related mortality in Brazil, 2000–2011: epidemiology of a neglected neurologic cause of death

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ContentslistsavailableatScienceDirect

Acta

Tropica

j ourna l h o m e pa g e :w w w . e l s e v i e r . c o m / l o c a t e / a c t a t r o p i c a

Neurocysticercosis-related

mortality

in

Brazil,

2000–2011:

Epidemiology

of

a

neglected

neurologic

cause

of

death

Francisco

Rogerlândio

Martins-Melo

a,b

,

Alberto

Novaes

Ramos

Jr.

a

,

Marta

Guimarães

Cavalcanti

c

_,

_Carlos

_Henrique

_Alencar

a

_,

_Jorg

_Heukelbach

a,d,∗

a_Department_of_Community_Health,_School_of_Medicine,_Federal_University_of_Ceará,_Rua_Professor_Costa_Mendes,_1608,_Rodolfo_Teófilo,_60430-140

Fortaleza,CE,Brazil

b_Federal_Institute_of_Education,_Science_and_Technology_of_Ceará,_Rua_Engenheiro_João_Alfredo,_s/n,_Pabussu,_61600-000_Caucaia,_CE,_Brazil

c_Infectious_and_Parasitic_Diseases_Service,_Clementino_Fraga_Filho_University_Hospital,_Federal_University_of_Rio_de_Janeiro,_Rua_Rodolpho_Paulo_Rocco,_255,

CidadeUniversitária,21941-913RiodeJaneiro,RJ,Brazil

d_Anton_Breinl_Centre_for_Public_Health_and_College_of_Public_Health,_Medical_and_Veterinary_Sciences,_Division_of_Tropical_Health_and_Medicine,_James_Cook

University,Townsville,QLD4811,Australia

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received5June2015

Receivedinrevisedform

23September2015

Accepted16October2015

Availableonline23October2015

Keywords:

Neurocysticercosis

T.solium

Mortality Epidemiology

Timetrendanalysis

Spatialanalysis

Brazil

a

b

s

t

r

a

c

t

Neurocysticercosis(NCC)isanimportantcauseofsevereneurologicaldiseasemainlyinlow-and middle-incomecountries,butdataonNCCmortalityfromendemicareasarescarce.Hereweanalysedthe epidemiologicalpatternsofNCC-relatedmortalityinBrazil.WeincludedalldeathsrecordedinBrazil between2000and2011,inwhichNCCwasmentionedondeathcertificates,eitherasunderlyingor asassociatedcauseofdeath.NCCwasidentifiedin1829/12,491,280deaths(0.015%),1130(61.8%)as underlyingcause,and699(38.2%)asassociatedcause.Overallage-adjustedmortalityratefortheperiod was0.97deaths/1,000,000inhabitants(95%confidenceinterval[CI]:0.83–1.12).ThehighestNCC-related mortalityrateswerefoundinmales,elderly,whiterace/colourandresidentsinendemicstates/regions. Age-adjustedmortalityratesatnationalleveldecreasedsignificantlyovertime(annualpercentchange [APC]:−4.7;95%CI:−6.0to−3.3),withadecreaseintheSoutheast,SouthandCentral-Westregions, andanon-significantincreasingtrendintheNorthandNortheastregions.Weidentifiedspatialand spatiotemporalhigh-riskmortalityclusterslocatedmainlyinNCC-endemicareas.Conditionsrelatedto thenervoussystemwerethemostcommonlyassociatedcausesofdeathwhenNCCwasmentionedas anunderlyingcause,andHIV/AIDSwasthemainunderlyingcausewhenNCCwasanassociatedcause. NCCisaneglectedandpreventablecauseofsevereneurologicdiseaseanddeathwithhighpublichealth impactinBrazil.Thereisaclearneedtostrengthennationwideepidemiologicalsurveillanceandcontrol forthetaeniasis/cysticercosiscomplex.

1. Introduction

Neurocysticercosis(NCC)isaparasiticinfectionofthehuman centralnervoussystemcausedbythelarvalform(cysticerci)ofthe porktapewormTaeniasolium(Carpio,2002;WHO,2002,2010a). NCCisconsideredaneglectedandpoverty-relateddisease,with highpublichealthandsocialimpactindevelopingcountries, espe-ciallyinAfrica,Asiaand LatinAmericaand theCaribbean(LAC)

∗_{Corresponding}_author_at:_Department_of_Community_Health,_School_of_Medicine,

FederalUniversityofCearáRuaProfessorCostaMendes,1608,5.andar,Bairro

RodolfoTeófilo,60430-140Fortaleza,Brazil.

E-mailaddresses:rogerlandio@bol.com.br(F.R.Martins-Melo),

heukelbach@web.de(J.Heukelbach).

(WHO,2002;DelBrutto,2014).NCCisthemainpreventablesingle causeofacquiredepilepsy(Flisseretal.,2003;WHO,2002,2010a; DelBrutto,2014).About5millioncasesofepilepsyworldwideare causedbyNCC(Nashetal.,2013).InLAC,anestimated75million peopleliveatriskofinfection,with0.45–1.35millionpeople suf-feringfromepilepsyattributabletoNCC(Coyleetal.,2012).NCCis alsoemerginginnon-endemiccountries(particularlyUSA,Canada andEuropeancountries),duetoincreasedmigrationand travel-relatedexposure(WallinandKurtzke,2004;Coyleetal.,2012;Del Brutto,2012a,b,2014).

InBrazil,theconditionisendemicparticularlyintheSoutheast, SouthandCentral-Westregions(Agapejev,1996,2003;Almeida andTorres,2011).However,itspublichealthimpactthroughout thecountryisnotknown,becausethereisneithercompulsory noti-fication,noractivediseasesurveillanceinmoststates(Takayanagui

http://dx.doi.org/10.1016/j.actatropica.2015.10.011

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Table1

EpidemiologicalcharacteristicsandNCC-relatedmortalityrates(per1,000,000inhabitants)bysex,agegroup,race/colourandregionofresidenceinBrazil,2000-2011.

Variables Deaths Cruderate(95%CI)a _Age-adjusted_rate_(95%_CI)a,b _CRR _p_-value

n %

Overall 1,829 100.0 0.82(0.70–0.96) 0.97(0.83–1.12) – –

Sex

Male 1,024 56.0 0.93(0.76–1.15) 1.10(0.90–1.33) 1.31(0.95–1.81) 0.095

Female 805 44.0 0.71(0.56–0.90) 0.84(0.67–1.04) Ref. –

Agegroup(years)c

0–14 16 0.9 0.02(0.01–011) – Ref. –

15–29 184 10.1 0.29(0.18–0.48) – 12.05(2.05–70.75) <0.001

30–39 349 19.1 1.05(0.73–1.51) – 43.34(7.64–245.89) <0.001

40–49 396 21.7 1.57(1.12–2.20) – 64.76(11.46–365.75) <0.001

50–59 326 17.9 2.00(1.38–2.91) – 82.57(14.51–469.72) <0.001

60–69 250 13.7 2.36(1.54–3.61) – 97.26(16.89–560.16) <0.001

>70 305 16.7 3.72(2.53–5.47) – 153.42(26.89–875.24) <0.001

Regionofresidence

North 16 0.9 0.09(0.02–0.42) 0.13(0.04–0.49) Ref.

Northeast 225 12.3 0.37(0.23–0.57) 0.44(0.30–0.67) 4.07(0.70–23.59) 0.089

Southeast 1,030 56.3 1.09(0.88–1.34) 1.20(0.98–1.46) 12.11(2.19–66.97) <0.001

South 382 20.9 1.17(0.83–1.66) 1.27(0.91–1.77) 13.07(2.31–73.92) <0.001

Central-West 176 9.6 1.12(0.67–1.85) 1.42(0.91–2.23) 12.44(2.11–73.21) <0.001

Race/colourc

White 1,106 66.8 1.01(0.83–1.24) – Ref.

Black 118 7.1 0.79(0.43–1.46) – 0.78(0.40-1.50) 0.456

Brown 425 25.7 0.48(0.34–0.66) – 0.47(0.32-0.70) <0.001

Yellow 5 0.3 0.29(0.03–3.24) – 0.29(0.01-6.02) 0.391

Indigenous 3 0.2 0.54(0.05–5.96) – 0.32(0.01-16.07) 0.545

CI:confidenceintervals;CRR:cruderateratio;notcalculated.

a_Average_annual_crude-_and_age-adjusted_mortality_rates_(per_1,000,000_{inhabitants),}_calculated_using_the_average_number_of_NCC-related_deaths_as_a_numerator_and

populationsizeinthemiddleofthestudiedperiod(centralyear:2005.5)asadenominator.Populationdataonrace/colourwasderivedfromtheBrazilianNationalCensuses

(2000and2010).Populationsizeinrelationtorace/colourforthemiddleoftheperiodwasderivedfromanaverageofthe2000and2010censuses.

b_{Age-standardized}_to_the₂₀₁₀_Brazilian_population.

c _Data_not_available_in_all_cases_(age_group:_3,_and_race/colour:_172).

andLeite,2001;Agapejev, 2003).In acomprehensiveliterature review of epidemiological data available in Brazil covering the period1915–2002,thefrequencyofNCCrangedfrom0.12%to9% inautopsiesandfrom0.03%to13.4%inclinicalstudies(Agapejev, 2003).The casefatalityrateofNCC rangedfrom4.8%to25.9%, andasymptomaticformsofNCCweredetectedin48–55%ofcases withautopsy-confirmeddiagnosis(Agapejev,2003).Despiteofthe epidemiological,socio-economicandclinicalrelevance,the bur-den of NCC-related mortalityalso remains largely unknown in endemiccountries(Bhattaraietal.,2013).Thereareverylimited population-baseddataandfewlarge-scalestudiesonNCC-related deaths (Sorvillo et al., 2004;Townes et al., 2004; Santo, 2007; Sorvilloetal.,2007).Herewepresentasystematicassessmentof theepidemiologicalpatterns,timetrendsandspatialdistribution ofNCC-relatedmortalityinBrazil,from2000to2011.

2. Materialandmethods

2.1. Studyarea

Brazil, South America’s largest country, is extended over 8.5millionkm2 _with_a _population _of _about ₂₀₃_million inhabi-tantsin 2014.It is dividedpolitically andadministratively into five geographic regions (South, Southeast, Central-West, North andNortheast),27FederalUnits(26statesandoneFederal Dis-trict)and5570municipalities(InstitutoBrasileirodeGeografiae Estatística—IBGE;http://www.ibge.gov.br).Thereisawide demo-graphic,culturaland socioeconomicdiversitybetweenBrazilian regions.Forinstance,bothNorthandNortheastregions compre-hendtheareaswiththelowestincomeofthecountry.Inaddition, thesameregionsalsopresentparticularepidemiological disease-related patterns suchas those related to poverty (Lindoso and Lindoso,2009;HotezandFujiwara,2014).

2.2. Studydesignandpopulation

Weperformedanationwidepopulation-basedstudyusing mor-talitydata,includingtime trendandspatialanalyses.Thestudy includedalldeathsinBrazilthatoccurredbetween2000and2011, inwhichNCCwasmentionedonthedeathcertificateseitheras underlyingorasassociated(non-underlying)causeofdeath (so-called multiple causesof death) (Redelings et al., 2006; Santo, 2007).Inthiscontext,underlyingcauseofdeathisdefinedasthe diseasethatinitiatedtheeventsleadingdirectlytodeath.Foreach death,onlya singleunderlyingcauseisreported(WHO,2010b; AustralianInstituteofHealthandWelfare,2012).Associatedcauses ofdeathrefertotheotherconditions(immediate,intermediateand contributingcauses),whichintervenedorsignificantlycontributed tothedeath(AustralianInstituteofHealthandWelfare,2012).

NCC as cause of deathcorresponds to theB69.0 code (Cys-ticercosisofcentralnervoussystem[includedwithinthecategory Cysticercosis—B69code])oftheTenthRevisionoftheInternational StatisticalClassificationofDiseasesandRelatedHealthProblems ICD-10)(WHO,2010b).

2.3. Datasources

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UnifiedHealthSystem(DepartamentodeInformáticadoSistema Único deSaúde—DATASUS; http://tabnet.datasus.gov.br/cgi/sim/ dados/cid10indice.htm).Downloadingofthe324mortalitydata setswithabout12.5millionentries,anddataprocessinghasbeen describedindetailpreviously(Martins-Meloetal.,2012a,b,2015). Population data were obtained from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografiae Estatística—IBGE,2010),basedontwocensuses(2000and2010), andpopulationestimatesforinter-censusyears(2001–2009and 2011) (IBGE; http://tabnet.datasus.gov.br/cgi/deftohtm.exe?ibge/ cnv/popuf.def).

2.4. Variablesandstatisticalanalyses

Variablesanalysed fromdeathcertificatesincluded:sex,age, race/colour(white,black,brown[PardoBrazilian],yellow[Asian descendant]andindigenous),placeof residence(regions,states andmunicipalities),placeofoccurrence,dateofdeathandcausesof death(underlyingandassociated).Wecalculatedmeansand stan-darddeviations(SD)forcontinuousvariables,andpresentabsolute numbersand proportions withtheirrespective 95% confidence interval(95%CI)forcategoricalvariables.

Crudemortalityratesandtheir95%CIswerecalculatedbysex, agegroup,race/colourandplaceofresidencebydividingthe num-berofNCC-relateddeathsbythepopulationineachcalendaryear, expressedper1,000,000inhabitants. Age-adjustedratesfor sex andregions/statesofresidencewerecalculatedbythedirect stan-dardizationmethod,usingtheBrazilian populationofthe2010 Censusasstandard.Agecategoriesforstandardizationand calcula-tionofage-specificrateswere:0–14,15–29,30–39,40–49,50–59, 60–69,and≥70years.Basedonthecruderates,wecalculatedrate

ratios(RRs)withtheir95%CIs.Statisticalsignificanceofdifferences amonggroupswasevaluatedbythechi-squaredtest(2).Weused theStudent’st-testtocomparethemeanageatdeath(inyears) betweengroups.

Timetrendanalysiswasperformedusingjoinpointregression models(Kimetal.,2000),withage-adjusted(sexandtheBrazil’s geographicregions)andage-specificratesasdependentvariables, andtheyearofoccurrenceasindependentvariable.Thisanalysis identifiedjoinpointsviaalog-linearmethod,wherethedirectionor themagnitudeoftrendschangedsignificantly(Kimetal.,2000).The analysisstartedwith0joinpoint(astraightlinewithoutinflection points),andverifiedwhethertheinclusionofoneormore join-points(inouranalysisuptothree)inthemodelweresignificant (Kimetal.,2000).Eachsignificantjoinpointthatindicatedachange intheslopewasretained.Statisticalsignificancewastestedusing theMonteCarlopermutationtest,whichchoosesthebestsegment foreachmodel(Kimetal.,2000).Theannualpercentchange(APC) and95%CIwerecalculatedforeachsegment(Kimetal.,2000).To simplifytrendcomparisonfortheepidemiologicindicatorswith morethanoneslope,wealsocalculatedtheaverageannualpercent change(AAPC)overtheentireperiod.Thiswasestimatedasthe geometric-weightedaverageoftheAPC,withtheweights reflect-ingthelengthofeach timeinterval segment(Kim etal.,2000). TrendwasconsideredstatisticallysignificantwhentheAPCand AAPCpresentedp<0.05.

Weanalysedthespatialdistributionandspatiotemporal pat-ternsofNCC-relatedmortalityusingtheBrazilianmunicipalities ofresidenceasunitsofanalysis(territorialdivisionof2010).We calculatedcrudeNCC-relatedmortalityrates(per100,000 inhab-itants)forthe12-yearstudyperiod,andthesmoothedmortality ratesbymeansoftheLocalEmpiricalBayesianmethodtoreduce randomvariationsandprovidegreaterstabilityofmortalityrates inmunicipalitieswithsmallpopulationsandrareevents(Assunc¸ão etal.,1998).

We usedGlobalMoran’s Iindex (rangingfrom −1to +1)to

assessthepresenceofglobalspatialautocorrelation(CliffandOrd, 1981).Thenweevaluatedtheexistenceoflocalautocorrelation (LocalIndexofSpatialAssociation—LISA)bymeansofLocalMoran’s Iindex (Anselin,1995).Theobjective of this procedurewasto identifysignificanthotspots(High-High:highvaluesspatial clus-ters),coldspots(Low–Low:lowvaluesspatialclusters),andspatial outliers(High–Low: highvalues surrounded withlow value or Low–High:Lowvalues surroundedwithhighvalues)of mortal-ityrates (Anselin,1995).For spatialrepresentationof theLocal Moran’sindex,MoranMapswerecreated,includingmunicipalities withdifferencesonp<0.05.

WeusedretrospectiveKulldorff’sspace-timescanstatisticsto identifyhigh-risk spatiotemporal clusters(Kulldorff, 1997). We usedfurtheraPoissonprobabilitymodelscanningforareasofhigh NCC-relatedmortality,withamaximumspatialclustersizeof30% ofthepopulationatrisk,andamaximumtemporalclustersizeof 50%ofthestudyperiod.Themostlikelyorprimaryclusterand secondaryclustersweredetectedthroughtheloglikelihoodratio (LLR)test.Wecomputedstatisticalsignificanceusing999Monte Carlosimulations.

Wepresentthecausesofdeath(diseasesanddisorders)that mostcommonlywereassociatedwithNCC-relateddeaths.Foreach deathcertificatethatlistedNCCasanunderlyingcause,the asso-ciatedcauseswereexamined,andforeachdeathcertificatethat listedNCCasanassociatedcause,theunderlyingcausewere inves-tigated.Allcausesreportedonthedeathcertificateswereanalysed, evenill-defined(classifiedinChapterXVIII—R00-R99oftheICD-10) andthosecharacterizedbytheWHOasmodesofdeath,suchas cardio-respiratoryarrestandmultipleorganfailure(Santo,2007). DataanalysiswasperformedwithStatasoftwarepackage ver-sion11.2(StataCorporationLP,CollegeStation,TX,USA).Joinpoint regression analyseswere carried out withJoinpointRegression Program version 4.0.4 (United States National Cancer Institute, Bethesda, MD, USA).ArcGIS softwareversion 9.3 (Environmen-tal Systems Research Institute—ESRI, Redlands, CA, USA), and TerraViewsoftwareversion 4.2(InstitutoNacionaldePesquisas Espaciais—INPE,São JosédosCampos, SP, Brazil)were usedfor input, processing, analysis, calculation of autocorrelation indi-cators,and construction ofthematic maps.Scan statistics were performedusingSaTScan softwareversion9.1.1(Harvard Medi-calSchool,BostonandInformationManagementServiceInc.,Silver Spring,MD,USA).

2.5. Ethics

Analysiswasbasedonpubliclyavailablesecondaryanonymous data,withnopossibilityofidentificationofindividuals.TheEthical ReviewBoardoftheFederalUniversityofCeará(Fortaleza,Brazil) approvedthestudy.

3. Results

3.1. Neurocysticercosis-relateddeaths

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3.2. Epidemiologicalcharacteristicsofdeaths

Thepredominatingsocio-demographiccharacteristicsof NCC-relateddeathswere:malesex(66.0%[1024/1829),age40–50years (21.7%[396/1826]),whiterace/colour(66.8%[1106/1657),and res-idencyintheSoutheastregion(56.3%[1030/1829])(Table1).The stateofSãoPaulo(Southeastregion)hadthelargestproportionof deathsintheresidentpopulation(31.4%[575/1829]).Thehighest proportionofdeathsbyageinthecaseofNCCasunderlyingcause wasinthe40–50years-olds(24.5%[277/1129]),andinthecaseas associatedcauseinthe≥70years-olds(24.4%[170/697]).

Themean(SD)andmedianageatdeathofNCC-relateddeaths was50.8years(±17.4)and49.1years(range:1.1–95.3),

respec-tively.Themean(SD)ageatdeathintheNCC-relateddeathsas underlyingcausewassignificantlylowerthanthatforthe NCC-relateddeathsasassociatedcause(48.3±16.6vs.54.9±17.9years,

respectively;p<0,001).Themean(SD)ageatdeathwashigherin femalesthaninmales,butnotstatisticallysignificant(51.7±18.6

vs50.1±16.3years;p=0.055).

Overall,83.3%(1522/1827)oftheNCC-relateddeathsoccurred in hospitals,and decedent’s residencewasreportedasplace of occurrencein13.4%(244/1827)ofdeaths.

3.3. Mortalityrates

TheaverageannualcrudeNCC-relatedmortalityratewas0.82 deaths/1,000,000 inhabitants (95% CI: 0.70–0.96) and the age-adjustedrate0.97deaths/1,000,000inhabitants(95%CI:0.83–1.12) (Table 1). Mortality rates increased steadily with age, with a maximumin≥70years-olds(3.72deaths/1,000,000inhabitants)

(Table1).Age-adjustedmortalityrateswerehigherinmalesthan females, withno significantdifference (Table 1). Individualsof whiterace/colourhadthehighestrates(Table1).Therewasa con-siderableregionaldistribution,withtheCentral-West,Southand Southeastregionsshowinghighestrates(RRvalues>12,as com-paredtotheNorthregion)(Table1).Thehighestaverageannual age-adjustedmortalityratesbystateofresidencewereobserved inParaná(Southregion,2.38deaths/1,000,000inhabitants),Minas Gerais(Southeastregion,1.64deaths/1,000,000inhabitants),and Goiás (Central-West region, 1.59 deaths/1,000,000 inhabitants) (Fig.1).

3.4. Timetrends

Age-adjustedNCC-relatedmortalityratespresenteda signifi-cantdecreasingtrendatnationallevel(APC:−4.7;95%CI:−6.0

to−3.3.)over the12-yearstudyperiod, withdifferentpatterns

betweenregions(Fig.2;Table2).Similartothenationwidepattern, therewasasignificantdecreaseofmortalityfiguresinthe South-east(APC:−6.5;95%CI:−8.8to−4.2),South(APC:−3.4;95%CI: −6.7to−0.1),andCentral-West(APC:−6.0;95%CI:−11.0to−0.8)

regions.TheNorth(APC:5.2;95%CI:−7.8to20.0)andNortheast

(APC:1.8;95%CI:−1.7to5.4)regionspresentedanon-significant

increasingtrend(Fig.2;Table2).

Bothmalesandfemalesshowedsignificantdecreasing mortal-itytrendsinthestudyperiod(Table2).Inallagegroups,mortality decreased duringtheobservationperiod;thetrends intheage groups0–14yearsand40–49yearswerenotsignificant(Table2).

3.5. Spatialdistributionandhigh-riskclusteranalysis

Intotal,14.6%(813/5,565)ofBrazilianmunicipalitiesin24of the27statesrecordedatleastoneNCC-relateddeath.Thespatial distributionoftheaverageannualcrudeandsmoothedmortality ratesarepresentedinFig.3AandB,respectively.Averageannual crude NCC-relatedmortalityrates rangedamongmunicipalities

from0.0to4.49deaths/100,000inhabitants,andsmoothed mortal-ityratesfrom0to1.21deaths/100,000inhabitants.Municipalities withhighNCC-relatedmortalityrateswerelocatedmainlyinstates ofSoutheast,SouthandCentral-Westregions(Fig.3AandB).

Global Moran’sI index for thestudy period showed signifi-cantpositivespatialautocorrelation(0.282,p<0.001),evidencing theexistenceofspatialdependenceamongmunicipalities.Fig.4A presentsthehigh-riskclustersofmunicipalitiesidentified accord-ingtotheLISAanalysis.Weidentifiedalargehigh-risk(High/High) concentricclusterforNCC-relatedmortalityincentralBrazil, cover-ingseveralgeographicregions(Fig.4A).Clustersofmunicipalities withlowrates(Low/Low)coveredlargeareasintheNortheastand NorthregionsandinsmallareasintheMatoGrossoandRioGrande doSulstates(Fig.4A).

Byscanspace-timeanalysis,weidentifiedtwosignificant spa-tiotemporalhigh-riskclustersinNortheast,Southeast,Southand Central-Westregions (Fig.4B).Themostlikely cluster(primary cluster)wasdetectedintheperiod2000–2004,andincluded1211 municipalitiesofstatesofMatoGrossodoSul,Goiás,Distrito Fed-eral,MinasGerais,SãoPaulo,ParanáandSantaCatarina,withatotal of482deaths.Therelativeriskwas2.66(LLR:142.63;p<0.001) andtheannualmortalityratewas0.2deaths/100,000inhabitants (Fig.4B).Thesecondaryhigh-riskclusterincluded709 municipali-tieslocatedinthestatesofBahia,MinasGerais,EspíritoSantoand RiodeJaneirowiththedurationfrom2002to2007.Thiscluster had163deaths,witharelativeriskof1.88(LLR:24.81;p<0.001) andannualmortalityrate0.1deaths/100,000inhabitants(Fig.4B).

3.6. CausesofdeathassociatedtoNCC-relateddeaths

Themainassociatedcausesofdeathmentionedondeath certifi-catesinwhichNCCwasidentifiedastheunderlyingcauseincluded nervous/neurological diseases (73.1%), in particular intracranial hypertension,hydrocephalusandcerebraloedema (Supplemen-tary Table 1). The second group with the highest number of mentionsasassociatedcausewererespiratorydiseases(49.1%, par-ticularlypneumoniaandrespiratoryfailure).Sepsisandrespiratory arrestwerementionedin15.3%and10.4%ofdeaths,respectively (SupplementaryTable1).

WhenNCCwasmentionedasanassociatedcause,themost com-monunderlyingcausesincludedcardiovasculardiseases(31.5%), infectiousdiseases(23.7%)andneurologicaldiseases(10.9%) (Sup-plementaryTable2).HIV/AIDS(17.3%)wastheprincipalspecific underlyingcause,followedbystroke(9.2%)andother cerebrovas-culardiseases(6.7%)(SupplementaryTable2).

4. Discussion

Tothebestofourknowledge,thisisthefirstnationwide sys-tematicstudyonNCC-relatedmortalityinBrazil.Wehighlighted several epidemiological and clinical aspects of the disease: we observeda decreasingtrendofmortalityovera 12-yearperiod, with significantvariations among Brazilian regions; we identi-fiedspatial and spatiotemporal high-risk clustersfor mortality, locatedmainlyintraditionalNCC-endemicareasinthecountry;we describedhigh-riskgroupssuchasadvancedage,males, individu-alsofwhiterace/colour,andresidentsinendemicstates/regions; andwedescribeddiseasesofnervousandrespiratorysystemsas themostcommonlyassociatedcausesofdeathwhenNCCwasthe underlyingcause,andHIV/AIDSasthemostfrequentunderlying causewhenNCCwaslistedanassociatedcauseofdeath.

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Fig.1. Spatialdistributionofaverageannualage-adjustedNCC-relatedmortalityrates(per1,000,000inhabitants)bystatesofresidenceinBrazil,2000–2011.

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Table2

JoinpointregressionanalysiswithcorrespondingAPCofNCC-relatedmortalityratesinBrazil,2000–2011.

Variable Trend1 Trend2 Trend3 Entireperiod

Period APC 95%CI Period APC 95%CI Period APC 95%CI AAPC 95%CI Sex

Male 2000–2011 −4.6a −5.9to−3.2

Female 2000–2011 −4.8a −7.5to−2.0

Agegroup(years)

0–14 2000–2004 −22.7 −49.1to17.3 2004–2007 72.6 −40.2to398.4 2007–2011 −43.9a −66.1to−7.2 −14.4 −34.3to11.6

15–29 2000–2011 −6.1a −10.0to−2.0

30–39 2000–2011 −6.1a −9.3to−2.7

40–49 2000–2011 −2.7 −6.8to1.5

50–59 2000–2011 −5.5a −8.8to−2.1

60–69 2000–2011 −5.7a −9.6to−1.6

≥70 2000–2011 −3.2a −5.7to−0.7

Regionofresidence

North 2000–2011 5.2 −7.8to20.0

Northeast 2000–2011 1.8 −1.7to5.4

Southeast 2000–2011 −6.5a −8.8to−4.2

South 2000–2011 −3.4a −6.7to−0.1

Central-West 2000–2011 −6.0a −11.0to−0.8

Brazil 2000–2011 −4.7a −6.0to−3.3

APC:annualpercentchange;AAPC:averageannualpercentchange;CI:confidenceintervals.

a_{Significantly}_different_from₀₍_p_<_0.05).

Fig.3. SpatialdistributionofNCC-relatedmortalityratesbymunicipalityofresidenceinBrazil,2000–2011:(a)averageannualcrudemortalityrates(per100,000inhabitants),

(b)averageannualBayesian-smoothedmortalityrates(per100,000inhabitants).

intheincidenceand/orcasefatalityratebyNCCinrecentyears (Santo, 2007).In theabsenceofsystematic diseasesurveillance andcontrolprogramsinmostendemicareas,nonspecificmeasures, suchasimprovedgenerallivingandsanitaryconditions,improved healtheducationand accesstohealthservicesmayhaveplayed animportantrole inreducingNCCincidenceand,consequently, severeandfatalcases(TakayanaguiandLeite,2001;Santo,2007). Furthermore,theuseofbetterdiagnosticapproaches,early diag-nosisandaccesstobothclinicalandsurgicaltreatmentsmaybe importantfactorsinvolvedindecreasedcasefatalityandmortality inendemicregions(TakayanaguiandLeite,2001;Santo,2007).

Astudyin Mexicousingnational dataverifiedanimportant decreaseofthefrequency ofcasesofcysticercosisandtaeniasis from1990to2009;theimplementationofnationalcontrol pro-gramforT.soliumandthegeneralimprovementoflivingconditions inMexicowereconsideredasthemaindrivingfactors(Flisserand

Correa,2010).Themostsocio-economically deprivedregionsin Brazil(NorthandNortheast)despitehavingthelowestrates,did notpresentadecreasingtrendofNCC-relatedmortalityinthestudy period.Intheseareasthereareusuallynospecificcontrolprograms, thereislimitedaccesstohealthservices,andlivingconditionsare poor(Agapejev,2003;WHO,2010a;Agapejev,2011;DelBrutto, 2014).

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Fig.4.Spatialandspatiotemporalclusteranalysisofschistosomiasis-relatedmortalityratesbymunicipalityofresidenceinBrazil,2000–2011:(a)LISAclusteranalysis

(MoranMap),(b)scanspace-timeclustersanalysis.

endemicareas(WHO,2010a;Agapejev,2011),thehighoccurrence ofthediseasein Southand Southeast regionsmayalsobe due tohighercoverageandaccesstodiagnosisbyneuroimagingtests (computedtomography[CT]or/andMagneticResonanceImaging [MRI]),andclinicalandsurgicaltreatment,andthepresenceof spe-cificcontrolprogramsanddiseasenotification(Pfuetzenreiterand Pires,2000;Agapejev,2003,2011).ThelowoccurrenceofNCCin someareas,suchasNorthandNortheastregions,canbeexplained bythelackofnotificationanddifficultyofaccesstomedicalcare anddiagnosticmethods,whichcanreducethefrequencyof diag-nosisandresultinunderreportingofthedisease(Pfuetzenreiter and Pires,2000; Agapejev, 2003).Internal migration processes, especiallyofpeoplefromruralareasindisease-endemicregions tourbancentres,mayhavealsoaffectedtheendemicpatternsof diseaseinthecountry(Mendesetal.,2005;Benedetietal.,2007; Gonzalesetal.,2015).

ThehigherNCC-relatedmortalityratesobservedinmales con-firmfindingsofotherlarge-scalemortalitystudiescarriedoutin thestateofSãoPaulo,Brazil(Santo,2007),andintheUSA(Sorvillo etal.,2004,2007).TherelationshipbetweensexandNCCinfection riskiscontroversial.Somestudiesshowedahigherfrequencyof thediseaseinmales(Chimellietal.,1998;Chagasetal.,2003; Lino-Junioretal.,2007;AlmeidaandTorres,2011),whileothersshowed ahigherprevalenceofNCCinfemales(Pfuetzenreiterand Avila-Pires,1999;Mendesetal.,2005;Benedetietal.,2007;Grazziotin etal.,2010;Coral-Almeidaetal.,2015).Apreviousliteraturereview onNCCepidemiologyinBrazilshowedahigherprevalenceofNCC amongmales, withmore frequentinvolvement of severe man-ifestationsin femalepatients(Agapejev, 2003,2011).Infact, in studiesthatshowedahigherfrequencyofNCCinmales, gener-allymostcaseswereconsideredasymptomatic(Shanderaetal., 1994;Chimellietal.,1998;MontemorNettoetal.,2000;Almeida andTorres, 2011).Studies showedthatsomeforms ofNCC are moresevereinwomen,withamoreintenseinflammatoryresponse againsttheparasite,indicatingapossiblehormonalinfluenceon thediseasedevelopmentorsusceptibility(DelBruttoetal.,1988; PfuetzenreiterandAvila-Pires,1999;Fleuryetal.,2004;Mendes etal.,2005;Benedetietal.,2007).Gender-specifichealthcare seek-ingbehaviourmayalsoplayarole.Themorefrequentoccurrenceof clinicalmanifestationsinwomenwouldleadthemtoseekmedical

assistancemorefrequentlyand,consequently,tocarryoutmore diagnostictestingthanmen(PfuetzenreiterandAvila-Pires,1999; Grazziotinetal.,2010).

ThehighNCC-relateddeathratesamongelderlyreflectthe pat-terns of chronicand debilitatingnature of this disease(Croker etal.,2012).Thereisalongerexposuretoparasiteswith increas-ingage,andprobablypatientsarecontinuouslyinfectedwithNCC during theirlifetime (Freitas et al., 2005; Mendes et al., 2005; Cavellanietal.,2007,2012;Coral-Almeidaetal.,2015).Studieshave demonstratedthatolderpeoplearemoretoleranttotheparasite thanyounger,withNCClesssymptomaticinolderpeoplethanin youngerpeople(Cavellanietal.,2007,2012).Somestudieshave indicatedhigherlevelsofactiveinfectioninelderlypeople,which wassuggestedtobeduetoaloweredhostimmuneresponse(Praet etal., 2010;Seckaet al.,2011; Mwapeet al.,2013).Thiscould indicatethatsusceptibilitytobecomeinfectedincreaseswithage, whereasthereis adecreaseofresistanceagainstseveredisease (Cavellanietal.,2012).Theseeffectsmayexplainhighermeanage atdeathandhigherproportionofdeathsinolderagegroupsforNCC asanassociatedcausewhencomparedtoNCCasanunderlying cause,whichhadhigherpredominanceofdeathsinmiddle-aged adults.Thesimultaneousoccurrenceofcommonchronicdiseases intheelderly,suchascardiovasculardiseasesandcancer,mayeven increaseseverityandcasefatality(Cavellanietal.,2007).

The high proportion and death rate in people of withe race/colour can be mainly explained by the higher population ofEuropeandescendantsinBrazil’sSoutheastandSouthregions (IBGE, 2010). However, an important number of missing data regardingrace/colourlimitsthevalidityandtheinterpretationof thisinformationshouldbeperformedwithcaution.

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Sorvilloetal.,2007;Carabinetal.,2011).Thepresenceofassociated causesofdeathconsideredterminalconditions,suchas respira-toryfailure,pneumonia,respiratoryarrestandsepsismayreflect theseverityoftheNCC-relatedcomplicationsprocessleadingto death(Santo,2007).ConsideringdeathsinwhichNCCwas iden-tifiedas anassociated cause,the predominanceofHIV/AIDS as underlyingcausewassimilartofindingsofapreviousmortality study(Santo,2007).HIV/AIDScanaggravatetheconditionofNCC patients(Delobeletal.,2004;Santo,2007),butfurtherstudiesare necessarytoestablishtheeffectofNCC-HIVco-infectionin aggra-vatingordeteriorationofbothdiseases(Anandetal.,2014).Stroke, arelativelycommonbutneglectedcomplicationofNCC,iscaused byinflammatoryocclusionofthearteriesofthebrain(Rochaetal., 2001;Santo,2007).

Thetaeniasis/cysticercosiscomplexisnotacompulsory notifi-ablediseaseandthereisnotaspecificnationalcontrolprogram inBrazil(TakayanaguiandLeite,2001;Agapejev,2003).Although theBrazilianMinistryofHealthrecommendstheimplementation of compulsorynotification of taeniasis/cysticercosiscomplex in endemicareas, onlysomestates (SantaCatarina,Paraná,Minas GeraisandMatoGrossodoSul)andthemunicipalityofRibeirão Preto (São Paulo state) have deployed taeniasis/cysticercosis controlprograms(Takayanaguietal.,1996;Agapejev,2003). Con-sequently,dataonincidenceandprevalenceofNCCremainwidely unknown,anddiseaseoccurrenceismostprobablyunderestimated in Brazil (Agapejev, 2003). The implementation of appropriate surveillancemechanismsanda mandatoryreportingsystemfor taeniasis/cysticercosiscomplexthroughoutthenationalterritory couldprovidemoreaccurateepidemiologicaldataonthe popu-lationprevalenceandwouldallowgeographicalmappingofthe affectedareastoimproveeffectivenessofsurveillanceandcontrol measures(TakayanaguiandLeite,2001;Agapejev,2003).Control measuresshouldincludefreeaccesstopreventivechemotherapy, earlydiagnosisandtreatmentoftaeniasiscases,improvedpig hus-bandrypractices,strictmeatproductinspection,andanthelmintic treatmentandvaccinationofpigs(WHO,2002,2010a;Crokeretal., 2012).Thesespecificcontrolactionsshouldbedeveloped along withmoregeneralmeasures,suchasimprovementsofliving con-ditions,accesstoadequatewaterandsanitation,improvedaccess tohealthcareandhealtheducation(WHO,2010a;Torres,2015).

Ourstudyhassomelimitations.Secondary datamaypresent incompleteandbiasedinformation,despitetheimprovedcoverage andqualityofSIMdatasetsduringthepastyears(Martins-Melo etal.,2012a,b,2014a).For example,anincreasingtrendmaybe causedpartiallybyincreasedcoverageandimprovementsofdeath recordsofSIMduringthestudyperiod, aswellasby improve-mentofaccesstohealthcareservices(Martins-Meloetal.,2014b). SIM coverage in 2011 was lowest in Maranhão state (79.1%) in Northeast regionand highest in the states of the Southeast andSouthregions,with100%coverage(http://tabnet.datasus.gov. br/cgi/idb2012/a1801b.htm).Consequently,changesin mortality trendsamongregionsshouldbeinterpretedwithcare.The under-lyingcauseofdeathmayhavebeenencoded asacomplication or aggravation associated with NCC (such as cerebral oedema, hydrocephalusandintracranialhypertension).Wecollected infor-mationbasedonmultiplecausesofdeath, ratherthanonlythe underlyingcause,toreduce this errorand toidentifyall death certificatesinwhichNCCwasmentionedinanyfield.Infact,an additional32%ofcaseswereidentifiedbyusingmultiplecauses of death. However, it still can beassumed that the number of deathsbyNCChasbeenunderestimatedtosomeextent.First,about 8% of cysticercosis-relateddeaths (ICD-10:B69) were recorded asunspecifiedcysticercosis(ICD-10:B69.9)(156/2007);acertain number of NCC may be included in this group, withoutbeing reported adequately. Second, diagnosis of NCC requires confir-mationofinfectionthroughneuroimagingandserologictesting,

biopsyorautopsy(Sorvilloetal.,2004,2007).SomefatalNCCcases maythusnothavebeendiagnosed,withconsequentmiscodingof NCC-relateddeathsasotherconditions(Sorvilloetal.,2004).

Anotherlimitationisrelatedtotheuseofscanstatistics,which hasimplications onresultsinterpretation.Thecircular window imposed for scan space-time analysis to identify clusters may include places oflow rates or withabsenceof deaths, if these placesaresurroundedbyplacescharacterizedbyhighmortality rates(Lutambietal.,2010;Shabanietal.,2010).Inaddition,the resultsproducedareverysensitivetotheparametersettingofthe statisticalprogram(Cheungetal.,2013).

Mortalitydatamaybelimitedtoidentifyspecificareasofhigh transmissionandendemicityofNCC,sincemostdeathsmayhave beenaresultofinfectionsacquiredmanyyears ago,and dueto internal migration ofinfected people,thelocation ofdeathnot necessarilyreflectsthelocationofinfection(Mendesetal.,2005; Martins-Meloetal.,2015).

5. Conclusions

NCCis animportantbutneglectedand preventablecauseof deathinBrazil.Asindicatedbytheanalysisofmultiplecausesof death,NCC-relateddeathsmaybelargelyunderestimatedinthe country.DespitethedeclineofNCC-relatedmortality,thispattern wasnotobservedintheregionswithlowratesandwithworse socioeconomicconditions,suchastheNorthandNortheastregions. Clustersof municipalitieswithhighmortalityrates werefound mainlyinstatesandregionsconsideredhighlyendemicfordisease. Specificpublichealth measuresincludingsurveillanceand con-trolsystemsandcompulsorynotificationfortaeniasis/cysticercosis complexshouldbeimplementedthroughoutthecountry.

Acknowledgements

TheauthorsthanktheCoordenac¸ãodeAperfeic¸oamentode Pes-soaldeNívelSuperior(CAPES/Brazil)forgrantingaPhDScholarship toFRM.JHisaclass1researchfellowattheConselhoNacionalde DesenvolvimentoCientíficoeTecnológico(CNPq/Brazil).

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.actatropica.2015. 10.011.

References

AustralianInstituteofHealthWelfare,2012.MultipleCausesofDeathinAustralia:

AnAnalysisofAllNaturalandSelectedChronicDiseaseCausesofDeath

1997–2007.AIHW,Canberra,Availablefromhttp://www.aihw.gov.au/

publication-detail/?id=10737422603(accessed20.10.13.).

Agapejev,S.,1996.EpidemiologyofneurocysticercosisinBrazil.Rev.Inst.Med.

Trop.SaoPaulo38,207–216.

Agapejev,S.,2003.[Clinicalandepidemiologicalaspectsofneurocysticercosisin

Brazil:acriticalapproach].Arq.Neuropsiquiatr.61,822–828.

Agapejev,S.,2011.Neurocysticercosis:theenigmaticdisease.Cent.Nerv.Syst.

AgentsMed.Chem.11,261–284.

Almeida,S.M.,Torres,L.F.B.,2011.Neurocysticercosis-retrospectivestudyof

autopsyreports,a17-yearexperience.J.Commun.Health36,698–702.

Anand,K.S.,Wadhwa,A.,Garg,J.,Mahajan,R.K.,2014.HIV-associated

neurocysticercosis.J.Int.Assoc.Provid.AIDSCare14,120–122.

Anselin,L.,1995.Localindicatorsofspatialassociation—LISA.Geogr.Anal.27,

93–115.

Assunc¸ão,R.M.,Barreto,S.M.,Guerra,H.L.,Sakurai,E.,1998.[Mapsof

epidemiologicalrates:aBayesianapproach].Cad.SaudePubl.14,713–723.

Benedeti,M.R.,Falavigna,D.L.M.,Falavigna-Guilherme,A.L.,Araújo,S.M.,2007.

[Epidemiologicalandclinicalprofileofneurocysticercosispatientsassistedby theHospitalUniversitárioRegionaldeMaringá,Paraná,Brazil].Arq. Neuropsiquiatr.65,124–129.

Bhattarai,R.,Budke,C.,Carabin,H.,2013.Theburdenofcysticercosis.In:Sibat,H.F.

(9)

from: http://www.intechopen.com/books/novel-aspects-on-cysticercosis-and-neurocysticercosis/the-burden-of-cysticercosis(accessed15.12.14.).

BrazilianMinistryofHealth,2001.ManualdeprocedimentosdoSistemade

Informac¸õessobreMortalidade.BrazilianMinistryofHealth,Brasília.

Carabin,H.,Ndimubanzi,P.C.,Budke,C.M.,Nguyen,H.,Qian,Y.,Cowan,L.D.,Stoner,

J.A.,Rainwater,E.,Dickey,M.,2011.Clinicalmanifestationsassociatedwith

neurocysticercosis:asystematicreview.PLoSNegl.Trop.Dis.5,e1152.

Carpio,A.,2002.Neurocysticercosis:anupdate.LancetInfect.Dis.2,751–762.

Cavellani,C.L.,Faleiros,A.C.G.,deSouzaLino,R.,dosReis,M.A.,Teixeira,V.P.A.,

2007.Cysticercosisintheelderly.Ann.Diagn.Pathol.11,330–333.

Cavellani,C.L.,Corrêa,R.R.M.,Ferraz,M.L.F.,Rocha,L.P.,Faleiros,A.C.G.,LinoJunior,

R.S.,Reis,M.A.,Teixeira,V.P.A.,2012.Influenceofgenderoncardiacand

encephalicinflammationintheelderlywithcysticercosis:acasecontrolstudy. J.Trop.Med.,540858.

Chagas,M.G.L.,D’OliveiraJúnior,A.,Tavares-Neto,J.,2003.[Clinicalaspectsof

neurocysticercosisatsemi-desertregionofBraziliannortheast].Arq. Neuro-Psiquiatr.61,398–402.

Cheung,Y.T.D.,Spittal,M.J.,Williamson,M.K.,Tung,S.J.,Pirkis,J.,2013.Application

ofscanstatisticstodetectsuicideclustersinAustralia.PLoSOne8,e54168.

Chimelli,L.,Lovalho,A.F.,Takayanagui,O.M.,1998.[Neurocysticercosis:

contributionofautopsiestoconsolidationofthecompulsorynotificationin RibeirãoPreto-SP,Brazil].Arq.Neuropsiquiatr.56,577–584.

Cliff,A.D.,Ord,J.K.,1981.SpatialProcesses:Models&Applications.Pion,London.

Coral-Almeida,M.,Gabriël,S.,Abatih,E.N.,Praet,N.,Benitez,W.,Dorny,P.,2015.

Taeniasoliumhumancysticercosis:asystematicreviewof

sero-epidemiologicaldatafromendemiczonesaroundtheworld.PLoSNegl. Trop.Dis.9,e0003919.

Coyle,C.M.,Mahanty,S.,Zunt,J.R.,Wallin,M.T.,Cantey,P.T.,WhiteJr,A.C.,O’Neal,

S.E.,Serpa,J.A.,Southern,P.M.,Wilkins,P.,2012.Neurocysticercosis:neglected

butnotforgotten.PLoSNegl.Trop.Dis.6,e1500.

Croker,C.,Redelings,M.,Reporter,R.,Sorvillo,F.,Mascola,L.,Wilkins,P.,2012.The

impactofneurocysticercosisinCalifornia:areviewofhospitalizedcases.PLoS Negl.Trop.Dis.6,e1480.

DelBrutto,O.H.,2012a.NeurocysticercosisinWesternEurope:are-emerging

disease?ActaNeurol.Belg.112,335–343.

DelBrutto,O.H.,2012b.AreviewofcasesofhumancysticercosisinCanada.Can.J.

Neurol.Sci.39,319–322.

DelBrutto,O.H.,2014.Neurocysticercosis.Neurohospitalist4,205–212.

DelBrutto,O.H.,García,E.,Talamas,O.,Sotelo,J.,1988.Sex-relatedseverityof

inflammationinparenchymalbraincysticercosis.Arch.Intern.Med.148, 544–546.

Delobel,P.,Signate,A.,ElGuedj,M.,Couppie,P.,Gueye,M.,Smadja,D.,Pradinaud,

R.,2004.UnusualformofneurocysticercosisassociatedwithHIVinfection.

Eur.J.Neurol.11,55–58.

Fleury,A.,Dessein,A.,Preux,P.M.,Dumas,M.,Tapia,G.,Larralde,C.,Sciutto,E.,

2004.Symptomatichumanneurocysticercosis.J.Neurol.251,830–837.

Flisser,A.,Sarti,E.,Lightowlers,M.,Schantz,P.,2003.Neurocysticercosis:regional

status,epidemiology,impactandcontrolmeasuresintheAmericas.ActaTrop. 87,43–51.

Flisser,A.,Correa,D.,2010.Neurocysticercosismaynolongerbeapublichealth

probleminMexico.PLoSNegl.Trop.Dis.4,e831.

Freitas,F.I.D.S.,Meza-Lucas,A.,Lima,C.B.,Costa,W.D.,Melo,A.,2005.

[Cysticercosisresearchinepilepticpatientsdwellingintownsofthewestern CaririintheStateofParaíba,Brazil].Arq.Neuropsiquiatr.63,656–660.

Gonzales,I.,Miranda,J.J.,Rodriguez,S.,Vargas,V.,Cjuno,A.,Smeeth,L.,Gonzalez,

A.E.,Tsang,V.C.,Gilman,R.H.,Garcia,H.H.,2015.Seizures,cysticercosisand

rural-to-urbanmigration:thePERUMIGRANTstudy.Trop.Med.Int.Health20, 546–552.

Grazziotin,A.L.,Fontalvo,M.C.,Santos,M.B.,Monego,F.,Grazziotin,A.L.,Kolinski,

V.H.,Bordignon,R.H.,Biondo,A.W.,Antoniuk,A.,2010.Epidemiologicpattern

ofpatientswithneurocysticercosisdiagnosedbycomputedtomographyin Curitiba,Brazil.Arq.Neuropsiquiatr.68,269–272.

Hotez,P.J.,Fujiwara,R.T.,2014.Brazil’sneglectedtropicaldiseases:anoverview

andareportcard.MicrobesInfect.16,601–606.

InstitutoBrasileirodeGeografiaeEstatística-IBGE,2010.SíntesedosIndicadores

Sociais2010.IBGE,RiodeJaneiro,Availablefrom:http://www.ibge.gov.b/

home/estatistica/populacao/condicaodevida/indicadoresminimos/ sinteseindicsociais2010/SIS2010.pdf(accessed23.01.15.).

Kim,H.J.,Fay,M.P.,Feuer,E.J.,Midthune,D.N.,2000.Permutationtestsfor

joinpointregressionwithapplicationstocancerrates.Stat.Med.15,335–351.

Kulldorff,M.,1997.Aspatialscanstatistic.Commun.Stat.TheoryMethods26,

1481–1496.

Lindoso,J.A.L.,Lindoso,A.A.B.P.,2009.NeglectedtropicaldiseasesinBrazil.Rev.

Inst.Med.Trop.SaoPaulo51,247–253.

Lino-Junior,R.S.,Faleiros,A.C.,Vinaud,M.C.,Oliveira,F.A.,Guimarães,J.V.,Reis,

M.A.,Teixeira,V.P.,2007.Anatomopathologicalaspectsofneurocysticercosis

inautopsiedpatients.Arq.Neuropsiquiatr.65,87–91.

Lutambi,A.M.,Alexander,M.,Charles,J.,Mahutanga,C.,Nathan,R.,2010.Under-f

IveMortality:Spatial-temporalClustersinIfakaraHDSSinSouth-Eastern Tanzania.Glob.HealthAction3.

Martins-Melo,F.R.,Alencar,C.H.,RamosJr.,A.N.,Heukelbach,J.,2012a.

EpidemiologyofmortalityrelatedtoChagas’diseaseinBrazil,1999–2007. PLoSNegl.Trop.Dis.6,e1508.

Martins-Melo,F.R.,RamosJr,A.N.,Alencar,C.H.,Lange,W.,Heukelbach,J.,2012b.

MortalityofChagas’diseaseinBrazil:spatialpatternsanddefinitionof high-riskareas.Trop.Med.Int.Health17,1066–1075.

Martins-Melo,F.R.,daSilveiraLima,M.,RamosJr,A.N.,Alencar,C.H.,Heukelbach,

J.,2014a.MortalityandcasefatalityduetovisceralleishmaniasisinBrazil:a

nationwideanalysisofepidemiology,trendsandspatialpatterns.PLoSOne9, e93770.

Martins-Melo,F.R.,Pinheiro,M.C.C.,Ramos,A.N.,Alencar,C.H.,deMoraesBezerra,

F.S.,Heukelbach,J.,2014b.Trendsinschistosomiasis-relatedmortalityin

Brazil,2000–2011.Int.J.Parasitol.44,1055–1062.

Martins-Melo,F.R.,Pinheiro,M.C.C.,RamosJr,A.N.,Alencar,C.H.,Bezerra,F.S.M.,

Heukelbach,J.,2015.Spatiotemporalpatternsofschistosomiasis-related

deaths,Brazil,2000–2011.Emerg.Infect.Dis.10,1820–1823.

Mendes,E.C.,Silva,S.S.,Fonseca,E.A.L.T.,Souza,H.R.R.,Carvalho,R.W.,2005.

[HumanneurocysticercosisinBaixadaFluminense,RiodeJaneiroState,Brazil]. Arq.Neuro-Psiquiatr.63,1058–1062.

MontemorNetto,M.R.,Gasparetto,E.L.,Faoro,L.N.,ReisFilho,J.S.,Toni,G.S.D.,

CarvalhoNeto,A.D.,Torres,L.F.B.,2000.[Neurocysticercosis:aclinicaland

pathologicalstudyof27necropsiedcases].Arq.NeuroPsiquiatr.58,883–889.

Mwape,K.E.,Phiri,I.K.,Praet,N.,Speybroeck,N.,Muma,J.B.,Dorny,P.,Gabriël,S.,

2013.TheincidenceofhumancysticercosisinaruralcommunityofEastern

Zambia.PLoSNegl.Trop.Dis.7,e2142.

Nash,T.E.,Mahanty,S.,Garcia,H.H.,2013.Neurocysticercosis–morethana

neglecteddisease.PLoSNegl.Trop.Dis7,e1964.

Pfuetzenreiter,M.R.,Avila-Pires,F.D.,1999.[Clinicalmanifestationsinpatients

withcomputerizedtomographydiagnosisofneurocysticercosis].Arq. Neuro-Psiquiatr.57,653–658.

Pfuetzenreiter,M.R.,Pires,F.D.A.,2000.[Epidemiologyofteniasis/cysticercosisby

TaeniasoliumandTaeniasaginata].Cienc.Rural30,541–548.

Praet,N.,Speybroeck,N.,Rodriguez-Hidalgo,R.,Benitez-Ortiz,W.,Berkvens,D.,

Brandt,J.,Saegerman,C.,Dorny,P.,2010.Age-relatedinfectionand

transmissionpatternsofhumancysticercosis.Int.J.Parasitol.40,85–90.

Redelings,M.D.,Sorvillo,F.,Simon,P.,2006.Acomparisonofunderlyingcauseand

multiplecausesofdeath:USvitalstatistics,2000–2001.Epidemiology17, 100–103.

Rocha,M.S.,Brucki,S.M.,Ferraz,A.C.,Piccolo,A.C.,2001.[Cerebrovasculardisease

andneurocysticercosis].Arq.Neuropsiquiatr.59,778–783.

Santo,A.H.,2007.Cysticercosis-relatedmortalityintheStateofSãoPaulo,Brazil,

1985–2004:astudyusingmultiplecausesofdeath.Cad.SaudePubl.23, 2917–2927.

Secka,A.,Grimm,F.,Marcotty,T.,Geysen,D.,Niang,A.M.,Ngale,V.,Boutche,L.,Van

Marck,E.,Geerts,S.,2011.Oldfocusofcysticercosisinasenegalesevillage

revisitedafterhalfacentury.ActaTrop.119,199–202.

Shabani,J.,Lutambi,A.M.,Mwakalinga,V.,Masanja,H.,2010.Clusteringof

under-fivemortalityinRufijihealthanddemographicsurveillancesystemin ruralTanzania.Glob.HealthAction3.

Shandera,W.X.,WhiteJr,A.C.,Chen,J.C.,Diaz,P.,Armstrong,R.,1994.

NeurocysticercosisinHouston,Texas:areportof112cases.Medicine (Baltimore)73,37–52.

Sorvillo,F.J.,DeGiorgio,C.,Waterman,S.H.,2007.Deathsfromcysticercosis,United

States.Emerg.Infect.Dis.13,230–235.

Sorvillo,F.J.,Portigal,L.,DeGiorgio,C.,Smith,L.,Waterman,S.H.,Berlin,G.W.,Ash,

L.R.,2004.Cysticercosis-relateddeaths,California.Emerg.Infect.Dis.10,

465–469.

Takayanagui,O.M.,CastroeSilva,A.A.,Santiago,R.C.,Odashima,N.S.,Terra,V.C.,

Takayanagui,A.M.,1996.[CompulsorynotificationofcysticercosisinRibeiräo

Preto-SP,Brazil].Arq.Neuropsiquiatr.54,557–564.

Takayanagui,O.M.,Leite,J.P.,2001.Neurocysticercosis.Rev.Soc.Bras.Med.Trop.

34,283–290.

Townes,J.M.,Hoffmann,C.J.,Kohn,M.A.,2004.NeurocysticercosisinOregon,

1995–2000.Emerg.Infect.Dis.10,508–510.

Torres,J.R.,2015.CysticercosisdiseaseburdeninLatinAmerica.In:

Franco-Paredes,C.,Santos-Preciado,J.I.(Eds.),NeglectedTropical Diseases-LatinAmericaandtheCaribbean.Springer,Vienna,pp.225–232.

Wallin,M.T.,Kurtzke,J.F.,2004.NeurocysticercosisintheUnitedStatesreviewof

animportantemerginginfection.Neurology63,1559–1564.

WHO,2002.Controlofneurocysticercosis:peportbythesecretariat.In:Fifty-fifth

WorldHealthAssembly;ProvisionalAgendaItem13.18.WorldHealth Organization,Washington,DC,Reportno.A55/23.

WHO,2010a.FirstWHOReportonNeglectedTropicalDiseases:Workingto

OvercometheGlobalImpactofNeglectedTropicalDiseases.WorldHealth Organization,Geneva.

WHO,2010b.StatisticalClassificationofDiseasesandRelatedHealthProblems

(ICD):10thRevision.Version2010.WorldHealthOrganization,Geneva,

Availablefrom:http://apps.who.int/classifications/apps/icd/icd10online/