Predictors of quality of life and their interrelations in Korean people with epilepsy: A MEPSY study

Predictors of quality of life and their interrelations in Korean people with epilepsy: A MEPSY study

Se-JinLee^a,1, Ji-EunKim^b,1,Jong-Geun Seo^c,Yong Won Cho^d,Jang-Joon Lee^e, Hye-JinMoon^d,Sung-PaPark^c,*

aDepartmentofNeurology,YeungnamUniversityCollegeofMedicine,Daegu,RepublicofKorea

bDepartmentofNeurology,CatholicUniversityofDaeguSchoolofMedicine,Daegu,RepublicofKorea

cDepartmentofNeurology,SchoolofMedicine,KyungpookNationalUniversity,Daegu,RepublicofKorea

dDepartmentofNeurology,DongsanMedicalCenter,KeimyungUniversitySchoolofMedicine,Daegu,RepublicofKorea

eDepartmentofNeurology,DaeguFatimaHospital,RepublicofKorea

1. Introduction

Peoplewithepilepsy(PWE)appeartohavepoorerqualityoflife (QOL)thanthegeneralpopulationnotonlybecauseoftheseizures but also because of comorbid conditions such as medical, psychiatric, and psychosocialproblems.¹ Moreover, when PWE takeanantiepilepticdrug(AED)foraperiodoftime,thatdrugcan elicit adverse effects that further impair their QOL.² For these reasons,theidentificationofpredictorsofreducedQOLinPWEis criticalfor improvingthetargetingand optimizationofexisting and emerging interventions and management strategies for epilepsy.³

PredictorsofQOLinPWEhavebeenthoroughlysummarizedin asystematicreviewfromtheUK.³Thisreviewincluded93 QOL studiesthat wereidentifiedby Medline,Embase,and Cochrane LibrarysearchesuptoJuly2010.Increasesinseizurefrequency, seizure severity,levels ofdepression, levelsofanxiety, and the ARTICLE INFO

Articlehistory:

Received22March2014

Receivedinrevisedform16June2014 Accepted18June2014

Keywords:

Epilepsy Predictor Qualityoflife Depression Adverseeffect Seizurecontrol

ABSTRACT

Purpose:Peoplewithepilepsy(PWE)aremorelikelytohaveimpairedqualityoflife(QOL)thanthe generalpopulation.WestudiedpredictorsofQOLandtheirinterrelationsinKoreanPWE.

Methods:Subjects who consecutively visited outpatient clinics in four tertiary hospitalsand one secondarycarehospitalwereenrolled.ThesesubjectscompletedtheKoreanversionoftheNeurological DisordersDepressionInventoryforEpilepsy(K-NDDI-E),theGeneralizedAnxietyDisorder-7(GAD-7), theQualityofLifeinEpilepsy-10(QOLIE-10),andtheKoreanversionofLiverpoolAdverseEventProfile (K-LAEP). We evaluated the predictors of QOL by multiple regression analyses and verified the interrelationsbetweenthevariablesusingastructuralequationmodel.

Results:Atotalof702PWEwereeligibleforthestudy.ThestrongestpredictoroftheoverallQOLIE-10 scorewas theK-LAEP score (b= 0.375, p<0.001), followed bytheK-NDDI-E score(b= 0.316, p<0.001),seizurecontrol(b= 0.152,p<0.001),householdincome(b= 0.375,p<0.001),andGAD- 7score(b= 0.119,p=0.005).Thesevariablesexplained68.7%ofthevarianceintheoverallQOLIE-31 score.DepressionandseizurecontrolhadabidirectionalrelationshipandexerteddirecteffectsonQOL.

ThesefactorsalsoexertedindirecteffectsonQOLbyprovokingadverseeffectsofAEDs.Anxietydidnot haveadirecteffectonQOL;ithadonlyindirecteffectthroughtheadverseeffectsofAEDs.

Conclusion:Depression, anxiety, seizure control, and adverse effects of AEDs have complex interrelationsthatdeterminetheQOLofPWE.

ß2014BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.

Abbreviations:PWE,peoplewithepilepsy;QOL,qualityoflife;AED,antiepileptic drug;TLE, temporallobeepilepsy;WCE,well-controlledepilepsy;PCE, poorly controlledepilepsy;UCE,uncontrolledepilepsy;PDD,prescribeddailydose;DDD, defined daily dose; K-NDDI-E, Korean version of the Neurological Disorders DepressionInventoryforEpilepsy;GAD-7,GeneralizedAnxietyDisorder-7;K-LAEP, KoreanversionofLiverpoolAdverseEventProfile;QOLIE-10,QualityofLifein Epilepsy-10;NFI,NormedFitIndex;CFI,ComparativeFitIndex;GFI,GoodnessofFit Index;RMR,rootmean-squareresidual;LSSS,LiverpoolSeizureSeverityScale;

DSM-IV-TR,DiagnosticandStatisticalManualofMentalDisorders,FourthEdition;

SCID,StructuredClinicalInterviewforDSM-IVaxisIdisorders.

* Corresponding authorat: Department of Neurology, School of Medicine, KyungpookNationalUniversity,680Gukchaebosang-ro,Jung-gu,Daegu700-842, RepublicofKorea.Tel.:+82534205769;fax:+82534224265.

E-mailaddress:sppark@mail.knu.ac.kr(S.-P.Park).

1Theseauthorscontributedequallytothemanuscriptasfirstauthorsinthis study.

ContentslistsavailableatScienceDirect

Seizure

j o urn a l hom e pa g e : ww w . e l se v i e r. c om / l oca t e / y se i z

http://dx.doi.org/10.1016/j.seizure.2014.06.007

1059-1311/ß2014BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.

presenceofcomorbiditieswerestronglyassociatedwithreduced QOL.However,age,gender,maritalstatus,typeofseizure,ageat diagnosis,anddurationofepilepsywerefoundtobeunlikelytobe associated with QOL. The predictive values of educational and employmentstatuses,thenumberofAEDsandtheadverseeffects ofAEDsforQOLwerenotdetermined.

Many studies have consistently reported that the strongest predictors of QOL in PWE are depression and anxiety among variousotherfactors.^4–9Depressionandanxietyhavebeenfound tobebetterpredictorsthatseizurecontrolortheadverseeffectsof AEDs.However,somestudieshavereportedthatothervariables havethegreatestpredictivevalues.AnItalian,multicenterstudyof peoplewithpharmacoresistantepilepsyreportedthattheadverse effects of AEDs were the strongest predictor, followed by depression symptoms,pharmacoresistance grade, age,and lack ofadrivinglicense.¹⁰Ahospital-based,Chinesestudyofpeople withvariousseizurefrequenciesalsoreportedtheadverseeffects ofAEDswerethestrongestpredictor,followedbythenumberof AEDs,depressionsymptoms,andanxietysymptoms.¹¹Ahospital- based, Russian studyfound seizure frequency tobe a stronger predictorofQOLthandepression;indeed,seizurefrequencywas foundtobethestrongestpredictorinthatstudy.¹²

Therefore,thefactorwiththestrongest influenceon QOLin PWEhasyettobeelucidated.

Depressionandanxiety,theadverseeffectsofAEDs,andseizure control are related to each other. Regarding the relationship betweenseizurecontrolanddepressionandanxiety,peoplewith drug-refractory epilepsy have been reported to exhibit higher frequencies of depression and anxiety than those with well- controlledepilepsy.^13,14Regardingtherelationshipbetween the adverse effects of AEDs and depression and/or anxiety, PWE, depressionandanxiety,eventhosepresentingwithsubsyndromic types,aremorelikelytoexperienceadverseeffectsofAEDsthan thosewithoutthesedisorders.¹⁵Peoplewithpharmacoresistant epilepsyalsoexhibithigherfrequenciesofadverseeffectsofAEDs when they also have depression symptoms.¹⁰ Regarding the relationshipbetween seizurecontrol and theadverseeffects of AEDs,seizurecontrolisoneofpredictorsofadverseeffectsofAEDs inPWE.^16,17Taken together,theseresultssuggestthatcomplex interrelationsbetweenthesevariablesandtheircontributionsto QOLlikelyexist.

TheinterrelationsbetweenthepredictorsofQOLinPWEhave not been well studied. In an Asian, hospital-based study, the interrelationsbetweenthevariablesintermsoftheircontributions toQOLwereclarifiedinPWE.⁴Depression,anxiety,seizurecontrol, the number of AEDs, and sleep disturbances had complex interrelationsintheircontributionstoQOLasdocumentedbya structuralequationmodel. However,duetotherelativelysmall samplesize,onlyalimitednumberofvariablescouldbeexamined in this study. For example, socioeconomic status, the adverse effectsofAEDs,theunderlyingepilepsysyndrome,andtheseizure focuswerenotconsideredasvariables.Therefore,ouraimswereto performacross-sectionalstudytodeterminethepredictorsofQOL inalargesampleofPWEandtoclarifytheirinterrelations.

2. Methods 2.1. Subjects

We invited subjects who consecutively visited the epilepsy clinicsofsecondaryandtertiarycarehospitals.Thesubjectswere adultsbetweentheagesof20–70yearswithcurrentdiagnosesof epilepsywhohadtakenoneormoreAEDsforattheyearpriorto recruitmentandwerecapableofprovidinginformedconsentand agreeing to the study protocol. Subjects with insufficient informationintheirmedicalrecords,withmentalretardationor

serious medical, neurological, or psychiatric disorders that prevented them from understanding the questionnaire and cooperatingwiththestudy,andthosewhodeclinedtocomplete thequestionnaireswereexcluded.

2.2. Studydesign

The multicenter trial of epilepsy and psychiatric diseases (MEPSY)isamulticenter,cross-sectionalstudyassessingdepres- sion,anxiety,suicidality,theburdenoftheadverseeffectsofAEDs, andthequalityoflifeofKoreanPWE.Thesubjectswereenrolled consecutively beginning in November 2012 at the outpatient epilepsyclinicsoffourtertiaryandonesecondarycarehospitals inDaegucity,whichlocatedinthesouthernpartofKorea.Thisstudy wasperformedasapartoftheMEPSYstudy.Theinstitutionalreview boardofeachcenterapprovedthestudy,andallsubjectsprovided written informed consent beforeparticipatingin thestudy.The subjects were diagnosed according tothe ILAE classification of seizuresandepilepticsyndromes.^18,19Allpatientswereinterviewed bytrainedepileptologistswhoalsoreviewedthesubjects’medical chartstocollectdemographic,socioeconomic,andclinicalinforma- tion, which was entered into a computerized database. The socioeconomicvariablesincludedthefollowing:havingajobversus nothavingajob;earningatleastonemillionKoreanwon(KRW)per month(equivalenttoUS$900permonth)versusearninglessthan onemillionKRWpermonth;havingadrivinglicenseversusnot havingadrivinglicense;andbeingmarriedversusbeingdivorced, bereaved, or unmarried. The clinical variables included the following: age at onset,disease duration,seizuretype,etiology, epilepsy syndrome,seizure control,MRI abnormality, history of febrileconvulsion,familyhistoryofepilepsy,durationofAEDintake, AEDtherapyregimen,andAEDload.Wedividedtheetiologiesinto idiopathic/cryptogenicandsymptomaticepilepsy.Wedividedthe epilepticsyndromesintofourgroups:temporallobeepilepsy(TLE), extraTLE,generalizedepilepsy,andunknownsyndromes.extraTLE included epilepsy syndromes in which the epileptic attacks originated fromthe frontal, parietal, oroccipital lobes.We also dividedseizurecontrolintothreegroups:well-controlledepilepsy (WCE),poorlycontrolledepilepsy(PCE),anduncontrolledepilepsy (UCE). WCE was defined by freedom from seizures over the precedingyear.UCEwasdefinedaccordingtothecriteriausedto determine drug-refractory epilepsy (i.e., the failure of adequate trialsoftwoAEDs,anaverageofmorethanoneseizurepermonthfor 18monthsandnoseizure-freeperiodslongerthanthreemonths²⁰).

PCEwasdefinedasanintermediatedegreeofseizurecontrolthat did not meet the criteria for WCE or UCE. The seizurecontrol classificationforeachPWEwasdeterminedbasedoninformation about seizure frequency that was obtained from the medical records.TheAEDloadofeachindividualpatientwasestimatedas thesumoftheprescribeddailydose(PDD)/defineddailydose(DDD) ratiosforeachAEDincludedinthetreatmentregimen²¹whereDDD correspondstotheassumedaveragemaintenancedailydoseofa drugthatisusedforitsmainindication.²²

Eligiblesubjectscompletedseveralself-reportquestionnaires that included theKorean version of theNeurologicalDisorders DepressionInventoryforEpilepsy(K-NDDI-E),²³theGeneralized AnxietyDisorder-7(GAD-7),²⁴theKoreanversionoftheLiverpool Adverse Event Profile (K-LAEP),¹⁷ and the Quality of Life in Epilepsy-10(QOLIE-10).²⁵

2.3. Questionnaires

2.3.1. TheKoreanversionoftheNeurologicalDisordersDepression InventoryforEpilepsy

The K-NDDI-E is a reliable and valid screening tool for the detectionofmajordepressioninKoreanPWE.²³Thistoolconsists

ofabrief,6-itemquestionnaire.Theitemsareratedonafour-point scalethatrangesfrom1to4.Totalscoresrangefrom6to24,and higherscoresindicatemoreintensedepression.TheCronbach’sa

coefficientis0.898,andtotalscoresof12orgreateraresuggestive ofmajordepressivedisorder.

2.3.2. GeneralizedAnxietyDisorder-7

TheGAD-7consistsofaself-reportquestionnairethatallows fortherapid detectionofGAD.²⁴Subjectsareaskedabouthow muchtheyhavebeenbotheredbyanxiety-relatedproblemsover theprevioustwoweeksviasevenitemsthattheyrateonafour- pointscale.TotalGAD-7scorerangefrom0and21,andtotalscores of10orgreaterareconsideredtoindicatethepresenceofGAD.We usedaversionoftheGAD-7thathasbeentranslatedintoaKorean language and is freely downloadable on the Patient Health Questionnairewebsite(www.phqscreeners.com).²⁶

2.3.3. TheKoreanversionofLiverpoolAdverseEventProfile The K-LAEP is an appropriate instrument for measuring common adverse effects of AEDs that have occurred in the preceding four weeks.¹⁷ The K-LAEP consists of a 19-item questionnaire.Eachitemisevaluatedonafour-pointLikertscale onwhich1indicatesthattheitemisneveraproblem;2,rarelya problem; 3, sometimes a problem; and 4, always or often a problem.Totalscoresrangefrom19to76,andhigherscoresare indicativeofgreaterburdensoftheadverseeffects.TheCronbach’s

acoefficientofthisinstrumentis0.9.Inthepresentanalysis,the 21-itemversion,which includestwoadditional items(thinking clearlyandslurredspeech),wasusedaccordingtotheQOLstudy byBaker et al.²⁷ Therefore, theAEP scorescouldrange from a minimumof21toamaximumof84.Weconsideredtheitemsthat weregiventhreeorfourpointstoberelatedtotheadverseeffects ofAEDs.

2.3.4. 2.3.4QualityofLifeinEpilepsy-10

TheQualityofLifeinEpilepsy-10(QOLIE-10)wasderivedfrom the QOLIE-31. The Korean version of the QOLIE-10 is a valid screeningtoolformeasuringtheQOLofKoreanPWE.²⁵TheQOLIE- 10iscomprisedofsevencomponents,fiveofwhichcorrespondto singleitemforeachoffivesubscales(seizureworry,overallQOL, emotionalwell-being,energy/fatigue,andcognitivefunctioning), onecomponentincludestwoitemsabouttheeffectsofmedica- tions(physicaleffectsandmentaleffects),andthelastcomponent includesthreeitemsaboutsocialfunctioning(work,driving,and sociallimitations).ThetenitemsoftheQOLIE-10weregrouped intotwofactors: EpilepsyEffects/Role Functioning(i.e.,driving, social,work, physical,mental, andmemory effects)and Mental Health(i.e.,overall quality oflife, depression,and energy).The Cronbach’sawas0.843fortheEpilepsyEffects/RoleFunctioning subscaleand0.606fortheMentalHealthsubscale.TheQOLIE-10 wassignificantlycorrelatedwiththesourcescalesoftheKorean versionoftheQOLIE-31.

2.4. Statisticalanalyses

Datafromcontinuousvariablesareexpressedasthemeanthe SD values, and those for categorical variables are expressed as frequencies. Not only demographic, socioeconomic, and clinical variables but also the questionnaire scores were included as independentvariablesto measurethe predictorsofthe QOLIE-10 overallandsubscalescores bymultiplelinearregressionanalyses withstepwiseselection.Theprobabilitiesofentryandexitwere0.05 and 0.1, respectively. Collinearity was addressed by performing collinearity statisticalanalyses.Variables selected fromthe linear regressionanalyses were usedto constructa structural equation model to test the interrelations between the variables and the

QOLIE-10overallscore.Basedonareviewofpreviousstudies,^4–17we developedahypotheticalmodelthatoutlinedthepathsofdepression, anxiety,seizurecontrol,theadverseeffectsofAEDs,andsocioeco- nomicburdentoQOL.Wehypothesizedthatall ofthesevariables directlyinfluencedQOL directlyandthat depression,anxiety,and seizurecontrolinfluencedQOLindirectlythroughthemediationof theadverseeventsofAEDs.Thehypothesizedpathmodelwastested withstructuralequationmodeling.Themodelfitwasevaluatedusing path analysis, which is a method that estimates the relative importancesofthedifferentpathsoftheindependentvariablesonto thedependentvariables.Anacceptablemodelfitwasdefinedbythe presenceofanonsignificantchi-square(x²)value,anormedfitindex (NFI)0.9,acomparativefitindex(CFI)0.9,agoodnessoffitindex (GFI)0.9,andarootmeansquareresidual(RMR)0.05.Structural equation modelingwas used to estimate the totaleffect ofeach predictortoestablishalinearmodelforthepredictionoftheoverall QOLIE-10 score that accountedfor these interrelations. With the exceptionofthestructuralequationmodel,all statisticalanalyses were conductedwithSPSS (version19.0,IBM Inc.).LISREL8.8for Windows (SSI Inc., Skokie, IL, USA) was used for the path and structuralequationmodelingcomponentsoftheanalysis.Thelevelof statisticalsignificancewassetat0.05.

3. Results

Initially, 861PWE wereenrolled in thestudy.Among these PWE, 159 were excluded due to refusal to complete the questionnaires(n=34),inabilitytocompletethequestionnaires due to mental retardation (n=49) or serious diseases (n=50), youngage(n=5),andoldage(n=21).Therefore,702PWE(mean age:41years;57.7%male)wereincluded.Thedemographicand clinical characteristics and the results of the self-report ques- tionnairesoftheeligiblesubjectsarelistedinTable1.Approxi- mately 50% of the patients had a job and a driving license.

Concurrentmedicaldiseaseswerepresentin147patients(20.9%) andincludeddiabetesandotherendocrinologicdisorders(n=41), hypertensionandothercardiovasculardisorders(n=37),cerebro- vasculardiseaseandotherneurologicdisorders(n=24),hepatic andgastrointestinaldisorders(n=20),renaldisorders(n=8),and otherdiseases(n=48).Partialonsetofseizuresandcryptogenicor symptomaticetiologiesaccountedforgreaterproportionsthandid generalizedseizureandidiopathicetiology.Sixty-onepercent of thepatients had experiencedoneyearof seizurefreedom.MRI abnormalitieswerefoundin281patients(40%),andtheetiologies of these abnormalities were hippocampal sclerosis (n=79), vascular lesions (n=54), traumatic injury (n=48), congenital anomalies (n=45), infection (n=37), tumor (n=8), and others (n=34).ThedurationofAEDintakewas13.910.7years(range:

1–54years). Nearly 50% ofthe patientshadreceived AEDmono- therapy.TheAEDloadwas1.51.2(range0.1–7.7).TheK-NDDI-E, GAD-7, and K-LAEP scores were 9.74.1 (range 6–24), 4.14.9 (range0–21),and34.012.4(range21–81),respectively.TheQOLIE- 10overallscorewas76.118.2(range3–100).

ThepredictorsoftheoverallQOLIE-10scorefromthemultiple linear regression analyses are documented in Table 2. The strongest predictor was the K-LAEP score (b= 0.375, p<0.001), followed by the K-NDDI-E score (b= 0.316, p<0.001), seizure control (b= 0.152, p<0.001), the GAD-7 score(b= 0.119,p=0.005),andhouseholdincome(b= 0.101, p<0.001). Stepwise regression produced a five-variable model thatexplained68.7%ofthevarianceintheoverallQOLIE-10score.

Accordingtothestandardizedb,thecontributionoftheK-LAEP scoretotheoverallQOLIE-10scorewas1.19timesgreaterthan thatoftheK-NDDI-Escore,2.47timesgreaterthanthatofseizure control,3.15timesgreaterthanthatoftheGAD-7score,and3.71 timesgreaterthanthatofhouseholdincome.Thevarianceinflation