Long-Term Mortality Risk of People with Epilepsy Who Underwent Seizure Monitoring.

AIM: The aim is to study survival outcome and sudden unexpected death in epilepsy (SUDEP) of people with epilepsy who underwent epilepsy monitoring. SUBJECTS AND METHODS: Between 2000 and 2004, 558 persons were admitted to the epilepsy monitoring unit of SCTIMST who fulfilled the selection criteria. Their survival status as on December 31, 2013, was ascertained by clinic attendance record and by mail or telephone contact.
RESULTS: Five hundred and fifty-eight persons with epilepsy (males 319, 6408 person-years) were included in this study. There had been 20 deaths till December 31, 2013, and 5 additional deaths were reported when followed up till May 2016. The standardized mortality ratio was 5.35 and higher for males (6.25) than for females (3.52). Those with generalized seizures (tonic and myoclonic seizures), electroencephalography (EEG) showing multifocal and generalized interictal discharges, and polypharmacy had a higher risk of mortality. SUDEP accounted for 5 deaths.
CONCLUSION: People with refractory epilepsy who had undergone presurgical video EEG monitoring had higher mortality risk. Generalized or myoclonic seizures, multifocal or generalized interictal discharges, and polypharmacy independently increased their risk of mortality. SUDEP is an important cause of death. Copyright:

INTRODUCTION

Epilepsy carries an excess mortality[123] although majority of the affected have good prognosis. There is increasing concern regarding the premature mortality and sudden unexpected death (SUDEP) accounting for a substantial proportion of mortality in persons with epilepsy.[3456] Several clinical and demographic factors have been associated with mortality such as remote symptomatic seizures, congenital and acquired neurological deficits, male sex, younger age, longer duration of epilepsy, noncompliance to antiepileptic drug (AED) treatment, and status epilepticus.[789101112] SUDEP is another cause of death that has drawn more attention in the recent past.[1314] There are meager data on the mortality risk of epilepsy, particularly of SUDEP in developing countries. It is important to have reliable mortality statistics of epilepsy before effective interventions can be designed to reduce mortality in epilepsy in these countries. Our objectives were to study survival/mortality outcome of the persons evaluated in an epilepsy monitoring unit and to assess the magnitude and risk factors for SUDEP.

SUBJECTS AND METHODS

This study was carried out in the comprehensive epilepsy care service of a tertiary care center in South India. All persons admitted to this epilepsy monitoring unit (n = 1148) between January 1, 2000, and December 31, 2004, who fulfilled the International League Against Epilepsy (ILAE) definition of epilepsy[15] were considered for this study. We excluded those who had nonepileptic conditions (35), had domicile outside Kerala state (333), or had moved from known address (58). Participants were classified as survivors as on December 31, 2013, if they had attended the clinic later than that date. We contacted all others by telephone or two mails to the last known addresses to verify their survival status. As of December 31, 2013, there were 538 survivors (had attended the clinic attendance later than December 31, 2013 [279], or had responded to our postal or telephonic inquiry [259]) and 20 deaths (total 558). Those who failed to respond to two mails or telephone contacts (n = 164) were treated as lost to follow up and were excluded from the study. An age- and sex-matched control group of 56 survivors was selected by random allocation from among the survivors to compare the clinical and therapeutic variables with the mortality group.

After obtaining informed consent from the relatives, we gathered the details regarding death, including cause of death, situations leading to death, risk factors and medications, compliance with treatment, and comorbidities. Medical records of hospitalization and/or postmortem examination if any were scrutinized whenever available. Verbal autopsy[16] was done to ascertain cause of death when the relatives were willing for the same. We followed the Nashef criteria for SUDEP.[17]

The crude death rate and age-specific death rate of the cohort were compared with that of the population of Kerala state obtained from the sample registration system.[18] The data were analyzed using statistical software (SPSS Inc., Chicago, IL, USA). Fisher's extract test and Chi-square test were used to test statistical significance.

RESULTS

This study included 558 persons (319 males) and total follow-up period of 6408 patient-years. Their age ranged from 2 to 61 years (mean 27.5 ± 11.89). There were 25 deaths (20 deaths till December 31, 2013, and additional 5 deaths until May 2016) as per the communications from the families. The crude death rate was 3.2/1000 patient-years. Their age-specific death rates are compared with that of the Kerala population in Tables 1–3. The standardized mortality rate (SMR) for the cohort (based on 20 deaths till December 2013) was 5.35. The SMR was higher for male persons (6.2) than female persons (3.52). The survival curve for the study sample is given in Figure 1.

Table 1

Age-specific death rate and standardized mortality rate for the epilepsy group compared with that of Kerala state

Age group	Number of deaths	Population	Death rate/1000	Kerala ASDR	Expected death	Observed deaths/expected deaths=SMR
0-4	0	3	0	3.2	0.01	0
5-9	2	27	76.9	0.2	0.00	468.2
10-14	0	53	19.2	0.2	0.01	0.0
15-19	2	68	20.2	0.3	0.02	84.5
20-24	5	76	66.7	1.0	0.07	68.8
25-29	0	94	0	1.5	0.14	0
30-34	2	81	25.6	1.1	0.09	22.5
35-39	2	70	58.0	2.0	0.14	13.99
40-44	4	38	135	1.9	0.07	54.75
45-49	1	29	35.7	3.4	0.10	10.14
50-54	1	11	200	5.3	0.06	17.15
55-59	1	7	200	9.2	0.06	15.57
60-64	0	1	1000	15.3	0.02	0.00
65-69	0	0	0	24.8	0.00	0.00
70+	0	0	0	76.6	0.00	0.00
All ages	20	558	35.8	6.7	3.74	5.35

SMR=Standardized mortality rate, ASDR=Age-specific death rate

Table 3

Age-specific death rate and standardized mortality rate for the epilepsy group (female) compared with that of Kerala state (females)

Age group	Number of death	Population	Death rate/1000	Kerala ASDR	Expected death	Observed deaths/expected deaths=SMR
0-4	0	3	0	3.4	0.01
5-9	1	15	117.6	0.1	0.00	622.99
10-14	0	25	0	0.3	0.01	0.00
15-19	0	30	33.3	0.3	0.01	0.00
20-24	1	37	0	0.7	0.03	36.78
25-29	0	40	25	0.8	0.03	0.00
30-34	0	27	0	0.7	0.02	0.00
35-39	0	27	74	1.1	0.03	0.00
40-44	2	15	0	0.9	0.01	140.73
45-49	0	14	142.8	2.5	0.03	0.00
50-54	1	3	0	2.6	0.01	129.44
55-59	0	3	0	5.8	0.02	0.00
60-64	0	0	0	10.2	0.00	0.00
65-69	0	0	0	17.9	0.00	0.00
70+	0	0	0	72.3	0.00	0.00
All ages	5	239	20.92	5.9	1.42	3.52

SMR=Standardized mortality rate, ASDR=Age-specific death rate

Figure 1

Kaplan–Meier curve for mortality in epilepsy (a) according to gender 1 = male, 2 = female and (b) according to seizure frequency 1 = no seizures; 2: ≤6 seizures/year; 3: >6 seizures/year

Predictors of mortality

Out of the 25 deaths, 12 persons had temporal lobe epilepsy, 8 had extratemporal epilepsy, 4 with Lennox–Gastaut syndrome, and 1 had progressive myoclonic epilepsy. AED usage for the mortality (and survivor control groups) was as follows: monotherapy 3 (24), polytherapy 22 (32), carbamazepine 14 (34), clobazam 12 (18), phenytoin 7 (13), clonazepam 6 (1), valproate 3 (8), topiramate 3 (5), phenobarbitone 3 (7), levetiracetam 2 (3), lamotrigine 1 (0), and primidone 1 (0).

Mortality group had significantly (P = 0.001) shorter duration (20.8 ± 12.8 years) of epilepsy than survivors (30.9 ± 10.6 years) although both groups had a similar age of onset of epilepsy. The mortality group differed significantly from the survivor group with regard to more frequent myoclonus (16% vs. 3.5%) or tonic seizures (8% vs. nil) and multifocal (16% vs. 3.5%) or generalized (20% vs. 5.3%) epileptiform discharges in the electroencephalography (EEG) and higher proportion of seizure frequency more than 2/month (76% vs. 46%). They were more often on polytherapy (22/25) than survivors (32/57), P = 0.027. The AED usage was comparable between the two groups except for clonazepam which was significantly higher (P = 0.001) among the mortality group. The magnetic resonance imaging findings for the mortality group were comparable to survivor group except for more frequent mesial temporal sclerosis (MTS) with the survivor group (16% vs. 39%, P = 0.038). The two groups had a similar distribution of intelligence quotient (IQ), comorbidities, and surgery for epilepsy.

Cause of death

We received consent from the relatives of 15 of the 25 deceased participants (13 of the 20 who died before December 2013 and 2 of the 5 who died afterward) to participate in the verbal autopsy. Clinical autopsy reports were available for two participants and 4 deaths had occurred in hospital. The causes of death for the 15 participants were as follows: head injury following accidental fall 2, status epilepticus 1, brain tumor 1, pneumonia 3, suicide 2, accidental drowning 1, and SUDEP 5.

There were no clinical autopsy data available for SUDEP persons in our study. Four of the deaths were classified as probable SUDEP and one as possible SUDEP based on verbal autopsy. Circumstances of death in these patients is given in Table 4. The SUDEP incidence rate was 0.7/1000 patient-years. The SUDEP subgroup of the mortality differed from others in the mortality group by low IQ and generalized seizures. There was a significant (<0.05) association between epileptiform abnormalities (multifocal and generalized abnormalities) in EEG and mortality.

Table 4

Circumstances in which sudden unexpected death was observed

Sex	Age at death	Circumstances of death	Etiology	Evidence of seizures
Female	9	Clustering of seizures in morning. Death at 8.30AM	Frontal lobe epilepsy	No
Female	20	Found dead in prone position while reading Koran	Temporal lobe epilepsy	No
Male	37	Found dead in prone position	Temporal lobe epilepsy	No
Male	17	1 episode of seizure in the morning. Death at 11 AM	LGS	No
Male	63	Found dead in sleep	Frontal lobe epilepsy	No

LGS=Lennox-Gastaut syndrome

DISCUSSION

There are only a few estimates of mortality for epilepsy from India,[1920] largely because of paucity of prospective long-term studies and lack of autopsy confirmation of cause of death. We designed this modified retrospective cohort from participants who were hospitalized for seizure monitoring and followed up their survival status after a decade. We had 21% loss to follow up, but the clinical characteristics of those who were lost to follow up were not significantly different from those who were followed up. We customized the WHO schedule for verbal autopsy by including additional questions specific to epilepsy and use of AEDs.[16] A recent analysis of the million death study in India had shown that verbal autopsy is a reliable method to establish cause-specific mortality fraction for deaths under 70 years of age.[21]

Mortality rates

Our data indicated that there was five-fold increase in the mortality for epilepsy which was comparable to other publications.[722] The SMR for epilepsy for people attending to medical services and hospitals ranges from 1.4 to 5.3.[1238923] Recently, attention had been focused on the proportion of preventable deaths and premature deaths in epilepsy. In this series, one-third of deaths were potentially preventable, and there were no deaths among the seizure-free subgroup. Adequate treatment and better control of seizures could possibly reduce the mortality in epilepsy.

We found that myoclonic and tonic seizures in epilepsy persons were associated with early mortality. Multifocal and generalized discharges in the EEG and tonic seizures point toward epileptic encephalopathy that carries higher mortality. The association of mortality with treatment with clonazepam should be viewed in this light as out of the 6 persons on clonazepam, 4 had myoclonic jerks compared to one patient among survivors. Multiple studies have found a role of AEDs, especially carbamazepine in mortality, and this may be secondary to their cardioinhibitory role of these drugs; however, this has not been proved.[24252627]

This is the first study that had implemented verbal autopsy to ascertain the cause of death in epilepsy. Out of the 15 cases where cause of death could be ascertained, 10 (66%) were due to seizure-related accident, suicide, or other potentially preventable causes of death. More efficient treatment aiming seizure freedom, prevention of accidents, and early management of depression could probably reduce deaths.

Sudden unexpected death

Probable SUDEP accounted for a third of total epilepsy-related deaths. This is comparable to rates published from elsewhere.[32829] Probably 900–2940 SUDEPs occur per year in India. This study had shown that SUDEP can be detected by verbal autopsy and constitutes an important yet unrecognized cause of death for people with epilepsy.

CONCLUSION

Our data indicate that people with epilepsy have higher risk of mortality and those with severe epilepsy or epileptic encephalopathy are at higher risk of mortality. Verbal autopsy can identify the cause of death in epilepsy, and SUDEP constitutes a third of mortality from epilepsy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 2

Age-specific death rate and standardized mortality rate for the epilepsy group (male) compared with that of Kerala state (males)

Age	Number of deaths	Population	Death rate/1000	Kerala ASDR	Expected death	Observed deaths/expected deaths=SMR
0-4	0	0	0	3.0	0.00	0.00
5-9	1	12	83.3	0.2	0.00	401.50
10-14	0	28	107.1	0.2	0.00	0.00
15-19	2	38	119.9	0.4	0.02	119.78
20-24	3	39	26.3	1.2	0.05	64.85
25-29	0	54	37	2.3	0.12	0.00
30-34	2	54	75.5	1.5	0.08	24.14
35-39	2	43	23.3	3.1	0.13	14.99
40-44	2	23	87.0	3.0	0.07	28.76
45-49	1	15	0	4.4	0.07	15.31
50-54	0	8	375	8.3	0.07	0.00
55-59	1	4	0	12.7	0.05	19.76
60-64	1	1	0	20.8	0.02	48.10
65-69	0	0	0	32.8	0.00	0.00
70+	0	0	0	82.2	0.00	0.00
All ages	15	319	47.0	7.5	2.40	6.25

SMR=Standardized mortality rate, ASDR=Age-specific death rate