Long-term outcome of refractory status epilepticus in adults: A retrospective population-based study

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Long-term outcome of refractory status epilepticus in adults: A retrospective population-based study

Kantanen A-M

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http://dx.doi.org/10.1016/j.eplepsyres.2017.03.009

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Epilepsy Research

j o u r n a 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

Long-term outcome of refractory status epilepticus in adults: A retrospective population-based study

Anne-Mari Kantanen

^a,∗

, Matti Reinikainen

^b

, Ilkka Parviainen

^c

, Reetta Kälviäinen

^d

aDepartmentofNeurology,Neurocenter,EpilepsyCenter,KuopioUniversityHospital,Kuopio,Finland

bIntensiveCareUnit,NorthKareliaCentralHospital,Joensuu,FinlandandFacultyofHealthSciences,SchoolofMedicine,InstituteofClinicalMedicine, UniversityofEasternFinland

cIntensiveCareUnit,UniversityofEasternFinland,Kuopio,FinlandandFacultyofHealthSciences,SchoolofMedicine,InstituteofClinicalMedicine, UniversityofEasternFinland

dEpilepsyCenter,Neurocenter,KuopioUniversityHospitalandFacultyofHealthSciences,SchoolofMedicine,InstituteofClinicalMedicine,Universityof EasternFinland,Kuopio,Finland

a r t i c l e i n f o

Articlehistory:

Received11November2016

Receivedinrevisedform7February2017 Accepted28March2017

Availableonline2April2017

Keywords:

Refractorystatusepilepticus(RSE) Super-refractory

Epilepsy Mortality Incidence Riskfactor Predictor Etiology Semiology Deﬁnition Classiﬁcation

Internationalleagueagainstepilepsy(ILAE)

a b s t r a c t

Purpose:Refractorystatusepilepticus(RSE)isaneurologicalemergencywithsigniﬁcantmorbidityand mortality.Weaimedtoanalyzethelong-termoutcomeofintensivecareunit(ICU)-treatedRSEand super-refractorystatusepilepticus(SRSE)patientsinapopulationbasedcohort.

Methods:AretrospectivestudyofICU-andanesthesia-treatedRSEpatientsinKuopioUniversityHospital’s (KUH)specialresponsibilityareahospitalsinthecentralandeasternpartofFinlandfromJan.1,2010to Dec.31,2012wasconducted.KUH’scatchmentareaconsistsoffivehospitals—oneuniversityhospital andfourcentralhospitals—andcoversapopulationof840000.Weincludedallconsecutiveadult(16 yearsorolder)RSEpatientsadmittedintheparticipatingICUsduringthe3-yearperiodandexcluded patientswithpostanoxicetiologies.WeusedamodifiedRankinScale(mRS)asalong-term(1-year) outcomemeasure:good(mRS0–3,recoveredtobaselinefunction)orpoor(mRS4–6,majorfunctional deficitordeath).

Keyfindings:Weidentified75patientswithICU-andanesthesia-treatedRSE,correspondingtoanannual incidenceof3.0(95%confidenceinterval(CI)2.4–3.8).21%ofthepatientswereclassifiedasSRSE,withthe annualincidencebeing0.6/100000(95%CI0.4–1.0).ForRSE,theICUmortalitywas0%,hospitalmortality was7%(95%CI1.2%–12.8%)(n=5),andone-yearmortalitywas23%(CI95%13.4%–32.5%)(n=17).48%

(n=36)ofRSEpatientsrecoveredtobaseline,and29%(n=22)showedneurologicaldeﬁcitat1year.Poor outcome(mRS4–6)wasrecordedfor52%(n=39)ofthepatients.Olderagewasassociatedwithpoorer outcomeat1year(p=0.03).ForSRSE,hospitalmortalitywas6%(n=1)and1-yearmortalitywas19%

(n=3)(95%CI0%–38.2%).

Signiﬁcance:During1-yearfollow-up,nearly50%oftheICU-treatedRSEpatientsrecoveredtobaseline function,whereas30%showednewfunctionaldefectsand20%died.SRSEdoesnothaveanecessarily pooreroutcome.Theoutcomeisworseinolderpatientsandinpatientswithprogressiveorfataletiolo- gies.SEshouldbetreatedwithgeneralizedanesthesiaonlyinrefractorycasesafterfailureofadequately usedﬁrst-andsecond-lineantiepilepticdrugs.

1. Introduction

Statusepilepticus(SE)isaconditionresultingfromthefailure ofthemechanismsresponsibleforseizureterminationorfromini- tiationmechanismsthat leadto abnormallyprolongedseizures (Trinkaetal.,2015).ThemorbidityandmortalityofSEcorrelate

∗Correspondingauthorat:EpilepsyCenter,Neurocenter,KuopioUniversityHos- pital,P.O.Box100,70029KYS,Finland.

E-mailaddress:anne-mari.kantanen@kuh.ﬁ(A.-M.Kantanen).

withthedurationofepilepticactivity,rapididentificationofthe causeofSE,andageandcomorbidityofthepatients(Trinkaand Kälviäinen,2017).SEbecomesrefractory(RSE)iffirst-andsecond- linetreatmentswithantiepilepticdrugs(AEDs)failtoterminatethe seizure.SEisdefinedassuper-refractory(SRSE)ifitcontinuesfor morethan24hafterthefirstadministrationofgeneralanesthesia (ShorvonandFerlisi,2012).

TheincidenceindifferentEuropeancohortsforSE(lastingover 30min)is10–16/100000(Coeytauxetal.,2000;Knakeetal.,2001).

Population-basedincidencedatafor RSEand SRSEarescarce.A recenthospital-based9-yearcohortstudyofRSEandSRSEfrom

http://dx.doi.org/10.1016/j.eplepsyres.2017.03.009

0/).

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14 A.-M.Kantanenetal./EpilepsyResearch133(2017)13–21

Switzerlandsuggeststhat33%ofSEbecomesRSEandonly4%of SEbecomesSRSE(Delajetal.,2016),resultinginincidenceforRSE 3.3–5.3/100000andforSRSE0.4–0.6/100000.Thehighestinci- dencerateforRSEandSRSEwasreportedintheUS:7.2/100000 forRSE(SEduration2–24h)and4.6/100000forSRSE(SEduration

>24h);however,thisdeﬁnitionwaspurelytime-based(Hesdorffer etal.,1998).Wehaverecentlyreportedthenationwidepopulation- basedincidenceinFinlandforRSE(SEtreatedinintensivecareunit (ICU)withgeneralanesthesia)3/100000andforSRSE0.7/100000 (Kantanenetal.,2015).

TheunderlyingetiologyofSEisconsideredthemostimportant prognosticfactordeterminingtheoveralloutcome(Neliganand Shorvon,2010;Sutteretal.,2013).Bothclinicalstudiesandexper- imentaldatahaveshownthatthelongerthedurationofSEbefore theinitiationoftreatmentandthetimerequiredtocontrolSE,the worseistheprognosis(Towneetal.,1994;Mazaratietal.,1998;

NeliganandShorvon,2011).TheoutcomeofSEalsovarieswithage, withthebestoutcomesinyoungchildrenandtheworstonesin theelderly.However,itisunclearwhetherageisafactorindepen- dentofetiology(Towneetal.,1994;Mazaratietal.,1998;Neligan andShorvon,2011).Olderage(>65years),noseizurehistory,spe- ciﬁcseizuretypes,andimpairedconsciousnesstogetherseemto predictaworseoutcome(Sutteretal.,2013).Othernegativeout- comepredictorsarethepresenceofacutebrainlesions,infections, respiratoryfailure,orpostictalperiodicepileptiformdischargesin electroencephalogram(EEG)signals(NeliganandShorvon,2010;

Sutteretal.,2015)

Thelong-term outcome of ICU-treated RSE hasbeen poorly studied.Inacomprehensiveliteraturereview(ShorvonandFerlisi, 2012)through1981–2011,596caseswithRSEandtreatedwith generalanesthesiawithvariablelong-termoutcomedatacouldbe found.Overall,35%ofthepatientsdied,30%showedneurologi- caldeﬁcit,and35%recoveredtobaseline.Between2011andOct.

2016,wefound427newlypublishedcases(Table1);however,this seriesisstillsmall,follow-uptimeswerevariable,andtheoutcome seemedessentiallyunchanged.Inthenewseries,forSRSE,55%of patientsdied,25%wereimpaired,and20%recoveredtobaseline.

Nodataisavailableforthepredictorsofthelong-termoutcome.The presentstudyaimstodeterminethe1-yearoutcomeofICU-treated RSEandSRSEinapopulation-basedstudy.

2. Methods 2.1. Patients

Weretrospectively analyzedtheFinnishIntensiveCareCon- sortium(FICC)databasetoidentifyICU-treatedRSEpatientsina

population-basedcohortfromKuopioUniversityHospital’s(KUH) specialresponsibilityareainthemiddleandeasternpartofFinland duringathree-year-period(Jan.1,2010toDec.31,2012).KUH’s catchmentareaconsistsoffivehospitals—one universityhospi- talandfourcentralhospitals—thattogetherprovideICUandacute neurologicalcaretoapopulationof840000(Fig.1).Wesearched theFICCdatabasebyusingtheICD-10codesforepilepsy,SE,and convulsions(G40.x,G41.x,R58.6)andtheAcutePhysiologyand ChronicHealthEvaluation(APACHE)II(Knausetal.,1985)diag- nosticgroup“seizure”toidentifyallpatientstreatedinanICUfor seizuredisorders.Weincludedalladult(≥16years)patientswho weretreatedintheICUforatleast48h(approximateminimum durationoftreatmentforpatientstreatedwithgeneralanesthesia inICUs).Thedatawasre-evaluatedusingmedicalrecordsbyanICU physicianoraneurologistineachhospitaltoidentifyRSEpatients accordingtothestudycriteria.ThediagnosticcriteriaforRSEwas ICU-treatedSEthatshowedrecurrentorcontinuousseizureactiv- ityafterfirst-andsecond-lineAEDtreatmentsandthatwastreated withgeneralanesthesia.Wealsoidentifiedpatientsmeetingthe criteriaofSRSE(RSEcontinuingorrecurringformorethan24h afterthefirstadministrationofgeneralanesthesia).Patientswith postanoxicetiologieswereexcluded.

2.2. Clinicalfactors

FICCisabodycoordinatinganationalbenchmarkingprogram inintensivecare.Theconsortiumdatabasecollectsdatafromevery ICUadmissionfromallgeneraladultICUsinall20Finnishhospital districts.Informationontheclinicalcharacteristics,severityofill- ness,andoutcomeislocallyvalidatedineachICUbeforesubmission tocentraldatabase(Reinikainenetal.,2012).InadditiontoFICC- providedclinicaldata,weperformedaretrospectivemedicalrecord reviewforSEtype,SEetiology,ﬁrst-and second-lineAEDsand intravenousanestheticsused,andlong-term(1-year)outcomes.

Thepatientageandgenderwereobtainedfromthedatabase.

The SE type and seizure semiology were analyzed from the medicalrecordsusingaclinicalclassificationofSEtypesaccord- ing to the seizure semiology and ILAE taxonomic criteria of prominent motor symptoms and impairment of consciousness (Trinkaetal.,2015).Theetiologywascategorizedastheknown cause(acute/remote/progressivesymptomatic)SEdefinedinclin- icalelectrophysiologicalsyndromes andunknown (cryptogenic) (Trinkaetal.,2015).AnacutesymptomaticcauseofSEwasdefined asSEwithin7daysofanacutesystemicorCNSinsult(Beghietal., 2010).

Independenceinactivitiesofdailyliving(ADL)wascodedas independentor dependent(with supervision, direction,or per-

Table1

Long-termoutcomeofrefractoryandsuper-refractorystatusepilepticusinseriespublishedduring2012–2016(longestavailablefollow-upfrom1to12months).

Authors AllN DeadN FunctionaldeﬁcitN RecoverytobaselineN Statustype

Hockeretal.(2013) 53 33 4 16 RSE

Marchietal.(2015) 50 13 27 10 RSE

Giovanninietal.(2015) 26 14 7 5 RSE

Gaspardetal.(2015) 91 31 10 50 RSE

Bellanteetal.(2016) 33 20 6 7 RSE

Madzaretal.(2016) 69 23 19 27

RSEtotalN(%) 322 134(41%) 73(23%) 115(36%)

Galletal.(2013) 4 1 1 2 SRSE

Kilbrideetal.(2013) 58 26 18 14 SRSE

Lietal.(2014) 11 4 2 5 SRSE

Puginetal.(2014) 31 18 10 3 SRSE

Laietal.(2015) 70 46 12 12 SRSE

SRSEtotalN(%) 174 95(55%) 43(25%) 36(20%)

RSE(refractorystatusepilepticus),SRSE(super-refractorystatusepilepticus).

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Fig.1.KuopioUniversityHospitalspecialresposibilityareaandhospitals.Population840000(2010–2012).

sonalassistance)asameasureofpatients’pre-morbidfunctional capacity.Sequentialorganfailureassessment(SOFA)(Vincentetal., 1998)was used as a prognostic outcome score describing ICU patients’severityofillnessbydifferentorganfailuresattheﬁrst 24h:respiratory,cardiovascular,hepatic,coagulation,renal,and neurologicalsystems.TheGlasgowComaScale(GCS)(Teasdaleand Jennet,1974)fordescribingtheimpairmentofconsciousnesswas assessedatthetimeofICUadmissionbeforeanysedativemedica- tionwasadministered.Thestatusepilepticusseverityscore(STESS) wascalculatedretrospectivelyusingtheGCS,seizuretypeatonset, ageatonset,andhistoryofseizuresatonset(Rossettietal.,2008).

Thetime(inh)fromhospitaladmissiontoICUadmissionwas obtainedfromthedatabase.Thedataontheavailabilityofdiag- nosticEEG,continuousEEGmonitoringduringanesthesia,andof diagnosticEEGtoconﬁrmthecessationofrefractorystatusafter anesthesiawasreviewedfromthemedicalrecords.Thefrequency ofpropofolinfusionsyndrome(PRIS)andneedforvasoactiveswere evaluated.TheLengthofstay(LOS)intheICUandhospital(includ- ingICUstay)wereobtainedfromtheFICCdatabase.Thehospital dischargestatuswasdeﬁnedin theFICCdataasbacktohome,

specialistcarefacility(othercentralhospitalorrehabilitationcen- ter),orprimaryhealthcareward.AmodiﬁedRankinScale(mRS) wasusedasthelong-term(1-year)outcome measure(Bamford etal.,1989):recoverytobaseline(0–3);functionaldeﬁcit(4–5);

anddead(6).ThemRSoutcomewasassessedbyusingthebest descriptionavailablefromthemedicalrecordsandwasclassiﬁed aseithergood(mRS0–3,recoveredtobaseline)orpoor(mRS4–6, majorfunctionaldeﬁcitordeath).

2.3. Statistics

Thepopulationincidencewith95%CIwascalculatedforsin- gleincidencerate.StatisticalanalyseswereconductedusingSPSS softwareversion22(IBMCorp,Armon,NY,USA)Thechi-square testandFischer’sexacttestwereusedtocomparethecategorical variables,andnon-parametric(Mann-WhitneyUformedian)tests wereused withcontinuous variables. Binarylogistic regression analysiswasnotperformedowingtotherelativelysmallsample size(n=75).

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Fig.2.Datacollectionﬂowchart.KuopioUniversityHospital’s(KUH)catchmentareahad14261intensivecareunit(ICU)admissionsduring2010–2012.FICCand75admissions metthecriteriaofICUandanesthesia-treatedrefractorystatusepilepticus(RSE).

48%

29% 23 %

69 %

13 % 19%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Recovery to baseline

Functional deicit Dead RSE SRSE

Fig.3. Functionalone-yearoutcomeofrefractory(alln=75)andsuper-refractory (n=16)statusepilepticus.

2.4. Standardprotocolapprovals,registrations,andpatient consents

Weconductedaretrospectiveobservationalstudybasedonthe nationalICUregistryandmedicalrecords.Authorizationforusing themedicalregistrydatawasgrantedbytheregulatoryauthority responsiblefortheadministrationofsaiddatainFinland,namely, therespectivehospitaldistricts.

3. Results

3.1. Incidence,mortality,andmorbidity

KUH catchment area ICUs had 14 261 admissions during 2010–2012.Fig.2showsthedatacollection.Seventy-fivepatients (0.5%ofallICUadmissions)withRSEfulfillingthecriteriawere treatedattheICUsintheKUHcatchmentareabetweenJanuary 2010andDecember2012.TheannualincidenceofRSEwas3.0/100 000(95%confidenceinterval(CI)2.4–3.8)andSRSE0.6/100000 (95%CI0.4–1.0)inthecohortpopulation.

TheICUmortalityforthewholecohort(RSE)was0%,hospital mortalitywas7%(95%CI1.2%–12.8%),and1-yearmortalitywas23%

(CI95%13.4%–32.5%).Thirty-sixofthe75(48%)patientsrecovered tobaseline,and22(29%)showedneurologicaldeﬁcitat1year.Poor outcome(mRS4–6)wasrecordedfor39/75(52%)patients.Thehos- pitalmortalityforSRSEpatientswas6%(n=1)(95%CI0%–17.6%), and1-yearmortalitywas19%(n=3)(95%CI0%–38.2%).Fig.3shows thefunctionaloutcomeforRSEandSRSE.

3.2. Demographicsandpredictorsby1-yearoutcomeinRSE

Table2showsthepatients’demographicsandclinicalpredictors forthewholeRSEcohortandaccordingtothefunctionaloutcomeat 1year.Themedianageofthepatientswas56years(range18–82).

Olderagewasassociatedwithpooreroutcomeat1year(p=0.03).

FocalonsetevolvingtobilateralconvulsiveSEwasthemostcom- monseizuretype(75%,56/75)inpatients;non-convulsiveSEwith comaaccountedfor19%(14/75) ofpatients.BaselineADLfunc- tioning,seizuretype,etiologycategory,STESSscore,orvariables indicatingthedurationofSEdidnotpredicttheoutcome.

Table3showsthedetailedetiologiesaccordingtotheoutcome.

Nineof75(12%)patientshadcerebrovasculardisease,8/9(89%) hadpooroutcome,11/75(15%)hadheadinjury,and7/11(63%) hadpooroutcome.PatientswhoseSEturnedouttohaveprogres- siveorfataletiologieslikeCreutzfeldt-Jacobdisease,MELAS,orglial tumors showedpoorlong-termprognosis.Thirteenof75 (17%) patientsshowedalcohol-withdrawal-related SE, and6/13 (46%) showedapooroutcome.Twenty-fourof75(32%)hadpre-existing epilepsy,and8/24(33%) showedapooroutcome.The unfavor- ableoutcomeinpatientswithpreexistingepilepsywasrelatedtoa remotesymptomaticetiologylikestrokeorbraininjuryortoapro- gressivesyndrome.Allofthepatientswithnopre-existingepilepsy (denovoRSEpatients)wereleftwithatleastoneAEDafterhospi- talizationandthereforewerediagnosedashavingriskforfurther seizures.

3.3. AdherencetoAEDandEEGguidelines

Diazepamwasusedin69%(49/75)ofpatientsastheﬁrst-lineIV medication,fosphenytoinwasusedin84%(63/75)asthesecond- linemedication,andpropofol12-hinfusionwasusedin80%(60/75) astheﬁrstgiventhirdlineagent(Table4).FinnishSEguidelines (Kälviäinenetal.,2009)werefollowedandrecordedaccordingly in90%ofthecasesattheearlyphaseandin93%attheestablished phaseofSE.IVanestheticswereusedaccordingtoguidelinesinall cases.Sixty-eightof75(90%)patientshaddiagnosticEEGavailable and71/75(93%)hadcontinuousEEGmonitoringduringanesthesia.

EEGwasalsoperformedaftertreatmentin71/75(93%)ofpatients.

TwopatientshadonlyclinicaljudgmentwithnodiagnosticEEG, EEGmonitoring,orafter-treatmentEEG(3%).

3.4. Super-refractorystatusepilepticus

SixteenpatientsofthecohortRSE(21%)wereclassiﬁedasSRSE patients.Themedianagewas51(range18–71),and8weremale (50%).Theetiologywasremotesymptomaticin56%(9/16)ofthe cases(Table5).Five(31%)patientshadpre-existingepilepsy.Focal onsetevolvingtobilateralconvulsiveSEwasthemostcommon typeofseizurein12/16(75%)patients.Themedianlengthofstay intheICUwas8days(range4–12)andthatinthehospital,17days (8–45days).ThesecondIVanestheticusedwasthiopental12hin 10/16(63%)patients,thiopental24hin3/16(19%),andpropofol 24hin2/16(13%).

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Table2

Demographicsandclinicalcharacteristicsofpatientswithrefractorystatusepilepticusby1-yearoutcome.

Alln=75 By1-yearoutcome

Good(mRS 0–3) n=36

Poor(mRS4–6) n=39

p-value

Malen(%) 50(67%) 22(61%) 28(72%) 0.341

Age,medianyears,(IQR) Range

56(48–67) 18–82

53(36–70) 18–79

61(73–69) 40–82

0.03

SEtype 0.270

ASEwithprominentmotorsymptoms

A1aGeneralizedconvulsive 2(3%) 2(6%) 0

A1bFocalonsetevolvingtobilateral convulsiveSE

56(75%) 24(67%) 32(82%)

A1cUnknownwhetherfocalorgeneralized 2(3%) 1(3%) 1(3%)

A2aMyoclonicSEwithcoma 1(1%) 0 1(3%)

BSEwithoutprominentmotorsigns

B1NSCEwithcoma 14(19%) 9(25%) 5(13%)

Etiologyn(%) 0.204

Known

Acutesymptomatic 31(41%) 14(39%) 17(44%)

Remotesymptomatic 38(51%) 21(58%) 17(44%)

Progressivesymptomatic 4(5%) 0 4(10%)

Unknown(cryptogenic) 2(3%) 1(3%) 1(3%)

Pre-existingepilepsyn(%) 24(32%) 16(44%) 8(21%) 0.178

IndependentinADL 49(65%) 23(64%) 26(67%) 0.813

SOFAscore,median(IQR) Range

8(7–9) 2–15

8(7–9) 3–13

8(7–10) 2–15

0.357 STESSscore,median(IQR)

Range

3(2–4) 1–6

2(1–3) 1–6

3(2–4) 1–5

0.225

STESS≥3 37(49%) 15(46%) 22(65%) 0.144

GCSmedian,(IQR) 9(5–12) 10(6–14) 9(7–12) 0.443

Admissionfromn(%) 0.162

ER 48(64%) 21(58%) 27(69%)

Ward 18(24%) 8(22%) 10(26%)

Observationunit 9(12%) 7(19%) 2(5%)

TimefromERtoICUadmission,hours(IQR) 3(1–13) 5(0–11) 2(0–6) 0.167

range,hours 0–89 1–90 0–27

TimefromhospitaladmissiontoICUadmission (fromward/observationunit),hours,median (IQR)

40(18–90) 48(12–85) 34(0–72) 0.860

Range,hours 0–195 0–195 7–145

LOSICU,days,median(IQR) 6(4–9) 6(3–9) 6(4–8) 0.433

Range 2–33 2–23 2–33

LOSHospital,median(IQR) 14(9–22) 16(8–24) 13(8–18) 0.488

Range 5–61 5–45 5–61

HospitalDischargeton(%) 0.063

DeadHospital 5(7%) 0 5(13%)

Home 18(24%) 12(33%) 6(15%)

Specialistcare 13(17%) 7(19%) 6(15%)

Primarycare 38(51%) 16(44%) 22(56%)

ADL(activitiesofdailylife),SOFA(sequentialorganfailureassessment),LOS(lengthofstay),STESS(statusepilepticusseverityscore),ER(emergencyroom),IQR(interquartile range).

4. Discussion 4.1. Mainﬁndings

Tothebestofourknowledge,thisretrospective, population- basedstudyofICU-andanesthesia-treatedRSEandSRSEpatients isthelargestcohortwith1-yearfunctionaloutcomereportedto date(Table1)(ShorvonandFerlisi,2011).Our1-yearoutcomedata agreeswiththemostrecentseriesreportinglong-termmortality ratesof26%–34%andwithvariablefollow-uptimesof1–12months withoverall poorfunctional outcomein11–28%ofthepatients (Table1).WecanconﬁrmthatevenwithRSEtreatedwithanesthe- siaintheICU,halfofthepatientsshowedfunctionalimprovement overtimeandrecoveredby1year.Thisoutcomewasbetterthan

that ofanearlier seriespublishedfor 1981–2011(Shorvonand Ferlisi,2011),inwhichonly30%ofpatientsrecovered.

Ourshort-termmortalityratesarelow,being7%forRSEand 6%forSRSE;theseareinagreementwiththedatafromtheFinnish nationalstudywehavepublished,whichare6%forRSEand10%for SRSE(Kantanenetal.,2015),butconsiderablylowerthanrecently publishedshort-termmortalityratesof25%forRSEand38%for SRSEthatwerereportedinSwitzerland(Delajetal.,2016).Delaj etal.(2016)suggestedintheirdiscussionthatthisdifferencemight beduetomortalityassessmentperformedbeforeanearlytrans- fertoanotherhospitalintheFinnishnationalstudy.Thelengthof hospitalstayinthepresentstudyinourRSEpatientswasmedian 14days(range5–61)andmedian17days(range8–45),whichgives amedianof14daystoassesshospitalmortality;thisdoesnotdiffer

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Table3

Etiologiesidentiﬁedforrefractorystatusepilepticus.

Etiology n(%) By1-yearoutcome

Deadn=17 Functionaldeﬁcitn=22 Recoverytobaselinen=36

1.Cerebrovasculardiseases 9(12%) 2(12%) 6(27%) 1(3%)

Stroke

2.CNS–infections 3(4%) 0 2(9%) 1(3%)

Encephalitis,unknown Encephalitis,neurosyphilis Bacterialmeningitis

3.Headinjury 11(15%) 4(24%) 3(14%) 4(11%)

Subduralhemorrhage/traumaticbraininjury

4.Intracranialtumors 2(3%) 1(6%) 1(5%) 0

Glialtumors

5.Neurodegenerativediseases 2(3%) 1(6%) 1(5%) 0

Creuztfeldt-Jacobdisease Alzheimer’sdisease

6.Alcoholrelated(withdrawal) 13(17%) 1(6%) 5(23%) 7(19%)

7.Chromosomal 2(3%) 0 0 2(6%)

DownSyndrome(trisomy21) Chromosome11deletion

8.Mitochondrialdiseases 2(3%) 1(6%) 0 1(3%)

MELAS POLG1

9.Metabolicdisorders 5(7%) 1(6%) 1(5%) 3(8%)

Hepaticencephalopathy Glucoseimbalance

10.Pre-existingepilepsy 24(32%) 5(30%) 3(14%) 16(44%)

Symptomaticepilepsy

Focalsymptomatic(posttraumatic/poststroke/MS)

Refractoryfocalepilepsy 14(19%) 4(24%) 2(9%) 8(22%)

Focalepilepsy,nocurrentAEDtreatment 2(3%) 0 0 2(6%)

Geneticepilepsysyndrome 2(3%) 0 1(5%) 1(3%)

Epilepticencephalopathy

Juvenilemyoclonicepilepsy 3(4%) 0 0 3(8%)

Generalizedepilepsywithtonic-clonicseizures 1(1%) 0 0 1(3%)

Progressivemyoclonicepilepsytype1(EPM1) 1(1%) 0 0 1(3%)

11.Unknown 1(1%) 1(6%) 0 0

2(3%) 1(6%) 0 1(3%)

considerablyfromanotherrecentstudyreportingthelengthofhos- pitalstayinRSEpatientsandahospitalmortalityof18%(Madzar etal.,2016).Giovanninietal.(2015)reportedmortalityof37%at

30days.Hospitalandshort-termmortalitiesareindeedestimated atdifferenttime-pointsandarethereforedifﬁculttocompare.Our long-termmortalityrateforSRSEpatientsisalsolow(19%)com-

Table4

Outcomebypharmacologicaltreatmentinpatientswithrefractorystatusepilepticus.

Medication Alln=75 By1-yearoutcome

Good(mRS0–3) Poor(mRS4–6)

n=36 n=35

1^st-lineAED

Lorazepam 14(20%) 8(22%) 6(17%)

Diazepam 49(69%) 27(75%) 22(63%)

Midazolam 1(1%) 0 1(3%)

Notevidentfrommedicalrecords

Medicalrecords 7(10%) 1(3%) 6(17%)

2^nd-lineAED

Fosphenytoin 63(84%) 32(89%) 31(80%)

Levetiracetam 6(8%) 4(11%) 2(5%)

Valproicacid 1(1%) 0 1(3%)

Notevidentfrommedicalrecords

Medicalrecords 5(7%) 0 5(14%)

1stIVAn(%)

Propofol12h 60(80%) 31(86%) 29(74%)

Propofol24h 11(15%) 2(6%) 9(23%)

Thiopental12h 4(5%) 3(8%) 1(3%)

PRIS 5(7%) 2(3%) 3(8%)

Vasoactivesneededduringtreatment(noradrenalin)n=68 58(85%) 28(88%) 30(83%)

1stlineAED(ﬁrst-lineantiepilepticmedication),2ndline(secondline),IVA(intravenousanesthetic),PRIS(propofolinfusionsyndrome).

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Table5

Demographicsandclinicalcharacteristicsand1-yearoutcomeinpatientswithsuper-refractorystatusepilepticus.

Alln=16 By1-yearoutcome

Good(mRS0–3) Poor(mRS4–6)

n=11 n=5

Malen(%) 8(50%) 4(36%) 4(80%)

Age,medianyears(IQR) 51(41–59) 53(35–71) 50(45–55)

(range) 18–71 18–71 40–53

SEtype

ASEwithprominentmotorsymptoms

A1aGeneralizedconvulsive 1(6%) 1(9%) 0

A1bFocalonsetevolvingtobilateralconvulsiveSE 12(75%) 7(64%) 5(100%)

A1cUnknownwhetherfocalorgeneralized

A2aMyoclonicSEwithcoma 1(6%) 1(9%) 0

BSEwithoutprominentmotorsigns

B1NSCEwithcoma 2(13%) 2(18%) 0

Etiology Known

Acutesymptomatic 4(25%) 2(18%) 2(40%)

Remotesymptomatic 10(63%) 8(73%) 2(40%)

Progressivesymptomatic 1(6%) 0 1(20%)

Unknown(cryptogenic) 1(6%) 1(9%) 0

Pre-existingepilepsy 5(31%) 4(36%) 1(20%)

IndependentinADL 8(50%) 5(46%) 3(60%)

SOFAscore,median(IQR) 8(6–10) 8(6–10) 10(7–11)

STESSscore,median(IQR) 2(2–3) 3(2–4) 3(2–4)

STESSscore≥3 6(38%) 4(36%) 2(40%)

GCSmedian,(IQR) 7(3–12) 11(7–15) 9(5–13)

TimefromERadmissiontoICUadmissionn(%) 9(56%) 5(45%) 4(80%)

median,hours(IQR) 5(2–17) 10(0–20) 10(0–20)

range 1–25 1–25 2–5

TimefromhospitaladmissiontoICUadmissionn(%)(fromward/observationunit) 7(44%) 6(55%) 1(20%)

median,hours(IQR) 73(14–132)

range 0–195

LOSICU,median(IQR) 8(6–11) 10(8–12) 6(4–8)

Range 4–12 4–12 4–10

LOSHospital,median(IQR) 17(13–30) 17(7–27) 16(11–21)

Range 8–45 8–45 10–19

HospitalDischargeton(%)

Dead 1(7%)

Home 4(25%) 3(27%) 1(20%)

Specialistcare 2(12.5%) 1(9%) 1(20%)

Primarycare 9(56%) 7(64%) 2(40%)

IVAnesthetics 1stIVA(+weaningtime)

Propofol12h 15(94%) 10(91%) 5(100%)

Thiopental12h 1(6%) 1(9%) 0

2ndIVA(+weaningtime)

Propofol24h 2(13%) 1(9%) 1(20%)

Thiopental12h 10(63%) 6(55%) 4(80%)

Thiopental24h 3(19%) 3(27%) 0

Vasoactivesneededduringanesthesian(%) 10(63%) 8(80%) 2(50%)

PRISn(%) 0

ADL(activitiesofdailylife),SOFA(sequentialorganfailureassessment),LOS(lengthofstay),STESS(statusepilepticusseverityscore),ER(emergencyroom),NYHA(New YorkHeartAssociationfunctionalclassiﬁcation),IQR(interquartilerange),PRIS(propofolinfusionsyndrome)

paredtootherstudies(Table1.)andtotheFinnishnationalstudy, whichshowed12-monthmortality36%forSRSE(Kantanenetal., 2015).Webelievethatthereasonforthismightbepurelythesmall samplesizeandrandomselectionoflesssevereetiologies,however,itshowsthattheSRSEdoesnotnecessarilyhave apoorer outcome.

Pooroutcome wasassociated witholderage,although indi- vidualpatientswithhigherageofupto79years couldrecover functionallyafterRSE.Wecouldnotconﬁrmtherecentlyshown predictivevalueofSTESS,especiallyofscores≥3,inpredictingnot onlymortalityafterRSEbutalsofunctionaloutcome(Madzaretal., 2016).Wewerealsounabletoconﬁrmthepositivepredictivevalue

ofearlierepilepsy(DodrillandWilensky,1990;Madzaretal.,2016).

Thepooroutcomeinpatientswithpreexistingepilepsywasrelated toremotesymptomaticetiologylikestrokeorbraininjuryortoa progressivesyndrome.Therefore,althoughtheywereoftenindica- tiveofbetterprognosis,earlierseizuresandepilepsydidnotalways predictafavorableoutcome.

Overall, thetreatment response and outcome werestrongly inﬂuencedbytheunderlyingetiology(NeliganandShorvon,2010;

Sutteretal.,2013).Wecouldidentifytheputativeetiologyin97%of patientsandcouldrecognizespeciﬁcprogressiveetiologiesduring thetreatmentprocessthatwouldeventuallycausedeathorpoor outcome.In literatures,acute symptomaticetiologyis themost

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common,beingreportedinupto72%ofcases(DeLorenzoetal., 1996;Coeytauxetal.,2000),anditsoutcomeisreportedtobeworse thanthatofotheretiologies(DeLorenzoetal.,1996;Claassenetal., 2002;Logroscinoetal.,2002;Rossettietal.,2006;Delajetal.,2016).

Inourseries,acutesymptomaticetiologywasnotrelatedtopoorer outcomeasagroup.Oneofthemostevidentacutesymptomaticeti- ologiesforRSEinourpopulationwasalcohol-withdrawal-related seizures,in17%ofthepatients,whereasinotherstudiesofSE,it was3%–13%(DeLorenzoet al.,1995;Trinkaet al.,2012;Ferlisi etal.,2015;Rohracheretal.,2016).Alcohol-withdrawal-related RSEhad a similar,but not poorer, prognosistoRSE ingeneral, andthisexplainswhyacutesymptomaticetiologywasoverallnot associatedwithpooreroutcomeinourstudy.

Wecouldnotreliablymeasure thedurationofSEandcould thereforenotshowwhetherthedurationof RSEhadanimpact onthefunctionaloutcome(Sutteretal.,2013).Regardingthedelay oftreatment,fromourdataset,wecoulddeterminethetimefrom emergencydepartment(ED)admissiontoICUadmissionandthe timefromhospitaladmissiontoICUadmission;itdidnotdiffer, and,infact,itshowedatrendofbeingshorterinpatientswithpoor outcome.Thisseemstoindicatethatpatientswithmoreserious disordersandcorrespondinglyunfavorableoutcomeswererecog- nized.ThelengthofstayintheICU,whichmightcorrelatetothe durationofRSE, didnot differbetweenpatientswithgood and pooroutcomes;however,inthepooroutcomegroup,therange waslarger,indicatingcaseswithlongerstayanddurationofSE.

Astaged protocol dividing diagnostics and therapy toearly, established,refractoryandsuper-refractorystagesisthehallmark of current SE treatment (Trinka and Kälviäinen, 2017). In the presentstudy,theuseofEEG,first-andsecond-lineAEDs,andIV anestheticswasingoodagreementwiththecurrentnationalguide- linesInFinland(Kälviäinenetal.,2009);first-linetreatmentwas alreadystartedout-of-hospital.Ontheotherhand,individualcases showedatrendtowardapooreroutcome,whereitwasnotclear whethertheprotocolwasfollowedorwhatAEDswereadminis- tered.Thelowermortalityratesmayalsoreflectthequiterigorous adherencetothetreatmentprotocolinourarea,asadequateini- tialtreatmenthasbeenshowntobeassociatedwithmorerapid seizurecessation(Arandaetal.,2010).Recently,itwasalsohypoth- esizedthatthepolicyofearlyandaggressivetreatmentmayhave ledtoanevidentdecreaseinSEdeathsintheUKandWalesduring 2001–2013(NeliganandWalker,2016).

AllofthedenovoRSEpatientstreatedatICUwereleftwith atleastoneantiepilepticdrugafterhospitalization.Sotheywere thoughttobeatriskforfurtherseizuresandwerediagnosedas havingepilepsy.Itisverydifﬁculttoestimatewhoreallydevel- opedepilepsyandwhowouldinfactbeenabletomanagewithout furtherAEDtreatment.Wedonothavelong-termfollow-updata ofthesepatientsregardingtheprognosisoftheirepilepsy.

4.2. Limitationsandneedforfuturework

Aweaknessofthisstudyistheretrospectivedatacollectionof theotherwise comprehensiveand population-basedcohort.Our incidence rates are at the same level as the whole of Finland andEurope(Kantanenetal.,2015;Delajetal.,2016)andlower thanthoseintheUS(Hesdorfferetal.,1998).Ourstrengthisthe population-basedICU registry data and clear deﬁnition of RSE, whichallowsustocompareresultswithpreviousworks.Wehave beenabletocollectdataofalladultpatientswhoseRSEwastreated withanesthesia;however,wedonotexactlyknowwhetherthe samecriteriawereusedtotreatRSEateachICUintheﬁvehos- pitals.Inadditionwehavenodataaboutthosepatientswhomay havehadRSEbutwerenottreatedinICUwithanesthesiabecause ofpresumedfutilityofintensivecare.Wewerenotabletoretrieve pediatricdatareliablyandthereforechlldrenareexcludedfromthe

analyses.Retrospectivedatacollectionfrommedicalrecordslim- itsourunderstandingoftheexactdurationofSEandevaluationof thefullextentofallpossibleprognosticfactorsincludingdetailed EEGparameters.Arecentstudy(Leitingeretal.,2015)hasvali- datedanewscore(epidemiology-basedmortalityscoreinstatus epilepticus,EMSE)thattakesintoconsiderationtheetiology,age, EEGpatterns,andcomorbiditytopredictoutcomes.Thisapproach necessitatesaprospectiveevaluationofthepredictorsbythetreat- ingphysiciansandcapturingstructureddatainthemedicalrecords.

AnotherapproachisaglobalauditofthetreatmentofRSE(Ferlisi etal.,2015), inwhich neurologistsorintensivists prospectively enterpatientswhorequiregeneralanesthesiatocontrolSE.

5. Conclusions

During1-year follow-up,nearly 50%ofICU- and anesthesia- treatedRSEpatientsrecoveredtobaselinefunction,30%showed newfunctionaldefects,and20%died.SRSEdoesnotnecessarily haveapooreroutcome.Theoutcomeisworseinolderpatientsand inpatientswithprogressiveorfataletiologies.SEshouldbetreated withgeneralizedanesthesiaonlyinrefractorycaseswithreason- ablelong-termprognosisandafterfailureofadequatelyusedﬁrst- andsecond-lineAEDs.

Disclosures

Anne-Mari Kantanen has received speaker’s honoraria from Orion,UCB,andMSD.ReettaKälviäinenhasreceivedspeaker’shon- orariafromEisai,UCB,andOrion;honorariaformembershipof advisoryboardsfromEisai,Fennomedical,GWPharmaceuticals, Pﬁzer,SageTherapeutics,andUCB;andresearchsupportforher institutefromtheAcademyofFinland,VaajasaloFoundation,Saas- tamoinenFoundation,UCB,andEisai.

MattiReinikainenandIlkkaParviainenhavenodisclosures.

Acknowledgements

Theauthorswouldliketothanktheintensivecarephysicians RailiLarusompa(CentralFinlandCentralHospital),PekkaSaasta- moinen(SavonlinnaCentralHospital),andHeikkiLaine(Mikkeli CentralHospital)fortheirhelpwiththedata.Theyalsospecially thankJuusoTamminen,M.D.,forprovidingthemapusedinthis article.

ThisstudywassupportedbygrantsfromtheKuopioUniversity HospitalVTR,FinnishEpilepsyResearchFoundation,andFinnish Cultural Foundation and Saatamoinen Foundation. The funding agencies had norole in thedata collection,analysis and inter- pretation, reportwriting, and decision to submit thepaper for publication.

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