Estimated Incidence of Multiple Sclerosis Among United ... · Estimated Incidence of Multiple Sclerosis Among United States ... the diagnosis of MS negatively impacts military read-

MILITARY MEDICINE, 177, 5:594, 2012

Estimated Incidence of Multiple Sclerosis Among United StatesArmed Forces Personnel Using the Defense Medical

Surveillance System

LCDR Eric C. Deussing, MC USN*; CAPT Christopher J. Jankosky, MC USN*;Leslie L Clark, PhDf; Jean L. Otto, DRPHf

ABSTRACT Background: The comprehensive longitudinal medical records of the U.S. Armed Forces provide avaluable tool to study the epidemiology of multiple sclerosis (MS) in persons from a diverse demography. Objectives:This study's objectives were to estimate the frequencies, incidence rates (IRs), trends, and correlates of MS amongactive component U.S. military members from 2000 to 2009. Methods: An Intemational Classification of Diseases,9th Revision, code algorithm was used to identify MS cases from the Defense Medical Surveillance System database.IRs were determined by dividing the number of cases of MS by the total person-time of the active component duringeach year. Results: During the 10-year period, there were 1,827 incident cases of MS with an overall IR of 12.9 per100,000 person-years (p-yrs). Black non-Hispanics had a higher IR: (18.3 per 100,000 p-yrs) than White non-Hispanics(12.5 per 100,000 p-yrs). The incidence of MS by birth month and geographic home did not show a clear trend ofseasonality or latitudinal gradient. Conclusions: This investigation is the first longitudinal study of MS incidence in U.S.Armed Forces personnel. The study demonstrates higher IRs than seen in other populations and reveals a novel pattemof MS incidence by race.

INTRODUCTIONThe diagnosis of multiple sclerosis (MS) is particularly sig-nificant to the military population on two accounts. First, thecost associated with treatment, potential disability, and pos-sible separation from military service may be substantial.Second, the diagnosis of MS negatively impacts military read-iness and worldwide deployability of affected individuals.The military's comprehensive, longitudinal medical recordsand data accession resources provide a unique opportunity toexplore the impact of MS on the U.S. Armed Forces and havethe potential to further elucidate its epidemiology.

Risk factors of MS have been previously studied in the U.S.military population using the Physical Evaluation Board'sdatabases and the Department of Defense Serum Reposi-tory.'" These studies examined the association of Fpstein-Barr virus and serum 25-hydroxyvitamin D levels to MSdiagnosis within the military population. Alternatively, epide-miological characteristics of the U.S. veteran population havebeen studied by Kurtzke et al̂ and Wallin et al.'* Althoughthese studies have examined risk factors and epidemiologicalcharacteristics of militaty and veteran populations, no study

*Department of Preventive Medicine and Biometrics, Uniformed Ser-vices University of the Health Sciences, 4301 Jones Bridge Road, Bethesda,MD 20814-4712.

t Armed Forces Health Surveillance Center, 11800 Tech Road, Suite 220,Silver Spring, MD 20904.

This manuscript has not been previously published, but some of the datawas reported in the Medical Surveillance Monthly Report, January 2011.This intemal report is not peer reviewed and has a limited distribution.

The views expressed in this article are those of the authors and do notnecessarily reflect the official policy or position of the Department of theNavy, Department of Defense, or the U.S. Government.

has examined the IR of MS in the active component of theU.S. military. We report the frequencies, IRs, trends, andcoiTelates of MS among active component U.S. military mem-bers from 2000 to 2009.

METHODSThe cohort for this study included all uniformed personnelwho served in an active component of the U.S. military dur-ing any point in time from January 2000 to December 2009.National Guard and reserve component service memberswere not included. Incident cases of MS during the studyperiod were determined using medical records of the DefenseMedical Surveillance System (DMSS). Although medicalencounter data has been available in the DMSS since 1997,for convenience we chose to examine a 10-year period. TheDMSS includes all inpatient and ambulatory care providedat a U.S. military treatment facility or purchased throughthe military health system. Incident cases for this study weredefined as (1) an individual with one outpatient encounterof Intemational Classification of Diseases, 9th Revision,Clinical Modification (ICD-9) 341.xx (demyelinating dis-ease) or ICD-9 340 (MS), followed by one outpatient orinpatient encounter with ICD-9 340; or (2) One inpatientencounter for ICD-9 341.xx, followed by an outpatientencounter with ICD-9 340; or (3) One inpatient encounterfor ICD-9 340.

Several additional parameters were established. First,only the primary diagnostic position (dxl) was considered;this is the first provider-assigned diagnostic code in an elec-tronic medical record entry. Second, an individual could onlybecome a case once per lifetime, and if a case was determinedto have been a prevalent case (i.e., they had a MS diagnosis

594 MILITARY MEDICINE, Vol. 177, May 2012

Estimated Incidence of MS Among U.S. Armed Forces Personnel

before the study period), they were removed from the study.Finally, in those individuals who were defined as MS casesbased on two or more medical encounters there was no timelimit restriction placed on the period between initial presen-tation and the case-defining diagnosis.

Demographic data contained in DMSS for these individ-uals included: age, race, sex, service, rank, birth month, andhome-of-record state. Home-of-record state served as a sur-rogate for birth state in this study, and individuals with ahome-of-record state listed as Califomia were divided by zipcode into Northern and Southern Califomia for latitude anal-ysis. The time between the initial and case-defining encounterwas collected. The total number of inpatient and outpatientmedical encounters for MS during the surveillance period foreach incident case was also obtained.

Incidence density rates were determined by dividing thenumber of cases of MS by the total person-time of the activecomponent population during each year. These rates, referredto here as incidence and IRs, were calculated for separatedemographic subgroups of interest. Incidence by birth monthand home-of-record state was determined by dividing thenumber of cases of MS by the total population within eachcategory for this time period. Denominators were calculatedin the standard way for epidemiologic study of IRs. All indi-viduals in the surveillance population (active component ser-vice members of the U.S. Armed Forces) began contributingperson-time at the beginning of the study period (January2000). Person-time was censored once an individual becamean MS case, once they left service or died, or at the end ofthe study period.

DMSS has a demographic record for all active componentservice members, which allowed us to calculate the completetime an individual contributed to the denominator. For exam-ple, if a service member began service on January 1, 2005 andleft service on January 1, 2009 she/he would have contributed4 years of person-time to the denominator. If that servicemember was determined to be an incident case of MS onJanuary 1, 2006, they would only have contributed 1 year ofperson-time to the denominator. All person-time after theservice member became a case would have been censored,because they were no longer "at risk" of becoming a case.

RESULTSBetween 2000 and 2009, there were 1,827 incident cases ofMS among active component armed forces members, for anoverall IR of 12.9 per 100,000 person-years (p-yrs) (Table I).Dtiring the 10-year period, the IRs of MS were stable (Fig. 1).

The overall IR was greater among females (« = 660; IR:32.0 per 100,000 p-yrs) than males (« = 1,167; IR: 9.6 per100,000 p-yrs), and this trend was consistent throughout the10-year surveillance period. The IR increased with age atdiagnosis, from 2.1 cases per 100,000 p-yrs in those lessthan 20 years old to 26.9 per 100,000 p-yrs in those 40 yearsold or older.

TABLE I. MS: Counts and Rates,Active Component, 2000-2009

Variable

TotalSex

MalesFemale

Age at Diagnosis<2020-2425-2930-3435-3940+

RaceWhite non-HispanicBlack non-HispanicHispanicOther

ServiceArmyNavyAir ForceMarinesCoast Guard

Count

1,827

1,167660

30323401339390344

1,124462133108

57144463910865

Pereentage

100.0

6436

21822192119

622576

31243564

Rate per100,000

person-years

12.9

9.632.0

2.16.7

13.816.721.926.9

12.518.39.48.4

11.512.518.36.0

16.8

IR Ratio

-3.3

0.3-

2.12.53.34.0

-1.50.80.7

1.92.13.1-

2.8

Black non-Hispanics had an overall higher IR {n = 462;IR: 18.3 per 100,000 p-yrs) than White non-Hispanics (« =1,124; IR: 12.5 per 100,000 p-yrs), Hispanics (« = 133; IR:9.4 per 100,000 p-yrs), and those categorized as "Other" (n =108; IR: 8.4 per 100,000 p-yrs). These higher rates amongBlacks were consistent in both males and females throughoutthe 10-year period (Fig. 2 and Table I).

IRs were higher in the Air Force (n = 639; IR: 18.3 per100,000 p-yrs) than any other service during this time (IRs,Army: 11.5 per 100,000 p-yrs; Navy: 12.5 per 100,000 p-yrs;Marines: 6.0 per 100,000 p-yrs; Coast Guard: 16.8 per100,000 p-yrs), and these rates were consistently higherthroughout all 10 years (Fig. 3 and Table I). The Coast Guardwas not included in trend analysis because of low frequencyof cases, which led to unstable rates.

The incidence of MS by birth month did not show a cleartrend of seasonality among cases and specifically did notindicate increased incidence in spring months (Fig. 4). Inci-dence by home-of-record state did not show a clear latitudi-nal gradient from North to South (Fig. 5).

The time interval between the initial presentation and thecase-defining encounter was between 0 and 90 days for 54%(n - 983) of the cases, and 23% were diagnosed by a timeinterval >365 days (Fig. 6). There were 18,536 medicalencounters for MS following initial presentation among casesduring this 10-year period; 18,289 were outpatient encountersand 247 were inpatient encounters. The majority of cases(n = 1,650) were defined by the first case definition: anindividual with one outpatient encounter of ICD-9 341.xx orICD-9 340, followed by one outpatient or inpatient encounter

MILITARY MEDICINE, Vol. 177, May 2012 595


25.0 r-

20.0os§•r-

15.0

10.0

I 3.0

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

YearFIGURE 1. MS overall IRs active component 2000-2009.

with ICD-9 340 (Table II). A third of all cases (n = 604) hadpreviously deployed to support Operation Iraqi Freedom orOperation Enduring Freedom.

DISCUSSIONIncidence of MS varies by geographic location and latitude.Hirtz et al'' performed a systematic review of worldwide MSincidence and found the median estimate of the annual inci-dence was 4.2 per 100,000 p-yrs (range 0.8-12.0). The onlyincidence study cited from North America (Minnesota) useddata from 1985 through 2000, and reported 7.5 cases per100,000 population per year.* This higher IR may be indica-tive of Minnesota's latitude. The paucity of MS incidencestudies in the United States may reflect the limited numberof comprehensive, longitudinal databases available to char-acterize the disease in this way.

Our study was ideally suited to contribute to the incidencedata of MS because of the unique characteristics of theDMSS database. DMSS integrates data from sources world-

wide to continuously track the military and medical experi-ences of service members throughout their military careers.As a longitudinal relational database currently containingdata relevant to more than 12 million individuals since 1990,DMSS enables calculations of rates.^ This study demon-strated stable IRs of MS diagnoses from 2000 to 2009 amongactive component members. These rates (cumulative IR = 12.9per 100,000 p-yrs) are much higher than the reported median IRworldwide (4.2 per 100,000 p-yrs) and higher than those foundin the other North American study.̂ Our eases of MS representindividuals from all 50 states as well as U.S. territories andforeign countries.

The high incidence of MS in our study may reflect theimprecision of an ICD-9-based case definition. It may alsorepresent an increased risk for MS among active componentmembers of the armed forces. The U.S. military is composedof mostly young and middle aged adults, whereas generalpopulations include all age groups including the very youngand very old, who are at much less risk of incident clinical

80.0

00 p

-yrs

)

Ö

i

(per

£Isoc

nee

u

70.0

60.0

50.0

40.0

30.0

20.0

10.0

—»— White Female non-Hispanic

—•— Black Female non-Hispanic

White Male non-Hispanic

—•— Black Male non-Hispanic

0.0-2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Year

FIGURE 2. MS IRs by sex and race (Black and White), active component 2000-2009.



25.0

-<»~ Army

—'— Navy

- " — Air Force

- * - Marines

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Year

FIGURE 3. MS IRs by Service, active component 2000-2009.

presentation of MS. Additionally, access to health care isvery high in the military; this increased access to care mayaccount for these increased rates. The factor(s) that mayelevate this risk and lead to increased rates of MS is a subjectfor further study.

The IR of MS remained stable over the 10-year period.This is of interest since previous studies have suggestedsevere stressful life events may increase the risk of MS,but the evidence has not been consistent.**'̂ This risk isgenerally thought to become evident years or decades later.Our study has stable and consistent data collection for 2 yearsbefore the onset of large-scale troop deployments to Afghanistanand Iraq, and the following 8 years of sustained combat opera-tions with associated environmental, physical, and mentalstresses. When viewed over the past decade, these Stressorsdid not appear to influence the complex neurological etiologyof MS. It is certainly possible that enough time has notelapsed to observe an increase in MS incidence in this

population, and we will continue to follow IRs over thecoming decade.

Females had a much higher incidence of MS comparedto males in our study. Hirtz et al"'' found an incidence twiceas high among females compared to males, whereas wefound an incidence 3.3 times higher among females. Thisincreased risk among females compared to males is a char-acteristic commonly seen in other autoimmune diseases.The peak age of onset has previously been regarded asbeing between 20 and 30 years, whereas we found anincreased incidence in the 35 and older category. This isconsistent, though, with more recent literature, where theage at diagnosis appears to be in the mid to late 30s. Arecent study in Iceland reported a mean age at diagnosisof 36.3 years, and an analysis from the North AmericanResearch Committee on Multiple Sclerosis repotted an MSdiagnosis from 34.5 to 37.4 years, depending on racial/ethnic groupings.'""

70.0 T~

If) 60.0

January February March April

FIGURE 4. MS IRs by birth month, active component 2000-2009.

June July August September October November December

Month



Alaska

Pacific Ocean

Hawaii

Incidence Rate(per 100,000 persons)

< 13.6-32.5

^ B 32.6-46.1

••46.2-56 2m 56.3 - 73.9

^ H 74.0-104 5

PacificOcean

0 250 500 1,000 1500 2,000I Kilometers

FIGURE 5. MS IRs by state, active component 2000-2009.

IRs of MS diagnoses among blacks, and specifically blackfemales, were higher than their white counterparts (incidencerisk ratio = 1.5). This relationship in an adult population hasnot been previously seen in literature and has only recentlybeen described in children.''^ The novelty of this finding isperplexing. Do these results represent an unidentified riskfactor in our population among black females, or are theseresults representative of actual risk not previously appreciatedin the general U.S. population? The active component ofthe armed forces represents a diverse racial composition. This

1-30 31-90 91-180 181-364Time Interval (days)

365-̂

population has high access to free health care irrespectiveof race or socioeconomic background. This combination ofrobust racial representation and increased access to caremay reveal a racial group at increased risk unrecognized inprevious studies.

Service specific rates observed in our study may reflectdifferences in demographic characteristics. For instance,there may be more females in the Air Force than the otherservices, or perhaps the age stratifications differ betweenthe services and contribute to these IRs. Another possibleexplanation for service specific rates is differences indiagnostic practices between services. Multiple regressionanalysis in future studies is required to further evaluatethese findings.

The latitude gradient observed in MS has frequently beencorrelated with a proxy such as vitamin-D.^"'^ This studyused home-of-record state and birth month as surrogates forlatitude and possible early childhood or in utero vitamin D

TABLE II. Total Counts per Case Definition

FIGURE 6. Time interval between initial diagnosis and case definitiondiagnosis, among cases.

Case Definition Total

Case Definition 1 : One Outpatient Encounter for ICD-341 1,650or 340, Followed by One Outpatient or InpatientEncounter for ICD-340

Case Definition 2: One Inpatient Encounter for ICD-341, 41Followed by One Outpatient Encounter With ICD-340

Case Definition 3: One Inpatient Encounter for ICD-340 136

598 MILITARY MEDICINE, Vol. 177. May 2012


exposure. We did not find a pattern of correlation betweencases of MS and home-of-record state or birth month. Thiscould be as a result of a number of factors. Though a previousstudy using Veterans Affairs data showed a strong correlationbetween measures of effect for birth state and state of entryinto the service, we recognize that home-of-record statetnay not be an accurate proxy for birth state."* Another pos-sibility is that over the past half century the associationbetween latitude of birth and subsequent MS diagnosis hasgradually weakened because of changes within society. Ithas recently been suggested that this association is weakening,or perhaps altogether erroneous."*'̂

The bimodal distribution of time interval between initialpresentation and the case-defining encounter is likely as aresult of several factors. The high access to care in this pop-ulation enables individuals who may have a provisional diag-nosis of MS to be followed-up within a short time interval.This characteristic is also likely reflected in the overall fre-quency of inpatient and outpatient encounters observed. Onthe other hand, the natural history of MS is often indolent,and exacerbations of symptoms may have intervals of severalmonths to years. This characteristic might contribute to thelater, lower mode in the distribution.

This study's findings should be interpreted with consid-eration of certain limitations. The cases in this study weredetermined exclusively with ICD-9 code diagnoses, whichreflected a case definition based on healthcare provider-assigned diagnostic codes entered into the electronic medicalrecord of service members. Similarly, Diaz et al'^ used adiagnostic code-based case definition of MS to obtain IRsin Chile. Our algorithmic case definition was attributable tothe nature of the DMSS data; its reliability in identifyingactual cases of MS is unknown. However, the VA Centerof Excellence on MS used a similar algorithmic methodol-ogy to identify MS cases in the Veterans Health Affairsdatabase to populate their MS surveillance registry.'^ Thus,a statistical algorithm was applied to an administrative data-base to ascertain cases. This process produces an estimate ofactual cases of MS.

Our case definition required either an inpatient diagnosisof MS or at least two outpatient diagnoses of MS or anoutpatient or inpatient diagnosis of demyelinating diseasefollowed by one outpatient or inpatient diagnosis of MS. Thisflexibility increased the likelihood of our definition capturing"true" cases of MS, though limitations remained. MS is aclinical diagnosis with no single confirmatory lab or radio-logic test, and it often requires several months to make adiagnosis. Ideally, a neurologist specialized in evaluatingand treating MS should make the diagnosis. As a result, adetailed chart review with accurate application of clinicalcriteria is the only standardized way to define a case of MS.An adjudication of our cases through this type of process infuture studies may reveal an overestimated incidence of MS.Such an analysis was beyond the scope of this initial descrip-tive epidemiologic study.

This study was also limited because our data was part of apassively collected electronic health database. As a result,there may be missed cases. The high access to health caremitigates this limitation, but it cannot be entirely eliminated.The Healthy Worker/Warrior Effect also should be con-sidered; this effect would potentially result in lower ratesof MS in the military population compared to the generalpopulation. Additionally, our study cannot be generalizedbeyond the active component of the armed forces populationduring this time period.

CONCLUSIONSIn summary, this study provides the first evaluation of MSincidence among U.S. Armed Forces. Constructed from arobust and consistent data collection system, this studydemonstrates a stable incidence of MS before and duringsustained combat operations and foreign deployments, wheresignificant physical and emotional stress has been placed onindividuals serving in the U.S. Armed Forces. This studydescribes higher rates of MS than generally seen in otherpopulations and reveals a novel pattem of MS by race. Fur-ther studies are being developed that rely on data collectiondirectly from military neurology clinics, reducing potentialmisclassification and providing opportunities to explore diag-nostic and treatment research questions.

ACKNOWLEDGMENTSThe authors gratefully acknowledge and thank Cecili Sessions, MD, MPH,for her technical expertise, Harry Haverkos, MD, MPH, for his thoughtfulreview, and Penny Masuoka for her GIS technical support.

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Estimated Incidence of Multiple Sclerosis Among United ... · Estimated Incidence of Multiple Sclerosis Among United States ... the diagnosis of MS negatively impacts military read-