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.

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.

Cerebral mucormycosis (Phycomycosis) in a heroin addict.

Cerebral mucormycosis was found at autopsy in a 27-year-old male narcotic addict with rapidly progressive focal neurologic signs. There was no evidence of rhinocerebral involvement of systemic illness, and a nuclide brain scan suggested brain abscess.

Cortical blindness after metrizamide myelography. Report of a case and proposed pathophysiologic mechanism.

Metrizamide, a nonionic, water-soluble contrast medium, has been increasingly used for myelography. We saw a patient with cortical blindness, seizure, organic psychosis, and asterixis after undergoing attempted metrizamide myelography via C1-2 puncture. Computed tomography demonstrated early penetrance of metrizamide into the brain parenchyma, most prominently in the occipital lobes. A mechanism of direct metrizamide neurotoxicity was proposed.

Comparison of clinic, home, and deferred language treatment for aphasia. A Veterans Administration Cooperative Study.

Aphasic patients who met stringent selection criteria were assigned randomly to three groups: clinic treatment by a speech pathologist for 12 weeks, followed by 12 weeks of no treatment; home treatment by a trained volunteer for 12 weeks, followed by 12 weeks of no treatment; or deferred treatment for 12 weeks, followed by 12 weeks of treatment by a speech pathologist. At 12 weeks after entry, language measures indicated that the clinic-treatment patients made significantly more improvement than did the deferred-treatment patients, and improvement in home-treatment patients did not differ significantly from either clinic- or deferred-treatment patients. At 24 weeks after entry, after deferred-treatment patients had received clinic treatment, there were no significant differences among the groups. These results suggest that clinic treatment for aphasia is efficacious, and delaying treatment for 12 weeks does not compromise ultimate improvement.

Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).

One method of evaluating the degree of neurologic impairment in MS has been the combination of grades (0 = normal to 5 or 6 = maximal impairment) within 8 Functional Systems (FS) and an overall Disability Status Scale (DSS) that had steps from 0 (normal) to 10 (death due to MS). A new Expanded Disability Status Scale (EDSS) is presented, with each of the former steps (1,2,3 . . . 9) now divided into two (1.0, 1.5, 2.0 . . . 9.5). The lower portion is obligatorily defined by Functional System grades. The FS are Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, and Other; the Sensory and Bowel & Bladder Systems have been revised. Patterns of FS and relations of FS by type and grade to the DSS are demonstrated.

The current neurologic burden of illness and injury in the United States.

Estimates of the need for neurologists must be based ultimately on the frequency of neurologic disease. Community-based population surveys for diseases or injuries that have come to medical attention provide annual incidence rates per 100,000 population, point prevalence rates per 100,000, and average duration in years. For 61 disorders, including for 8 only those fractions that were thought to require neurologic attention, the annual incidence rates summed to 2500 per 100,000 or 2.5% of the population. For 55 of these conditions, including for 6 only the neurologic fraction and excluding all mental retardation, blindness, deafness, or psychosis, the point prevalence rates summed to 9500 per 100,000 population. Even if we also excluded all headache, all trauma, all alcoholism, and all vertebrogenic pain states, 3.6% of the general population at any one time should be under neurologic care. Substracting all these exclusions from the incidence rates similarly leaves more than 1 person in every 100 who each year will have a new neurologic disorder that requires the attention of a physician competent in clinical neurology.

Patterns of neurologic involvement in multiple sclerosis.

Specific patterns of neurologic involvement within the 8 Functional Systems (Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, Other) in a well-documented series of early MS patients have been presented in rank order of expected frequency. The first 35 and the first 86 of the 256 possible patterns comprised respectively 71% and 90% of all cases expected or observed. Patterns with increasingly higher rank orders provided increasingly greater likelihood for the diagnosis of MS. For 1 of the 4 most common patterns, the likelihood of MS was 17 times that without consideration of any pattern. In this series, the occurrence of any of the first 35 patterns was well above expectations, while patterns ranked beyond 86 were highly unlikely.

Is Parkinson's disease acquired? Evidence from a geographic comparison with multiple sclerosis.

In the coterminous United States, MS mortality rates demonstrate a north-south gradient, which is confirmed by more sophisticated--and more expensive--prevalence studies. Mortality rates from idiopathic Parkinson's disease show a similar north-south gradient, and they correlate significantly with the MS mortality and prevalence data. This demonstration that Parkinson's disease may be place-related provides support for the hypothesis that Parkinson's disease, like MS, is an acquired, environmental illness.

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.

Parkinsonism death rates by race, sex, and geography.

Age-adjusted death rates for Parkinson's disease (PD) in the United States from 1959 to 1961 demonstrated significantly lower rates for blacks than for whites, with rates for Oriental Americans the same as for whites. All racial groups showed a male preponderance. Both whites and blacks had a similar excess of PD death rates for residents of the four northern census regions of the US over their rates for the three southern regions. Within each region the sex and race differences remained. Thus, blacks in the US appear to be "protected" against PD, but they share the north: south gradient seen for whites. Race, sex, and geography would therefore seem to be independent risk factors for PD, providing further evidence that this may then be an acquired, environmental disease.

Epidemiology of multiple sclerosis in US veterans: VII. Risk factors for MS.

In previous papers of this series, we explored the epidemiology of MS, examining the effects of race, sex, geography, latitude and climate, migration, age at onset, population ancestry, and individual ethnicity on the risk of MS, using an unusually large cohort of MS cases and pre-illness matched controls comprising US veterans of World War II (WWII) and the Korean Conflict (KC). In this paper, we examine primarily the effect of other factors on the risk of MS in this cohort and their relation to those previously studied. We found here that latitude tier of residence at entry into active duty (EAD), years of education, and socioeconomic class (coded from occupation) were similarly associated with MS risk among white men, black men, and white women. Higher levels of each factor showed increased MS risk. Multivariate analyses indicated that for white male WWII subjects an urban address, 9 or more years of education, uncorrected visual acuity less than 20/20 at EAD, a more northern latitude, and a higher proportion of the subject's EAD state population reporting Swedish ancestry each significantly increased the risk of MS. White male KC subjects showed roughly the same patterns, except that uncorrected visual acuity less than 20/20 was associated with lower MS risk (ancestry/ethnicity was not studied). For black male WWII and KC subjects combined, a similar analysis (omitting ancestry/ethnicity) showed that only latitude at EAD and 9 or more years of education were independently associated with a significantly higher MS risk, and for WWII plus KC white women (also without ancestry/ethnicity), only latitude was a significant risk factor in these multivariate analyses. The smaller number of subjects, especially in these last two groups, limited the power to detect statistically significant risks in these last analyses. Similarities to white men of WWII in univariate analyses for all other groups suggest that findings for the former would otherwise apply to the latter. Although the interpretations of these associations may be obscure, in addition to geography, age, sex, and race, per se, higher socioeconomic status is significantly associated with higher MS risk in black and white men and in white women in the United States.

The changing patterns of death rates in parkinsonism.

Annual crude death rates due to parkinsonism in Denmark, 1956 to 1985, and the United States, 1950 to 1984, showed a consistent hierarchy, with white male rates greater than white female than black male than black female. Rates rose sharply in both lands and sexes between 1976 and 1984. Age-specific death rate curves for whites in the 1960s and 1980s were very similar between the countries with a regular male excess. Both countries drastically changed the configuration of all the death rate age curves in parallel fashion between the 2 periods: rates were now nearly twice those of the earlier interval for each sex, age, and race, and were then maximal at age 82 or 85+ as opposed to the prior peak at age 77 or 80. Age-adjusted rates did not consistently reflect this change, being markedly lower for US white females despite their age-specific rate increases. This discrepancy appears to be an artifact of changing population distributions which increasingly differ by age between sexes and countries over time. When the recent age-specific death rates were recalculated with the thesis that all deaths had occurred at ages 5 years younger, all the 1980s death rate configurations returned to those of the 1960s, with but modest increases at most ages. This is evidence that age at death, and thus survival, has increased at all ages by about 5 years since the introduction of levodopa, released in the US in 1970 and in Denmark in 1971.(ABSTRACT TRUNCATED AT 250 WORDS)

In defense of death data: an example with multiple sclerosis.

In epidemiologic studies, mortality data can provide large numbers of cases of broad geographic extent, but diagnostic errors and case ascertainment bias may be present. We found that the geographic distribution of MS in the United States, as derived from mortality data, was comparable with that derived from a large, nationwide case-control study. In MS, evaluation of mortality provides an accurate picture of national geographic distribution supportable by more sophisticated methods. Although conclusions drawn from mortality data could be misleading, they may be accurate and are certainly worthy of further study.

Multiple sclerosis in Iceland: 1. Evidence of a postwar epidemic.

Since 1974 we have attempted to ascertain all cases of MS beginning 1900-1975 in Iceland. As of October 1979 they numbered 168; all but 5 met all diagnostic criteria of the Schumacher Committee. Virtually all cases had been examined by a least one of the authors. Cases were few and sporadic from 1900 to 1922, then increased to a plateau for 1923-44, then again increased in 1945 with an irregular plateau thereafter. Average annual incidence rate for 1945-1954 was 3.2 per 100,000 population, significantly higher than the 1.6 for 1923-1944 or the 1.9 for 1955-1974. Age at onset was significantly decreased for cases with onset 1945-1949 and then sharply increased for those with 1950-1954 onsets. The occurrence of MS in 1945-1954 meets the criteria for a point-source epidemic, whose tail thereafter mérged into what may be "baseline" for Iceland. This postwar epidemic is then similar to that recently described for the Faroe Islands, a land that shares its history, culture, and peoples with Iceland.

On the production of neurologists in the United States: an update.

Based primarily on a survey of all neurology residency training programs in the United States conducted in 1985-1986, the average annual production (incidence) of general neurologists for 1980-1986 was 363.6 and of child neurologists for 1982-1986, 53.8. About 1/4 of these general neurologists and 1/3 of child neurologists are women; about 1/4 of either are foreign medical graduates, predominantly foreign-born. Data routinely published by the AMA well match the questionnaire information. First postgraduate year of training was in internal medicine for 2/3 of general neurologists. Board certification have recently averaged 290.9 (general) and 37.1 (child) per annum. From life-table calculations, prevalence of general neurologists in 1990 is estimated at 7,500 fully-trained and 5,500 board-certified, and of child neurologists near 1,100 trained and over 600 certified. The number of neurologists is predicted to plateau near the year 2020 at some 13,700 trained, including 1,700 child neurologists, and 9,800 certified (1,100 child). The maximal prevalence rate for all neurologists will be 4.75 per 100,000 population in 2010, declining then to 4.42 by 2050; those rates provide shortfalls of 30% and 35%, respectively, compared with previously calculated needs for neurologists.

Epidemiology of multiple sclerosis in U.S. veterans: 1. Race, sex, and geographic distribution.

Five thousand three hundred five World War II and Korean conflict veterans who have been compensated by the Veterans Administration for multiple sclerosis (MS) were matched to controls on the basis of age, date of entry into military service, and branch of service. Case/control ratios for white males, white females, and black males were 1.04, 1.86, and 0.45, respectively. The coterminous 48 states, divided into three tiers on the basis of latitude, exhibited the well-known north-south gradient in risk: For all races and both sexes, case/control ratios were 1.41, 1.00, and 0.53 for the North, Middle, and South tiers. Both white females and black males showed this same north-to-south variation in risk. The case/control ratio for males of races other than black or white was 0.23, with possible deficits in risk for American Indians and Japanese-Americans. Filipinos and Hawaiian Japanese were significantly low-risk groups. These findings suggest that both a racial and a possibly genetic predisposition, as well as a geographically determined differential exposure to an environmental agent, are related to the risk of MS.