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.

Analysis of the 'epidemic' of multiple sclerosis in the Faroe Islands. II. Biostatistical aspects.

A series of biostatistical tests were applied to the data upon which the Faroe epidemic hypothesis was constructed. Temporal, cluster analysis using three commonly applied methods were unsuitable because of the very small size of the sample (32 cases of MS). Methods to detect non-random clusters of disease identified a cluster of 16 cases with date of onset between 1941-1950 (p less than 0.05). However, when 1 questionable case of MS was excluded, the resulting cluster did not support the epidemic hypothesis. The overlapping 95% confidence limits of 5- and 10-year based incidence rates of MS, by date of onset (Poisson distribution) argues against the presence of an epidemic. Analysis of the exposure data, i.e. contacts between the Faroese and the British troops, yielded only borderline statistical significance but changing a single case of MS from the exposed to the unexposed category failed to support the exposure theory. All calculations were also carried out using the probable date of acquisition of the disease, between the ages of 5 and 14 years; these also failed to substantiate the hypotheses of epidemic and transmissibility. Since the validity of statistical analysis to test for the presence of epidemics with small sample sizes is not well established, the lack of concordance between the results of the various approaches leads to the conclusion that there was no epidemic of MS in the Faroes.

Analysis of the 'epidemic' of multiple sclerosis in the Faroe Islands. I. Clinical and epidemiological aspects.

The claim has been made that British troops introduced multiple sclerosis (MS), a transmissible disease, into the Faroe Islands during World War II, causing a three-tier epidemic which resulted in the appearance of 32 cases from 1943 until 1973. Assumptions underlying this hypothesis include the belief that the disease was absent from the Faroe Islands before 1940, the view that ascertainment of cases was complete and that Faroese patients who had either been born in Denmark or had been away from the Islands for 3 or more years before the onset of the disease had to be excluded. All the calculations were based on the presumed date of appearance of the first symptoms of MS. We reject the hypotheses of an epidemic and of the transmissibility of MS for several reasons. The most important one is that the date of onset of illness bears no relationship to the probable date of acquisition, which is widely believed to occur between the ages of 5 and 15 years. The criteria for exclusion of cases are arbitrary and instead of the accepted 32 cases, we believe that 42 cases should be counted in all analyses, including at least 2 with onset of illness before 1940. Only 15 of these 42 were in the age range 5-14 years during the British occupation. We cannot accept the statement that the disease was unknown in the Faroes before 1940 and believe that case ascertainment was incomplete in the Islands, which share close geographic, ethnic, and environmental similarities with other North Sea countries of high MS incidence. The theory of transmission is unconvincing and the characteristics of the putative agent unrealistic. The extremely high incidence of disease, which has statistical significance, is based on a very small number of cases in a very small population, and is of very doubtful biological significance.

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.

Comparison of survival times of mice inoculated with brain tissue from various neurological diseases.

Mice inoculated intracerebrally before the age of 5 days with homogenates of autopsied brain tissue from patients with Creutzfeldt-Jakob (C-J), Alzheimer's, or Pick's diseases showed highly significant decreases in life span when compared with sham-inoculated control mice. With C-J disease there was strong indication of horizontal transmission of the agent to uninoculated mice caged with the inoculated mice. While the results with C-J disease were not unexpected in view of the known infectious etiology of the disease, the results obtained with Alzheimer's and Pick's diseases suggest that previously undetermined infectious or toxic agents may be associated with these two diseases, which currently have unresolved etiologies. Mice inoculated with autopsied brain tissue from patients with multiple sclerosis or subacute sclerosing panencephalitis had life spans similar to those of the control mice.

Multiple sclerosis and age at exposure to childhood diseases and animals: cases and their friends.

Eighty-eight multiple sclerosis case-friend pairs were interviewed by telephone to elicit information about early-life exposures. Available mothers were also interviewed. Risk factors included childhood diseases, exposures to animals, and residence. We found a positive association between MS and having measles at a later than usual age. Analysis of the data in the literature showed that this was the third statistically significant association between MS and later age for measles. This is consistent with the hypothesis that the pathogenesis of MS includes an age-dependent host response to measles.

Defining and measuring exposure in epidemiologic studies of potential zoonoses.

Articles suggesting the zoonotic potential of certain human diseases (eg, multiple sclerosis, rheumatoid arthritis, and leukemia) periodically appear in the literature and frequently receive considerable attention in the popular press. Although various epidemiologic study designs have been utilized to test these hypotheses, defining and accurately measuring animal exposure has been a problem common to most of these studies and in some instances has limited their usefulness. The relative strengths and limitations of the definitions and measurements used most commonly by investigators evaluating potential zoonoses are discussed. In addition, several recommendations for assessing animal exposure in future studies are made.

Donor to host transmission of disease via corneal transplantation.

A literature search was conducted to report all cases of documented transmission of infectious diseases from donors to recipients of corneal transplants. Fourteen such cases have been reported. There is no experimental or clinical evidence to suggest the transmissions of either hepatitis or syphilis via corneal grafting. Available evidence regarding a number of neurologic and other disorders in which a slow virus etiology has been implicated were reviewed. On the basis of this review, we are able to draw certain conclusions and guidelines for selection or rejection of donor material for transplant surgery.

Multiple sclerosis and viruses: an overview.

The evidence for a viral etiology of MS has been reviewed. The strongest evidence favoring a virus is based primarily on epidemiologic considerations. Less convincing evidence comes from pathologic studies, serology, lymphocyte reactivity to viral antigens, and reports of identification of virus in MS tissues. Animal models of viral demyelination exist, which may provide insight into possible etiologic agents and pathogenetic mechanisms. Considering all the data, it is clear that no agent can be convincingly linked to MS at the present time. If a single virus causes the majority of cases of MS, then a morbilliform virus--canine distemper--is a leading contender, because this agent is consistent with the epidemiologic and serologic findings and is highly neurovirulent for animals ranging from mice to primates. Since no virus fulfills the usual criteria for linking an infectious agent to a disease, other possibilities must be considered. If MS is caused by a single virus, it may be a common virus not presently considered as being associated with MS, or an agent as yet unidentified. It is also conceivable that multiple agents, acting alone or in concert, initiate the MS process, perhaps through a common immune-mediated pathway. In this regard, another human demyelinating disease--the Guillain-Barré syndrome--which may in some instances become a chronic remitting and relapsing disorder, is thought to be initiated by multiple infectious agents but to have an immunologic pathogenesis.

Multiple sclerosis and housedogs: a case-control study.

A case-control study was conducted to examine the possible association between ownership of housedogs early in life and later development of multiple sclerosis (MS). Sixty MS patients were compared with 60 neighborhood controls matched for age, sex, and race. There was no significant difference between cases and matched controls in housedog ownership, duration of ownership, or age at first exposure to housedogs over the interval from birth to 19 years of age.

Multiple sclerosis-associated agent. Failure of MS brain and serum to depress the polymorph count in normal mice and mice inoculated with cells containing C/type particles.

The groups that originally reported and confirmed the demonstration of a multiple sclerosis associated agent (MSAA) are now, along with others, unable to reproduce this effect. In view of this confusion and the potential importance of this work for multiple sclerosis (MS) we have done a strict double-blind trial using larger groups of mice (10) and counting more cells (900) than in previous reports to offset the high variability of mouse polymorphonuclear neutrophil (PMN) counts. Sera from 5 active MS patients and 4 normal subjects were tested in mice, half of which had previously been injected with PAM line cells (containing C-type particles and subject to reduced cell yield when cultured with MS brain extract). No significant PMN depression was found in either MS or normals on any basis of comparison. However, a significant depression was seen following PAM cell injection irrespective of serum origin. Higher counting accuracy did not reduce PMN variability. A single MS brain specimen was also without effect. consequently we have been unable to confirm the existence of an MSAA as defined by PMN depression in mice.