Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 10
Mortality
Samden D. Lhatoo
Josemir W. Sander
Törbjorn Tomson
Introduction
The majority of patients with epilepsy have a good prognosis that allows them long periods of seizure freedom.9,10,43 Despite this, it is known that the mortality rate in epilepsy is raised to two to three times that of the general population8,19,28,29,32,39,53 and life expectancy in some of these patients is reduced.17 Studies in the last two decades have thrown considerable light on the various factors that influence mortality and also on the various causes of mortality in epilepsy in the developed world.8,19,28,29,32,39,53 However, there are no large-scale studies of mortality in epilepsy from resource-poor countries.7
There are many problems inherent to the study of mortality in epilepsy, including the problems of case ascertainment. Death certificates have been found to be an unreliable source of case ascertainment,3 and prospective studies of cohorts of people with epilepsy are more likely to provide accurate data on mortality.
Several aspects of epilepsy may affect mortality:
  • Seizures themselves can be a cause of death, either directly as in prolonged status epilepticus or indirectly because of increased risk of accidental death, especially drowning.
  • Some of the risk factors for epilepsy (e.g., brain tumors, cerebrovascular disease, traumatic brain injury) are associated with increased mortality whether or not epilepsy is present.
  • There is an increased risk for sudden unexpected death in epilepsy (SUDEP).
  • The long-term use of antiepileptic drugs (AEDs) has been thought to increase the incidence of malignant neoplasia and osteoporosis, thereby potentially affecting long-term mortality rates in persons with epilepsy, especially in younger adults (ages 15 to 49 years). Although rare, other adverse effects of idiosyncratic type can also occasionally be fatal.
The objectives of this chapter are to review the evidence for, and patterns of, mortality in persons with epilepsy and to evaluate the current understanding of these factors.
Overall Mortality
The most often used and preferred statistical measure of epilepsy mortality is the standardized mortality ratio (SMR). This is the ratio of the number of observed deaths in a study population to the expected number of deaths in the age- and sex-matched general population in that time period. Older studies utilize the proportional mortality ratio (PMR), which expresses mortality as a ratio of the number of observed deaths due to a particular cause in a study population to the total number of deaths in that study population. This method is subject to more bias, depending on the kind of cohort studied, where deaths due to any one cause may be overrepresented, and is not a measure of the mortality rate in epilepsy versus the general population. SMRs among people with epilepsy have been evaluated in several population-based studies (Table 1) and vary from 1.6 to 8.8. Although these studies span several decades and countries, follow incidence or prevalence cases, and vary in terms of the age composition and characteristics of the patients studied, most are consistent in reporting a twofold to threefold increased mortality rate for people with epilepsy. Similarities between the population-based epidemiologic studies and the more selective hospital-based studies are not truly consistent with each other but probably the result of compensating biases. It should also be noted that the overall relative increased premature mortality of twofold to threefold should not be applied to all people with epilepsy; this is a summary measure that masks very important differences among those with epilepsy. The most important of these are the etiology of epilepsy, age, duration, and type of epilepsy.
Etiology of Epilepsy
The increased mortality rates of epilepsy reflect both the effects of epilepsy and also the effects of central nervous system (CNS) insults, such as brain tumors, cerebrovascular disease, and head trauma, which are the presumed cause of approximately one third of all epilepsy cases.33 In epidemiologic studies, seizure disorders have often been classified into four broad groups according to presumed etiology:
  • Idiopathic (or cryptogenic) epilepsy.
  • Remote symptomatic epilepsy, related to CNS lesions acquired postnatally from trauma, brain tumors, cerebrovascular disease, infection, or chronic degeneration.
  • Acute symptomatic seizures, related to CNS insults where seizures manifest within a week of the acute insult (e.g., head injury, cerebral hemorrhage, or infarction).
  • Major neurologic dysfunction of uncertain cause but presumed to have been present at birth and manifested by gross neurologic deficit (spasticity, hemiparesis), or mental retardation (IQ <70).
Table 1 Overall Mortality in Epilepsy—Standardized Mortality Ratios (SMR)
Author Country Study design Age Follow-up years SMR (95% CI)
Population-based studies
Zielinski 197453 Poland Prevalence All   1.8 (1.6–2.1)
Hauser 198019 United States Retrospective All 33 2.3 (1.9–2.6)
Cockerell 19948 United Kingdom Prospective All 9 2.5 (2.1–2.9)
Olafsson 199839 Iceland Retrospective All 30 1.6 (1.2–2.2)
Lindsten 200029 Sweden Prospective Adult 11 2.5 (1.2–3.2)
Lhatoo 200128 United Kingdom Prospective All 14 2.1 (1.8–2.4)
Camfield 20026 Canada Retrospective Children 20 5.3 (2.29–8.32) First 10 years
8.8 (4.10–13.4) Second 10 years
Berg 20044 United States Prospective Children 8 7.54 (4.38–12.99)
Hospital-based studies
Klenerman 199322 United Kingdom Retrospective Adults   1.9 (1.6–2.3)
Nilsson 199738 Sweden Retrospective Adults >16 3.6 (3.5–3.7)
Shackleton 199944 Netherlands Retrospective All 30 3.2 (2.9–3.5)
Callenbach 20015 Netherlands Clinical series Children 5 6.6 (2.2–15.5) Males
          7.4 (2.0–19.0) Females
CI, confidence interval; SMR, standardized mortality ratio.
SMR = Observed deaths/expected deaths.
Table 2 Standardized Mortality Ratios (with 95% Confidence Intervals) According to Etiology
Country Idiopathic Remote symptomatic Acute symptomatic Neurodeficit
United States 198019 1.8 (1.4–2.3) 2.2 (1.8–2.7)   11.0 (6.9–16.4)
United Kingdom 19948 1.6 (1.0–2.4) 4.3 (3.3–5.5)   50.0 (10–146)
France 199932 1.5 (0.4–3.9) 6.5 (3.8–10.5)    
Sweden 200029 1.1 (0.5–2.4) 3.3 (2.4–4.5)    
United Kingdom 200128 1.3 (0.9–1.9) 3.7 (2.9–4.6) 3.0 (2.0–4.3) 25 (5.1–73.1)
United States 20044 1.43 (0.36–5.73) 33.46 (18.53–60.43)    
NB—idiopathic, idiopathic or cryptogenic or nonsymptomatic.
The level of increased premature mortality appears greatest in patients with epilepsy in association with a neurologic deficit present from birth. Such patients had a considerably high SMR of 7.0 (95% confidence interval [CI], 4.6 to 10.2) in the Rochester, Minnesota, study19 and of 25 (95% CI, 5.1 to 73.1) in the UK General Practice Study (although this latter SMR was based on only a few deaths).28 The extremely high SMR in the neurologic deficit group reflects the large number of observed deaths at relatively young ages, when few deaths are expected. Mortality is also high in individuals with symptomatic epilepsy compared to those in other groups. In the Rochester study,19 persons with epilepsy as a result of postnatal CNS insults had an SMR of 2.76 (95% CI, 2.3 to 3.4). In the UK study, the SMR for postnatally acquired epilepsy was 3.7 (95% CI, 2.9 to 4.6).28 The higher relative mortality in the British study may
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be a consequence of the comparatively shorter mean follow-up period, as SMRs decline with duration.
Studies that present SMRs for all patients and separate SMRs for persons with idiopathic (or cryptogenic) epilepsy (epilepsy without a presumed cause) show considerably lower SMRs for patients with idiopathic epilepsy than for all patients with epilepsy. The mortality rates among those with idiopathic epilepsy from Rochester,19 Sweden,29 and the UK General Practice Study28 are still raised above those of the general population, but only by 50% to 60% and not significantly so in the latter two studies (Table 2). The UK General Practice Study also studied patients with acute symptomatic seizures as a separate category as defined above and found an SMR of 3.0 (95% CI, 2.0 to 4.3) in this group.28
Age
The population-based studies that present age-specific SMRs are shown in Table 3. Mortality rates are increased at all ages among persons with epilepsy, but the increase is not uniform across age groups. There is a sharp decline in SMRs with age in these study populations. The higher SMRs in persons under 50 years of age are caused in part by the extremely high relative death rates for patients with epilepsy in association with neurologic deficits and the low expected mortality in these age groups. However, in the UK General Practice Study, the 50- to 59-year age group had higher mortality rates than all other age groups, and this may be explained by the high incidence of brain tumors in this population.28 Head trauma in younger patients may be another contributory factor. Another factor is the increased risk for sudden death in younger adults with epilepsy; it is uncertain whether this increased risk persists among elderly patients with epilepsy. Although the SMRs decrease with age, the death rates among the elderly (>65 years of age) with epilepsy are still 50% to 60% above the rates in the general population and remain significantly elevated even in patients over the age of 80 years.19
Table 3 Standardized Mortality Ratios (SMRs) According to Age
Age (y) SMRs (95% CI)
Poland United States19 United Kingdom28 Sweden29
0–24   8.5 (5.4–12.9)    
0–29 3.5      
0–49     7.6 (4.2–12.5)  
15–39       9.5 (3.1–29.4)
25–44   7.7 (5.1–11.0)    
30–49 3.4      
45–54   3.5 (2.0–5.7)    
40–59       10.7 (6.5–17.6)
50–59 2.5   8.6 (4.7–14.1)  
55–64   3.0 (2.0–4.5)    
60–69 1.8      
60–79       2.4 (1.6–3.8)
65–74   1.5 (1.0–2.2)    
70–79     1.9 (1.2–2.8)  
≥70 1.5      
≥75   1.4 (1.1–1.9)    
≥80     2.6 (1.8–3.6) 1.3 (0.7–2.4)
CI, confidence interval.
Table 4 Standardized Mortality Ratios (SMRs) for Each Year of Follow-up after Index Seizure in Patients with Newly Diagnosed Epilepsy and Patients with Newly Diagnosed Idiopathic Epilepsy in the UK National General Practice Study of Epilepsy
Years after index seizure No. of deaths No. at risk SMR 95% CI
Observed Expected
Definite epilepsy (n = 564)
0–1 564 49 7.4 6.6 4.8, 8.7
1–2 515 16 6.1 2.6 1.5, 4.2
2–3 499 13 5.7 2.3 1.2, 3.9
3–4 486 16 5.1 3.1 1.8, 5.1
4–9 470 33 21.6 1.5 1.0, 2.1
9–14 437 22 12.3 1.8 1.1, 2.7
Idiopathic epilepsy (n = 346)
0–1 346 6 2.8 2.2 0.8, 4.7
1–2 340 3 2.5 1.2 0.2, 3.5
2–3 337 5 2.3 2.2 0.7, 5.2
3–4 332 5 1.9 2.7 0.8, 6.3
4–9 327 11 9.4 1.2 0.6, 2.1
9–14 316 4 7.0 0.6 0.1, 1.5
CI, confidence interval; NB—idiopathic, idiopathic or cryptogenic.
From Lhatoo SD, Johnson AL, Goodridge DM, et al. Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort. Ann Neurol. 2001;49(3):336–344.
Table 5 Causes and Categories of Death in Epilepsy
Epilepsy-related deaths
Directly related
   SUDEP
   Status epilepticus
Indirectly related
   Accidents as a consequence of seizures
   Aspiration pneumonia after seizures
   Iatrogenic; drug toxicity and idiosyncratic reactions
   Suicides
Underlying disease related deaths
Primary and secondary CNS neoplasia
Cerebrovascular disease
CNS infections
Inherited neurodegenerative disorders
Unrelated deaths
Non-CNS neoplasia
Ischemic heart disease
Pneumonia
Accidents unrelated to seizures
CNS, central nervous system; SUDEP, sudden unexpected death in epilepsy.
Duration of Epilepsy
Due to a high proportion of so-called “agonal” seizures in patients with newly diagnosed epilepsy who have serious underlying brain pathologies such as brain tumors and cerebrovascular disease, mortality is highest in the first few years
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following diagnosis. This is well illustrated by the UK General Practice Study where the highest SMR of 6.6 (95% CI, 4.8 to 8.7) was reported in the first year compared to an SMR of 1.5 (95% CI, 1.0 to 2.1) at 4 to 9 years (Table 4).28 The Swedish study reported a similar trend with an SMR of 7.3 (95% CI, 4.4 to 12.1) in the first year and no elevation of SMR at 6 years after diagnosis.29 In the Rochester study,19 persons with idiopathic epilepsy had significantly increased mortality rates (SMR 1.9) during the first 10 years after the diagnosis of epilepsy but only slightly increased rates thereafter. Persons with epilepsy caused by a postnatal neurologic insult had a threefold increased death rate during the first decade after diagnosis and a twofold increased rate after 10 years. Those with epilepsy in association with a neurologic deficit
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had high mortality rates throughout follow-up. A late increase in mortality, thought to be directly caused by epilepsy, occurred in the third decade.19 It is an interesting observation, since the influence of underlying pathologies on mortality could be expected to be much less than at diagnosis, and mortality due to status epilepticus and SUDEP in those with refractory seizures may conceivably become more prominent. This remains speculative at the current time. A small but similar late rise in mortality occurred after 9 years in the UK study, but with only three direct epilepsy-related deaths in this cohort during this time, this rise is not easily explained.28 The Swedish study also reported a late increase in mortality after 9 to 11 years.29
Table 6 Cause-specific Mortality in Epilepsy (SMRs with 95% Confidence Intervals)
Cause Study
United States19 United Kingdom28 Sweden29
Cerebrovascular 2.6 (1.8–3.6) 3.7 (2.3–5.5) 5.3 (4.9–5.8)
Heart disease 1.1 (0.8–1.5)a    
Ischemic heart disease   1.1 (0.6–1.7) 2.5 (2.3–2.7)
Myocardial insufficiency      
Other circulatory 7.1 (3.4-13)    
Neoplasms 2.9 (2.1–3.9) 3.5 (2.6–4.6) 2.6 (2.4–2.8)
Neoplasms excluding brain tumors 1.8 (1.1–2.6) 2.4 (1.7–3.4) 2.0 (1.9–2.2)
Pneumonia 3.5 (1.6–6.6) 7.3 (4.8–10.6) 4.2 (3.6–4.8)
Accidents 2.4 (1.3–3.7)   4.7
SMR, standardized mortality ratio; CI, confidence interval.
aSignificant increases in ages 25–44 years (SMR 5.7 [95% CI 1.8–13.3]) and 45–64 years (SMR 2.5 [95% CI 1.4–4.1]).
Cause-specific Mortality in Patients with Epilepsy
Causes of death (Table 5) vary in both epilepsy-related and -unrelated mortality according to the populations studied. The commonest causes of death in community-based analyses are usually pneumonia, cerebrovascular disease, and CNS-related, as well as non–CNS-related, neoplasia, whereas the hospital-based analyses have larger representations of sudden unexpected deaths and epilepsy-related mortality. Table 6 shows the SMRs of cause-specific mortality in these studies.
Sudden Unexpected Death in Epilepsy
SUDEP is defined as a sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death in patients with epilepsy, with or without evidence of a seizure having occurred, excluding documented status epilepticus, in which postmortem analysis does not reveal an anatomic or toxicologic cause of death.33 Studies in the United Kingdom suggest that there are approximately 500 deaths per year attributable to SUDEP.18 Several studies have attempted to examine the incidence of SUDEP and these are represented in Table 7. Their results reflect the varying case ascertainment methods and study populations used.
Population-based studies, with less selection bias, provide lower figures for SUDEP incidence (0.09 to 2.7 per 1,000) than do selected cohorts that constitute large numbers of patients with refractory epilepsy (0.2 to 9.3 per 1,000). In one comprehensive and often quoted population-based study, the estimated incidence of SUDEP was 0.35 per 1,000 person-years, occurring in 8.6% of recorded deaths in people aged 15 to 44 years.16 The SMR for sudden death in the 20- to 40-year age group was 23.7, suggesting a large increased risk for sudden death in patients with epilepsy compared to that of sudden death in the general population. Although fairly uncommon in population-based incidence cohorts, SUDEP may be the leading cause of death in patients with refractory epilepsy.51
The mechanisms that underlie SUDEP are unknown, but there is mounting evidence that it is a seizure-related
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phenomenon. Risk factors for SUDEP have been analyzed in case-control studies.51 These and the hypothetic mechanisms behind SUDEP are discussed in more detail in a separate chapter (Chapter 189).
Table 7 Rates of SUDEP (per 1,000 Person-years) in Community-based Studies of Epilepsy and in Studies of Selected Epilepsy Cohorts
Reference SUDEP
Population Case Ascertainment Incidence
Community-based studies
Terrence et al., 197549 Communitya Retrospective review of autopsy records 0.9
Leestma et al., 198426 Communitya Retrospective review, medical examiner 0.5–0.9
Leestma et al., 198927 Communitya Prospective, medical examiner 0.9–2.7
Jick et al., 199220 “Primary epilepsy,” age 15–49 years, based on AED prescriptions Retrospective review of death certificates and autopsy reports 1.3
Tennis et al., 199548 “Primary epilepsy,” age 15–49 years, based on AED prescriptions Retrospective review of death certificates and autopsy reports 0.5–1.4
Ficker et al., 199816 Community Retrospective review of all deaths in Rochester 0.35
Langan et al., 199824 Community Retrospective review of autopsy reports 1.5
Lhatoo et al., 200128 Community Prospective, general practice based 0.09
Camfield et al., 20026 Community Retrospective 0.11
Selected epilepsy cohorts
Dasheiff, 199112 Referrals for epilepsy surgery Prospective 9.3
Lip and Brodie, 199230 Epilepsy clinic Retrospective 4.9
Timmings, 199350 Epilepsy clinic Retrospective review of medical records and death certificates 2.0
Nashef et al., 199534 Epilepsy and learning disabilities Retrospective 3.4
Nashef et al., 199535 Tertiary referral center Retrospective 5.9
Derby et al., 199614 >2 AEDs per patient (refractory epilepsy, age <50 years) Retrospective 2.2
Leestma et al., 199725 Lamotrigine trials (refractory) Retrospective 3.5
Nilsson et al., 199938 Case series based on hospital admissions Retrospective 1.5
Annegers et al., 19981 Vagus nerve stimulation (refractory patients) Retrospective 4.5
Donner et al., 200115 Coroners, children Retrospective 0.2
Racoosin et al., 200141 Drug development programs In epilepsy centers Retrospective 3.8
Nilsson et al., 200337 Epilepsy surgery register Retrospective 2.4
AED, antiepileptic drug; SUDEP, sudden unexpected death in epilepsy.
aEstimates based on assumed epilepsy prevalence data.
Status Epilepticus
The incidence of status epilepticus (SE) in population-based studies varies from 9.9 in Switzerland11 to 57 per 100,000 in a nonwhite population in Richmond, Virginia.13 Case fatality rates similarly vary from 7.6% in the same Swiss study to 31% in a study from Bologna in Italy.52 The etiology of SE is the most important determinant of mortality, and most deaths in the first 30 days are due to acute symptomatic causes such as anoxic brain damage, CNS infections, brain trauma, and cerebrovascular events. In one large study, no deaths were found in those cases with SE due to idiopathic causes, whereas almost 90% belonged to the acute symptomatic group.31
Accident-related Deaths
The risk of death due to injury in patients with epilepsy is estimated at 2.68 per 100,000 persons per year.21 Other studies quote up to 16% of deaths in epilepsy patients arising as a consequence of accidents, and SMRs for accidents are thus significantly increased at 2.4 to 10.4.19,38,44 These most often occur in water or as a result of burns or trauma. In one Canadian study, 5% of all drownings were attributable to seizures, 60% of which occurred in bathtubs.42 Fatalities in motor vehicle accidents due to seizures were found to be uncommon in an American study where only 0.2% of over 44,000 deaths were attributable to seizures.45 In the UK General Practice Study,
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there were three accidental deaths (a bathtub drowning, a fall resulting in a cervical fracture, and severe burns) in over 11,400 person-years of follow-up, suggesting that accidental deaths in community-based populations may be rare.28
Suicides
The risk of suicide is said to be higher in patients with epilepsy, and most studies that have attempted to address this issue have been of selected cohorts, reporting up to a fivefold elevation in suicide rates compared to that of the general population. However, community-based studies such as the Rochester study and the UK General Practice Study have found no increased risk. The attendant psychiatric comorbidity in many patients with refractory epilepsy may be an important factor that explains this disparity. Depression may occur in up to 62% of patients with epilepsy. A recent case-control study from Sweden identified 49 epilepsy patients who had committed suicide (26 definite and 23 possible) and found that there was a ninefold increase in suicide risk with concurrent mental illness and a 10-fold increase with the use of antipsychotic drugs. A softer association of increased risk was found with high seizure frequency and antiepileptic drug polytherapy.36
Neoplasia
Increased mortality due to primary and secondary brain tumors in patients with epilepsy is to be expected and so is consistently reported by many studies. High SMRs due to non-CNS neoplasia, particularly lung cancer, in patients with epilepsy have been noted in several studies, although the design and interpretation of many of these studies are easy to criticize. A carcinogenic effect of antiepileptic drugs has been postulated, although this has not really been substantiated and indeed, most neoplasia related deaths occur soon after diagnosis, rendering this association unlikely.8,28,46 Some studies show a trend toward an increased incidence of lymphatic malignancies,22,40,46 although this is not significant and has not been confirmed in larger studies. In animal studies, phenobarbital has been shown to be associated with liver and thyroid malignancies, phenytoin with liver and lymphoid malignancies, valproate with uterine adenocarcinoma, carbamazepine with hepatic and testicular tumors, and gabapentin with pancreatic tumors. In humans, only phenobarbital and phenytoin are considered possibly carcinogenic by the International Agency for Research on Cancer.47
Pneumonia
Pneumonia is a frequent cause of death in epilepsy (SMR 3.5 to 7.2) in community-based studies8,19,43 as well as in hospital-based studies.22,23,38,53 This is a common terminal event in the elderly, and the mean age of patients who died of pneumonia in the UK General Practice Study was 81.3 years.8,28 The consistently raised SMRs that reflect this may represent an increased tendency in elderly patients with epilepsy to hospitalization in comparison to those of a similar age without epilepsy in the general population.
Vascular Disease
As with CNS neoplasia, the significantly increased mortality due to cerebrovascular disease in epilepsy in community-based studies (SMR 2.5 to 3.78,19,28) as well as in hospital-based studies (2.5 to 5.338,44) reflects mainly on the increased mortality associated with the underlying pathology. Ischemic heart disease, however, does not appear to be a significant cause of mortality in epilepsy, and in both the Rochester study19 and the UK General Practice Study,8,28 SMRs did not reach significance. This was similarly true of hospital-based studies.44 Other studies have found elevated SMRs, especially in patients under the age of 65 years, although these may reflect methodology rather than a true increase in mortality.2,38
Summary and Conclusions
Individuals with epilepsy have mortality rates in the order of two to three times that of the general population. However, much of this increase is due to the causes of acquired epilepsy-brain tumors, cerebrovascular disease, traumatic brain injuryrather than epilepsy itself. Increased mortality is not consistently associated with idiopathic epilepsy. The relative mortality of individuals with epilepsy is influenced by age, as the younger ages have higher relative mortality rates than older individuals with epilepsy. In addition to the excess mortality associated with the causes of acquired epilepsy, the major contributors to increased mortality among individuals with epilepsy are deaths associated with accidents and those attributed to SUDEP.
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