Lucia- Incidence and Isk Factors in Sudden Unexpected Death in Epilepsy

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leptic drugs in Saskatchewan, Canada. Epilepsia 1995;36:2936.

4. Nashef L, Fish DR, Sander JWAS, Shorvon SD. Incidence ofsudden unexpected death in an adult outpatient cohort withepilepsy at a tertiary referral centre. J Neurol Neurosurg Psy-chiatry 1995;58:462464.

5. Nashef L, Fish DR, Garner S, Sander JWAS, Shorvon SD.Sudden death in epilepsy: a study of incidence in a youngcohort with epilepsy and learning difficulty. Epilepsia 1995;36:11871194.

6. Dashieff RM. Sudden unexpected death in epilepsy: a seriesfrom an epilepsy surgery program and speculation on the re-

lationship to sudden cardiac death. J Clin Neurophysiol 1991;8:216222.

7. Leestma JE, Annegers JF, Brodie MJ, et al. Sudden unex-plained death in epilepsy: observations from a large clinicaldevelopment program. Epilepsia 1997;38:4755.

8. Annegers JF, Coan SP, Hauser WA, Leestma J, Duffell W,Tarver B. Epilepsy, vagal nerve stimulation by the NCP sys-tem, mortality, and sudden, unexpected, unexplained death.Epilepsia 1998;39:206212.

9. Katz R. Perspective of the Food and Drug Administration. In:Porter RJ, Schoenberg BS, eds. Controlled clinical trials inneurological disease. Boston, MA: Kluwer Academic Publish-ers, 1990:8596.

10. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T.Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 1999;353:888 893.

11. Walczak T, Leppik IE, Rarick JO, et al. Risk factors for sud-

den death in epilepsy. Epilepsia 1999;40(suppl 2):191192.Abstract.

12. Derby LE, Tennis P, Jick H. Sudden unexplained deathamong subjects with refractory epilepsy. Epilepsia 1996;37:931935.

Incidence and risk factors in sudden

unexpected death in epilepsy

A prospective cohort studyT.S. Walczak, MD; I.E. Leppik, MD; M. DAmelio, MD; J. Rarick, MA; E. So, MD; P. Ahman, MD;

K. Ruggles, MD; G.D. Cascino, MD; J.F. Annegers, PhD; and W.A. Hauser, MD

Article abstractObjective: To determine incidence of and risk factors for sudden unexpected death in epilepsy

(SUDEP). Methods: Three epilepsy centers enrolled 4,578 patients and prospectively followed these patients for 16,463

patient-years. The cohort was screened for death annually. Deaths were investigated to determine whether SUDEP

occurred. Potential risk factors were compared in SUDEP cases and in controls enrolled contemporaneously at the same

center. Results: Incidence of SUDEP was 1.21/1,000 patient-years and was higher among women (1.45/1,000) than men

(0.98/1,000). SUDEP accounted for 18% of all deaths. Occurrence of tonic-clonic seizures, treatment with more than two

anticonvulsant medications, and full-scale IQ less than 70 were independent risk factors for SUDEP. The number oftonic-clonic seizures was a risk factor only in women. The presence of cerebral structural lesions and use of psychotropic

drugs at the last visit were not risk factors for SUDEP in this cohort. Subtherapeutic anticonvulsant levels at the last visit

were equally common in the two groups. No particular anticonvulsant appeared to be associated with SUDEP. Conclu-

sions: These results support the idea that tonic-clonic seizures are an important proximate cause of SUDEP. This

information creates a risk profile for SUDEP that may help direct preventative efforts.

NEUROLOGY 2001;56:519525

Sudden unexpected death in epilepsy (SUDEP) is acommon cause of death among patients with epilep-sy.1,2 Estimated SUDEP incidence ranges from 0.7 to1.3 per 1,000 patient-years in large cohorts of pa-

tients with epilepsy3,4

and from 3.5 to 4.1 per 1,000patient-years in anticonvulsant drug trials, medicaldevice registries, and epilepsy surgery programs.5-8 Apopulation-based study of incident cases of epilepsy9

found a SUDEP incidence of 0.35/1,000 patient-years, a24-fold increase compared with that expected in thegeneral population. These reports demonstrate thatSUDEP is a genuine entity and a common cause of

death in patients with epilepsy.Less is known about risk factors for SUDEP. This

information would identify patients at higher riskand direct potential preventative or treatment pro-

Deceased.

From MINCEP Epilepsy Care and the Department of Experimental and Clinical Pharmacology (Drs. Walczak and Leppik, and J. Rarick), University of

Minnesota, Minneapolis; G.H. Sergievski Center (Drs. DAmelio and Hauser), College of Physicians and Surgeons, Columbia University, New York; Epilepsy

Division (Drs. So and Cascino), Department of Neurology, Mayo Clinic, Rochester MN; Department of Neurology (Drs. Ruggles and Ahman), Marshfield

Clinic, WI; Department of Epidemiology (Dr. Annegers), School of Public Health, University of Texas, Houston.

Supported in part by NIH-NINDS Grant P50:NS16308, Dainippon Pharmaceutical USA, GlaxoWellcome, Hoescht Marion Roussel, Inc., Ortho-McNeil

Pharamceutical, Parke-Davis Pharmaceutical, Inc., SmithKline Beecham, and UCB Pharma, Inc.

Received November 8, 2000. Accepted in final form January 5, 2001.

Address correspondence and reprint requests to Dr. Thaddeus Walczak, MINCEP Epilepsy Care, 5775 Wayzata Boulevard, Suite 255, Minneapolis, MN

55416; e-mail: [email protected]

Copyright 2001 by AAN Enterprises, Inc. 519


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grams appropriately. Early studies based at medicalexaminers offices found male gender,10-12 develop-mental delay,11,13 and structural cerebral lesions10,11

more often in SUDEP cases than would be expectedin the general population with epilepsy. Generalizedtonic-clonic seizures were reported in virtually allpatients.10-13 Postmortem anticonvulsant levels wereusually subtherapeutic,10-12 suggesting that noncom-pliance was a contributing factor. These observations

were all uncontrolled. Patients with epilepsy in coro-ners case series may not fairly represent any clini-cally useful segment of the epilepsy population.

Two population-based, case-control studies haveprovided some information regarding risk factors.3,4

Seizure frequency and epilepsy duration could be as-sessed in one study and both were increased amongSUDEP cases.4 Both the number of anticonvulsantdrugs used and psychotropic drug use were higheramong SUDEP cases in both studies.3,4 WhetherSUDEP is more common among young males re-mains unresolved, with different trends in thecohort-based studies3,4,9 addressing this issue. Con-

trolled studies have also questioned the idea thatnoncompliance is more common in SUDEP.14 Thusthe risk profile for SUDEP remains unclear.

All of the above studies failed to clearly establishthe diagnosis of epilepsy. Most reports were retro-spective, and it is not clear that medical records wereconsistently obtained and the diagnosis of epilepsyconfirmed. A retrospective diagnosis of epilepsybased on incomplete records may be inaccurate. Oneof the population-based case-control studies basedthe diagnosis of epilepsy on the number of prescrip-tions of anticonvulsant drugs used, which could leadto substantial inaccuracies. Results of previous EEG

studies may help to establish the diagnosis of epi-lepsy. The single study reporting this information11

found epileptiform discharges in only approximately30% of the SUDEP cases in which EEG results wereavailable.

We determined SUDEP incidence and risk factorsin a prevalence cohort of people with epilepsy pro-spectively enrolled at three epilepsy centers. Becausemost patients had been intensively evaluated, the diag-nosis of epilepsy was more certain than in previousstudies. Furthermore, detailed information regardingpossible risk factors for SUDEP was available andcould be compared with an appropriate control group.

Methods. We prospectively enrolled patients evaluated at

three upper midwestern epilepsy centers (MINCEP Epi-

lepsy Care, Minneapolis, MN; Mayo Clinic Epilepsy Divi-

sion, Rochester, MN; and Marshfield Clinic Epilepsy

Section, Marshfield, WI). After consent was obtained, de-

mographic information, seizure type, and current anticon-

vulsants were recorded. The great majority of patients

underwent extensive evaluation (see below). A surveillance

system was set up to identify deaths in this prevalence

cohort. All reported deaths were investigated as soon as

possible after death in a systematic manner designed to

distinguish between SUDEP and other causes of death.

Investigation included interviews with relatives and wit-

nesses, and review of medical records, death certificates,

and autopsy reports when available. Unreported deaths

were detected and reported deaths confirmed by comparing

all enrolled patients against the Social Security Death In-

dex (Epidemiology Resources Inc., Newton Falls, MA) an-

nually. This index lists all deaths reported to the US Social

Security Administration.

A committee, which included investigators at each cen-

ter one other expert in SUDEP, evaluated all deaths. Com-

mittee members independently assessed and classified

each death using previously reported criteria.5 Briefly, def-

inite SUDEP required the following; 1) a history of epi-

lepsy (more than one epileptic seizure during a period of

less than 5 years); 2) that the death occur suddenly; 3) that

the death was unexpected (i.e., there was no life-

threatening illness); and 4) that the death remained unex-

plained after all investigative efforts, including autopsy.

Probable SUDEP required criteria 1 through 3. Autopsy

was not available in these patients, but SUDEP was con-

sidered likely because there was no alternative explana-

tion for death. Possible SUDEP required criteria 1 though

3 above. However, an explanation for death other than

SUDEP was found. In these patients, committee memberscould not establish with certainty whether SUDEP or the

other possible cause was responsible for the death. In non-

SUDEP cases, the cause of death was thought due to doc-

umented injury or medical illness. In insufficient data

cases, information allowing classification into the above

categories was insufficient. Agreement among committee

members after an initial independent review was excel-

lent. In 13/20 cases all four observers agreed on the ulti-

mate classification, in 4/20 cases three of four observers

agreed on the ultimate classification, and in the remaining

3/20 cases two of four observers agreed on the ultimate

classification. Differences were easily resolved after open

discussion by the four committee members.We analyzed all deaths occurring in this cohort between

the first enrollment (June 1, 1991) and December 31, 1996.

Definite and probable SUDEP in this group of deaths were

determined and grouped together. Four controls were ran-

domly selected for each SUDEP case from among the pa-

tients enrolled during the same month at the same

epilepsy center. Potential risk factors in SUDEP cases and

controls were identified by chart review.

We studied the following risk factors: age at enrollment,

gender, number of seizures of any sort in the year preced-

ing the last visit (calculated as seizures per month), num-

ber of tonic-clonic seizures in the year preceding the last

visit, and duration of epilepsy (age at onset to age at en-rollment). Mental retardation was defined as Full-Scale

Wechsler Intelligence Scale Quotient of less than 70. Pa-

tients who had been severely impaired since birth, unable

to communicate, and had not been considered testable

were also classified as mentally retarded. Three SUDEP

cases and four control cases met these criteria and were

included with patients that had a measured IQ of less than

70. Epileptogenic structural lesions were defined as focal

areas of cortical abnormality that were sufficient to cause

seizures and were found on brain CT or MRI or at autopsy.

Anticonvulsant compliance was evaluated by reviewing an-

ticonvulsant serum levels at the last visit. Many patients

were treated with more than one anticonvulsant. Results

520 NEUROLOGY 56 February (2 of 2) 2001


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were classified as all levels therapeutic, at least one level

therapeutic, or no levels therapeutic.

The occurrence of risk factors in SUDEP patients andcontrols was compared. We used logistic regression analy-

sis with logistic procedure in SAS (version 7.0, SAS Insti-

tute, Cary, NC) to obtain the maximum likelihood

estimates of the OR for duration of epilepsy, Full-Scale IQ,

presence of epileptogenic lesions, use of psychotropic

drugs, seizure frequency, and number of generalized tonic-

clonic seizures. Using the same statistic, the OR estimates

were adjusted for seizure frequency, number of generalized

tonic-clonic seizures, and number of antiepileptic medica-

tions when indicated. Age- and gender-specific incidences

were calculated by comparing SUDEP cases to the remain-

der of the cohort.

Results. Incidence of SUDEP. Four thousand, five hun-dred seventy-eight patients were enrolled between June 1,

1991 and December 31, 1996 and followed for a total of

16,463 patient-years (table 1). One hundred eleven pa-

tients died during this period, resulting in a mortality of

6.74/1,000 patient-years. Following the above criteria, 10

deaths were due to definite SUDEP, 10 probable SUDEP,

eight possible SUDEP, 78 non-SUDEP, and five had insuf-

ficient information to determine whether SUDEP was

present or not. Clinical features and cause of death in

non-SUDEP cases will be reported separately. Definite andprobable SUDEP were combined and considered to repre-

sent SUDEP for subsequent analysis. Overall incidence of

SUDEP was 1.21/1,000 patient-years. The incidence was

highest in patients aged 50 to 59 years. Incidence in fe-

males (1.45/1,000 patient-years) was higher than in males

(0.98/1,000 patient-years, p 0.0512). SUDEP accounted

for 18% of the deaths in the patients with epilepsy in this

cohort.

Studies performed. Both SUDEP cases and controls

had been thoroughly evaluated (table 2). Nearly 90% of

both SUDEP and control cases had either interictal epilep-

tiform discharges or electrographic seizures recorded at

some point during their evaluation. This provided secure

diagnosis of epilepsy in almost all patients in this study.Anticonvulsant levels at the last visit and cerebral imaging

had been obtained in the great majority of patients.

Autopsy in the 10 definite SUDEP cases revealed no

cause of death other than SUDEP. Toxicologic examination

and gross examination of heart, lungs, and brain were

performed in all. Coronary atherosclerosis was absent in

five cases, minimal in two, mild in one, and moderate in

one. No cases had myocardial infarction or coronary artery

obstruction. Pulmonary edema was noted in 7/10 and con-

gestive hepatosplenomegaly in 3/10 cases. Cerebral edema

was found in two cases and cerebral atrophy in two; gross

examination of the brain was otherwise normal. These

findings have been described in previous SUDEPseries.11,14

Risk factors for SUDEP (tables 3, 4, and 5). We found

a progressive increase in the risk for SUDEP with in-

creased seizure frequency, though these results achieved

significance only when patients experienced more than 50

seizures of any type per month. In contrast, the occurrence

of as few as one to three tonic-clonic seizures per year was

associated with an increased risk for SUDEP. Increased

frequency of tonic-clonic seizures may be associated with

an increased frequency of seizures of any type and may

explain the risk associated with the latter variable. We

assessed this possibility with a multivariate model includ-

ing both of these variables and the number of anticonvul-

Table 1 Incidence of sudden unexpected death in epilepsy

Age group, y

Males Females Total

Cases, n Patient-years Incidence Cases, n Patient-years Incidence Cases, n Patient-years Incidence

0 9 0 959 0 0 580 0 0 1,539 0

1019 0 1,127 0 0 958 0 0 2,085 0

2029 2 1,594 1.25 4 1,872 2.14 6 3,466 1.73

3039 4 2,084 1.92 3 2,222 1.35 7 4,306 1.63

4049 1 1,209 0.83 3 1,518 1.98 4 2,728 1.47

5059 1 585 1.71 2 644 3.11 3 1,230 2.43

6069 0 355 0 0 282 0 0 636 0

7079 0 198 0 0 165 0 0 363 0

80 0 65 0 0 44 0 0 110 0

Total 8 8,176 0.98 12 8,285 1.45 20 16,463 1.21

Incidence per 1,000 patient-years.

Table 2 Studies performed in sudden unexpected death in

epilepsy (SUDEP) patients and controls

Studies

SUDEP

(n 20)

Control

(n 80)

Seizures recorded during video EEG

monitoring

11 (55) 51 (74)

Interictal epileptiform discharges or

seizures recorded

18 (90) 71 (89)

Brain MRI 14 (70) 58 (73)

Brain MRI or CT scan 18 (90) 73 (91)

Neuropsychometric testing 12 (60) 52 (65)

AED levels at last visit 17 (85) 63 (79)

Values expressed as n (%).

AED antiepileptic drug.

February (2 of 2) 2001 NEUROLOGY 56 521


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sant drugs used. The number of tonic-clonic seizures

remained a strong risk factor (OR 7.0 [2.0 to 24.2]),

whereas the frequency of all seizures was no longer a risk

factor (OR 1.1 [0.3 to 4.0]). Of interest, a high frequency of

seizures of any type and the occurrence of tonic-clonic sei-

zures were risk factors only in women (see table 4).

A long duration of epilepsy (30 years) and mental

retardation were also risk factors for SUDEP. Mental re-

tardation remained a risk factor after adjustment for sei-

zure frequency (OR 4.6 [1.2 to 18.0]).

The number of anticonvulsant drugs used remained a

risk factor after adjusting for the number of all seizures

(OR 3.8 [1.3 to 11.1]) and the number of tonic-clonic sei-

zures (OR 3.0 [1.0 to 9.2]). No specific antiepileptic drug

appeared to be associated with SUDEP. Carbamazepine

levels exceeding 10 g/mL were present in one SUDEP

patient and two controls. Mean carbamazepine level in

SUDEP patients (8.0 3.8, n 7) and control patients

(7.3 2.8, n 34) did not differ significantly. Phenytoin

levels exceeding 20 g/mL were present in four SUDEP

patients and six controls and were also not associated with

SUDEP. Nor did mean phenytoin level in SUDEP patients

(16.2 5.8, n 8) and control patients (16.5 8.8, n 22)

differ significantly. Compliance with anticonvulsant treat-

ment as assessed by anticonvulsant levels at the last visit

was high in both groups (see table 5) and did not differ

statistically. All SUDEP patients were taking anticonvul-

sant drugs at the last visit. Anticonvulsant drugs had been

discontinued under medical supervision in two control pa-

tients and were being tapered at the time of last visit in

another two control patients.

Neither structural lesions nor use of psychotropic drugs

were risk factors for SUDEP in this cohort. Potentially

epileptogenic lesions in SUDEP patients included low-

grade neoplasm in one, encephalomalacia in two, and me-sial temporal sclerosis in two. Psychotropic drug use in

SUDEP patients included anxiolytic drugs in one, antipsy-

chotic drugs in two, and antidepressant drugs in two.

Beta-blocking drugs were used rarely in both SUDEP and

control patients.

Discussion. Our study identified three apparentlyindependent risk factors for SUDEP: 1) exposure totonic-clonic seizures, 2) mental retardation, and 3)the number of anticonvulsant drugs used. Nillson etal.4 reported that a higher seizure frequency in-creases risk of SUDEP; however, the impact of tonic-

clonic seizures was not distinguished from that ofother seizure types. Our study also found that in-creased seizure frequency is associated with SUDEP.However the risk appeared to be associated withtonic-clonic seizures rather than with seizures of anytype. This finding strongly supports the idea thattonic-clonic seizures are an important proximatecause of SUDEP. This concept is further supportedby three lines of evidence. The great majority of re-ported cases of SUDEP experienced tonic-clonic sei-zures before death.9,11-13,15,16 The majority of SUDEPcases in which circumstances of death are carefullyexamined show evidence of tonic-clonic seizure pre-

ceding death.11-13,15,17 Finally, death has been directlyrelated to generalized convulsive seizures in an ani-mal model of SUDEP.18,19

Our study has clearly demonstrated mental retar-dation to be a risk factor for SUDEP, even afteraccounting for seizure frequency. Previous reportshave provided only weak evidence for the associationbetween SUDEP and mental retardation. Mental re-tardation was thought to be more common in medicalexaminers series of SUDEP.11,13 Two large,population-based studies did not find mental retar-dation to be a risk factor.3,20 One found a trend to-ward increased SUDEP risk.21 Mental retardation

Table 3 Risk factors for sudden unexpected death in epilepsy

Risk factors

Patients,

n

Controls,

n OR (95% CI)

Any seizures, average/mo

0 2 23 1.0 (reference)

1 3 16 2.2 (0.314.4)

1 to 15 10 30 3.8 (0.819.2)

15 to 50 2 5 4.6 (0.540.9)

50 3 3 11.5 (1.399.3)

Unknown 0 3

No. of tonic-clonic seizures

in past year

0 4 54 1.0 (reference)

1 to 3 6 11 2.4 (1.830.5)

3 9 15 8.1 (2.230.0)

Unknown 1 0

Duration of epilepsy, y

0 to 15 5 42 1.0 (reference)

15 to 30 5 29 1.5 (0.46.0)30 8 8 13.9 (3.457.1)

Unknown 2 1

Full-scale IQ

79 5 36 1.0 (reference)

70 to 79 3 10 2.2 (0.410.6)

70 or too impaired to

test

7 10 5.0 (1.319.3)

Unknown 5 24

No. of AED used at last

visit

0 to 2 11 62 1.0 (reference)

2 8 15 4.0 (1.411.7)

Unknown 1 3

Epileptogenic structural

lesions

No 11 43 1.0 (reference)

Yes 5 27 0.7 (0.22.3)

Unknown 4 10

Psychotropic drug use

No 15 65 1.0 (reference)

Yes 4 11 1.6 (0.45.6)

Unknown 1 4

AED antiepileptic drug.



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was determined by observer impressions rather thanby IQ examination in all previous studies.

Increased SUDEP risk in mentally retarded pa-tients can be explained in terms of one theory of thepathophysiology of SUDEP. The animal model ofSUDEP,18,19 clinical observations,11,17,22,23 and video-EEG incidentally recorded during SUDEP24,25 sug-gest that a combination of postictal central apnea,prone position, and neurogenic pulmonary edemacauses death in this entity. There is some evidencethat mentally retarded patients are more likely to ex-perience prolonged postictal encephalopathy,26 whichmay decrease postictal respiratory drive. Furthermore,the neurologic abnormalities often associated with

mental retardation may preclude movement and right-ing reflexes if the patient is prone or supine following ageneralized tonic-clonic seizure. For both of these rea-sons, mentally retarded patients may be more suscep-tible to the postictal central apnea and positionalasphyxia that may cause SUDEP. This idea is sup-ported by observations at a boarding school for epilepsyand learning difficulty. No SUDEP cases occurredwhile patients were on the school premises, where epi-

leptic seizures initiated immediate treatment and ap-

propriate positioning. All SUDEP cases occurred whilepupils were off the school premises, and usually whilethey were alone.22

A previous study3 reported that simultaneoustreatment with more than one anticonvulsant drugwas associated with SUDEP and concluded that thenumber of anticonvulsants used was a surrogate forthe severity of epilepsy. However a more recentstudy4 and this report have found that treatmentwith multiple anticonvulsants is a risk factor evenafter adjustment for seizure frequency. Uncontrolledreports27 have suggested that carbamazepine mayplay a role in SUDEP; however, neither our study

nor the other controlled study of SUDEP4

have impli-cated any particular drug or drug combination.Treatment with multiple anticonvulsants is likely tocause sedation. Pharmacologically induced sedationmay prolong recovery from the postictal state andcause greater susceptibility to the postictal centralapnea and positional asphyxia that may play a rolein SUDEP. Determining whether postictal apnea ismore common or is of longer duration with mentalretardation or following treatment with multiple an-ticonvulsants would provide information to supportthis idea. Studies based at video-EEG monitoringunits have found that postictal central apnea is com-

mon.28,29 However, whether mental retardation ortreatment with multiple anticonvulsants increasesthe prevalence or severity of postictal apnea isunknown.

We did not find male gender to be associated withSUDEP. In fact, SUDEP appeared to be more com-mon in females and the SUDEP risk associated withincreased seizure frequency was significant only infemales. One previous study9 also found SUDEP-related mortality to be elevated only in females. An-other3 found incidence to be increased in males,though the diagnosis of epilepsy in this study wasbased on anticonvulsant use and may not have been

Table 4 Seizure frequency stratified by sex

Seizure frequency

Males Females

SUDEP, n Controls, n OR (95% CI) SUDEP, n Controls, n Females

Any seizures, n/mo

1 2 17 1.0 (reference) 2 19 1.0 (reference)

15 3 11 3.4 (0.522) 5 5 5.7 (0.643.9)

5 3 16 1.0 (0.17.9) 5 9 7.4 (1.343.0)

Unknown 0 0 0 3

No. of tonic-clonic seizures/y

0 2 26 1.0 (reference) 2 28 1.0 (reference)

13 2 6 4.3 (0.537.3) 4 5 11.2 (1.678.4)

3 3 12 3.3 (0.522.1) 6 3 28.0 (3.8205.8)

Unknown 1 0 0 0

SUDEP sudden unexpected death in epilepsy.

Table 5 Anticonvulsant levels at last visit

Anticonvulsant levels SUDEP(n 17) Controls(n 67)

No levels therapeutic 1/17 (6) 10/67 (15)

At least one but not all levels

therapeutic

6/17 (35) 30/67 (45)

All levels therapeutic 10/17 (59) 27/67 (40)

No AED levels were available in three sudden unexpected death

in epilepsy (SUDEP) patients and nine control patients. Four

control patients had medications tapered or discontinued under

physician instruction. These were not included in the table.

Values expressed as n/N (%).

Differences between SUDEP and control groups were not signifi-

cant (2 2.0, df 2).



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accurate. A third study4 found increased seizure fre-quency to be a more powerful risk factor for SUDEPin males, though other risk factors were more power-ful in females. This last study was not designed toassess sex as a risk factor for SUDEP. Our analysiswas based on a firm diagnosis of epilepsy in SUDEPcases and complete information regarding age andsex for the entire cohort. Though the issue is notsettled, the weight of the evidence argues that nei-

ther sex nor any particular age group is a strong riskfactor for SUDEP.

The idea that cerebral structural lesions are a riskfactor for SUDEP is based on medical examinerscase series. These observations were not controlledand probably reflect selection bias. The currentstudy is the only properly controlled assessment ofstructural lesions in SUDEP and did not find anincreased frequency of structural lesions in thisentity.

Speculations that patients with SUDEP are lesscompliant with anticonvulsant treatment began withthe observation that postmortem anticonvulsant lev-

els in medical examiners case series of SUDEP werefrequently subtherapeutic.10-12 Again, these were un-controlled observations and selection bias may haveplayed a substantial role. One controlled study ofpostmortem anticonvulsant levels30 found that sub-therapeutic levels were significantly more commonin SUDEP cases than in epilepsy patients dying ofother causes, but another study14 found no differ-ence. Multiple factors such as redistribution andcontinuing metabolism can affect postmortem anti-convulsant levels and it is not clear whether levelsobtained at various times after death accurately re-flect levels shortly before death.31 Until this study,

no reports of antemortem anticonvulsant levels inSUDEP were available. The great majority of bothSUDEP cases and controls in this study had thera-peutic anticonvulsant levels at the last visit. Thus,noncompliance appears not to be a risk factor, atleast in this cohort of closely followed patients. Ana-lyzing all available anticonvulsant blood levels andtheir variation over serial visits would further sup-port this conclusion. Compliance with treatmentclearly influences the frequency of tonic-clonic sei-zures, which we found to be a strong risk factor forSUDEP. Therefore, compliance may prevent SUDEPin an epilepsy population that is less closely followed

and should be encouraged. However, the evaluationof noncompliance as a risk factor for SUDEP musttake into account the finding that the frequency oftonic-clonic seizures is also a risk factor.

This study has several limitations. Only half ofthe cases underwent complete autopsy. However, weused a consistent definition of SUDEP, multiple re-

viewers independently analyzed information for eachdeath, and interobserver agreement was high. Sec-ondly, the number of SUDEP cases was relativelylow. Although our results are statistically valid, in-ternally consistent, and consistent with other re-ports, the small number of cases did not provide

adequate power to detect less powerful risk factorsfor SUDEP. This may explain, for example, why wedid not find psychotropic drug use to be a risk factorfor SUDEP. Finally, we studied patients presentingto epilepsy centers. Such patients may have moresevere epilepsy than that encountered in a generalclinical practice.

Information regarding risk factors for SUDEP re-mains limited and further controlled studies are

needed. However, the results reported by Nillson etal.4 and this report are consistent and help to definea population at increased risk for SUDEP. We be-lieve that it is reasonable to discuss the possibility ofSUDEP with patients at high risk. This potentiallydistressing topic should be discussed in a sensitivemanner taking into account the individual situation.It is important to emphasize that the great majorityof patients tolerate the great majority of seizureswithout much difficulty. The discussion of SUDEPcan be used to emphasize the serious nature of se-

vere epilepsy and the need for regular follow-up andcompliance so that seizures can be brought under the

best possible control.Unfortunately, the current state of information

does not allow firm recommendations for preventingSUDEP. Certainly, every effort should be made toprevent tonic-clonic seizures with the fewest anticon-

vulsants possible. The possibility of SUDEP can beconsidered when epilepsy surgery is being contem-plated. Epilepsy surgery appears to decrease mortal-ity,8 though it is not yet clear that surgery decreasesthe rate of SUDEP. Ideally, caregivers should be ableto deliver appropriate first aid after epileptic sei-zures, position the patient properly, and assure thatthe airway remains open. Vigorous stimulation after

a tonic-clonic seizure may be reasonable becausesome believe that this decreases the duration of pos-tictal apnea. It is also reasonable to encourage epi-lepsy patients to sleep in the supine rather than theprone position. It is not clear that these practiceswill prevent SUDEP, but they may be reasonablemeasures to suggest when discussing this issue withpatients.

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