Katrien Jansen , Steven Vandeput , Sabine Van Huffel , Lieven Lagae Cardiac autonomic dysfunction in West syndrome

j o ur na l ho me p ag e :w w w . e l s e v i e r . c o m / l o c a t e / e p i l e p s y r e s

Cardiac

autonomic

dysfunction

in

West

syndrome

Katrien

Jansen

,

Steven

Vandeput

,

Sabine

Van

Huffel

,

Lieven

Lagae

a_{DepartmentofPediatrics,UniversityHospitalsLeuven,Belgium} b_{DepartmentofElectricalEngineering,ESATKULeuven,Belgium}

Received13February2012;receivedinrevisedform23April2012;accepted28May2012 Availableonline23June2012

KEYWORDS Infantilespasms; Autonomicdiseases; Cardiac

Summary

Background:Westsyndromeisanage-dependentepilepticencephalopathy.Autonomicchanges are increasingly being recognized in patients with epilepsy: cardiac autonomic function is mediatedbysympatheticandparasympatheticefferentactivitytotheheartandcanprovide informationonthefunctionalstateoftheautonomicnervoussystem.Thegoalofthestudyis toevaluatetheeffectofanearlyepilepticencephalopathyontheautonomicnervoussystem bymeasuringheartratevariability.

Methods: Cardiacautonomicfunction was evaluated in13 patients with West syndromeby measuringheart ratevariabilityduring5minepochsofECGinwake,stage2andslowwave sleep.In5patientswhodevelopedsubsequentlyanothertypeofepilepsy,asecondevaluation wasperformedafter3yearsoffollow-up.

Results:Resultsshowedalowerheartrateinstage2sleepinpatientswithWestsyndrome. Spectralcomponentsdidnotshowsignificantdifferencescomparedtoagematchedcontrolsat themomentofpresentation.Afterfollow-upof3yearswewereabletodemonstratehigher lowfrequency(LF),lowerhighfrequency(HF)andahigherLF/HFratioduringslowwavesleep.

Conclusion:Thisstudyshows alowerheart rateinpatientspresentingwithWestsyndrome, alreadyattheonsetofthesyndromeandbeforeACTHtreatment.Theepilepticencephalopathy isnotsufficientto alterspectralcomponentsofheart rateatthemomentofpresentation. However,alreadyafter3yearsofepilepsy,chronicautonomicchangesappear.

©2012ElsevierB.V.Allrightsreserved.

∗_{Correspondingauthorat:DepartmentofPediatrics,University} HospitalsLeuven,Herestraat49,3000Leuven,Belgium.

Tel.:+3216343845;fax:+3216343842. E-mailaddresses:lieven.lagae@uzleuven.be, Lieven.Lagae@uz.kuleuven.ac.be(L.Lagae).

Introduction

West syndrome is an age-dependent epileptic syndrome characterizedby epilepticspasms,hypsarrhythmiaonEEG andarrestorregressioninpsychomotordevelopment.The epileptic spasms resolve over time but they are often replacedbyothertypesofrefractoryseizures(Commission onPediatric Epilepsy of the International LeagueAgainst Epilepsy,1992).Autonomicchanges areincreasinglybeing recognizedin patients withepilepsy (Baumgartner etal., 0920-1211/$—seefrontmatter©2012ElsevierB.V.Allrightsreserved.

168 K.Jansenetal. 2001).Onewaytolookattheautonomicsystemistostudy

heart rate variability. Heart rate variability is defined as thefluctuationin length inconsecutive RRintervals. This variabilityismediatedbysympatheticandparasympathetic efferentactivitytotheheartandcanshowinformationon thefunctionalstateoftheautonomicnervoussystem.The vagalinfluencesontheheart aremostpronouncedduring sleepandreachamaximum insynchronized orslowwave sleep.

Acutechangesofcardiacfunctionatthetimeofaseizure inpatients with epilepsyis caused by involvementof the centralautonomiccontrolcentersinseizureactivity.Onthe otherhand,patientswithlonglastingorrefractoryepilepsy arepronetochronicdysfunctionofautonomiccardiac con-trol(Chronietal.,2008;Harnodetal.,2008;Ferrietal., 2002).

Thegoalofthisstudywastoinvestigatetheimmediate and long-term effect of an early epileptic encephalopa-thy onthe autonomic nervoussystem. We evaluate heart ratevariability at the momentof diagnosis toinvestigate the short-termeffect of the epileptic encephalopathy on autonomicfunction.Furthermore,weperformed asecond evaluationafter3yearsofepilepsytomonitorthechronic effectsofepilepsyontheautonomicnervoussystem.

Methods

Consecutivepatients whopresented withinfantilespasms andhypsarrhytmiaonEEGattheepilepsyclinicofUZ Leu-ven between 2003 and 2010 were included. All patients wereincludedandmonitoredbeforetreatmentwithACTH at the moment of their referral and first EEG. Control subjects were referred to the epilepsy clinic with sus-picion of epilepsy but were found to have benign sleep myoclonus and had normal EEG findings. All EEGs were reviewed by 2 independent EEG specialists. The control subjects wereage and sex matched to take into account age-dependentdifferences. EEGrecordingswereobtained usingthe 10—20 International System of Electrode Place-ment.Samplingratewas250Hz.5minepochsofECGwere extracted randomly during wake, stage 2 sleep and slow wavesleepofthefirstsleepcycle.AllEEGshadcontinuous interictaldischargesbutnoseizures.Inpatientswho subse-quentlydevelopedanothertypeofepilepsy,5minepochsof ECGwereextractedagainduringthethreetimepointsafter minimal3 yearsoffollow-up. Againage-matched controls wereusedforcomparisonofthefollow-upcases.Wakeand sleepstagesweredeterminedbytheinvestigatorbyvisual analysisof the EEGand spectralanalysis (OSG, Belgium). RRintervalswerecalculatedafterautomaticQRS-complex detection.Finally,allRRintervaltimeserieswerechecked manually.

Heartratevariabilitycanbeusedasatooltoshow infor-mation onthe functional state of the autonomic nervous system.Frequencydomain analysiswasperformedusinga non-parametricmethodoffastFouriertransformation. Bor-dersofspectralcomponentsweredefinedaccordingtoage. Timeandfrequencydomainanalysisofheartratevariability wasdoneaccordingtothestandardsoftheTaskForceofthe EuropeanSocietyofCardiology(TaskForceofTheEuropean Society of Cardiology and The North AmericanSociety of Pacing and Electrophysiology, 1996). Spectral analysis of

heartratecanprovidemoreinformationonthesympathetic andparasympatheticcontributiontoautonomicoutflowto theheart.Thehighfrequency(HF)componentsarerelated toparasympatheticactivity,whereasthelowfrequency(LF) reflectssympatheticcardiacfunction.

Spectralcomponentsinthefirstcohortweredefinedas 0.04—0.15HzforLFand0.30—1.30HzfortheHFcomponent, covering the breathing frequencies of all the young sub-jects.Inthesecondcohort,spectralcomponentsbetween 0.04and0.15HzweredefinedasLF,thosebetween0.15and 0.40HzweredefinedasHF. Normalizedunitswereusedto comparespectrawithdifferenttotalpower.LFnu=LF/(total power− VLF)× 100, HFnu=HF/(total power−VLF)×100. The LF/HF ratiowas used toquantify the sympathovagal balance as an indicator of autonomic modulation. Differ-encesbetweenepilepticpatientsandthecontrolgroupwere obtainedviatheMann—WhitneyUtest.P<0.05was consid-eredstatisticallysignificant.

Results

13 patients with infantile spasms at presentation were includedandanequalnumberofagematchedcontrols.The meanageofonsetwas7.3months(range4—10months).

Ten patients developed subsequently another type of epilepsy,9hadgeneralizedand1partialepilepsy,8ofthem wererefractorycases.Allpatientshadmildtosevere men-talretardation.5ofthesesubjectshadafollow-upperiod ofminimal3years.Otherpatientcharacteristicsand treat-ment before theencephalographic evaluation is shown in Table1.

ComparisonbetweenWestsyndromepatientsand controlsattheonsetofepilepsy

Resultsintimeandfrequency domainmeasurementswere comparedbetween West syndromeand controls usingthe firstsetofdata.

In timedomain the mean RR intervalwas significantly higher in patients versus controls during stage 2 sleep (535.9±47.5msversus 491.4±51.4ms;p=0.03). The dif-ference was also observed during wake (450.5±46.6ms versus 411.5±41.2ms; p=0.12) and slow wave sleep (518.5±56.6ms versus 482.7±39.4ms; p=0.09) but not statisticallysignificant.Othertimedomainanalysesshowed nosignificant differences.Inthefrequency domain,there werenostatisticallysignificantdifferencesinpowerspectra ofpatientsversuscontrolsinthedifferentsleepstages. ComparisonbetweenWestsyndromepatientswho subsequentlydevelopedepilepsyandcontrols Resultsintimeandfrequency domainmeasurementswere comparedbetweenformerWestsyndromepatientsafterat least3yearsoffollow-upandcontrols,usingthesecondset ofdata.

Intimedomaintherewerenosignificantfindings.Onthe otherhand,infrequencydomainthereisanimportant dif-ferenceinLF(0.363±0.154versus0.160±0.109;p=0.03) andHF(0.494±0.157versus0.737±0.153;p=0.01)power

autonomic dysfunction in W est syndrome 169

Table1 Patientcharacteristics. Caseno. Ageat

onset (months)

Sex

(male/female)

Treatment Etiology Subsequent

epilepsy

Treatment AgeatfirstEEG

evaluation (months) Ageatsecond EEGevaluation (years) 1 6 M Vigabatrin, Sodiumvalproate Cryptogenic Yes, generalized Sodiumvalproate, clobazam, sulthiame 8 4.5

2 5 F Sodiumvalproate Cryptogenic Yes,

generalized Sodiumvalproate 6.5 7.5 3 8 M Vigabatrin, sodiumvalproate Symptomatic: trisomy21 Yes, generalized Topiramate 9 6.5 4 9 M Sodiumvalproate Cryptogenic No — 9 — 5 7 M Vigabatrin, sodiumvalproate Symptomatic:ACM infarct Yes, generalizee Sodiumvalproate, topiramate, clobazam 9 —

6 10 M Sodiumvalproate Symptomatic Yes,

generalized Sodiumvalproate, vigabatrine, clonazepam 10 — 7 10 M Vigabatrin, sodiumvalproate Symptomatic No — 10 — 8 10 M Vigabatrin, carbamazepine Symptomatic: tuberoussclerosis

Yes,partial Sodiumvalproate, topiramate, clobazam 11 6 9 6 F Vigabatrin Symptomatic: tuberoussclerosis Yes, generalized Sodiumvalproate 6 3 10 5 M Sodiumvalproate, topiramate Symptomatic: tuberoussclerosis Yes, generalized Sodiumvalproate, topiramate 10 — 11 6 M Sodiumvalproate Cryptogenic No — 7 — 12 4 F Vigabatrin Symptomatic: trisomy21 Yes, generalized Sodiumvalproate 4 — 13 9 M None Symptomatic: trisomy21 Yes, generalized Sodiumvalproate, levetiracetam 10 —

170 K.Jansenetal.

Figure1 LFnu,HFnuandLF/HFratioinpatientsandcontrolsafter3yearsoffollow-up.Figureshowsthehighercontribution

ofLFandlowercontributionofHFcomponentstothespectralpowerofpatientswithWestcomparedtocontrols.Thisleadstoa higherLF/HFratio.

inpatientswithepilepsyduringslowwavesleepcompared tocontrols.ThisisalsoobservedintheLF/HFratio(patients 0.997versuscontrols0.247;p=0.03).Thesefindingsarenot observedinwakeorstage2sleep(seeFig.1).

Discussion

Lookingatshort-termeffectsinourpatientpopulation,we were able to demonstrate a lower heart rate in patients

withWestsyndromealreadybeforeACTHtreatment,in con-trasttothefindingsofHattorietal.(2007).Thedecreasein heartratecanbeasignofparasympatheticpredominance ontheautonomicoutflowtotheheart.Thefindingismost significant during stage 2 sleep,where vagal components arephysiologicallylesspronounced.Duringslowwavesleep vagalcomponentsarephysiologicallymostprominent.Our findingssuggestthatthereisalreadyadifferenceinheart rateregulationinpatientspresentingwithWestsyndrome. OneofthepathophysiologicalhypothesesinWestsyndrome isthe activationofa stressresponseandreleaseof corti-cotropin releasing hormone (CRH). An early insult on the brain e.g. cerebral infarction provokes a stress response. ThismediatesanexcessivereleaseofCRH.Inthe develop-ingbrain,thisexcessivereleasecancauseepilepticspasms andneuronalcelldeath,mostimportantinamygdalaeand hippocampus(Rho,2004;Brunsonetal.,2001).Ahighlevel of CRHwill causea rise in cortisolthrough productionof ACTH.The autonomic vagal response couldbe a counter-balance for the cortisol-induced effects onbloodpressure andcardiacfunction.Thisiscomparablewiththefindingsin patientswithCushing,whoalsohavearelativelyincreased parasympatheticactivityandlowerheartrate(Falloetal., 2009).TreatmentwithACTHcouldmakethesefindingseven morepronounced,asobservedbyHattori.

Lookingatthefollow-updata,wewereableto demon-stratehigherLF, lowerHFandahigherLF/HFratioduring slowwavesleepin patientswhodeveloped epilepsyafter West syndrome compared to controls. These findings are alreadypresentafter3yearsofepilepsy.Innormalsleep, vagalcomponentsarealwaysmostpronouncedduring syn-chronizedorslowwavesleep.Thisnormalphenomenonisno longervisibleinourcohortofpatientswithformerWest syn-drome.Vagalreductioninpatientswithlonglastingepilepsy has been previously observed in adultsaswell asin chil-dren(Tomsonetal.,1998;Evrengületal.,2005;Jansenand Lagae,2010).The explanationof this phenomenonis still uncertain.Apossiblemechanismisthatdisruptionofnormal autonomicfunctionisduetochronicepilepticactivity.Ina studybySathyaprabhaetal.(2006),theautonomicchanges weremoresevere,thelongerthedurationofepilepsywas. Inthisstudypatientswithlongerdurationofepilepsy(23.2 years)hadmoreseveredysfunctionthanpatientswith rel-ativelyshorterduration(17.5years)ofepilepsy.Therefore, itisnotimpossiblethatchronicdysautonomiacanalready bepresentafterarelativelyshortphaseofsevereepileptic encephalopathy.

Theclinicalrelevanceofthesechangesinpatientswith epilepsyremainanopenquestion.Reducedheartrate vari-abilityisamarkerofdysfunctionoftheautonomicnervous systemandcanbeconsideredariskfactorinchronicdisease e.g.myocardialinfarction(Buccellettietal.,2009).Various diseases including epilepsy are now known to be accom-panied by a loss of autonomic functionality and reduced HRV(Chronietal.,2008).Oneofthepossiblemechanisms underlying sudden unexplained death (SUDEP)are seizure relatedcardiacarrhythmiaswithtachyarrhythmiasleading toventricularfibrillationandbradycardiaandictalasystole (Tomsonetal.,2008).

We did consider the possible effect of confounding factorse.g.theetiologyoftheWestsyndromeandthe dif-ference between cryptogenic andsymptomatic cases, the

numberofseizuresorinfluenceofmedication,butwewere unabletoinvestigate thisfurtherdue tosample size con-straints.Howevertheobservedresultsaresoconsistentthat we believethat thesefactors can onlybe responsible for insignificantdifferences.

Althoughourresultsareconsistent,weneedmorestudies toshowhowtheepilepticencephalopathychange theANS indetail.

In conclusion, our results show that there is a lower heartrateinpatientswithWestsyndrome,alreadyatthe onsetofthesyndrome,evenbeforetreatmentwithACTH. The epileptic activity at onset itself is not sufficient to alterspectralcomponentsofheartrateontheshortterm. However,afterfollow-upof3yearsofepilepsy,chronic auto-nomicchangesappear.

Conflicts

of

interest

Theremainingauthorshavenoconflictsofinterest.

Acknowledgements

AuthorsandSabineVanHuffelweresupportedby:Research CouncilKUL: GOA Ambiorics, GOA MaNet,CoE EF/05/006 Optimization in Engineering (OPTEC), IDO 05/010 EEG-fMRI, IDO 08/013 Autism, IOF-KP06/11 FunCopt, several PhD/postdoc & fellow grants. Flemish Government: o FWO:PhD/postdocgrants,projects:FWOG.0302.07(SVM), G.0341.07(Datafusion),G.0427.10N(IntegratedEEG-fMRI) researchcommunities(ICCoS,ANMMM);oIWT: TBM070713-Accelero, TBM070706-IOTA3, TBM080658-MRI (EEG-fMRI), PhD Grants. Belgian Federal Science Policy Office: IUAP P6/04 (DYSCO, ‘Dynamical systems, control and opti-mization’, 2007—2011); ESA PRODEX No 90348 (sleep homeostasis). EU: FAST (FP6-MC-RTN-035801), Neuromath (COST-BM0601).

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