Seizure (2007) 16, 153—159

www.elsevier.com/locate/yseiz

SUDEP in the Netherlands: A retrospectivestudy in a tertiary referral center

M.C.G. Vlooswijk a,*, H.J.M. Majoie b, M.C.T.F.M. De Krom a,I.Y. Tan b, A.P. Aldenkamp a,b

aDepartment of Neurology, University Hospital Maastricht, The Netherlandsb Epilepsy Center Kempenhaeghe, Heeze, The Netherlands

Received 27 December 2005; received in revised form 10 November 2006; accepted 10 November 2006

KEYWORDSSUDEP;Risk factor;Epilepsy;Sudden death

Summary

Objective: To evaluate risk factors for sudden and unexpected death in epilepsy(SUDEP) in a high-risk population, i.e. patients treated in a Dutch tertiary referralcenter for epilepsy.Methods: All patients who died between January 1999 and April 2004 while undertreatment of the epilepsy center were identified. Based on clinical data, deaths wereclassified as definite, probable, possible or non-SUDEP. Potential risk factors werecompared in SUDEP cases and non-SUDEP cases.Results: SUDEP incidence was 1.24 per 1000 patient years. SUDEP patients died at ayounger age than patients from the control group of non-SUDEP deaths with epilepsyand had an earlier onset of epilepsy. However, the frequently mentioned factors inprevious studies, i.e. male sex, generalized tonic—clonic seizures, high seizurefrequency, specific AEDs, polytherapy with several AEDs, mental retardation, psy-chiatric illness and psychotropic comedication, were not found to be correlated withSUDEP.Conclusions: Even in this high-risk population of patients with refractory epilepsy,treated in a tertiary referral center, SUDEP is not a frequently occurring phenomenon.Specific risk factors could not be identified within an already high-risk population.# 2006 Published by Elsevier Ltd on behalf of British Epilepsy Association.

‘Sudden Unexpected Death in Epilepsy’ (SUDEP) isan important cause of death among people withepilepsy. Thus far epidemiological data show widely

* Corresponding author. Tel.: +31 43 3876543.E-mail address: marielle.vlooswijk@neurologie.azm.nl

(M.C.G. Vlooswijk).

1059-1311/$ — see front matter # 2006 Published by Elsevier Ltd odoi:10.1016/j.seizure.2006.11.002

varying incidences: from 0.35 per 1000 patient yearsin population-based studies to 9.30 per 1000 patientyears in selected cohorts, for example in tertiaryreferral centers or cohorts of people who had epi-lepsy surgery.1—9 Although SUDEP has been relatedto a wide range of different factors, there are nospecific data to identify patients at highest risk for

n behalf of British Epilepsy Association.

154 M.C.G. Vlooswijk et al.

SUDEP, hence no ‘SUDEP risk profile’ is available forSUDEP prevention.

In previous studies a number of risk factors hasbeen identified such as male gender,3,10—15 an age of20—45 years,9,16,17 generalized tonic—clonic sei-zures,9—11,15,17—19 high seizure frequency,6,17,20—22

long duration of epilepsy,17,18,22 psychiatric comor-bidity17,23 and/or mental retardation.4,17,20 In manycases, there is evidence of a terminal epilepticseizure.4,11,16,17,19,24—26 SUDEP occurs relativelymore frequently during sleep or while lying inbed.10,16,19,20,27 It is not clear whether SUDEP occursmore in symptomatic or idiopathic epilepsy.9,11,15,18

Some authors have shown the influence of specificantiepileptic drugs (AEDs),15,28,29 in particular thoseaffecting cardiac rhythm such as sodium channelblockers. However, in most studies specific AEDsdid not play a role in SUDEP.4,14,16,19,30—32 Alsotreatment with multiple AEDs is suggested to be arisk factor for SUDEP,4,18,22,33 whereas other studiescould not confirm this factor13,15,16,19 or interferingfactors have been found, such as the severity of theepilepsy.20,34,35

Pathophysiological mechanisms underlyingSUDEP have been suggested to be centralapnea24,30,36—39 or cardiac arrhythmia.37,40—47

The purpose of this study is to evaluate riskfactors for SUDEP in a high-risk population, i.e.patients treated (both clinically and on an outpa-tient basis) in a Dutch tertiary referral center forepilepsy (‘Kempenhaeghe’).

Methods

Study population

Epilepsy center Kempenhaeghe in Heeze is a ter-tiary referral center in the south eastern part of theNetherlands that provides services for patientsfrom all parts of our country. The population basefor this study were deaths that occurred within theepilepsy population treated in the period betweenJanuary 1999 and April 2004. The population ischaracterized by a high percentage of patients withsevere or intractable epilepsy. In this study, wecompared the SUDEP group with control subjectswith a history of epilepsy who died from othercauses than SUDEP.

SUDEP definition

We used Leestma’s criteria for SUDEP: the victimsuffered from epilepsy, the victim died unexpect-edly in a reasonable state of health, death occurred‘suddenly’ (in minutes), when known, death

occurred during normal activities and benign cir-cumstances, an obvious medical cause of death wasnot found at post-mortem examination and deathwas not the direct result of the seizure or statusepilepticus.1,14 ‘Definite SUDEP’ cases meet all cri-teria, ‘probable SUDEP’ cases meet all criteria butlack post-mortem data, ‘possible SUDEP’ are caseswhere SUDEP cannot be ruled out but availableinformation is not conclusive and post-mortem dataare lacking, and non-SUDEP are those cases in whichanother cause of death is clear or SUDEP is highlyimprobable. Working definitions for SUDEP includeboth definite and probable SUDEP, because post-mortem examinations are not routinely performedin the Netherlands.

Assessment of clinical variables

An electronical patient record system available inKempenhaeghe facilitates easy and reliable accessto data for large patient groups. Using this systemthe patient’s medical history could be extracted.For each death the following data were included in adatabase and evaluated: epilepsy syndrome, type ofseizures, status epilepticus, age at seizure onset,seizure frequency in the last year before death,race, age at death, last AED therapy, comedication(antihypertensive, pulmonary, cardiac and antipsy-chotic medication, betablockers, anticoagulants),comorbidity — such as cardiovascular disease, pul-monary disease, stroke, diabetes, mental retarda-tion and psychiatric illness including dementia —alcohol and other substance abuse, EEG abnormal-ities, epilepsy localization, circumstances of deathand results of autopsy (if present). Classification ofepilepsy syndrome and seizure type occurredaccording to the International League Against Epi-lepsy system. Family doctors were asked about thedeath circumstances when documentation in Kem-penhaeghe was not conclusive. Data were evaluatedby two neurologists specialized in epilepsy, to cate-gorize the patients in non-, possible, probable ordefinite SUDEP groups. If there was any reason tosuspect that the patient had died of another causethan SUDEP, for example because of existing comor-bidity or old age, this patient was included in thenon-SUDEP group.

Statistical analysis

All data were entered in a database and evaluatedusing the SPSS statistical program. Descriptives(means, S.D. and frequencies) were evaluated.For all variables correlations (crosstabs, withChi-square non-parametric testing) betweenSUDEP and the clinical variables were calculated.

SUDEP in the Netherlands: A retrospective study in a tertiary referral center 155

p-Values < .05 (one-sided) were regarded as statis-tically significant. Those clinical variables thatyielded a statistically significant relationship withSUDEP the differential contribution was evaluatedwith linear regression with SUDEP as the dependentvariable.

Ethics approval was obtained from the ethicscommittee of Epilepsy Center Kempenhaeghe,Heeze.

Table 2 Patient data

Results

From January 1999 to April 2004, a mean number of4400 people with epilepsy were treated per year bythe epilepsy center and 274 deaths were reported atKempenhaeghe. Of those, 95 were excludedbecause they were not suffering from epilepsy orthey had not been under treatment of Kempen-haeghe when they died. From the remaining 179patients, cause of death was not identified in 25patients, 104 patients died from other causes thanSUDEP, 21 patients were classified as possible SUDEP,24 as probable SUDEP and five patients died ofdefinite SUDEP (Table 1). Our SUDEP group consistsof ‘definite plus probable SUDEP’ cases, that is 29patients. Presuming that the unknown cases werenon-SUDEP, 16.2% of deaths in this period werecaused by SUDEP. A higher percentage would bethe result of omitting the unknown cases from theanalysis (18.8%) or presuming all the unknown casesare due to SUDEP (30.2%). The 104 patients who diedof other causes than SUDEP form the control group.

Demography

The age at death in the SUDEP group ranged from 4to 69 years and in the control group 1—90 years. TheSUDEP group was significantly younger than thecontrol group (mean 29.0 � 16.0 S.D. versus52.5 � 23.1 years with p = 0.016) at time of death.

In the SUDEP group, 45% were male, 55% femaleand in the control group 52% male and 48% female.Although the female proportion was greater in theSUDEP group, Chi-square analysis indicated that thiswas not significant (p = 0.321).

Table 1 Cause of death in total study population

Cause of death n = 179 Percentage

Definite SUDEP 5 2.8Probable SUDEP 24 13.4Possible SUDEP 21 11.7Non-SUDEP 104 58.1Unknown 25 14.0

Clinical features

Age at onset of seizures was significantly lower inSUDEP subjects than in controls (mean 7.68 � 8.73years versus 20.69 � 21.47 years with p < 0.001).Duration of epilepsy was significantly less in theSUDEP group than in the control group (mean19.41 � 15.86 versus 31.77 � 24.94 with p = 0.001)(Table 2).

Number of seizures was not significantly differentbetween SUDEP cases and controls. In the controlgroup, relatively more patients were seizure freefor at least 1 year before death, but this was notsignificant (p = 0.220).

SUDEP subjects had more generalized tonic—clo-nic seizures — partial seizures secondarily general-ized and/or primary generalized tonic—clonicseizures — than controls, but this was not statisti-cally significant (p = 0.292). We also performedstatistical analysis for all separate seizure types,but none of the comparisons reached a statisticallysignificant correlation with SUDEP. There was nocorrelation between SUDEP and type of epilepsy(divided into idiopathic, symptomatic or crypto-genic epilepsy); also no correlation was seenbetween SUDEP and EEG abnormalities or the loca-lization of the seizures or other EEG-data.

The SUDEP group showed less comorbidity thancontrols. SUDEP subjects had significantly less car-diovascular and pulmonary disease than controls(respectively, p = 0.008 and p = 0.046). Stroke anddiabetes mellitus were observed less frequently inthe SUDEP group, but this was not statistically sig-nificant. Mental retardation and psychiatric illnessoccurred slightly more frequently in SUDEP sub-jects, but this was also not statistically significant.

Medication details

None of the AEDs that were used by the subjects inthis study had a statistically significant correlationwith SUDEP. A combination of sodium channel block-ers (carbamazepine, oxcarbazepine and phenytoin)did not show a correlation with SUDEP either. The

Clinical data SUDEP Non-SUDEP

Men 13 54Women 16 50Mean age at

death (S.D.)29.00 (15.98) 52.52 (23.12)

Age at onset ofepilepsy (S.D.)

7.68 (8.73) 20.69 (21.45)

Duration ofepilepsy (S.D.)

19.41 (15.86) 31.77 (24.94)

156 M.C.G. Vlooswijk et al.

number of AEDs did not show a statistically signifi-cant correlation with SUDEP (mean 2.17 in SUDEPversus 2.16 in non-SUDEP subjects, p = 0.645). In theSUDEP group, antihypertensive medication was usedsignificantly less than in the non-SUDEP group( p = 0.019). In other comedication, in particularbeta-blockers or antipsychotic medication, there

Table 3 SUDEP patients

Patient Gender Age Epilepsytype

Seizuretype

Mean seizurefrequency in layear before de

1 < 69 1.3 IB—IC 1 per month

2 < 31 1.2 IB 4 per month

3 , 47 1.3—2.1 IB—IC 0.7 per month

4 , 42 2.3.1—3 IIB—IID—IIE 1 per month

5 , 54 4.1 IIE—IV 0 per month6 < 12 1.3 IC 3 per month7 , 31 1.3 IB—IC—IV 0 per month8 , 33 1.2—2.3 IB—IIE 0.7 per month9 , 28 1.3 IB—IC—IV 1 per month

10 < 46 1 IB 0 per month11 < 31 1.3 IB—IC—IID 20 per month

12 < 23 1.2 IB 0 per month13 < 33 1.2 IB—IIB—IID 4 per month

14 < 28 1.2 IB—IC 6 per month

15 , 50 1.3 IA—IC 0 per month16 , 32 1 IB—IC 0.5 per month17 < 27 2.2 IIE 10 per month

18 , 18 1.2 IC 3.5 per month

19 < 7 1.3 IB 20 per month

20 < 4 1.3 IB—IC—IID 45 per month21 , 18 1.2 IC 15 per month22 < 16 1.2 IB—IC 8 per month

23 , 16 1.3 IB—IC 0.1 per month24 , 55 1.3 IB—IC—IV 2.5 per month

25b < 22 1.3 IB—IC 0.5 per month

were no statistically significant differences betweenSUDEP and non-SUDEP subjects.

Table 3 shows the main characteristics of the 29SUDEP patients.

For those three factors that reached a statisti-cally significant correlation with SUDEP, that is ageat death, age at onset and duration of epilepsy,

stath

Durationof epilepsy(years)

Timefound

Circumstances of death

67 Dinner Died suddenly duringdinner, no seizurewitnessed

22 Morning Found in bed, wascyanotic; had a fever;parents had not heardanything

NA 8.15 a.m. Found in bed on leftside with head in pillow

NA Morning Nocturnal seizures;found in bed

25 NA Found dead at home10 Morning Found in bedNA Morning Found beside the bed19 NA Found in bed6 Morning Found in bed; prone

position; head in pillowNA Morning Found in bed25 Morning Found in bed;

incontinent; proneposition; head inblankets

23 Afternoon Found in bedNA 7.30 a.m. Hospitalized for a

pneumonia; found inbed; warm; with bruises

28 NA Found on the groundbeside the sofa

35 Morning Found in bed27 Morning Found in bedNA Afternoon Found in bed after nap;

stiffened and cyanotic18 Afternoon Fever; vomiting; two

seizures; stoppedbreathing

6 Morning Found in bed; proneposition; warm

4 NA NAa

NA NA Found at home8 Morning Found in bed; recently

less seizures9 NA Found at home50 12.00 p.m. Went to bed at 5.00 PM

after a seizure; foundin bed; prone position;head in pillow

4 NA Found in shower

SUDEP in the Netherlands: A retrospective study in a tertiary referral center 157

Table 3 (Continued )

Patient Gender Age Epilepsytype

Seizuretype

Mean seizurefrequency in lastyear before death

Durationof epilepsy(years)

Timefound

Circumstances of death

26b , 7 1.2 IB—IIE 30 per month 7 3.20 a.m. Hospitalized fortonsillitis; found in bed

27b < 10 1.3 IC 1 per month 7 6.53 p.m. Seizures with apneas;witnessed seizure; apnea

28b , 30 1.3 IC 0.42 per month 7 NA Found in bed; proneposition

29b , 20 1.3 IB—IID 4 per month 20 Morning Found in bed, mouthwith blood and saliva,incontinent; proneposition

Epilepsy types: 1, partial epilepsy; 1.2, symptomatic partial epilepsy; 1.3, cryptogenic partial epilepsy; 2.1, idiopathic generalizedepilepsy; 2.2, cryptogenic/symptomatic generalized epilepsy; 2.3, symptomatic generalized epilepsy; 2.3.1, symptomatic general-ized epilepsy with non-specific etiology; 3, undetermined whether focal or generalized epilepsy; 4.1, situation-related seizures.Seizure types: IA, simple partial seizures; IB, complex partial seizures; IC, partial seizures evolving to secondary generalized seizures;IIB, myoclonic seizures; IID, tonic seizures; IIE, tonic—clonic seizures; IV, non-epileptic seizures. NA, not available.a Death was classified probable SUDEP by treating neurologist.b Definite SUDEP.

linear regression analysis was performed. The pre-viously mentioned factors were used as predictorsand SUDEP as the dependent variable. Regressionanalysis was carried out to inspect the differentialcontribution of each of these factors in relation toSUDEP. Regression analysis showed that only onefactor, age at death, correlated statistically signifi-cantly with SUDEP after removal of the intercorre-lation between those factors ( p < 0.001;Beta = �0.370; R square = 0.14), explaining 14% ofthe total variance of factors predicting SUDEP.

Discussion

In this study we analyzed the correlation betweenSUDEP and a wide range of factors reported inprevious studies as risk factors. Our study evaluatedpatients, treated in an epilepsy center with a highpercentage of patients suffering from chronicrefractory epilepsy. A high percentage of SUDEPcases was found (16.2% of the total deaths in theevaluated period of 5 years and 3 months). We founda SUDEP rate of 1.24 per 1000 patient years in theepilepsy population of the epilepsy center. Otherstudies report SUDEP rates up to 9.30 per 1000patient years; highest in cohorts with surgical can-didates.48 However, in studies performed at epilepsycenters and epilepsy referrals, SUDEP rates reportedrange from 2 to 5.9 per 1000 patientyears.1,12,15,49,50 Our data therefore show a loweryearly incidence of SUDEP than reported in otherstudies. We conclude that SUDEP cannot be consid-ered as a frequently occurring phenomenon.

There were only three differences between theSUDEP and the non-SUDEP subjects that reachedstatistical significance. In the SUDEP group, subjectsdied at a significantly younger age than in the non-SUDEP group. Furthermore, age at onset of epilepsywas younger than in controls. This finding concurswith some studies,19,22 but conflicts with otherdata.16 The duration of epilepsy was significantlyshorter than in controls. This finding is in contrastwith most previous studies which reported a longeror no difference in duration of epilepsy in SUDEPgroups compared to controls.11,15,16,50 We believethat our finding can be partly attributed to thedifference in age at death between SUDEP andcontrol groups (mean 29.00 years versus mean52.52 years).

For those three factors that reached a statisti-cally significant correlation with SUDEP, that is ageat death, age at onset and duration of epilepsy,linear regression analysis showed that only ageat death correlated statistically significantlywith SUDEP. Our finding that the SUDEP group wassignificantly younger than the control groupconcurs with most previous studies that indicatedyoung adults to be particularly at risk forSUDEP.3,9,11,14,16,17,50

Young (adult) age at death can however not beseen as a real risk factor for SUDEP. Part of thisdifference in age at death can be explained by thedefinition of SUDEP. In elderly people deaths aremore likely to be attributed to the presence ofcomorbidity, for example cardiovascular or pulmon-ary disease, or to old age itself which causes thatSUDEP in the higher age ranges will go undetected.

158 M.C.G. Vlooswijk et al.

Most studies suggest that SUDEP occurs morecommonly in male subjects,3,10—13,15 but some likeour study find no association between SUDEP andgender.19

Most of the SUDEP subjects had generalizedtonic—clonic seizures (76%), confirming previousstudies,4,9—11,15,17,19,30,47 although this differednot much from the control group (68%).

We could not confirm previous studies thatreported a correlation between SUDEP and particu-lar epilepsy types,9,15,18 in agreement with twoother studies.11,16 Where most studies reportedhigher SUDEP occurrence in subjects with frequentseizures,2,14,15,17,22,50,51 some like our study find nocorrelation between SUDEP and a high seizure fre-quency.15,16,19 We could not prove a significant dif-ference in epilepsy localization between SUDEP andnon-SUDEP subjects.

No significant differences were found in comor-bidity. Cardiovascular and pulmonary disease wasreported less in the SUDEP subjects than in controls,but we believe this can be attributed to the agedifferences and to SUDEP definitions. Subjects withmajor comorbidity were more likely to be diagnosedas possible or non-SUDEP than healthy subjects.Mental retardation and psychiatric illness werereported slightly more in the SUDEP group, but thiswas not significant. These findings are in contrastwith previous reports of association of SUDEP withmental retardation4,17,20 and psychiatric ill-ness,17,23 but agree with another study that didnot confirm an association.16

We found no significant differences in medicationbetween SUDEP and control groups. No particularAED was associated with SUDEP, confirming previousstudies,16,17,19,30 but in contrast with other stu-dies.28,35,52 Polytherapy with AEDs was not con-firmed to be a risk factor for SUDEP, in agreementwith previous reports,13,16,19,28 but differing fromother studies.4,22,30,33 This finding may be related tothe high percentage of subjects with severe epi-lepsy, and as a consequence a high percentage ofsubjects on polytherapy, in both the SUDEP as thecontrol groups. In comedication, SUDEP subjectsused significantly less antihypertensive medication,probably as a result of both younger age and lesscardiovascular disease in this group. Other comedi-cation did not differ appreciably between ourgroups. In particular, this contrasts with previousfindings that psychotropic medication is likely to beassociated with SUDEP.33

Previous studies reported signs of seizures, forexample fresh bites, cyanosis or blood on the pillow,preceding death in most of SUDEP subjects.11,14,16,19

In our study, we also see a trend towards deathspreceded by seizures, but data were not sufficient

to compare with the control group. However, SUDEPdid also occur in subjects who had been seizure freein the last 12 months before their death. Most of theSUDEP subjects were found in bed and where posi-tion at death was reported, prone position wasfrequently the case. Unfortunately, we cannot com-pare these findings with results from the controlgroup, because these data are lacking about thecontrol subjects.

In conclusion even in this high-risk population ofpatients with a refractory epilepsy, treated in atertiary referral center, SUDEP occurs a fourfoldtimes more than in the overall population of epi-lepsy patients, but is not as frequent as reported inother studies with highly selected patients popula-tions. In absolute numbers it is not a frequentlyoccurring phenomenon with a yearly incidence of1.24/1000. Our study showed that SUDEP patientsdied at a younger age than a control group of non-SUDEP deaths with epilepsy and had an earlier onsetof epilepsy but no real risk factors could be identi-fied. The frequently mentioned factors in previousstudies, i.e. male gender, generalized tonic—clonicseizures, high seizure frequency, particular AEDs,polytherapy of AEDs, mental retardation, psychia-tric illness and psychotropic comedication, were notfound to be correlated with SUDEP in our study.

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