The Gulf War era multiple sclerosis cohort: 3. Early clinical features.

OBJECTIVES: To present clinical features at diagnosis for a large nationwide incident cohort of multiple sclerosis (MS) among those serving in the US military during the Gulf War era (GWE). MATERIALS & METHODS: Medical records and databases from the Department of Veterans Affairs (VA) for cases of MS with onset in or after 1990, active duty between 1990 and 2007 and service connection by the VA, were reviewed for diagnosis and demographic variables. Neurological involvement was summarized by the Kurtzke Disability Status Scale (DSS) and the Multiple Sclerosis Severity Score (MSSS). RESULTS: Among 1919 cases of clinically definite MS, 94% had a relapsing-remitting course and 6% were primary progressive at diagnosis. More males of all races and blacks of both sexes were progressive. At diagnosis, functional system involvement was pyramidal 69%, cerebellar 58%, sensory 55%, brainstem 45%, bowel/bladder 23%, cerebral 23%, visual 18%, and other 5%. Mean DSS scores were: white males, females 2.9, 2.7; black males, females 3.3, 2.8; and other-race males, females 3.2, 2.6. Mean and median MSSS were marginally greater in black males and other males compared to the other sex-race groups. CONCLUSIONS: In this incident cohort, males and blacks had significantly higher proportions of primary progressive MS. DSS at diagnosis was significantly more severe in blacks and significantly less so in whites and in women vs men, but MSSS was only marginally greater in black males and other-race males. This morbidity assessment early in the course of MS provides population-based data for diagnosis, management, and prognosis.

Serum proteomic analysis of a pre-symptomatic multiple sclerosis cohort.

BACKGROUND AND PURPOSE: Susceptibility to multiple sclerosis (MS) is determined by environmental and genetic factors, but the cause remains unknown. Changes to the proteome prior to first symptom onset may reflect the underlying pathophysiology of the disease. METHODS: This preliminary study utilized pre-symptomatic and post-symptomatic serum from a sample of 100 incident population-based US military veterans with MS along with 100 matched healthy controls. All samples were obtained from the Department of Defense Serum Repository. Multidimensional protein identification technology tandem mass spectrometry analysis was performed on tryptic peptides of lectin-captured glycosylated serum proteins following albumin/immunoglobulin G depletion. Identified proteins were analyzed with the Ingenuity Pathway Analysis program. RESULTS: The mean intervals between first symptom onset and the collection of pre-symptomatic and post-symptomatic sera were -6.0 and +1.1 years, respectively. Pre-symptomatic proteins from the MS group were differentially regulated compared with both control groups indicating that proteomic changes are detected prior to symptom onset. Pathway analysis showed that proteins involved in the complement and coagulation pathways and lipid transport are significantly altered in the serum of subjects with MS compared with healthy donors. CONCLUSIONS: Compared with healthy controls, differential proteomic changes were noted in the serum of patients with MS that preceded the onset of symptomatic disease. Further work is in progress to confirm or refute these findings.

Migration and multiple sclerosis in United Kingdom and Ireland immigrants to Australia: a reassessment. II. Characteristics of early (pre-1947) compared to later migrants.

In our recent reassessment we explored the risk of MS by age at immigration in 258 migrants from United Kingdom and Ireland (UKI) to four states of Australia (New South Wales, Queensland, South Australia, and Western Australia) in the period 1947-1981 (Group II). In the present report we have compared their characteristics with 44 cases who migrated before 1947 (Group I), divided into two subsets: Group Ia (15 cases) was rather similar to Group II in age at immigration (means of 20 and 23 years), age at onset (39 and 33 years), and duration from immigration to onset (19 and 10 years). Group Ib (29 cases) was significantly different from Group II, with mean ages of 4 years at immigration and 40 years at onset, for a mean interval of some 35 years between immigration and onset. All onsets in Group Ib occurred after 1947. We concluded that the Group Ib cases had most probably acquired their MS in Australia. Immigrants from high MS risk countries, including UKI, were modest in number before 1947, but some 770,000 entered from 1947-1981. They may have been the source of MS for the Group Ib migrants.

Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration.

A previous study of the prevalence of multiple sclerosis (MS) in 1981 among immigrants from the United Kingdom and Ireland to Australia found that the prevalence for those with age at immigration (AAI) under 15 years of age did not differ from the older immigrants. We have reanalysed the original materials as well as census data for 1901-1981 for UKI and other high MS risk country immigrants. There was a highly significant trend in the prevalence rates of all Australians from New South Wales (NSW) to South Australia (SA) to Western Australia (WA) to Queensland (QLD). Rates by state among the Australian-born were almost identical to these, but there was no prevalence gradient for the UKI-born. The denominator population at risk of MS by AAI was calculated from special census tables of length of residence in Australia by age 0-79 in 1981 for UKI immigrants 1947-1981. The numerator was limited to the subset of 258 MS (Group II) also immigrating in 1947 and later, and age 0-79 in 1981. The absolute risk of MS for these migrants to the four states entering at age 0-14 was 22/100,000, significantly less than for all older age groups; age 15-39 immigrants had a risk of 54/100,000. Similar risk ratios for 0-14 versus 15-39 by state were 31 versus 61 (NSW), 29 versus 44 (QLD), 11 versus 50 (SA), 15 versus 51 (WA).

Multiple sclerosis in the Faroe Islands. 8. Notifiable diseases.

OBJECTIVE: To seek evidence for a possible infectious origin of the type 1 epidemic of multiple sclerosis (MS) in the Faroe Islands. This began in 1943 coincident with their British military occupation throughout World War II. MATERIALS AND METHODS: Data obtained from the Danish National Health Service were assessed for all notifiable diseases in the Faroe Islands reported from 1900 to 1977. RESULTS: Among 38 disorders, selective increases were found for acute infectious gastroenteritis (AIGE) and paradysentery, with outbreaks in late 1940 and in 1943 shortly after the introduction and later marked influx, respectively, of British troops. Five other infections showed elevated numbers in 1941 and 1942. CONCLUSIONS: There is a temporal association of AIGE and paradysentery in the Faroe Islands with the first arrival and later marked augmentation of British forces stationed there during the war. Rises in the incidence of other diseases in 1941-1942 seem more likely a consequence of increased foreign commercial travel by Faroese at that time.

Some contributions of the Department of Veterans Affairs to the epidemiology of multiple sclerosis.

The first class 1 treatment trial ever conducted in multiple sclerosis (MS) was a Veterans Administration Cooperative Study. This led us to explore MS in the military-veteran populations of the United States in three main series: Army men hospitalized with final diagnoses of MS in World War II, all veterans of World War II and the Korean Conflict, and veterans of later service up to 1994. In each series, all cases had been matched with pre-illness military peers. These series provide major information on its clinical features, course and prognosis, including survival, by sex and race (white men and women; black men), as well as risk factors for occurrence, course, and survival. They comprise the only available nationwide morbidity distributions of MS in the United States. Veterans who are service-connected for MS by the Department of Veterans Affairs and matched with their military peers remain a unique and currently available resource for further clinical and epidemiological study of this disease.

Origin of DSS: to present the plan.

The Disability Status Scale for multiple sclerosis was the direct result of World War II, in which 16.4 million persons served in the US military. Thereafter academic medicine enabled the modernization of the Veterans Administration in patient care, research, and training. Under the GI Bill, I attended Cornell University Medical College, where there was an intensive course in neurological diagnosis requiring detailed recording of positive and negative findings. This was used in junior and senior clinical clerkships and residency training, all of which I took at the Bronx VA Hospital. During my residency we assessed a possible treatment for MS, which required a comparison group and a means of measuring change. The former comprised the records of over 300 MS patients, whose neurological deficits were then consolidated into mutually exclusive Functional Systems, each with grades for severity. As rank-order scales they could not be summed or compared directly, but they were used as the basis for the DSS, which ranged from 0 (normal) to 10 (death due to MS). This scale was later expanded into the EDSS by halving each step 1 through 9. This bifid system is applicable to all patients with MS regardless of type or severity of neurological impairment.

Further considerations on the distribution of multiple sclerosis in Sweden.

OBJECTIVES: The geographic distribution of multiple sclerosis (MS) in Sweden over time was compared in order to analyze homogeneity. METHODS: The distribution of MS was compared among three nationwide resources: 1301 hospital cases 1925-1934; 5425 deaths 1952-1992; and 11,371 disability pension recipients 1971-1994. RESULTS: Distributions by county (lan) were markedly non-homogenous, with greatest variations in the early prevalence series (16-232% of the national mean), less within the death data (75-170%), and least for the disability series (87-128%). Maximal rates for MS in the early prevalence series were found for the cluster of seven counties surrounding the two major lakes of south central Sweden, as well as for one region on the northern shore of the Bay of Bothnia, and another also off the Bay north of Stockholm. CONCLUSION: Though the epidemiologic sources are quite different, they are internally consistent and thus provide three consecutive cross-sectional views of the distribution over time. When considered together the data may be compatible with a thesis of the origin and spread of MS within Sweden from the south-central inland lake regions of the country. Such spread within a half century is too rapid for a genetic cause, including HLA patterns.

Multiple sclerosis in the Faroe Islands: an epitome.

The Faroe Islands are a semi-independent unit of the Kingdom of Denmark and are located in the North Atlantic Ocean between Norway and Iceland. Efforts to identify all cases of multiple sclerosis (MS) since 1900 among Faroese have been continuing for over a quarter century. As of 1998 prevalence was 66 per 100,000, age adjusted to 1960 US population, with a rate of 100 for women and 34 for men. Median survival was at 29 to 34 years with no significant difference by sex. Faroese with overseas residence indicated that at least 2 years of exposure from age 11 on in a high-risk area are required for acquisition of MS. Among native resident Faroese the first instance of symptom onset was in 1943, heralding a type 1 epidemic of 21 cases. This was followed by three successive epidemics of 10, 10, 13 cases, with membership in each epidemic defined by calendar time and age of exposure. Age at exposure for epidemic I was 11 to 45 years; for later epidemics age 11 was the minimum. We believe the source of MS on the Faroes was their occupation by British troops for 5 years in World War II. We think they introduced a widespread, specific, persistent (but unknown) infection, probably asymptomatic, which we call the primary multiple sclerosis affection (PMSA). Only a small proportion of those affected with PMSA will years later show any clinical signs of MS. Models of transmission of PMSA through successive cohorts of Faroese fit the data for epidemics II and III, and predicted the occurrence of epidemic IV. The Faroese provide an ideal location to determine the nature of PMSA, since the disease has remained geographically stable for 50 years without further spread throughout the islands.

Epidemiology of multiple sclerosis in US veterans. VIII. Long-term survival after onset of multiple sclerosis.

Survival to 1996 was analysed for nearly 2500 veterans of World War II who were rated as 'service-connected' for multiple sclerosis as of 1956 by the then Veterans Administration. Survival from onset was defined for all white women and black men, and a random sample of white men. Median survival times from onset were 43 years (white females), 30 years (black males) and 34 years (white males). Crude 50-year survival rates were 31.5% (white females), 21.5% (black males) and 16.6% (white males), but only the white females and white males were significantly different. A proportional hazard analysis was used to identify risk factors for mortality from multiple sclerosis onset year. Significant risk factors included male sex (risk ratio: 1.57), older age at onset (risk ratio: 1.05 per year) and high socioeconomic status (risk ratio: 1.05 per socioeconomic status category). There were no statistically significant differences in survival following multiple sclerosis onset by race or latitude of place of entry into military service, both significant risk factors associated with the development of multiple sclerosis. Standardized mortality ratios utilizing national US data (for 1956-96) showed a marked excess for all three race-sex groups of multiple sclerosis cases, with little difference among them, but with a decreasing excess over time. Relative survival rates, used to compare the survival of multiple sclerosis cases with that of other military veterans, did not differ significantly by sex-race group, nor by latitude of place of entry into military service, but did differ significantly by socioeconomic class. The lack of difference in male and female relative survival rates suggests that the significant difference in survival between male and female multiple sclerosis cases is, at least in part, a result of sex per se and not the disease.

Multiple sclerosis in time and space--geographic clues to cause.

Geographically MS describes three frequency zones. High frequency areas (prevalence 30+ per 100 000) now comprise most of Europe, Israel, Canada, northern US, southeastern Australia, New Zealand, and easternmost Russia. Medium frequency areas include southern US, most of Australia, South Africa, the southern Mediterranean basin, Russia into Siberia, the Ukraine and parts of Latin America. Prevalence rates under 5 per 100 000 are found in the rest of Asia, Africa and northern South America. Migrants from high to lower risk areas retain the MS risk of their birth place only if they are at least age 15 at migration. Those from low to high increase their risk even beyond that of the natives, with susceptibility extending from about age 11 to 45. Thus MS is ordinarily acquired in early adolescence with a lengthy latency before symptom onset. MS occurred in epidemic form in North Atlantic islands: probably in Iceland and the Shetland-Orkneys; clearly in the Faroe Islands. In the Faroes first symptom onset was in 1943, heralding the first of four successive epidemics at 13 year intervals. The disease was presumably introduced by occupying British troops during World War II, with the postwar occurrences representing later transmissions to and from consecutive cohorts of Faroese. What was transmitted is thought to be a specific, widespread, persistent infection called PMSA (the primary multiple sclerosis affection) which only rarely leads years later to clinical MS. Search for PMSA is best attempted on the Faroes where there are regions still free of MS after 50 years.

Multiple sclerosis in North African migrants to France.

Among some 7500 respondents with known place of birth who had completed a nationwide questionnaire survey for multiple sclerosis (MS) in France in 1986, there were 260 born in former French North Africa (Algeria, Morocco, Tunisia). They had migrated to France between 1923 and 1986, but 66% came between 1956 and 1964. Two-thirds were from Algeria, where virtually the entire European population had emigrated in 1962 at the end of the Algerian war for independence. The migrants were younger at prevalence day (mean 43.4 years) and at onset (29.4 years) than the French-born MS (46.6; 31.3 years). Eight migrants lacked age information. The 225 migrants with onset more than 1 year after immigration presumably acquired their MS in France. They provided an age adjusted (US 1960) MS prevalence rate 1.54 times that for all France. If the latter is taken at 50 per 100,000 population their estimated adjusted rate is 76.8 with 95% confidence interval of 67.1 to 87.5. The other 27 with presumed acquisition in North Africa gave an estimated adjusted prevalence of 16.6 per 100,000 (95% CI 10.9-24.1). For those migrants with acquisition in France there was a mean interval of 13 years between immigration or age 11 and clinical onset, with a minimum of 3 years. This series provides further support for the theses: 1) that MS is primarily an environmental disease acquired after childhood; 2) that acquisition requires prolonged or repeated exposure (here 3 years for these medium-to-high MS risk migrants) followed by a prolonged latent or incubation period between acquisition and symptom onset (here 10 years); and 3) that this disease is most likely a widespread but unknown persistent infection which results in clinical MS in only a small proportion of those affected.

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.