A
EXAMPLES OF RISK FACTORS POSSIBLY RELEVANT TO MILITARY SERVICE

The committee summarizes below several studies of putative risk factors for amyotrophic lateral sclerosis (ALS) relevant to military personnel. This section is not a comprehensive review or critique; rather it highlights selected studies thought to be of relevance.

PHYSICAL ACTIVITY

A number of studies have examined the association between workplace and leisure-time physical activity and ALS. The most methodologically sound is a population-based case-control study conducted in western Washington state with 174 incident cases and 348 sex-matched and age-matched (within 5 years) controls (Longstreth et al. 1998). Using in-person interviews, the authors obtained information on a variety of measures of predisease physical activity. Workplace and leisure-time physical activity generally were not found to be associated with ALS. One exception was an increased risk associated with participation in organized high-school sports (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.03–2.25). All analyses were adjusted for age, sex, and education. More recently, a case-control study in the Netherlands reported on the physical activity of 219 ALS patients and 254 acquaintance controls (Veldink et al. 2005). Information on physical activity was obtained from mailed questionnaires, and cases were responsible for finding controls for the study. There was a weak and imprecisely estimated increase in risk among positive respondents to “engaged in sports as adult” (OR, 1.3; 95% CI, 0.8–2.1) and “ever extreme physical activity” (OR, 1.2; 95% CI, 0.6–2.3) but not those “engaged in sports as youngster” (OR, 1.0; 95% CI, 0.6–1.5). Results were adjusted for age, education, body mass index, alcohol use, and smoking. The



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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature A EXAMPLES OF RISK FACTORS POSSIBLY RELEVANT TO MILITARY SERVICE The committee summarizes below several studies of putative risk factors for amyotrophic lateral sclerosis (ALS) relevant to military personnel. This section is not a comprehensive review or critique; rather it highlights selected studies thought to be of relevance. PHYSICAL ACTIVITY A number of studies have examined the association between workplace and leisure-time physical activity and ALS. The most methodologically sound is a population-based case-control study conducted in western Washington state with 174 incident cases and 348 sex-matched and age-matched (within 5 years) controls (Longstreth et al. 1998). Using in-person interviews, the authors obtained information on a variety of measures of predisease physical activity. Workplace and leisure-time physical activity generally were not found to be associated with ALS. One exception was an increased risk associated with participation in organized high-school sports (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.03–2.25). All analyses were adjusted for age, sex, and education. More recently, a case-control study in the Netherlands reported on the physical activity of 219 ALS patients and 254 acquaintance controls (Veldink et al. 2005). Information on physical activity was obtained from mailed questionnaires, and cases were responsible for finding controls for the study. There was a weak and imprecisely estimated increase in risk among positive respondents to “engaged in sports as adult” (OR, 1.3; 95% CI, 0.8–2.1) and “ever extreme physical activity” (OR, 1.2; 95% CI, 0.6–2.3) but not those “engaged in sports as youngster” (OR, 1.0; 95% CI, 0.6–1.5). Results were adjusted for age, education, body mass index, alcohol use, and smoking. The

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature authors of both studies conclude that physical activity is unlikely to be a major contributor to ALS risk (Veldink et al. 2005; Longstreth et al. 1998). Veldink et al. also reported on a systematic review of 24 studies published from 1966 to 2003. They found that most studies were methodologically weak and that all studies that had reported a relationship between physical activity and ALS had less than rigorous designs. A recent study of 7,325 male Italian professional football (soccer) players over the period 1970–2003 revealed an increased incidence of ALS relative to what would have been expected given ALS incidence in the general population in Italy (Chio et al. 2005). Five cases were identified among the players compared with 0.77 expected from age- and sex-specific rates in the general population (standardized mortality ratio, 6.5; 95% CI, 2.1–15.1). The authors also reported an increased risk associated with number of years as a professional soccer player (≤5 years: standardized incidence ratio [SIR], 3.5; 95% CI, 0.4–12.7; >5 years: SIR, 15.2; 95% CI, 3.1–44.4). CIGARETTE-SMOKING AND ALCOHOL CONSUMPTION A case-control study of 110 newly diagnosed ALS patients from two centers in New England and 210 population-based controls examined demographic characteristics, family history of ALS, and histories of smoking and alcohol consumption (Kamel et al. 1999). With adjustment for age, sex, region, and education, “ever smoking” was associated with a 70% increase in ALS risk (OR, 1.7; 95% CI, 1.0–2.8). “Current smoking” was not found to be associated with ALS (OR, 0.9; 95% CI, 0.4–1.8), but risk was increased among those who reported having stopped smoking more than 5 years before the time of the interview (OR, 1.9; 95% CI, 1.1–3.3) and even more among those who had quit within the last 5 years (OR, 4.2; 95% CI, 1.7–10.7). Increases in risk were reported for every stratum of “cigarettes per day,” “years smoked,” and “pack-years”; a statistically significant trend (p=0.046) was observed in connection with “cigarettes per day.” In contrast, ever having used alcohol was not associated with increased ALS risk (OR, 1.1; 95% CI, 0.4–3.2). A weak and imprecisely estimated increase was noted among those who reported more than 31 drinks

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature per month 5 years before onset of ALS (OR, 1.4; 95% CI, 0.7–3.0), but the increase disappeared when smoking was taken into account in the analysis. Excluding two cases with a family history of ALS did not notably affect any of the results. The Washington state study also provided results on cigarette-smoking and alcohol consumption (Nelson et al. 2000). Smoking showed consistently positive relationships with ALS (for example, “ever smoked”: OR, 2.0; 95% CI, 1.3–3.2). Current smokers experienced a higher risk (OR, 3.5; 95% CI, 1.9–6.4) than smokers who had quit (OR, 1.5; 95% CI, 0.9–2.4). Risk increased linearly with smoking duration and with cumulative pack-years (p trend, 0.001 for both duration and cumulative pack-years). A case-control study of 219 ALS patients in the Netherlands reported an inverse association between “ever/current alcohol use” and ALS (OR, 0.6; 95% CI, 0.3–0.9), and a positive relationship between current smoking and ALS (OR, 1.8; 95% CI, 1.0–3.0; p=0.03) (Veldink et al. 2005). TRAUMA In 1980, Kurtzke and Beebe published one of the first studies of ALS in veterans (Kurtzke and Beebe 1980). On the basis of 504 ALS deaths in male veterans from 1963 to 1967, they conducted a case-control study, selecting military controls matched on sex, age, date of entry into military service, and branch of service. They reported a greater frequency of self-reported injury before service among cases (7.5% in cases vs 3.2% in controls; matched OR, 2.6; p<0.01). In addition, when they considered diagnoses responsible for hospitalizations or confinement to quarters during service, more of the ALS cases (163 of 504) than of the controls (115 of 504) had diagnoses related to accidents, poisonings, and violence. Given the number of hypotheses examined and the scarcity of some of the data, the authors themselves considered the study to be a “fishing expedition.” Nevertheless, the findings were intriguing and have led others to study the question of trauma and, in particular, fractures, in the etiology of ALS. A population-based case-control study of 103 patients in the Scottish Motor Neuron Disease Registry reported similar

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature findings (lifetime history of fracture: OR, 1.3; 95% CI, 0.7–2.5), although there was a more pronounced increase in the 5 years before diagnosis in matched analysis (OR, 15; 95% CI, 2.3–654) (Chancellor et al. 1993). Controls were nearest age- and sex-appropriate persons from the general practitioners’ files. In this study, however, risk-factor information was obtained from the cases and controls through in-person interviews conducted by the primary author of the paper. In a more recent case-control study of high methodologic quality conducted in Washington state, the authors found no consistently increased ORs for prior fractures or electric shock (Cruz et al. 1999). On the basis of in-person interviews and adjustment of all results for age, sex, education, and smoking, the authors reported a weak and imprecisely estimated increase in the odds of fractures in the interval 5 years before diagnosis in cases compared with controls (OR, 1.3; 95% CI, 0.7–2.3); they suggested that fractures may be consequences of subclinical ALS onset rather than potential risk factors. TRANSMISSIBLE AGENTS A few studies have examined the possible role of infection in the etiology of ALS, but these seroepidemiologic studies have generated inconsistent findings. One case-control study of 20 incident ALS cases and age-, sex-, and residence-matched population controls in Italy examined seropositivity of human herpesvirus-6 and -8 and echovirus-7 (Cermelli et al. 2003). Despite the small sample, strong but imprecisely estimated increases in ORs for the presence of antibodies to HHV-6 (OR, 3.2; 95% CI, 0.8–12.9), HHV-8(OR, 8.4; 95% CI, 0.9–79.4), and echovirus-7 (OR 3.0, 95% CI, 0.8–18.1) were reported. One limitation of this study is the difficulty in establishing whether infection occurred before ALS onset or was a consequence or correlate of the disease itself. Nicolson and colleagues (2002), studying eight Gulf War veterans with ALS and two comparison populations, reported that the Gulf War veterans all had serologic evidence of systemic myocoplasmal infection, as did the majority of nonveteran ALS patients. Seven of the eight veterans with ALS were positive for a

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature specific species (M. fermentans), compared with 13 of 22 positive (of 28 total) civilians with ALS and two of 70 total control patients without ALS. The authors suggest a link between a specific myocoplasmal infection and ALS; however, comparison subjects were not adequately described to support a judgment of the quality of the study. In addition, the ALS subjects were atypical in their clinical presentation. For these reasons, the data presented do not clearly support a relationship between mycoplasmal infection in Gulf War veterans and ALS. LEAD In a case-control study conducted in New England, 109 newly diagnosed ALS patients from two centers (the Neuromuscular Research Unit at New England Medical Center and the Neurophysiology Laboratory at Brigham and Women’s Hospital) and population controls were interviewed about lead exposure (Kamel et al. 2002). Self-reported occupational exposure to lead was associated with an increase in ALS risk (OR, 1.9; 95% CI, 1.1–3.3) and a dose-response relationship was observed with respect to lifetime days of exposure. No association with residential or recreational exposure to lead was found. In the case-control study conducted in Washington state (described above), lead exposure was also examined. McGuire et al. (1997) assessed 174 cases of ALS from three counties in Washington for various occupational exposures. Determination of exposure was obtained from self-reports and from an assessment by a panel of four industrial hygienists that reviewed self-reported job titles, tasks, durations, and exposures to specific agents. Self-reported exposure was found to be linked to ALS (OR, 1.9; 95% CI, 1.0–3.6), but the association was lost when the panel assessment was used as the basis of assigning exposure (OR, 1.1; 95% CI, 0.6–2.1). According to self-reports, there were four more cases and seven fewer controls reporting exposure than were classified by the panel as exposed. A small case-control study of 74 ALS patients from the Mayo Clinic in Rochester, Minnesota, and up to four controls per case, for a total of 201 controls, reported a strong association (OR,

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature 5.5; 95% CI, 1.44–21.0) with total lifetime exposure to lead in excess of 200 hours (Armon et al. 1991). PESTICIDES The case-control study of occupational exposures in Washington state reported that exposure to agricultural chemicals was associated with ALS (OR, 2.0; 95% CI, 1.1–3.5) on the basis of panel assessment of exposure (McGuire et al. 1997). The association was attenuated when analysis was based strictly on self-reported exposure (OR, 1.6; 95% CI, 1.0–2.7). Agricultural chemicals were defined as fertilizers and pesticides, which consisted of herbicides, fungicides, insecticides, and other pesticides. Separate analyses showed increases in risk associated with each of those components except “other pesticides,” which had only one exposed case. ENVIRONMENTAL TOXICANTS In the early 1950s, a much higher than expected incidence of ALS was reported in Guam (Rowland 2000; Siddique et al. 1999). Several environmental factors were proposed, including cycad flour (a part of the Guamanian diet) and exposure to low concentrations of calcium and magnesium in the local environment. Recent evidence indicates that a substituted amino acid, BMAA, produced by cyanobacteria and bioconcentrated through fruit bats, may be responsible for the ALS-parkinsonism-dementia complex of Guam (Banack and Cox 2003; Banack et al. 2006; Cox et al. 2003; Cox et al. 2005; Cox and Sacks 2002; Murch et al. 2004a; Murch et al. 2004b). REFERENCES Armon C, Kurland LT, Daube JR, O’Brien PC. 1991. Epidemiologic correlates of sporadic amyotrophic lateral sclerosis. Neurology 41(7):1077–1084.

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature Banack SA, Cox PA. 2003. Biomagnification of cycad neurotoxins in flying foxes: implications for ALS-PDC in Guam. Neurology 61(3):387–389. Banack SA, Murch SJ, Cox PA. 2006. Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands. Journal of Ethnopharmacology 106(1):97–104. Cermelli C, Vinceti M, Beretti F, Pietrini V, Nacci G, Pietrosemoli P, Bartoletti A, Guidetti D, Sola P, Bergomi M, Vivoli G, Portolani M. 2003. Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7. European Journal of Epidemiology 18(2):123–127. Chancellor AM, Slattery JM, Fraser H, Warlow CP. 1993. Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register. Journal of Neurology, Neurosurgery and Psychiatry 56(11):1200–1206. Chio A, Benzi G, Dossena M, Mutani R, Mora G. 2005. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128 (Pt 3):472–476. Cox PA, Sacks OW. 2002. Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam. Neurology 58(6):956–959. Cox PA, Banack SA, Murch SJ. 2003. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proceedings of the National Academy of Sciences of the United States of America 100(23):13380–13383. Cox PA, Banack SA, Murch SJ, Rasmussen U, Tien G, Bidigare RR, Metcalf JS, Morrison LF, Codd GA, Bergman B. 2005. Diverse taxa of cyanobacteria produce beta-N-methylamino-L-alanine, a neurotoxic amino acid. Proceedings of the National Academy of Sciences of the United States of America 102(14):5074–5078.

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature Cruz DC, Nelson LM, McGuire V, Longstreth WT Jr. 1999. Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-based case-control study. Neuroepidemiology 18(2):101–110. Kamel F, Umbach DM, Munsat TL, Shefner JM, Sandler DP. 1999. Association of cigarette smoking with amyotrophic lateral sclerosis. Neuroepidemiology 18(4):194–202. Kamel F, Umbach DM, Munsat TL, Shefner JM, Hu H, Sandler DP. 2002. Lead exposure and amyotrophic lateral sclerosis. Epidemiology 13(3):311–319. Kurtzke JF, Beebe GW. 1980. Epidemiology of amyotrophic lateral sclerosis: 1. A case-control comparison based on ALS deaths. Neurology 30(5):453–462. Longstreth WT, McGuire V, Koepsell TD, Wang Y, van Belle G. 1998. Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case-control study. Archives of Neurology 55(2):201–206. McGuire V, Longstreth WT Jr., Nelson LM, Koepsell TD, Checkoway H, Morgan MS, van Belle G. 1997. Occupational exposures and amyotrophic lateral sclerosis. A population-based case-control study. American Journal of Epidemiology 145(12):1076–1088. Murch SJ, Cox PA, Banack SA. 2004a. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proceedings of the National Academy of Sciences of the United States of America 101(33):12228–12231. Murch SJ, Cox PA, Banack SA, Steele JC, Sacks OW. 2004b. Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurologica Scandinavica 110(4):267–269. Nelson LM, McGuire V, Longstreth WT Jr, Matkin C. 2000. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. American Journal of Epidemiology 151(2):156–163.

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Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature Nicolson GL, Nasralla MY, Haier J, Pomfret J. 2002. High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with Amyotrophic Lateral Sclerosis (ALS). Journal of Clinical Neurosience 9(5):525–529. Rowland LP. 2000. Hereditary and acquired motor neuron diseases. In: Rowland LP, Editor. Merritt’s Neurology. 10th ed. Philadelphia, PA: Lippincott Williams &Wilkins. Pp. 708–714. Siddique N, Sufit R, Siddique T. 1999. Degenerative motor, sensory, and autonomic disorders. In: Goetz CG, Pappert EJ, Editors. Textbook of Clinical Neurology. 1st ed. Philadelphia, PA: W.B. Saunders Company. Pp. 695–717. Veldink JH, Kalmijn S, Groeneveld GJ, Titulaer MJ, Wokke JH, van den Berg LH. 2005. Physical activity and the association with sporadic ALS. Neurology 64(2):241–245.

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