McGuire Nelson EpiOfALS ALSTextbook MitsumotoHed

2Epidemiology of ALS

.alerie McGuire and Lorene M. Nelsoniivision ot"Epidemiology, Department of Health Research and Policy,

'/,1J7t"orrlUniversit\' Schoc: of Medicine, Stanford, Caiifornia, US.A.

INTRODUCTION

\myotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is the most commonmotor neuron disease. ALS is a late-onset rapidly deteriorating neurological disorderc'haracterized by the selective death of motor neurons in the brain and spinal cordthat innervate skeletal muscles, with clinical symptoms of progressive weakness.'nusc!e wasting, and spasticity (1). The median survival with ALS is usually threecars and the CaL:seof death is respiratory failure. pneumonia. or cardiac arrhyth-nias. Scientific advancements have been made over the past several years to under-'land the Mendelian forms of ALS and other diseases of the motor neuron. The'nost significant advancement has been the identification of genes causing some()nm offami!ial ALS (2.3). the spinal muscular atrophies (4,5), and frontotemporal

dementia (6). The epidemiologic observation of specific patterns of familial aggrega-iion in some individuals with motor neuron disease started the chain of events thatled to the identification of the underlying genes. Despite exciting advances intounderstanding the molecular genetic basis of some Mendelian forms of the disease,ilOwever, the causes of sporadic (non-familial) ALS are still unknown, and the;ipparent select:vi!:; for motor neurons remains unexplained.

EPIDEMIOLOGlC: CLASS!FiCAT[ON OF ~ORMS OF ALS

In the -:<3.5:5cr- epl(~e~-t~~':;~cg:c,U"lC"genetic fecl'L:"II"es.three 11'lajor forllls of ALS have'teE ide:.~'(i5.ec":i ~;:::'adic ~~~LS. ii ft~rniiic~:'0:' here6i:ary P~LS. anc (iii) the 'Vestern',"cine \1,~,':[.:',[. =s:[c',',ds fc: , -::->e :",:[:e:' "[,S E:'s': described arnO:1g the Chamorrc

eeple c':~ ;=-~_:c::-"-:.E.~-,6 'cl-_e p""=-~ ),Lier_:~ ::-. ":>:i~,~::'ec. 'Lcqillre ;JEThologic2J charact:eri-

;."CS sir:~~jE:' ".': ~:c~:'k::-~sc:r.'s Gisec~seF=1i c.EC.L_~z~-leiEle:-'sdisc2.se.referred to as A..LS;'i:'K~l:SC:-;.is:-t~-,;i'~r:~.::I.:~'.c.~\,::,:--,"pie~:F:CJ:= - S -:'-~-'CIndigeEcus )cpu~ation5 in Irian

~~Co '~'es~.er:-. F~-' ='-~i,i:-,"f,_ S S.~.;.,~':-~-',: ,'~:-e2,~ i:-. :I-_e Kii !?e:-~i:-:sL:I" cf Japan aisc- . .---

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18 McGuire and Nelson

METHODOLOGICAL CONSIDERATIONS IN ALS RESEARCH

The correct classification of subjects with ALS is important to identify disease-associated risk factors. The importance of a universally accepted case definitionfor ALS was the result of two major consensus conferences, the first convened bythe World Federation of Neurology (WFN) ALS Research Subcommittee (11),where disease definitions were developed, and a subsequent conference where casedefinition criteria were further refined (12). Table 1 summarizes the WFN "El Escor-ial" criteria for the diagnosis of ALS that require the presence, evolution, and pro-gression of upper motor neuron (UMN) and lower motor neuron (LMN) findings atmultiple levels. Progressive LMN signs alone may be accepted for the purpose ofdiagnosing ALS if the individual carries a gene for familial ALS and other causeshave been excluded (13). Patients with ALS may be classified as definite, probable,possible, or suspected. Ross et aJ. (12) reported a method whereby using a combina-tion of clinical, eIectrodiagnostic, and radiologic data, some patients would beclassified as having "possible" ALS according to the WFN El Escorial criteria,and others would be considered as having "laboratory-supported definite AL~."However, many clinicians avoid this categorization by stating that a patient eitherhas ALS or does not have ALS. The pathology and classification of ALS and othermotor neuron diseases will be described in detail in later chapters.

Another methodologic challenge when conducting epidemiologic studies ofALS is case ascertainment, that is, the best method for finding patients to includein the study. In a case-control study, recruitment of ALS patients from referral-based centers such as specialized clinics or tertiary centers will be under-representa-tive of the number of ALS cases available from the underlying population, resultingin referral bias. Older more debilitated patients or patients from lower socio-economic groups are less likely to be referred to specialized clinics. Yoshida et aJ.(14) noted that ALS patients from referral centers tend to be 10 years younger (meanage at diagnosis is 55 years) and have longer median survival (greater than threeyears) than do ALS patients recruited from defined populations such as residentsof a well-defined geographic area (15,16). ALS patients recruited from referral centers

Table 1 EI Escorial WFN Criteria for the Diagnosis of ALS

The diagnosis of ALS requires the presence of the following:Signs of LMN degeneration by clinical, electrophysiological, or neuropathological

examination in one or more of four regions (bulbar, cervical, thoracic, or lumbosacral).Signs of UMN degeneration by clinical examination and progressive spread of signs within a

region or other regions.Definite ALS: UMN and LMN signs in bulbar region and at least two of the other spinal

regions or UMN and LMN signs in three spinal regions and signs of progression over a12-month period following diagnosis.

Probable ALS: UMN and LMN signs in at least two regions with UMN signs rostral to aregion with LMN signs and signs of progression over a 12-month period following diagnosis.

Possible ALS: UNM and LMN signs in only one region or UNM signs in two or moreregions (i.e., progressive bulbar palsy, primary lateral sclerosis).

Suspected ALS: LMN signs in two or three regions (i.e., primary muscular atrophy).

Abbreviations: WFN. World Federation of Neurology: LMN. lower motor neuron; UMN. upper motorneuron: ALS. amyotrophic lateral sclerosis.Source: Adapted from Refs. 1]-13.

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Epidemiology of ALS 19

may be suitable fo~'ciinica: trials or other experimental studies. but less than idealfor participating in studies to identify causa] factors for the disease.

DESCRIPTIVE STUDIES

Incidence and Mortality Data

Excluding the western Pacific foci. the incidence of sporadic ALS in the UnitedStates is approximately::' per 100.000 per year in population-based studies with nearcomplete case ascertainment (\4.15.17-19). Internationally. ALS is referred to asmotor neuron disease (MND) and incidence rates for the disease worldwide rangesfrom 0.86 to 1.4 per 100.000 per year (20-26). With a median survival of three years,the prevalence ratio of ALS is approximately 6 per 100.000 per year or nearly threetimes the incidence rate. Since almost all patients with ALS die due to the disease,mortality rates for ALS should pal'allel incidence rates. However, the reported mor-tality rates for ALS in the United States are much lower than that for incidence rates(1.5 per 100.000 per year for all ages when compared to 2 per 100.000 per year). Thisphenomenon is probably due to underreporting of ALS on death certificates. Thecumulative probability of developing the disease during a lifetime in the UnitedStates is about I in 1000 deaths for those reaching adulthood. The incidence andmortality rates for MND are also higher in recent decades than those previouslyreported in industrialized countries (18.23.24). This increase may be accountedfor by improved ascertainment. better reporting. and loss of competing causes ofmortality in a susceptible cohort (27-29).

The incidence of sporadic ALS is 20% to 60'10higher in men than in women(! 9.12.15.30). Age-specific incidence rates appear to increase with age in population-based series peaking at ages 65 to 74 years (Fig. I) (14.19.21). ]n contrast. the incidenceof the disease peaks earlier at 55 to 60 years in referral-based studies (31,32).

Comparing age- and gender-specific rates among various studies is complicatedby methodological differences in ascertaining ALS cases or assigning diagnosticcriteria and different age distributions of the underlying populations. In order tomake meaningful comparisons. the calendar years studied should be similar in allstudies so that any differences in incidence rates are not due to changing rates overtime. Chancellor and Warlow (33) compared the age- and gender-specific rates fromeight surveys that were judged to have near complete case ascertainment andrestricted the analysis to men and women aged 45 to 74 years (14.3~0). McGuireet aI. (19) conducted a simila;' analysis and included the incidence rates from studiesfrom western \VashingtOli State (19). Texas (41). and Scotland (41). A recent studyfrom Italy addee d~ita ;ro111incidence studies conducted in Ireland. Sweden. andItaly (21.25.43-45 . Table 2 shows the incidence of ALS in men and women fromthese 16 differep, s.uGies, c;ge-adjusted to the 1990 U.S. population for those45 to -C4years old.. Ger;e:'ali). the rates tena te be higher for northern latitudes thanfor southern iatir~lcies."!though t!1emost recent survey in Piemonte Italy (25) showsI'ates that are sim;h,:' ,c ,he studies in Washington State (19). Scotland (42). andIreland (2::' . The :('''e:' ;;1Ci<.ience;'ates in ear!ier swdies could reflect underascertain-'11entof cases ::;"~J:ere:1ces ::, case-defini:ioi:. L the three L'.5. studies (14.19.41)Li1d tl-lt" F:E:':.~l: ~~;":"'~'. :: ~:~:e\..:~~~:erenceE;.. :'[~'~eEare ~e5s sTriking between ll1en

(='.e S',T e:s -"ese d:ffel'ei1CeS:n,,; reflect the differ-,-ce~ .._.~_,::.F_,-.. -.-\..


15-24 25-34 35-44 45-54

Age

55-64 65-74 75+

Figure 1 Age-specific incidence of ALS in men and women for western Washington State fromApril 1990 to March 1995. Abbreviation: ALS, amyotrophic lateral sclerosis. Source: From Ref. 19.

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10 I -+- MenMean age57.3

.. I -8- Women..

Meanage 64.5..;.. 8....CI.

gco::....CI.'"..J-<...C> 4...-'".....'".s


The incidence of ALS in racial or ethnic groups. other than Caucasians has notbeen well defined. A study by Annegers et a!. (41). in Texas, reported an overall inci-dence rate of 1.5 per 100,000 for African American and Hispanics combined. How-ever, the study did not achieve complete case ascertainment possibly due todifferences in access to health carl' when compared to Caucasians and may haveresulted in underestimation of the incidence of ALS in these groups. In the studyin Western Washington State. the age-adjusted incidence rates were 0.74 per100,000per year for non-white men and 0.53 per 100.000per year for non-white women(19). However, the number of non-white patients was small (11= 10),mainlycomprisedof African Americans. Future studies are thus needed to obtain estimates of theincidence of ALS in ethnic groups other than non-Hispanic Caucasians.

Mortality studies based on death certificate data have assessed racial and ethnicdifferences in death rates from ALS in the United States. These studies have shownthat the rates for whites exceeded those for non-whites by 70%, and were higheramong women and those older than 60 years (32,46). ALS mortality rates amongAfrican Americans were reported to be lower than mortality rates among U.S.Caucasians (47); however, using death certificates to identify ALS cases likely resultedin the under ascertainment of African American cases of ALS.

Epidemiology of Western Pacific ALS

The Western Pacific form of ALS was identified in the early 1950s, with incidence,prevalence, and mortality rates estimated to range from 50 per 100,000 per year to100 per 100.000 per year (48,49). Males were twice as likely as females to be diag-nosed with the disease and the median age at diagnosis was 44 years. Clusters ofALS, frequently in association with a PDC, were noted in three distinct geographicisolates (50): in Guam (Marianna Islands), in two villages of the Kii Peninsula ofJapan, and among the Auyu and Jakai people in a small area of Irian Jaya (westernNew Guinea). The ALS/PDC clusters differed from community-identified clustersin two ways: (i) the 100-fold excess of occurrence (rather than two- or three-foldgreater than the expected number of cases) and (ii) the continued excess incidenceover time (51).

Familial aggregation of ALS/PDC was first recognized in Guam in the 1950s(48.52.53). However, the pattern of transmission does not follow simple Mendelianpatterns of inheritance and suggests that an environmental agent may be associatedwith the disease. Plato et ai. (54) examined the incidence and prevalence of ALS/PDC in Guam over the past 40 years and reported significantly higher rates forALS and Parkinson's disease among relatives of ALS/PDC cases than in the generalpopulation of Guam, The rates were higher among siblings of patients with ALS andamong the children of patiems \vith PDC. However. excess risk for developing ALS orPO was alsc observed among wives, suggesting that ALS/PDC may be associatedwith an environmental factor and is not a Mendelian genetic disorder.

Another clue to the etiolcgy of ALS/POC is the prevalence of excessive neuro-libriliary tangles i::: asymptomatic Chamo:Tos, However. genetics alone do notexplain the cc,use 0:' Western Pacific ALS. given that people from three distinctgeogr"phic ,,:'eas c::c,'e:::igh:'ates cf ALS PDC ,,;::dthat Filipinos who emigrated to:Ju",n- c. c . : ~.:-:~~.~.: 'C.sc .12::: :-_:g:'_Co"~tes :' - _3 c- fDC 55!. Funhermore, Ege

~~:c~g:'::s.~ -..~5 4_~-~'-'?[>~ ~c~~ ~,::e~-. ::~_c:'="s::-:§: ..- ~~he scy.xd~.e:':.~_~.~nHges of GualT~

..

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Two environmentalhypotheseshave beenproposed to explain the epidemicofALS/POC in the western Pacific. The first hypothesis was centered on the possibledeficiency of essential minerals in the soil, specifically calcium and magnesium(56,57). Subsequent studies on Guam, however, demonstrated that the food andwater supply contained adequate concentrations of calcium and magnesium (58,59).

The second hypothesis regarding ALS/POC suggests an environmental agentor toxicant. The epidemic occurrence of ALS/POC in the western Pacific has focusedattention on a related glutamate analog found in the seed of the Cycas Circina/iscycad palm, ~-N-methylamino-L-alanine (BMAA) (60). This toxin is released duringthe preparation of flour from the cycad and has been reported to induce upper andlower motor neuron death in macaque monkeys (61,62). However, this finding iscontroversial since the concentration of BMAA in the flour that had been washed

is thought to be too low to induce disease (63).Recently, Cox and Sacks (64) proposed that high concentrations of BMAA or

its metabolites could have been ingested by the Chamorro people while consuming tflying foxes (bats), which feed on the cycad nut. Ifbiomagnification occurred, the batswould have high levels of BMAA. Although flying foxes are endangered today onGuam and the species thought to cause Western Pacific ALS is actually extinct,Banack and Cox (65) assessed museum specimens of these bats and reported that con-suming a single bat could contribute 3751mg of BMAA to the diet, which would beequivalent to eating 174 to 1014kg of processed cycad flour. Whether consumptionof flying foxes is associated with the etiology of the ALS/POC remains to be answered.

The persistence of a high prevalence of neurodegenerative disease in somevillages in Guam suggests the continued presence of an etiological mechanism, albeitin attenuated form. The changing spectrum may reflect improved case ascertainmentor temporal differences between the interaction of environmental factors and geneticsusceptibility among individuals at risk for ALS. The data are consistent with a con-stant level of exposure to an environmental toxin that peaked during World War IIand has declined, but not completely disappeared. Age-specific incidence rates andmortality rates have decreased and age at onset has increased by 16 years for ALSand by 13 years for POC (66). Individuals exposed to higher doses of toxin mightdevelop ALS at a relatively early age, with or without associated POc. Individualsexposed to a lesser dose might develop, at a later date, ALS with or without POC,POC alone, or dementia alone. However, a more recent report continues to suggesta possible genetic etiology (66). Environmental changes, especially in the diet ofChamorros, may have had a beneficial effect in a genetically susceptible population.

The Role of Clusters in ALS

Clusters arising from community reports of patients with ALS have yet to yield epide-miologically useful information about causes of ALS (67). Furthermore, very fewsuspected clusters are confirmed when rigorous criteria are applied and when multiplecomparisons and chance findings are taken into account (67). To compensate for theeffectof chance in assessing the potential significanceof clusters arising from the commu-nity (68), Armon et al. (67) proposed that the value for the ratio of observed to expectedcases that may be considered of epidemiological significance be increased. Preciousresources could then be spent on clusters that, if confirmed, were not due to chance alone.

Mundt et al. (69) investigated an increase in mortality from ALS among the32,000 civilian employees who had worked at Kelly Air Force Base in San Antonio,Texas. Patients and patient-interest groups joined forces with federal and state agencies,

,Epidemiology of ALS 23

and external scientificadvisors 10evaluate the cluster. The study assessed ALS mortalityin the context of overall mortality and other disease-specificmortality data. The inves-tigators concluded that the scientific evidence did not support excess mortality fromALS: however. follo",-up of this relatively young cohort continues. since only 10% ofthe civilian workers had died at the time of the investigation.

Reports from t\>vostudies suggest that the risk of ALS may be higher in youngservicemen who were deployed to the Persian Gulf War (70.71). Both studiesrecruited cases via military and health records and publicity campaigns amongmilitary personnel. In one study. Haley (70) identified 20 cases of ALS diagnosedbefore the age of 45 and calculated the expected incidence of ALS from nationalmortality statistics. The investigator noted an excess risk of ALS. In the secondstudy. two neurologists reviewed case records and supplemented their informationwith telephone and personal inquiries to confirm the cases of ALS (71). In addition,Horner et a!. (71) compared the incidence of ALS in those who were deployed to theGulf arena with those who were not deployed and found a two-fold increased risk ofdeveloping ALS. While analyzing the data according to the branch of service, therisk was significantly elevated in deployed personnel in the Air Force and the Army.A recent report from a cohort of men who were followed as part of an AmericanCancer Society study provided evidence that men who served in the military, regard-less of branch of service or time period. were 60% more likely to die from ALS thanthose who did not serve (72). This cohort did not include Gulf War veterans. Thesefindings raise the possibility that one or more exposures associated with militaryservice in general may increase the risk of developing the disease. However, other stu-dies are needed to confirn1 these findings and identify the reasons for the excess risk.

On the basis of the findings of Horner et al. (71). the Department of VeteranAffairs (VA) established a National Registry of Veterans with ALS. The primarygoals of the registry are (i) to provide the VA with data on the current numberand characteristics of veterans with ALS and to recruit newly diagnosed cases ofALS. (ii) to provide a mechanism to inform veterans with ALS about research stud-ies and clinical trials for which they may be eligible to participate, and (iii) to estab-lish a resource for the conduct of large-scale studies to identify epidemiological andgenetic factors that may be associated with the disease.

EPIDEMIOLOGY OF FAMILIAL AlS

Only 5"...to 10""of patients have one or more first degree relatives with ALS (1.14.73-76). Some cases with familial ALS have a Mendelian pattern of disease in their family,but many patients with familial ALS have no apparent Mendelian inheritance pattern.Familia] ALS may be inherited in either an autosomal dominant. autosomal recessive,or X-linked recessive pattern (:.3). In the aUtosomal dominant cases. the gender ratiois close to I: I. The most common form of inheritance is autosomal dominant (77,78).[n only rare instances is the inheritance aUtosomal recessive (79).

MUtations at the SOD! gene on chromosome 21 account for 20';;, of familialcases and are inhei'ited as autosomal dominant with over 100 SOD I mutations iden-,ified ""-. .\dditior:a! chrOmOSOJ1.1eSimplicated in autosomal recessive ALS are~hrol11osome:~ Sf ,',1",('chromosor',e .::(/8). as \'xelias an X-linked gene (81). Patients'rtb fa"lili,,!.~'-~ ,1:',0,"",: f"p.ge :: :0 ::0 : ta"s \ oLIngerthan patients diagnosed with

,.'o.'c,(J -'. ___:: 'C'.;: " :'., c ,:-::S:'1(' "f "'~'e--::' :- pes S':: Simi!e;!" to mutation

c, --ne:-e ..;.;, :"r . :Sr ~"S -- ~ "'~. :""ers~:' SO~ ,.n dt' t.C:; ALS. suggesting that

,


other unknown factors must be contributing to the penetrance of the SOD1 muta-tions. Chapter 3 provides more detail on the familial forms of ALS.

ANALYTICSTUDIES

Special Methodological Issues

The diagnosis of ALS generally occurs 12 months after the onset of clinical symp-toms (14,21,83,84). Since muscle weakness accrues in a gradual manner, the diseasemust be biologically active long before the first clinical signs. Biological onset couldpredate clinical onset by three years or even longer. This assumption is based on twopoints: (i) 90% of the anterior horn cells have degenerated by the time of the patient'sdeath, usually three years following the clinical onset of first symptoms, and (ii) ALSis diagnosed when at least half of the motor neurons have died (20).

A special consideration with regard to chronological relationship arises whentrying to identify risk factors for ALS because the biological onset of the diseasemay precede its clinical manifestation by months or years. When conducting case-control studies to identify etiological risk factors that may be associated with the dis-ease, the "reference date" should be one to five years prior to the date of diagnosis toexclude this preclinical period.

Types of Analytical Studies

The most appropriate scientific method to investigate the etiology of a rare diseasesuch as ALS is the case-control design. Ideally, a prospective study design wouldallow the collection of risk factors before the disease occurs, but assembling a largecohort of patients, only a few of whom would develop ALS, takes years and is verycostly. The cross-sectional study design would not be appropriate because the timingof exposure relative to the disease cannot be determined. If a case-control studyrevealed hypotheses, a retrospective cohort study might be utilized to follow up withregards to specific risk factors that have been measured in a cohort such as an occu-pational group (85). The chief disadvantages of case-control studies are the multiplesources of biases to which they are subjected (86) and the concern that testing multiplehypotheses may result in significant findings based on chance alone. Unfortunately,until recent years, most case-control studies of ALS have not been rigorouslydesigned, usually relying on a small number of prevalent ALS cases from referralcenters and choosing inappropriate control groups such as coworkers or spouses.Furthermore, publication bias is a major concern, since studies with positive findingsare more likely to be published than studies with negative findings (87,88). Fora more comprehensive review of the epidemiologic principles for the conduct ofneurological. studies, the readers should refer to Tanner and Ross (89) and Nelsonand McGuire (90).

RISK FACTORS FOR ALS

ALS research has undergone exciting progress in the past decade, with evidenceaccumulating that injury caused by free radicals, exogenous neurotoxicants, excito-toxins, or a cumulative effect of all these factors may play an important role in the


Environmental Agentsmetals pesticides

Amyotrophic Lateral Sclerosis

.. 'ial Pathological M,eChanismSI/glutamate C:\CJtotOX1CIl~oxidati,.c strcs~

impaired a\onal transportprotein agg.regation

apoptosis

"I

Genetic Susceptibility'" gene mutations in lamilial ALS (ALS 1-7)

candidate genes in sporadic ALS

Lifestyle Factors

cigarette smokingdiet (fat, fiber. antioxidants)

Figure 2 Etiological theories and pathogenic mechanisms for ALS. Abbreviation: ALS.amyotrophic lateral sclerosis.

pathogenesis of ALS (Fig. 2). Earlier theories purported that exposure to environ-mental toxicants, excessive physical activity, skeletal fractures, and electrical shockmay playa role in the pathogenesis of ALS, and most epidemiologic studies haveemphasized the investigation of these putative risk factors.

A notable limitation of previous case-control studies is that very few haveexamined risk factors for ALS among incident (newly diagnosed) cases, and almost:dl studies were conducted in referral centers with the exception of three studies thatwere conducted in population-based settings. A study in Scotland identified 103 inci-dent cases from a motor neuron disease registry (91): however, this study was not aIrue incidence cohort because 39 of the incident ALS cases in the registry died priorI,) the initiation of the case-control study and the investigators did not collect infor-Illation on the deceased subjects. A second study in New England included 109 ALS,'ases from two referral centers and recruited population-based control subjects usingandom digit dialing (92). A third population-based study from western Washington

"-late identified incident cases (93). All other published case-control studies haveIised prevalent cases. This feature over-represents long-lived cases and makes it,Iilficult for the investigators to distinguish etiological risk factors from prognostic:Ictors. Selecting incidem cases is extremely important. especially with a short dura-11)11disease such as ALS. A second limitation is that. with few exceptions (91.93,94).\ LS case-col1ll"c' studies ha\e not been conducted in defined populations. but in,,'condary stud~ bases such as hospitals. referral centers. or ALS societies. where':Ilients are nm likel:, ,0 be representative of ALS patients in the general population.\ third limitalioE of ;::"e\iOLlSstudies is the smallsamplesize(usuallyfewerthan 100

c~~ec'~s !ie 5I~~C~.s 512;LiSi.iCc~~:"'cv'e:. "c detect associations.u;: ..,:":: .:g _:~:-;~_c~.:~___ .-c~,=c ~'.::<:e C2.Sf-ccI"!trc: studies

- ~ . -'" .,- '='.:c C,c._ _''-~'- cC.~~~:£ ::.~... ~ ~:-~e ep1de:11101ogi-

-


Table 3 Risk Factors for ALS: Strength and Certainty of the Associations

Strength of association

Known risk factorsAgeDisease-causing mutations (SODl, alsin) in Mendelian ALSGender (male> female)Family history of ALSClusters (Persian Gulf War, Western Pacific ALS/PDC)Possible risk factorsNeurotoxicant exposures

Lead

MercuryPesticide exposure (insecticides, herbicides)Solvent exposure

Certain occupation characteristicsElectrical workersFarmers

Industrial occupationsTrauma

Skeletal trauma, fracturesSevere electrical shock (with unconsciousness)

Vigorous physical activityHeavy manual laborAthleticism

Lifestyle factorsCigarette smokingAlcohol intake

Anthropometric measures (weight, body mass index)Diet

High fat intake (saturated> monounsaturated)High glutamate intakeLow fiber intakeLow antioxidant intake

Factors not widely investigatedInfectious agentsMedical history

Other medical conditionsPrescription and over-the-counter medication useHormonal and reproductive factors (in women)

Other exposures or lifestyle factorsCaffeine intakeRecreational drug useHobbies, avocational exposuresResidential chemical and pesticide exposureResidential proximity to industry

iHHii RR 1.2-1.4i RR 3.0-4.0i RR 2.0-50+

Abbreviations: ALS. amyotrophic lateral sclerosis; SOD. superoxide dismutase: PDC, Parkinsonism-dementia complex.

...

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Physical Trauma

Fractures

Several cases-control studies have identified physical trauma or limb injuries as riskfactors for ALS. with odds ratios ranging from 1.3 to 10.0 (83,95-102). However, theoverall excess of fractures occurred closer to the time of diagnosis. In a population-based case-control study in Scotland, the investigators found a significant associa-tion with fractures that occurred five years prior to date of diagnosis [odds ratio(OR) = 15.0. 95°;;,confidence interval (CI) = 2.3-654], but reported no associationwith a lifetime history of fractures (91). A more recent study in western WashingtonState reported a similar finding with a lifetime history of previous fractures and onlya weak association five years prior to date of diagnosis (103). Cases may be moreprone to falls due to subclinical weakness prior to their diagnosis of ALS. A retro-spective cohort study of ALS also showed no increased incidence of ALS in patientswho had sustained head trauma (85).

Electromagnetic Field (EMF) Exposure. Electrical Occupations. andElectrical Shock

EMF exposure has been the subject of several epidemiological investigations of ALS(104-107) and a recent review (108). Johansen and Olsen (J05) conducted a large,retrospective cohort study among men employed in utility companies in Finlandand reported a twofold increase in mortality from ALS. In another cohort study,Savitz et a!. (106) reported a threefold increase in risk for ALS [relative risk(RR)= 3.1,95'% CI = 1.1-9.8] among men employed as electrical workers for 20 yearsor longer. Noonan et a!. (107) used death certificate data for the years 1987 to 1996to identify ALS cases in a case-control study conducted in Colorado. The investiga-tors obtained a mean magnetic field index using a job-exposure matrix, and foundno association between EMFs and ALS. However, individuals with a history ofwork in electrical occupations had a greater than twofold increased risk of ALS(OR = 2.30. 95'1.) CI = 1.3--4.1). Two recent studies from Sweden reportedconflicting results (109.110). Both studies addressed the association of EMF exposurewith neurodegenerative diseases and used a job-exposure matrix to assess EMFexposure using death certificate data to ascertain cases and Census data to determinethe person's occupation. Hakansson et a!. (109) assessed a cohort of 538,221 engi-neering industry workers and found a greater than twofold increase in risk forALS in cases with the highest exposure to EMF (OR = 2.2. 95% CI = 1.0--4.7).However. Feychting et a!. (110) found no association with EMF exposure and riskof ALS in a cohort of nearly five million individuals in the 1980 Swedish Census,although they did report a 40% increase in risk for electrical or electronics workers.

The findings of elevated risk with EMF is intriguing because past case-control studies have also shown elevated risks associated with electrical shock(95.99.103,111-113). aJthough many of the odds ratios were not statistically signifi-cant as the exposure to severe electrical shock was rare. Future studies are warrantedto pursue the possibility that electrica] occupations or EM F exposures are associatedwith ALS.

Physical Activity

Physic<:1i nc'l;\; -".. ':c,-'-~ ,'-C ;'lsk cC ;'\LS ~> n.-:od:fying the e\Ient of the exposurec' <:neur;:-ICAiC<?:", ',_ :!c'd;;-,§: 11le'o"in's [:'anspcn IC its t2.rget or making selective


motor neurons more susceptible to injury by the neurotoxin (1]4). Several epidemio-logical studies reported that vigorous physical activity at work and during leisuretime is associated with ALS (35,37,]] 5-120), while two case-control studies didnot report such an association (12],]22). Workers engaged in heavy physical laborhad a twofold increase in risk of developing ALS (1 ]5,]20). ALS patients whohad a history of athletic participation were significantly more likely to develop ALS.

In a population-based, case-contro] study of ALS conducted in WesternWashington State, detailed information on lifetime physical activity, both at workand at leisure, was obtained from incident cases (n = ]74) and population-basedcontrols (n = 348) (] 22). The investigators measured physical activity at work as per-cent of time spent at each of five levels ranging from sedentary activities to doingheavy physical work. For leisure time activity, they assigned a value to each activitythat reflected an estimate of the rate of energy as calories expended by the individual.In addition, the investigators examined physical activity in terms of indoor-outdoorand field-non-fie]d sports. Neither overall physical activity nor vigorous activityeither in workplace or leisure settings were associated with risk of ALS. The only sig-nificant result from the study was a 59% increase in risk for ALS among cases whoparticipated in organized sports in high school. Compared with previous studies, thisstudy was population-based, recruited a relatively large number of newly diagnosedcases of ALS, and collected very detailed quantitative information on lifetime physicalactivity from cases and their age- and sex-matched population-based controls subjects.

Recently, ChiC>and Mora (123) analyzed mortality data among 24,000 Italianprofessional and semiprofessional soccer players who played between ]960 and]997. During the study period, the investigators found a significant increase in mor-tality from ALS [standardized proportional mortality ratio (SPMR) = ]] .6, 95%

CI=6.7-19.9]. As a result, a population-based, case-contro] study is currentlyunderway in Italy to evaluate the association of profession a] sports activities withthe risk of ALS (124). This study may add important new information to determinewhether physical activity is associated with ALS.

Occupational

Metals

Severa] lines of investigation have linked ALS to heavy meta] exposure, including (i)the linkage of several ALS-]ike syndromes to chronic lead or mercury exposure, sug-gesting that chronic metal toxicity can have a selective deleterious effect on motorneurons, (ii) studies finding increased metal content in tissues of ALS patients,and (iii) epidemiological studies finding significant associations between ALS andself-reported exposure to lead, mercury, and other heavy metals.

Several epidemiological studies have investigated the association of heavymetal exposure and ALS and have consistently reported elevated risk associated withexposure to lead (9],94,] ]6,]25,]26), mercury (1 ]6,]27), or heavy metals as a class(127,]28). Control subjects were spouses, relatives, friends, and/or coworkers inall but three of the previous studies (9] ,94,] 26), possibly leading to overmatchingof cases and controls with respect to meta] exposure. The risk estimates associatedwith exposure to lead, mercury, or other heavy metals as a class ranged from 2.0 to6.0 and were significant in all studies but two (95,] 28). Only three studies assessedduration of exposure to lead (9] ,94, 126).Armon et al. (94) reported an increased riskof ALS among men exposed to greater than 200 cumulative lifetime hours of exposure

rjti

i

Ii


10 lead (OR = 5.5: 95' '" CI = 1.4-21.0). Similar results were reported in the study fromScotland for greater than 12 months of employment in occupations involving lead~xposures (OR = 5.7: 95"" CI = 1.6-30.0) (91). Kamel et al. (126) reported a significantlrend with increasing lifetime days of lead exposure. Among subjects who reportedmore than 2000 lifetime days of leac! exposure. the risk estimate was 2.3 (95%CI = I. 1-4.9) compared to subjects with no exposure to lead.

These studies relied on self-reporting and may be prone to recall bias. Cases aremore likely to over-report certain exposures while control subjects may under-report~xposures (101). In the study from western Washington State, McGuire .et al. (93)illustrated the potential for reca1l bias. The investigators presented risk estimatesbased on subjects' self-reported exposure to lead and based on an industrial hygienepanel's assessment of lead exposure based on job history information. Compared tosubjects who had never been exposed to lead. those who self-reported their lead,-'xposure had a nearly two-fold increase in risk for ALS (OR = 1.9, 95% ClI.O-3.6), while the expert panel's assessment showed no increase in risk for ALSlOR = 1.1 (95% CI 0.6-2.1)] (93).

Lead has been measured in bone in two epidemiological studies. A study in the~arly I970s reported no association between bone lead and risk of ALS, following~xamination of lead concentration in bone from 25 ALS cases and from 17 autopsycontrols (125). More recently. in a case-control study of ALS conducted in NewEngland. blood and bone lead were measured in 107 cases and a subset of 41 popula-lion-based controls (126). Blood lead levels were significantly higher in ALS caseslhan controls. and measures of lead concentration in tibia and patella were some-what higher among ALS cases than controls. The evidence from this study of apossible association between exposure to bone lead concentration and risk of ALSI\drrants further investigation.

The risk of ALS has been examined in occupations with the potential for expo-'lire to metal. Three case-control studies reponed an increased risk for ALS amongwelders (84,94,95): however. a fourth study noted no association with welding. Studies<II"metal working and metal casters also failed to observe any significant associationshetween these occupations and the risk of ALS (31.129,130).

\/l/l'e11Ts

( >rganic solvents are widely used in occupational settings and are a health concerndlle to their neurotoxic properties. High-dose exposure to solvents shows clear evi-,I~nce of dose-relateci acUte neurologic deficits: however. longer-term, lower exposureI,) ~olvents is more difficuit to quantify. Several epidemiologic studies have examinedIhe role of exposure to soh-ents with the risk of ALS and the results have been incon-",lent. Three studies reponed a two- to three-fold increase in risk (91,113,120), whileIhree other studies die'. not observe any association bet\veen solvent exposure and"I.. of ALS (84.S-.1 c: . A study from Western Washington state reported a 60%'I'-Teasein risk fe:' ALS v,hen solvent exposure \,,-asself-reported (OR = 1.6, 95%

( I. 1.1-2.5). bU, <'dO,e';pen pane1"s assessmenl 8f solvent exposure by reviewing.,h histor: infC"r,(i',icr fniJed to show a significant association (OR = 1.2. 95% CI

'i ~ 1,9). Howe\e:', "i:e panel did obsene significe,nt Hssociations between risk ofI " and e'\:;"cs' :-~ ;'~eci!:,- gr'OL1~'S0:" sc el.,. c-!",e",1;c2.!Si:1c!uding alcohols and

-- -'~.' --- - ,

-

j

30 McGuire and Nelson;

ftwo mortality studies in Eng]and and Wales found that leather workers were morelikely to die from ALS than the genera] population (13], 132). However, three otherstudies failed to show any significant associations between leather workers and riskof ALS (74,133-] 35). The study in Sweden also did not find any associations betweenALS and shoemakers or tanners (I 35}.

Paint products contain many types of solvents including hydrocarbons, alco-ho]s and ketones, glycol ethers and esters, and terpenes. Severa] studies evaluatedthe association of paint with risk of ALS. A study in England of twin pairs discordantfor disease and a case-control study in Italy found a greater than three-fold increase inrisk for ALS among those with previous exposure to paint (l00,]30). However,a large population-based case-control study in Sweden reported no excess risk forALS among painters (84), as did a smaller U.S. study with limited statistical power(l02), and two studies in the United Kingdom (132,133).

Pesticides

Exposure to agricultural chemicals may be a risk factor for ALS although few stu-dies have examined this relationship. Previous studies have observed an associationbetween the risk of ALS and farming. In case-control studies conducted in Greeceand Italy, agricultural workers and residents of rural areas were at increased riskfor MND (83,] 00,] 36), and surveys in Sweden and Scotland reported that patientswith MND were more likely to work in agrarian occupations compared to thegenera] population (45,]37). Investigators in the United States reviewed death certi-ficates and noted that mortality rates for ALS were higher among farm residents(l38). Despite these observations, many studies have found no association betweenrisk of ALS and farming or rural living (96,97,102,1O3,]21,132,133;139).

A few case-control studies have investigated the association between exposureto agricultural chemicals and risk of ALS. The most noteworthy finding was from apopulation-based study in Western Washington state that reported a two-foldincrease in risk for ALS among men exposed to agricultural chemicals {OR and95% CI=2.4 (] .2- 4.8)], but not in women [OR and 95% CI =0.9 (0.2-3.8)] (93), witha dose-response trend (p = 0.002). (93). These results were based on an industria]hygiene panel's assessment of exposure to agricultural chemicals. This study alsoexamined the possible timing of agricultural chemica] exposure and found that thehighest risk occurred for the decade between age 22 and 32 years, lending supportto the notion that injury to the motor neuron occurred years prior to the diagnosisof ALS (93). Two previous case-studies reported a two-fold increase in risk for ALSand exposure to pesticides, but the risk estimates were not statistically significant(95,] ]3). Three other studies showed no association (84,9],]20), although the studyfrom Italy reported a weak, statistically significant association between rural resi-dence and risk of ALS but no association with actual pesticide exposure (l20).

There are numerous challenges to the accurate assessment of occupation a]exposures. Many of the exposures of interest are oflow frequency so the risk estimatesmay be weak and not statistically significant. Other limitations include the lack ofgold standards, open-ended questionnaires that are prone to recall bias and the inac-cessibility of company records to verify job titles and tasks performed. The timingbetween exposure to a chemical agent and the onset of ALS is uncertain, making itunclear as to when the relevant exposures may have occurred. Biological samplesand measurement methods may vary among studies making comparisons betweenstudies problematic. Levels of chemica] substances differ by country and vary by

--


l.alendar period and job titles even within countries making it difficult to incorporateIhe industrial changes into the exposure assessment. Lastly, many studies rely on jobIitles and industries as surrogates for exposure to specific workplace exposures.

Lifestyle Risk Factors

1"0date. very few studies have investigated the association of ALS with lifestyleractors such as diet. cigarette smoking, and alcohol consumption.

Cigarelle Smoking {/nd Alcohol Consumption

Few studies have investigated the role of cigarette smoking and alcohol consumptionin the etiology of ALS. despite the possibility that an environmental exposure maybe associated with the disease (74.84,91.92,97.113,120,126,139-142). None of thesestudies reported an association with alcohol use. All but three of the studies(92,141.142) reported no association with cigarette smoking, possibly due to smallsample size, use of prevalent cases, and hospital-based control subjects. Kameld a!. (92), in a case-control study conducted in New England. reported a nearly two-rold increase in risk for ALS among ever smokers (OR = 1.7, 95% CI = 1.0-2.8),although a dose response was not apparent for average number of cigarettes perday, years smoked. or pack-years. In a population-based, case-control study inWashington State. the investigators noted a similar result among subjects who hadever smoked cigarettes (alcohol-adjusted OR =2.0,95% CI = 1.3-3.2),with a greaterthan threefold increase in risk among current smokers (alcohol-adjusted OR =3.5;95'1.)CI = 1.9-6.4)(141).A dose-responsetrend withincreasingpack-yearsof smokingwas significant. Weisskopf et a!. (142) examined the association of tobacco use andALS mortality among participants in the Cancer Prevention Study II cohort ofthe American Cancer Society. The authors reported a nearly 70% increase in ALSmortality among current smokers compared to never smokers (OR = J.67, 95%C] = 1.24-2.24); however. this association was noted in women only.

Nelson et a!. (141) proposed two mechanisms by which cigarette smoke couldcontribute to the risk of ALS. Cigarettes are comprised of thousands of chemicalconstituents. including pesticides. which may directly cause toxic injury to motorneuron cell components. A second possible mechanism is the formation of free radi-cals during the metabolism of the chemical constituents of cigarette smoke (143). Ashas been previously discussed. mutant superoxide dismutase enzyme has been postu-lated to induce cell death (144)or cause superoxide to bind with substrates such as nitricoxide that can lead to the production of damaging free radicals (145,146). One of themajor exogenous constituents of cigarette smoke is nitric oxide (147). The hypothesisthat cigarette smoking i~ associated with ALS warrants further investigation. ideallyusing studies that haw a prospective design.

Diet

Very little is kno\\J~ "bout the association of ALS to diet. Four early case-controlstudies examined differences in consumption or a re\\ food items (84.113.116.126).Onj~ one case-co"iL'ol slua:, used" food rrequenc~ questionnaire to assess nutrient'I1tc:ke A8 Jc., <, !maKe (>9:; g da: compared with <42 g day) was associ-~Ited \:":1:'" ( ;A,C,,- .~,~- ~ ;c i:.iCTe~l5c "lsk .~...:"-\ LS -::d..!c<1!ior:. si-noking. fiber intake.

C1 =(.';-8.0: ( for trend =0.06;.


Polyunsaturated fat, saturated fat, and linoleic acid all contributed to this positiveassociation. The brain contains high concentrations of polyunsaturated fatty acids,especially linoleic acid, which makes the brain particularly vulnerable to oxidativedamage (149-]5]). Since the membrane levels of polyunsaturated fatty acids aredetermined largely by dietary intake (149), the higher dietary consumption of po]y-unsaturated fatty acids could increase the amount of]ipid substrate or cause changesin brain lipid composition, contributing to enhanced lipid peroxidation (150).

Dietary fiber intake (>]8 gjday compared with <] 0 gjday) was associated witha 70% decrease in risk (fat-adjusted OR = 0.3,95% CI = 0.1-0.7;p for trend = 0.02)(148). Two possible mechanisms may explain why dietary fiber may protect againstthe development of ALS. Dietary fiber has been shown to cause lumina] dilution ofpotentia] carcinogens (152,] 53), which could potentially reduce absorption of a diet-ary toxin associated with ALS. Dietary fiber also shortens transit time in the largeintestine (] 52) and could reduce the contact time and the absorption of a dietary toxin.

The investigators also found that glutamate (>]5 gjday compared with <8.6gjday) increased the risk for ALS (OR= 3.2, 95% CI = ] .2-8.0; p for trend < 0.02)(148). The positive association with glutamate intake is consistent with those etio]ogi-ca] theories that suggest that glutamate excitotoxicity has a role in causing ALS.G]utamate is ubiquitous in the food supply, and it is possible that high levels ofglutamate in the diet, combined with a disordered glutamate metabolism in the brain,could cause excitotoxic cell death of motor neurons.

Two studies have evaluated whether dietary antioxidants have a protectiveeffect on the development of ALS in which free radicals play a role (148,]54).A recent prospective study assessed the relationship between the use of Vitamin E,Vitamin C, Vitamin A, and multivitamin supplements and ALS mortality (154).Vitamin data were obtained from a cohort of a million people surveyed as partici-pants in the American Cancer Society Prevention Study II. The investigators identi-fied 525 deaths from ALS through linkage with the National Death Index. Subjectswere classified as never users, occasional users (less than ]5 times per month), andregular users (] 5 times or more per month). Regular users of Vitamin E supplementswere at decreased risk of death from ALS. The investigators reported a dose-response trend with regular users of Vitamin E greater than ]0 years decreasing theirrisk of death from ALS by 62% (age- and smoking-adjusted OR = 0.38, 95%CI = 0.16-0.92). Vitamin C, Vitamin A, and use of multivitamins had no apparentaffect on the risk of ALS. This interesting finding has merit since animal studies haveshown that transgenic mice over-expressing one of the SOD I genes have delayedonset of motor neuron disease when given Vitamin E supplementation. However,in the population-based, case-contro] study from Washington State, the investiga-tors did not find an association of antioxidant vitamin consumption, either in thediet or as a supplement, with the risk of ALS (148). Additional studies using compar-able dietary methods are needed before firm conclusions are drawn regarding therole of diet in ALS.

FUTURE DIRECTIONS

The last two decades have seen significant advances in understanding the moleculargenetic basis of some forms of familial ALS, and these advances hold great promisefor identifying pathogenic mechanisms that may be involved in both familial andsporadic ALS. A goa] of the future should be to identify the causes of ALS in 90%

~


I,) 95°/"of individuals for whom no cause is apparent. With a forward-looking per-'pective, epidemiologists can build on the lessons learned from previous epidemio-I\\gical investigations of ALS. which have yielded disappointingly few clues as toIhe etiology of the disease, Ideally. future case-control studies would attempt to,lloid the methodological flaws of previous studies by: (i) conducting studies inlIell-defined populations that allow the inclusion of a large number of ALS cases,ll1d control subjects, (ii) recruiting incident rather than prevalent cases, to enableIhe identification of etiologic factors for the disease, (iii) increasing the sample size"I' ALS cases and controls to improve the statistical power to detect associations,i iv) including individuals from racial/ethnic groups other than Caucasian, (v) asses-,il1g exposures to environmental toxicants using the most rigorous and objectiveIllethods possible, including blinded exposure assessments and biological measuresII hen possible, and (vi) collectingand storing genomic DNA for both ALS cases;lI1dcontrols for the future evaluation of candidate susceptibility genes.

The epidemiological study of ALS would benefit from seeking existing large,'nhort studies that have accumulated enough person-years of observation to identify;111adequate number of ALS patients for study. Cohort studies collect information"11risk factors prior to the development of the diseases and thus avoid recall bias,which can plague case-control studies. Even if such cohorts can be identified, how-,'ver, the investigation is limited to factors that have been measured in the back-:2round study, which often have focused on behavioral risk factors such as,'igarette smoking, alcohol consumption, and physical activity to the exclusion ofI';\ctors that may be of particular interest in ALS research such as environmentalI,)xicants and electrical injuries.

CONCLUSION

(iiven the methodological limitations of early studies, the epidemiological study of\ LS is still in its infancy, and further research is needed to better understand genetic,hehavioral, and environmental risk factors for this condition, Existing data on theIl1cidenceof ALS in different racial or ethnic groups are too incomplete to character-I/Ceven crude differences between groups; therefore, further incidence studies thatIise comprehensive case ascertainment methods in racially diverse populations are11ceded.While advances have been made in identifying disease-causing genes forIhe Mendelian forms of ALS. very little is known about susceptibility genes or otherrisk factors for sporadic ALS. which comprises more than 90% of ALS cases.

The 1990s. the so-called "The Decade of the Brain;' saw great strides in stan-dardizing the diagnosis. evaluation. and treatment of patients with ALS (11,13,155),rhe great strides in ALS research have been at the genetic and biochemical levels

( 156).witl, mechanism-basedtreatments based on the most recent discoveriesyetI,) be developed and tested. \\lith great effort. it may be possible to demonstrateII ithin the next 10years the biochemicalchain of events by which genesfor autoso-lIlal dominant ALS set the disease in motion. and the extent to which genetics playa1,)lein sporadic ALS.

Epidemioiog: 's cnieCcontribution to ALS research has been in identifying the,( milieJforms of 'he disease. "mo in providing the conceptual basis for requiring"ll,'aC\ ::: c,.se:,,oh:<':: '. ",~C '.he s~atistica, .eels ',C compare treatment outcomes

:,F~11:::',~ ...:.- - U::-.~<""'C',-~cglca~ _:gc~' :'~ -'.e be~-~-jesigned population-

<.e6 Cc:5c-'"'::".': ::'. . :"--.~:-~:g:(':?~. s':"udies ~-~Et~~-::-s,-<;~c(~i~._~-:-!e.je~"'l:nkingof nlan~'

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,34 McGuire and Nelson

commonly held beliefs about the etiology of ALS, at the same time identifying newassociations and raising new hypotheses.

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