sibs, plus patient's spouse), and 21 Group C (distant matched controls, spouses, relatives living where MS patients never resided and British troops were not encamped during the war). No differences between cases and controls were found for education, occupation, types of residence, bathing, sanitary or drinking facilities, and nature of house construction or heating. Detailed dietary histories, available for half the subjects, revealed no differences, cases versus controls, for four age periods between age 0 and 30 years, and for 16 specified foodstuffs. Animal exposures showed overall no consistent differences by location or type of animal. There was a tendency to greater exposure to British troops during the war for cases versus Groups A and B but this did not attain statistical significance. Vaccinations for smallpox, tetanus and diphtheria were less common in the MS; no difference was found for other vaccinations. Except for a relative deficit in the cases for rubella and (insignificantly) for measles, mumps and chicken pox, reported illnesses were equally common among all groups. Operations, hospitalizations and injuries did not differentiate the groups, nor did age at menarche for women. Neurologic symptoms were significantly more common in the cases than in the controls.

[Survival in disseminated sclerosis in Denmark. A nation-wide study of the period 1948-1986]. / Overlevelsen ved dissemineret sklerose i Danmark. En landsdoekkende undersøgelse for perioden 1948-1986.

We estimated survival probability and excess death rates for patients with multiple sclerosis (MS) on the basis of data from the Danish Multiple Sclerosis Registry, which includes virtually all patients diagnosed with MS in Denmark since 1948. We reviewed and reclassified all case records according to standardized diagnostic criteria. By linkage to the Danish Central Population Registry and the National Registry of Causes of Death complete follow-up of all MS patients was achieved, with the exception of 25 patients who had emigrated. A total of 2300 of the 6727 MS patients included in the study had died before the onset of the disease was 28 years in men (compared with 40 years in the matched general male population) and 33 years in women (versus 46 years). The excess death rate between onset and follow-up (observed deaths per 1000 person-year minus the expected number of deaths in a matched general population) was 14.3 in men, which was significantly higher than in women (12.0). Excess mortality increased with age at onset of MS in people of each sex. The 10-year excess death rate has decreased significantly in recent decades. Excess mortality was highest in cases with cerebellar symptoms at onset.

Multiple sclerosis in the Faroe Islands: transmission across four epidemics.

As of 1991 we had ascertained 42 native resident Faroese plus 12 non-resident "migrant" Faroese with clinical onset of MS in this century. The resident series comprised four successive epidemics beginning in 1943 and then at 13-year intervals thereafter, a separation of very high statistical significance (p < 0.00001). We concluded that the first epidemic in the Faroes resulted from the introduction of a specific but unknown infection which we call the "primary MS affection" (PMSA) by occupying British troops during World War II. Clinical neurologic MS (CNMS) is then the rare late sequel of infection with PMSA. The first epidemic defined age of susceptibility to PMSA as age 11 to 45 at onset of exposure. Models of transmission used for the first three epidemics included the need for two years of exposure before PMSA acquisition and limitation of transmissibility of PMSA to age 13 to 26. With these conditions successive cohorts of susceptible Faroese were defined to account for the second and third epidemics, and they also predicted the occurrence of the fourth epidemic. Further consideration of these models suggests transmissibility is even more limited, perhaps to age 20 to 26 or so.

Survival of patients with multiple sclerosis in Denmark: a nationwide, long-term epidemiologic survey.

We estimated survival probability and excess death rates for patients with MS on the basis of data from the Danish Multiple Sclerosis Registry, which includes virtually all patients diagnosed with MS in Denmark (population, five million) since 1948. We reviewed and reclassified all case records according to standardized diagnostic criteria. By linkage to the Danish Central Population Registry, we lost to follow-up only 25 patients who had emigrated. The median survival time from onset of the disease was 28 years in men (compared with 40 years in the matched general male population) and 33 years in women (versus 46 years). The median survival time from diagnosis was 22 years in men (versus 37 years) and 28 years in women (versus 42 years). The excess death rate between onset and follow-up (observed deaths per 1,000 person-years minus the expected number of deaths in a matched general population) was 14.3 in men, which was significantly higher than in women (12.0). Excess mortality increased with age at onset of MS in people of each sex. The 10-year excess death rate has decreased significantly in recent decades. Excess mortality was highest in cases with cerebellar symptoms at onset.

Multiple sclerosis in the Faroe Islands. 5. The occurrence of the fourth epidemic as validation of transmission.

Based on 32 cases with clinical onset 1943-73, we previously described the occurrence of clinical neurologic multiple sclerosis (CNMS) on the Faroe Islands as constituting three consecutive epidemics, with 20, 9, and 3 cases respectively. As of 1991 there were seven additional cases of CNMS with clinical onset 1984-1989 constituting the fourth epidemic, as well as three more members of epidemic III. We have proposed that CNMS is the rare late result of infection with PMSA (the primary multiple sclerosis affection), a state requiring some two years of exposure from age 11+ for acquisition by Faroese, and that PMSA was first transmitted during World War II by affected but asymptomatic British troops to Faroese residents; part of this (F1) cohort of affected asymptomatic Faroese transmitted PMSA to the next (F2) cohort comprising Faroese reaching age 11 in the interval when that F1 subset was present, and the F2 cohort similarly transmitted PMSA to the third (F3) cohort. Cases of CNMS defining epidemic I-III were members of the respective F1-F3 cohorts. The existence of epidemic IV within the F4 cohort of Faroese may be taken as validation of our transmission models and of our theses as to the nature of multiple sclerosis.

Multiple sclerosis in the Faroe Islands. VI. Studies of HLA markers.

Occurrence of clinical neurologic multiple sclerosis (CNMS) among resident Faroese began between 1943 and 1973 and comprised three epidemics. The occupation by British forces for 5 years during World War II was interpreted to have been of major importance for the occurrence of these epidemics and led us to believe that CNMS is the rare, late result of a single, widespread, systemic and specific infectious disease which we have labelled the primary MS affection (PMSA). In this study we describe the occurrence of genetic markers of the HLA system in 16 Faroese MS patients, 25 of their siblings, 30 unrelated healthy neighbors and spouses to MS patients, 18 healthy controls from areas where no MS cases have been detected, and 80 unrelated normal Faroese. These studies show no significant deviations of HLA class I antigens, whereas the class II antigens do deviate: 50% of the Faroese MS patients carry the HLA-DR2 (DQ1/DRB 15) antigen, compared to a frequency of 15-20% among the control groups. Also the group of siblings of MS patients showed an increased frequency of DR4 (72%) compared to normal frequency among MS patients and other normal controls (43-47%). However, if DR15-positive individuals were excluded, this difference was further reduced. If PMSA was widespread within this group, DR4 or some closely associated genetic marker may confer protection against PMSA developing into CNMS. The occurrence of CNMS in these epidemics seems therefore associated to HLA class II-linked genetic factors similar to those found in studies of other caucasians with MS. This observation seems important in understanding the pathogenesis of this disease.

Suicide and multiple sclerosis: an epidemiological investigation.

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.

Multiple sclerosis in the Faroe Islands and the lack of protection by exposure in infancy.

Using data from 32 patients with symptom onset between 1943 and 1973, we described the occurrence of clinical neurologic multiple sclerosis (CNMS) in the Faroe Islands as then constituting three epidemics. We concluded that CNMS is the rare late result of infection with the primary MS affection (PMSA), a state requiring some 2 years of exposure for acquisition by Faroese. Our theses are that PMSA was first transmitted during World War II by affected by asymptomatic British troops to Faroese aged 11-45; that this (F1) cohort of affected asymptomatic Faroese under age 27 in 1945 transmitted PMSA to the next (F2) cohort of Faroese comprising those attaining age 11 each year from 1945 until F1 input ceased; that the F2 cohort similarly transmitted PMSA to the third (F3) cohort of Faroese. Cases of CNMS defining epidemics I-III were members of the respective F1-F3 cohorts. Within the F4 cohort of Faroese there is now a fourth epidemic of CNMS, with 7 patients with symptom onset between 1984 and 1989. Intermittency of the year of birth for CNMS cases is thus a reflection of membership in these separate population cohorts, and does not indicate 'protection' in infancy or childhood. There is no evidence for an extra-Faroese source of MS after the first epidemic. No model of acute infection with short transmissibility fits the data.

Incidence of multiple sclerosis in Denmark 1948-1982: a descriptive nationwide study.

The incidence rates of multiple sclerosis (MS) in Denmark were estimated as a result of a continuous nationwide epidemiological survey since 1948 by the Danish Multiple Sclerosis Registry (DMSR). Among cases notified to the DMSR, 6,478 met the diagnostic criteria and had onset of MS from 1948 through 1982. The crude annual incidence rate was 4.45/100,000 and the lifetime cumulative incidence rate was 0.32%. The female/male ratio was 1.37:1. Crude incidence rates declined during the period 1952-1967. After 1967 the incidence seemed to rise again but in an irregular pattern. The decline in incidence involved only cases up to the age of 35. The subsequent increase was most marked in females and in the age groups over 45 years.

Multiple sclerosis in the Faroe Islands. IV. The lack of a relationship between canine distemper and the epidemics of MS.

Clinical onset of multiple sclerosis (MS) occurred in 32 native resident Faroese between 1943 and 1973, comprising 3 consecutive epidemics of decreasing frequency. Relationship of MS with the appearance of canine distemper (CD) was explored by serologic studies, questionnaires, and veterinarian reports. Tested were sera from 12 MS patients and 112 controls among the 22 patients and 192 controls with questionnaires in 1978-1979. The daily treatment ledgers of the Veterinarian of the Faroes 1940-1961 were also reviewed and additional Faroese interviewed 1987-1988 as to CD. History of CD was determined for residence of all 32 MS. There was no evidence of elevated CD antibody titers in MS vs controls for neutralizing titers or ELISA values, nor to ELISA for measles. In the questionnaires only one patient and 2 of his sibs reported owning (the same) dog(s) with CD during the war. One other patient reported a possibly sick dog but not CD. CD occurred in one southern village 1941-1942, was present on Vágar from 1941-1950, and was epidemic on Streymoy 1944-1945 with scattered cases there and elsewhere through 1950. There was no significant correlation between villages with CD and MS residents. We conclude that the occurrence of multiple sclerosis was not related to the presence of canine distemper or sick dogs in the Faroe Islands.

Epidemiology of multiple sclerosis: incidence and prevalence rates in Denmark 1948-64 based on the Danish Multiple Sclerosis Registry.

The Danish Multiple Sclerosis Registry (DMSR) is a national register based upon the ethnically homogeneous Danish population of about 5 millions. The DMSR was founded in 1956 following a nationwide Danish prevalence survey of MS in 1949 and a continuous registration of incident cases of MS since January 1, 1948. Included in DMSR are all Danish cases of MS (or suspicion of MS) diagnosed by a neurologist or a department of neurology. The sources of notification are the 22 neurological departments in Denmark, the National Patient Registry, the neuropathological departments, the Registry of Causes of Death, and, up to 1975, the Disablement Insurance Court. Notified cases which do not comply with the standardized diagnostic criteria of the DMSR are excluded. An estimate of the completeness of the DMSR is 90-95% and the validity is around 94%. Age- and sex-specific incidence rates of MS for the interval 1948-64 are presented. The crude annual incidence rate of MS in Denmark was in the year 1948-64 4.42 per 100,000 population, 22% higher in females than males. There was a significant geographical variation of incidence rates and a significant downward trend in incidence rates during the interval, whereas the prevalence rates showed a slight increase.

Validity of the epidemics of multiple sclerosis in the Faroe Islands.

Concerns have been raised as to our diagnoses, exclusions, case ascertainment, definition of epidemics, and the role of the British occupation in the occurrence of multiple sclerosis among Faroese. We believe none of these points are substantiated, but rather that there did occur three consecutive and decreasing epidemics of clinical neurologic MS (CNMS) among native resident Faroese between 1943 and 1973, with no cases before or (so far) since. We have attributed these occurrences to the introduction into the Faroe islands of what we have called the primary MS affection (PMSA) by the British troops who occupied the islands in World War II. The first Faroese population cohort of PMSA-affected, which included the epidemic I cases, transmitted PMSA to the next cohort of Faroese comprising those attaining age 11 in 1945-1956, and they included the epidemic II cases. The second cohort thereafter similarly transmitted PMSA to the third Faroese cohort with its epidemic III cases. We conclude that PMSA is a single, widespread, specific, systemic infectious disease whose acquisition in virgin populations follows 2 years of exposure starting between age 11 and 45, which then produces CNMS in only a small proportion of the affected after a 6-year incubation period, and which is transmissible only during part or all of this systemic PMSA phase that ends before the usual age of CNMS onset. In endemic MS areas both the exposure and incubation periods may be twice as long, but otherwise PMSA may have there the same characteristics as inferred for the Faroes.

Multiple sclerosis in the Faroe Islands. III. An alternative assessment of the three epidemics.

Among 32 resident Faroese, clinical MS began between 1943 and 1973 and comprised 3 epidemics, each one significantly later in time and lower in incidence than the preceding. This is confirmed by the present division of the cases of the epidemics according to the calendar time when the patients attained age 11. The risk of MS for Faroese of Epidemic I, (those who acquired the disease from asymptomatic British troops in the World War II occupation), was 18 per 10,000. Depending on the minimum population number required for transmission, the MS risk for Epidemic II was 15 per 18 per 10,000, and for Epidemic III (under our second model) 9 or 11 per 10,000, none differing significantly from Epidemic I. We conclude that the primary MS affection (PMSA) is a single, widespread, specific, systemic infectious disease whose acquisition in virgin populations follows 2 years of exposure starting between age 11 and 45, which then produces clinical neurologic MS (CNMS) in only a small proportion of the affected after an incubation period of 6 (virgin populace) or 12 (endemic areas) years, and which is transmissible only during part or all of this systemic PMSA phase that ends by age 27 or younger.

MS epidemiology in Faroe Islands.

We found 41 Faroese with clinical onset of MS 1900-1983, including 9 "migrants" who had lived in (high MS risk) Denmark for 3+ years before onset. Their major foreign residence was during the 10 years or so before clinical onset, began at age 11-29 and was of at least 2 years duration, following which clinical onset occurred an average of 6 years later. Among the 32 resident Faroese, clinical MS began between 1943 and 1973 and comprised three epidemics, each one significantly later in time and lower in incidence than the preceding. The risk of MS for Faroese of epidemic I, who acquired the disease from asymptomatic British troops in the World War II occupation, was 18 per 10,000. Risk for those of epidemics II and III, who acquired the disease from asymptomatic but affected Faroese, was not significantly different. We conclude that the primary MS affection (PMSA) is a single, widespread infectious disease whose acquisition in virgin populations follows two years of exposure starting between age 11 and 45, which then produces clinical neurologic MS (CNMS) in only a small proportion of the affected after an incubation period of 6 (virgin populace) or 12 (endemic areas) years, and which is transmissible only during the systemic PMSA phase which ends by age 27 or younger.

Multiple sclerosis in the Faroe Islands. II. Clinical update, transmission, and the nature of MS.

In this century, 41 Faroese with MS were ascertained. One subset, after living in Denmark for 2 years between ages 11 and 31, had MS onset an average of 6 years later. In the Faroes, MS occurred as three separate and decreasing epidemics beginning in 1943 and ending in 1973. We believe that asymptomatic British troops introduced the first epidemic during 1941 to 1942, with the later epidemics resulting from transmission by affected but asymptomatic Faroese. We conclude that "MS" is a widespread, systemic, specific infectious disease only rarely causing neurologic symptoms and transmissible at most from ages 13 to 26.

Risk factors in multiple sclerosis: tuberculin reactivity, age at measles infection, tonsillectomy and appendectomy.

The purpose of the present study was to investigate whether risk of multiple sclerosis (MS) is associated with the occurrence of viral or bacterial diseases, with vaccinations, or with operative events during childhood. Our reference population was 198,000 persons recorded in the register of school health records from the Copenhagen council. We compared 92 MS patients contained in the register with matched controls from the register, three for each patients. Risk of MS was inversely associated with a positive tuberculin skin test at age 7 years, i.e. with exposure to tuberculosis before the age of 7, possibly also with the occurrence of measles infection before age 7 (not statistically significant). Disease risk was not significantly related to other viral or bacterial infections of childhood, nor to routine vaccinations, tonsillectomy, adenoidectomy or appendectomy. Our findings suggest a difference between MS patients and controls with respect to environment before school age, the former being less exposed to air-borne infections.

School contact between patients with multiple sclerosis.

We have investigated whether there was more school contact among patients with multiple sclerosis (MS) than expected by chance, suggesting that a transmissible infection occurring at school age might be an aetiologic factor. A case-control-within-a-cohort study was conducted using the 1930-1950 birth cohort. Of 198 000 persons 92 had developed MS in the period 1943-1975 and 3 matched controls for each case were selected. The number of links between all possible pairs of cases was estimated, as well as the number of cases involved in contact with at least one other case. Three measures of school contact were included in the analysis. No evidence of increased school contact among MS cases relative to controls was found.