Epileptic Disorders
MENUThe mortality of epilepsy revisited Volume 6, issue 1, March 2004
Auteur(s) : Athanasios Gaitatzis, Josemir W Sander
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK
Received September 11, 2003; Accepted October 29, 2003
Despite an overall good prognosis for seizure control [1, 2], epilepsy is a potentially life-threatening condition and is associated with increased mortality. This is consistently shown, both in population-based studies and in studies of more selected populations, such as institutionalised patients and clinic attendees [3, 4].
People with epilepsy have a mortality rate (the number of deaths that occur in a defined population divided by the person-years at risk in that population) 2-3 times higher than that of the general population [4]. This is better expressed as the standardised mortality ratio (SMR), which is the ratio of the observed number of deaths in an epilepsy population to that expected based on the age- and sex-specific mortality rates in a reference population, in a given time [5].
Causes of death in people with epilepsy can be classified into 3 groups: deaths that are unrelated to epilepsy; those that occur as a result of the cause of epilepsy; and those in which the epilepsy itself is the cause of death (table 1) [3].
Table 1. Causes of death in
epilepsy (adapted from Nashef et al., 1995 [8]).
Neoplasms outside the central nervous system |
Ischaemic heart disease |
Pneumonia |
Others |
Related to underlying disease |
Brain tumours |
Cerebrovascular disease |
Cerebral infection-abscesses and encephalitis |
Inherited disorders, e.g. Batten’s disease |
Epilepsy-related deaths |
Suicides |
Treatment-related deaths |
Idiosyncratic drug reactions |
Medication adverse effects |
Seizure-related deaths |
Status epilepticus |
Trauma, burns, drowning |
Asphyxiation, aspiration |
Aspiration pneumonia after a seizure |
Sudden unexpected death in epilepsy |
The proportion of deaths due to a particular cause in a cohort of patients in a given period can be described by the proportional mortality rate (PMR), which compares the relative contribution of various causes to the overall mortality in this population [4, 6]. PMR is not a direct measurement of the ratio of rates of death between populations, and does not express the risk of members of a population contracting or dying from a disease. Comparisons of PMR between groups or populations can be meaningful only if the cause-specific mortality rates are known so that differences between populations relate to variations either in the number of deaths of interest (numerators) or the total number of deaths (denominators) [4]. For example, an observed excess of a particular cause of death in an epilepsy group may represent a true increased risk, but may also merely represent a deficit of deaths due to other causes.
The underlying disease, of which epilepsy is a symptom, is the main cause of death in newly diagnosed cases, and is associated with increased mortality whether epilepsy is present or not [7]. Epilepsy itself, and probably to a very much lesser extent, its treatment, is a major cause of death in chronic epilepsy [8]. It has been suggested that the long term use of antiepileptic drugs (AEDs) increases the incidence of malignant neoplasia and osteoporosis, thereby potentially affecting long-term mortality rates in people with epilepsy [7].
Abbreviations: SMR = standardised mortality ratio; PMR = proportional mortality rate; SUDEP = sudden unexpected death in epilepsy; TLE = temporal lobe epilepsy; AEDs = antiepileptic drugs.
Measurements and methods
Methodological difficulties permeate studies of the mortality of
epilepsy. Definitions of epilepsy and classification of seizures
may differ between studies, as well as the accuracy of epilepsy
diagnoses and the classification of causes of death. The
International League Against Epilepsy (ILAE) has published
guidelines for epidemiological research [5], which deal with the
issue of definition and classification, and are based on the ILAE
classification of epileptic seizures and syndromes [9, 10]. For
example, until recently, the term cryptogenic was interchangeable
with idiopathic. In the new classification, the term “idiopathic”
is reserved for seizures occurring in epilepsy with a presumed
genetic origin, and “cryptogenic” characterises seizures occurring
in otherwise normal people, with no clear cause. Other problems
included the exact definitions of sudden unexpected death in
epilepsy (SUDEP) and other seizure-related deaths [11], as well as
the inclusion in the epilepsy group of patients with acute
symptomatic seizures, – a category known to be associated
with increased mortality [8].
The accuracy of information on the cause of death depends on the
collecting methods employed. Death certificates can be an
unreliable source [12-14] and, although autopsy and supplementary
clinical data improve accuracy, they are subject to bias and error
[8]. In the ongoing, UK National General Practice Study of Epilepsy
[15], epilepsy was mentioned in 10 of 181 patients with
definite epilepsy (Dr. Gail Bell, personal communication).
Furthermore, SMR cannot be calculated in studies utilising
registers of death certificates because the number of person-years
at risk in the study population is usually not known. Diagnostic
inaccuracy in life may be as high as 15-20%, owing to confusion
with syncope and psychogenic attacks or as a result of
overinterpretation of EEGs [16, 17]. Case ascertainment is subject
to bias: retrospective studies based on hospital records may
significantly underestimate the number of cases in the community
[17], especially in the elderly, the very young and individuals
whose seizures were not witnessed [18]; and population-based
studies may include people without epilepsy [19].
In addition to the small number of mortality studies in epilepsy,
different study types and reference populations have been used,
rendering comparison between studies and application to the general
population even more problematic [20]. Studies from selected
populations, such as hospital-based case series [16, 21-24],
residential epilepsy centre [25-27] and epilepsy centre case series
[28] offer the advantage of more reliable diagnoses and accurate
classification of cause of death. Their disadvantages are that most
include small numbers of patients and, most importantly, suffer
from selection bias, as they tend to represent more severe and
chronic cases. This is likely to exaggerate mortality and
epilepsy-related deaths, and results cannot be applied to the
general epilepsy population. Cross-sectional and prevalent
population studies fail to ascertain new cases of epilepsy and
therefore miss the high initial mortality of epilepsy, and can
misrepresent particular causes of death such as brain tumours [18].
Insurance cohorts [29, 30] represent highly selected, prevalent
cases and utilise the lower mortality rates of non-rated policy
holders as the standard [7].
The heterogeneity between studies was evident in a recent attempt
at a meta-analysis of comparative studies investigating mortality
in epilepsy patients [20]. The authors performed a detailed
quantitative review of relevant follow-up studies conducted in the
last 100 years, in order to investigate the extent and causes
of the differences found in studies of mortality in epilepsy.
Nineteen studies matched their criteria, assessing community,
general medical and institutional populations. However, a summary
estimate could not be calculated because of considerable variation
in mortality risk ratios of the studies. This variation was
explained mainly by differences in the “source population” (that
characterises the setting from which patients were recruited), and
secondarily by case selection.
The ideal approach is one of large scale, general
population-based, prospective incidence studies with comprehensive
case ascertainment, accurate diagnosis, sound aetiological
assignment, long follow-up and efficient tracing of patients [17].
The National General Practice Study of Epilepsy (NGPSE) studies in
the UK [18, 31], the study conducted in Rochester, Minnesota [14],
and the study in Västerbotten County in Northern Sweden [32] appear
to fulfil these criteria to a great extent.
Overall mortality
Premature mortality in patients with epilepsy is reported to be significantly higher than in the general population [20]. SMRs for community-based studies range between 1.3 and 3.1 (1.6 and 2.6 for studies using incident cases) (table 2).
Table 2. Community-based studies of overall mortality of epilepsy.
Study |
Setting |
Method |
Age at entry | Person-years | SMR (95% CI)* |
---|---|---|---|---|---|
Alström 1950 [21] | Sweden | Clinical series | 23 yrs | N/A | 2.4 (2.0-2.8) |
Voute 1967 [104] | Europe | Insurance policy holders | Adults | N/A | 3.1 |
Zielinski 1974 [12] | Warsaw | 3-yr prevalence cohort | All | ~ 20,000 | 1.8 |
Hauser et al., 1980 [14] | Rochester, MN, USA | 29-yr retrospective incidence cohort | All | 8,233 | 2.3 (1.9-2.6) |
Olafsson et al., 1998 [40] | Iceland | 30-yr retrospective incidence cohort† | N/A | 6,308 | 1.6 (1.2-2.2) |
Loiseau et al., 1999 [86] | Gironde, France | 1-yr prospective incidence cohort | All | 804 | 9.3 (7.9-10.9) |
Lindsten et al., 2000 [32] | Sweden | 11-yr prospective incidence cohort | ≥ 17 yrs | 850 | 2.5 (1.2-3.2) |
Lhatoo et al., 2001 [31] | United Kingdom | 14-yr prospective incidence cohort | All | 11,400 | 2.1 (1.8-2.4)‡ |
Camfield et al., 2002 [35] | Nova Scotia, Canada | > 15-yr retrospective incidence cohort | 28d-16yrs | N/A | 8.8 (4.1-13.4) |
†Early mortality was assessed.
‡The NGPSE study [18, 31] included patients with symptomatic and unprovoked seizures.
A community-based study of mortality in children aged
1-14 years, using a state-wide paediatric mortality
surveillance system in Victoria, Australia found an all-cause SMR
of 13.2 (95% confidence interval [CI]: 8.5-20.7) [33]. A long-term
study in which a cohort of 245 Finnish children with epilepsy
were followed up for more than 30 years reported an increased
risk of death and decreased probability of survival in those who
had not entered remission [34]. A community-based cohort study in
Nova Scotia, Canada, which followed 692 children who developed
epilepsy between 1977 and 1985, reported
SMRs > 5 in the first 15-20 years after
diagnosis [35]. The majority of deaths in people whose seizures
start in childhood occur in adulthood [34, 36, 37].
Studies of selected populations tend to have higher SMRs. In a
large cohort study of all patients over 15 years old, in whom
a diagnosis of epilepsy was recorded at discharge from any hospital
in Stockholm during 1980-1989, an SMR of 3.6 (CI 3.5-3.7) was
estimated [16]. This cohort comprised a total of
53,520 person-years and 4,001 deaths. In a retrospective
study of the survival status of out-patients seen in a Dutch
epilepsy centre over a 40-year period (38,665 person-years,
404 deaths), the SMR was 3.2 (CI 2.9-3.5) [28]. In a cohort of
adult outpatients with epilepsy at a tertiary referral centre in
the UK (1849 patient-years), the SMR was 5.1 (CI 3.3-7.6) [38].
SMRs for institutionalised populations (i.e., patients living in
residential epilepsy centres) range between 1.9 and
3.0 [20, 26, 27].
Risk factors determinants of mortality
The higher risk of premature death does not apply equally to all people with epilepsy and serves only as a summary measurement, masking important differences in mortality among the population with epilepsy. Studies of mortality in epilepsy calculate mortality rates according to aetiology, duration and type of epilepsy, age, and sex. In its published guidelines for epidemiological studies, the ILAE proposed that the epilepsies and epileptic seizures be categorised into aetiological groups: idiopathic, cryptogenic, acute symptomatic, remote symptomatic, and progressive symptomatic. [5]. No studies to date have strictly adhered to the new classification scheme. Prior to this new scheme, the three major aetiological groupings usually included the idiopathic (or cryptogenic, or primary) group, the remote symptomatic (or postnatally acquired secondary epilepsy) group, and the (congenital) neuro-deficit group.
Idiopathic (and/or cryptogenic) epilepsy has the lowest, long-term mortality, with SMRs ranging from 1.5 to 1.8 in population studies [14, 21, 39], suggesting that mortality rates in this group are above those of the general population by 50-80%. Other studies however, failed to show a significant increase in mortality in this group [31, 32, 40]. Studies in children follow the same population trends in mortality, in idiopathic and cryptogenic cases [24, 33, 34] as well as in cases without severe neurological deficit [35].
Although the overall chances of achieving remission are similar in patients with remote symptomatic epilepsy and idiopathic epilepsy, the same is not true of their relative risk of premature death [2]. Long-term mortality is greatly increased in remote symptomatic epilepsy with reported SMRs of 2.2 (CI 1.8-2.7) in the Rochester study [14], 2.3 (CI 1.4-3.5) in an Icelandic study [40], 3.7 (CI 2.9-4.6) in the NGPSE [31], and 3.3 (CI 2.4-4.5) in the Västerbotten County study [32]. Considering people with symptomatic epilepsy, the risk of death appears to be over ten times higher for those with congenital neurological deficit or CNS tumours, and 2-3 times higher in patients with cerebrovascular disease or alcohol abuse [31]. The reported SMR in a prevalent paediatric population with epilepsy in Australia was 49.7 (CI 31.7-77.9) for remote symptomatic epilepsy [33]. In a population-based study, children with disorders sufficient to cause functional neurological deficit were 22 times more likely to die prematurely than those without [35]. The authors concluded that children with remote symptomatic epilepsy and no neurological deficit are unlikely to die as a result of seizures [35].
The neuro-deficit group, consisting of patients with gross neurological deficit and/or learning difficulties presumed to have been present or acquired at birth, has the highest long-term mortality, with reported SMRs in the range of 11.0 (CI 6.9-16.4) [14] and 25 (CI 5.1-73.1) [31]. The excess mortality is attributed to the small number of deaths expected in the young age group and the high death rate among children with neurological deficit, irrespective of the presence of epilepsy [7].
Seizure type also plays a role: patients with absence seizures do not appear to be at greater risk of death [14], while those with generalised tonic-clonic seizures carry SMRs of 3.5-3.9 for the first 5-10 years from diagnosis [14, 32] and those with myoclonic seizures, 4.1 [14]. The SMR for complex partial seizures was not significantly increased in the Rochester study [14], but was reported as 2.1 (CI 1.2-3.6) in the Vsästerbotten County study [32].
Mortality risk increases with severity of epilepsy, usually assessed by seizure frequency. In one study, patients with “severe” epilepsy or frequent seizures had significantly higher SMRs compared with patients with “slight” epilepsy or free from seizures [23]. Patients whose seizures responded to AED treatment exhibited lower mortality than people with poorly controlled seizures (SMR 2.13 versus 3.77 respectively) [23]. In the Rochester study [14], patients entering remission had an SMR of 2 for the first five years of seizure freedom, but the SMR was not significantly elevated thereafter. These results were corroborated in two recent studies assessing long-term mortality in cohorts of patients who underwent epilepsy surgery [19, 41] SMRs in patients with persistent seizures were 4.69 (CI 2.33-7.75) [19] and 7.4 [41], with a reported rate of death of 1.37 per 100 person-years [19]. In contrast, mortality in patients who became seizure-free post-operatively did not differ from that of the general population [19, 41].
Age-specific SMRs show increased death rates at all ages among
people with epilepsy, although this increase is more pronounced in
people under 50 years of age and declines sharply after age
60 [12, 14, 16, 23, 28, 31, 40]. SMRs of between 6 to
8 have been reported for age groups up to 50 years, in
comparison to SMRs of < 2 for patients older than
70 years [3, 14, 23]. This may be explained by the high
mortality in patients with neurological deficit at birth and in
young patients with remote symptomatic epilepsy due to head trauma
and brain tumours, as well as the highly increased risk of sudden
death in younger adults with epilepsy [7, 14]. An important factor
contributing to the high SMRs in the young is also the very low
mortality observed in children and the younger age groups in the
general population.
Mortality rates in epilepsy vary over time, being higher in the
first years after diagnosis. SMRs reported for all cases for the
first year were 3.8 in the Rochester study [14], 6.6 in
the NGPSE study [31], and 7.3 in the Västerbotten County study
[32]. SMRs for the first four years ranged between 2.0 and
3.1 [3, 14, 40]. Mortality rates declined to near normal in
years 4-9 in the NGPSE study [31], in years 2-9 in the
Västerbotten County study [32], and after the first ten years in
the Icelandic [40] and Rochester studies. Rates increased again in
years 25-29 of follow-up in the Rochester study [14], in years
9-14 in the NGPSE (but not in the idiopathic epilepsy group)
[31] and in years 9-11 in the Västerbotten County study [32].
Trends in the Rochester study [14] persisted for the three
aetiological groups (idiopathic, remote symptomatic, neurodeficit)
when analysed separately, with much higher initial SMRs for the
neurodeficit group. Results similar to this last group were
reported by a study of mortality in attendees of a Dutch epilepsy
centre cohort [28].
Higher SMRs have been reported in males than in females in some
studies [14, 23, 28, 39, 42], but not in others [19, 27, 31, 32,
38].
Cause-specific mortality
Cause-specific mortality refers to deaths occurring in the population or a cohort due to a particular cause.
Epilepsy-related deaths
Deaths attributed to epilepsy itself include suicide,
treatment-related deaths, SUDEP, and seizure-related deaths, such
as deaths occurring in status epilepticus (SE) and accidents caused
by seizures such as drowning and burns (table
1). The proportion of deaths due to epilepsy is described
by the PMR, which tends to be higher in selected population
studies, ranging between 18 and 41% [22, 23, 25-28, 43], than in
community studies where it is between 1 and 13% [12, 14, 31,
33, 34)]. However, two community studies of children in Finland
[34] and Victoria, Australia [33] found the epilepsy PMR to be 45%
and 22% respectively. A review of the literature from 1910 to 1974,
which consisted mainly of studies in institutionalised patients,
reported an average epilepsy PMR of 42.7% [44]. The wide range of
the epilepsy PMR may be explained by differences in patient
characteristics and population selection, diagnostic criteria,
duration of follow-up, and classification of causes of death.
Deaths as a result of SE follow similar population trends and
comprise up to 12.5% of all deaths. SE appears to be an important
cause of death, especially for patients in epilepsy hospitals and
centres [25, 27, 43]. The case-fatality rate in SE may be as high
as 20%, but can be much higher in patients with acute symptomatic
seizures, myoclonic seizures, and in elderly patients (especially
those > 65 years) [45, 46]. In a study of cases
of generalised convulsive status epilepticus, the case fatality
rate was highest in patients with a diagnosis of anoxia, CNS
infection, or stroke [46]. The long-term mortality of SE was
assessed in patients who survived at least 30 days after a
first episode of SE, in Rochester, Minnesota [45]. The overall SMR
was 2.8 (CI 2.1-3.5), but the SMR was significantly elevated in all
subgroups with symptomatic SE: acute [3.8 (CI 2.5-5.4)], remote
[3.0 (CI 1.8-5)], and progressive [3.1 (CI 1.6-5)]. SE was
considered progressive symptomatic in the presence of non-static
central nervous system (CNS) conditions, such as CNS tumours and
degenerative neurological disorders [45]. There was no increase in
mortality in patients without an underlying cause of SE (i.e.,
idiopathic/cryptogenic), suggesting, according to the authors, that
SE by itself does not alter long-term mortality [45]. This finding
is further supported by other studies, which report that patients
who develop status following discontinuation of AEDs or as part of
unprovoked epilepsy, and children with epilepsy, have low mortality
rates [47-50].
Accident-related deaths comprise between 1.2 and 6.5% of all
deaths in community-based studies [12, 14, 31, 34] and between 7.3
and 42% in selected population studies, with SMRs ranging from
2.4 -5.6 [16, 20, 22, 23, 25-27, 39, 43]. People with
epilepsy may sustain a fatal accident either during a seizure or as
a consequence of a seizure. These could be due to traffic
accidents, burns, trauma, aspiration or drowning. The uniformly
elevated SMRs and PMR suggest that all people with epilepsy are at
higher risk of dying due to accidents, than the general population.
People with symptomatic epilepsy may be particularly at risk as is
suggested in a population-based incidence cohort study in Iceland.
The authors reported that the SMR for deaths due to accidents,
poisonings and violence was 7.27 (CI 1.96-18.62) for male patients
with remote symptomatic epilepsy and 1.76 (CI 0.47-4.51) for those
with idiopathic/cryptogenic seizures [39]. In countries where
bathing is favoured over showering, a higher rate of death from
drowning might be expected although this has never been properly
investigated.
SUDEP is defined as a sudden, unexpected, witnessed or
unwitnessed, non-traumatic and non-drowning death in patients with
epilepsy, with or without evidence of seizure and excluding
documented SE, in which post-mortem examination does not reveal a
toxicological or anatomical cause of death [51]. Specific criteria
may be applied to classify SUDEP into definite, probable and
possible. Patients who do not meet these criteria can be classified
as non-SUDEP deaths, and there is also a category of insufficient
data [52]. In the UK it is estimated that 500 deaths per annum
are SUDEP [53]. Reported risk factors for SUDEP include frequent
generalised tonic-clonic seizures; age 20-40 years; acquired
epilepsy (primarily from traumatic brain injury or
encephalitis/meningitis), intractable epilepsy, frequent changes of
AEDs, and early-onset epilepsy, with seizure severity being the
strongest factor [54-59]. AED polytherapy may be an additional,
independent factor in adults [56], but not in children [60]. Most
sudden epilepsy deaths are unwitnessed and occur during sleep [61].
When witnessed, most deaths occur in association with a seizure,
and respiratory compromise is a prominent feature [55]. In some
cases, the patient begins recovering from the seizure, but then has
a secondary, cardiac arrest, possibly related to hypoventilation
[62]. Proposed mechanisms for SUDEP include central and obstructive
apnoea and cardiac arrhythmia, although the exact mechanism remains
unknown. SUDEP has been reported to be responsible for 2-18% of all
deaths in epilepsy [44, 59, 63]. Interestingly, SUDEP accounted for
6 of 11 deaths in a selected group of patients with
recurrent seizures following epilepsy surgery [19]. Its incidence
rates range from 0.35-1.2 per 1,000 person-years in
population-based studies [55, 58, 63-68] to 5 per
1,000 in referral populations [26, 38, 54, 56, 69-71], and to
1 per 100 in surgical series [19, 72]. In a well-designed
study, the SMR for SUDEP was 23.7 (CI 7.7-55.0), compared with
sudden death in the general population [58]. The risk in children
remains uncertain, although a rate of 1:1,500 has been
estimated [11]. Children of school age with severe epilepsy and
learning difficulties appear to be at high risk of SUDEP, with an
incidence of sudden death 1:295 cases per year [68]. The
overall age, and sex-standardised mortality ratio in this young
cohort was 15.9 (CI 10.6-23).
It has been reported that people with epilepsy are at higher risk
of committing suicide than the general population [22, 25, 39] [16,
27, 28, 43, 73] but other investigators have been unable to
demonstrate such an increase [14, 18, 26, 74]. In these studies,
the suicide PMRs range between 0 and 20% and the SMRs between
1 and 5.8. Incidence cohorts [14, 31] are known to have lower
mortality rates than prevalence cohorts because they include small
numbers of cases with symptomatic or severe epilepsy, which are
over-represented in prevalence cohorts and which are associated
with higher mortality. In addition, people who attend hospitals
have higher morbidity and mortality than community cohorts. In the
large prevalence study of 9,061 adult patients, who were once
hospitalised for epilepsy in Sweden, the SMR for suicide was 3.5
(CI 2.6-4.6) [16]. The rate of suicide may be extremely high among
depressed patients with epilepsy. Major depression in epilepsy has
been associated with significantly decreased, self-reported quality
of life, increased disability and missed work, increased medication
and medical costs [75, 76]. Mental illness, drug addiction, early
onset of epilepsy (particularly onset during adolescence), and
personality disorder have been associated with increased risk, with
some evidence that risk of suicide may decline with duration of
epilepsy [73, 77]. People with epilepsy were reported to have a
five fold-increased risk of suicide attempts compared with the
general population. Anticonvulsants, particularly barbiturates,
were used in most cases of self-poisoning [78]. A literature review
based on studies published up to 1983 concluded that patients with
severe epilepsy had a suicide rate 5 times higher, and
patients with temporal lobe epilepsy (TLE) 25 times higher,
than the general population [73]. A later meta-analysis by the same
group concluded that the overall SMR for death due to suicide in
epilepsy was 5.1 (CI 3.9-6.6). This was based on studies mostly
published in the 1970s and 1980s, and mainly including patients
with TLE, institutionalised patients, patients from surgical
series, and out-patients [79]. In this analysis, the highest
suicide rates were observed in patients with surgically-treated TLE
whose risk was increased by a factor of 80 [SMR 87.5 (CI
35-180)] [79]. However, this was estimated on the basis of earlier
surgical series published in 1968 [80] and 1969 [81] that do not
reflect current standards of treatment and/or patient selection
criteria. Rates from these early studies may be higher than we
would expect today with modern management and decreased use of
barbiturates. The recently published follow-up results of the UK
NGPSE study with a total of 11,400 patient-years, did not show
any excess of suicides [31]. Another recent study reported five
suicides in a 12-year period in a total of 10,739 patients
with epilepsy seen at a single US centre from 1987 to 1999 [82].
This number is comparable with the average number of suicides in
the general US population of about one per 10,000 people per
year. All suicide cases had a history of early onset (mean age
9.5 years), long-standing CPS (mean duration 29 years)
and very high seizure frequency (often daily). Suicide occurred in
all patients after a short interval (3 months to 3 years)
of having obtained full seizure control for the first time after
temporal lobectomy (3 patients), vagal nerve stimulation, or
medication. These patients had been diagnosed with interictal
dysphoric disorder (IDD), a syndrome described previously by the
authors [83]. IDD comprises intermittent affective and somatoform
symptoms, presenting with intense depressive moods with suicidal
intensity in some, and with psychotic features and dysphoric
symptoms (i.e., irritability, fear, anxiety) in others [84].
According to the authors, suicide in epilepsy results from specific
neuropsychiatric disorders (including IDD and post-ictal
depression) associated with epilepsy rather than as the result of
unfortunate psychosocial difficulties imposed by the chronicity and
severity of epilepsy [83]. Management of specific psychiatric
disorders and, hence, prevention of suicide in epilepsy can be
attained by appropriate use of antidepressant (tricyclic
antidepressants and selective serotonin receptor inhibitors), and
psychotropic medication [82]. People with epilepsy and previous
psychiatric history, including a history of attempted suicide or
suicidal thoughts, should be referred to a neuropsychiatrist with
experience in epilepsy.
Deaths unrelated to epilepsy
Most deaths are not attributed to epilepsy and can be related or
unrelated to the underlying cause of epilepsy (table 1). Deaths in the remote symptomatic group
most commonly occur as a result of the underlying cause of epilepsy
or from a complication of it [14, 24, 31, 33-35]. Causes include
neoplasia, cerebrovascular disease (CVD), ischaemic heart disease
(IHD), and pneumonia. The first three causes do not contribute to
mortality in child populations [24, 33, 34].
Malignant neoplasia accounts for 16-29% of deaths in community-
and hospital-based studies and carries increased mortality with
SMRs ranging from 1.7-4.8 [12, 14, 16, 20, 31, 39, 85]. SMRs
are significantly higher in patients with remote symptomatic
seizures than in patients with seizures of unknown origin [39].
Epilepsy centre studies probably under-represent neoplasia, as
these patients tend to be admitted to other facilities [26].
Brain tumours are an important cause of epilepsy as well as cause
of death, and may contribute to between ¼ to 1/3 of all deaths
due to neoplasia in epilepsy [14, 16, 31]. It is estimated that the
incidence of primary brain tumours among patients with epilepsy is
22 times higher than in the general population [86]. Reported
SMRs range from 3.4-5.4 [20, 27, 32], although in one study,
hospitalised patients with epilepsy appeared to be at much higher
risk, with a reported SMR of 29.9 [16]. The question of brain
tumour association with anticonvulsant exposure and/or duration of
seizures was raised in a number of reports [87-94]. It appears that
the excess numbers of brain tumours occurred within 5-10 years
of the seizure disorder diagnosis and decreased significantly over
time, which suggests that the brain tumours account for the
seizures and are not due to AED exposure [27, 86, 95, 96]. The SMR
for neoplasia remains at 1.4-2.5 even when CNS tumours are
excluded [14, 16, 27, 28, 31]. No specific tumour type or site
showed significant excess of deaths in large studies [14, 16, 27],
with the exception of studies showing excess deaths due to lung
[28, 31] pancreatic and hepatobiliary cancer (although the latter
could be an artefact due to the small numbers involved) [26]. There
may be a small risk of developing cancer following exposure to
AEDs, and a relationship between lung cancer and barbiturates and
between non-Hodgkin’s lymphoma and phenytoin has been shown in two
large studies [96, 97]. The incidence of non-CNS cancers in a
population-based cohort of patients diagnosed with seizure disorder
in Rochester, Minnesota was not found to be elevated in comparison
to the general population [86]. In the same study, there was no
association between cancer incidence and duration of seizures or
use of AEDs.
People with learning difficulties and epilepsy are subject to
mortality rates that are 5-16 times higher than in the general
population [38, 98]. The risk of death appears to be highest in
those with generalised seizures (SMR 8.1, CI 5.7-11.5), lowest in
people with partial seizures without secondary generalisation (SMR
3.7, CI 1.0-13.6), and intermediate in people with secondarily
generalised seizures [98]. In comparison, people with learning
difficulties and no epilepsy have an SMR of 1.6 (CI 1.3-2.0) [98].
These results indicate that, in this group of patients, mortality
is either increased as a result of the seizures or reflects the
severity of the underlying condition. The risk of death among
children with epilepsy and learning difficulties or cerebral palsy
was reported as 1 per 100 person-years in one study
[39].
Cerebrovascular disease (CVD) PMR is 14-16% in population-based
series [12, 14, 31, 39] and in a large hospital-based series [16],
and 5-6% in referral populations [20, 23, 25-27]. SMRs range
between 1.8 and 5.3 reflecting a mortality spectrum from
epilepsy centre cohorts to general population cohorts, with
hospital cohorts in the middle [14, 16, 20, 27, 31, 32]. CVD is the
major cause of epilepsy among the elderly [99], and in a large
Swedish hospital-based study it accounted for 44% of deaths in
people with epilepsy over 75 years in whom the SMR was almost
4 [16]. Patients with remote symptomatic epilepsy are at
particular risk [14, 31], suggesting that the underlying pathology
is responsible for deaths in this group. This is supported by the
finding that people with idiopathic epilepsy in the Rochester Study
had an SMR for CVD of 1.4 (0.6-2.6) [14].
PMRs for ischaemic heart disease (IHD) are similar to those for
CVD [12, 14, 23, 25, 27, 28, 31, 43]. IHD events include angina
pectoris, myocardial infarction and sudden cardiac death. The
latter is defined as death in individuals who had no previous
clinical diagnosis of IHD and who died within 24 hours of
onset of symptoms suggestive of acute coronary insufficiency [100].
The vast majority of IHD deaths in epilepsy occur in patients over
45 years [16]. Mortality rates for IHD are not significantly
increased overall for people with epilepsy, with SMRs reported in
most studies between 1.1 and 1.6 [14, 27, 28, 31, 39,
101]. In contrast, an SMR for heart disease of 2.5 (CI 2.3-2.7) was
reported in a cohort of hospitalised persons over 15 years old
diagnosed with epilepsy [16]. Raised SMRs for heart disease in
epilepsy have also been reported for patients under 65 years
old [101], for patients with remote symptomatic epilepsy [31, 101]
and patients with neurodeficit [14, 101]. In the Rochester study
[101], there was an increase in the incidence of myocardial
infarction both in patients with idiopathic and remote symptomatic
epilepsy, and of sudden cardiac death in patients with remote
symptomatic epilepsy. There was no relationship between the use of
AEDs and incidence rates for IHD or sudden cardiac death [101]. In
the Västerbotten County study of a cohort with newly diagnosed
unprovoked seizures, myocardial infarction was not associated with
a significantly increased SMR in epilepsy [1.5 (CI 0.73-3.2)]
[32].
Pneumonia is a common cause of death in epilepsy, especially in
institutionalised patients, and often reflects a terminal event in
patients with poorly controlled seizures, poor general condition
and debilitation [12, 16, 25-27, 31]. PMRs for pneumonia range from
25% in studies of inpatients in epilepsy institutions and hospitals
[12, 25-27, 31] to 5% in studies of patients in the community [12,
14, 74], as well as in series based on hospital admissions and
epilepsy centre attendance [16, 28]. SMRs range between
3.5 and 10.3 [14, 16, 27, 28, 31]. The majority of deaths
due to pneumonia occur in elderly patients [12, 16, 26, 31], which
may denote increased susceptibility to pneumonia in this epilepsy
population [16, 18]. Pneumonia, however, is an important cause of
death in children with epilepsy, especially those with remote
symptomatic seizures [33], infantile spasms and severe psychomotor
retardation [24]. Pneumonia accounted for 30% of deaths in a study
of children with epilepsy in the community [33], as well as in
another study of a population with onset of seizures in childhood
[34]. The SMR due to pneumonia in young age groups appears to be
higher than in the elderly [16, 28], reflecting the low incidence
of this cause of death in the corresponding age group in the
general, non-epilepsy population, and the severity of the
underlying condition or its complications in children and young
adults with epilepsy. In a large, hospital-based study, the overall
SMR for pneumonia was 4.2 (CI 3.6-4.8) with 40% of deaths due to
pneumonia occurring in patients > 75 years, in whom
the SMR was 2.4 (CI 1.9-2.9).
The size of the problem
In the UK, at any one time, there are at least
300,000 people being treated for epilepsy [53]. The recently
published National Sentinel clinical audit of deaths in people with
epilepsy in the UK, commissioned by the National Institute for
Clinical Excellence (NICE), looked at the post-mortem
investigations and medical care received by patients who had died
and who had epilepsy mentioned in the death certificate [53]. The
audit found 2,412 deaths with epilepsy on the death
certificate among all individuals who died in the UK between
September 1999 and August 2000, although it could not establish the
true number of deaths in people with epilepsy from national data.
Epilepsy was considered to be the probable cause in 812 of
these deaths (~ 34%) based on examination of the death
certificate and clinical notes from primary and secondary care as
well as post-mortem findings. The audit identified a series of
shortcomings in the patients’ care that “may have contributed to a
substantial number of potentially avoidable deaths”. Findings
included poor record keeping throughout primary and secondary care,
deficient management (such as inadequate access to specialist care,
inadequate drug management in 20% of adults and 45% of children,
lack of appropriate investigations, and inconsistent follow-up),
poor information to patients and their families, and inadequacies
in the investigations of deaths. There were particular problems in
the management of epilepsy in patients with associated problems
such as learning difficulties. It is notable that only 3% of the
patients who died (none of them children) were known to be
seizure-free at the time of their last visit to a physician, but 7%
of patients were not on antiepileptic treatment at the time of
death. The audit estimated that deaths in 39% of adults and in 59%
of children were “potentially or probably avoidable”.
Specific measures for the prevention of SUDEP have been proposed
elsewhere based on the findings of this audit [102]. Patients at
risk should be identified, and they and their families educated
about this possibility. Early and aggressive treatment should be
directed to patients with continuing seizures (especially
generalised convulsions) and should include measures to promote
compliance and identification of seizure precipitants. Patients
with seizures not responding promptly to treatment should be
referred early to a neurologist for the classification of seizure
type and epilepsy syndrome, appropriate diagnostic work-up, and
development of a patient-specific treatment plan. Patients whose
seizures are refractory to treatment for more than 2 years,
despite best efforts, should be referred to an appropriate epilepsy
centre for re-evaluation with the possibility of surgery, or other
treatments such as vagal nerve stimulation and clinical trials of
AEDs under development. Finally, pathologists should be educated
about SUDEP and alert to its possible occurrence.
Conclusion
Patients with epilepsy are subject to higher standardised mortality rates than people in the general population, with overall SMRs of between 2 and 3. Although numbers may vary due to differences in methodology and the population studied, findings have been fairly consistent across studies. Mortality is significantly higher in people with symptomatic epilepsy, especially those with an accompanying neurological deficit, in which case it tends to follow the mortality of the underlying cause of epilepsy. SMRs are higher in the first 5-10 years after diagnosis of epilepsy, and in younger people due to the low, expected mortality in this age group. People with idiopathic epilepsy and people who enter long-term remission also seem to be affected, but to a much lesser extent. Major contributors to death in patients with epilepsy are brain tumours, cerebrovascular disorders, and pneumonia in elderly or institutionalised patients. SUDEP is the most important cause of epilepsy-related deaths, particularly in the young, and people with frequent seizures and/or suboptimal AED treatment. Despite the adverse prognosis for particular groups of patients, it is important to realise that a proportion of seizure-related deaths, as well as SUDEP, can be prevented by optimising treatment and care for these patients. In addition, patients and their families need to be aware of the risk of death associated with epilepsy. In the event of death, appropriate post-mortem investigations should be carried out in order to classify the cause of death. The circumstances of death and the medical care received should be looked at in order to identify any management inadequacies. n
Acknowledgements
A.G. was supported by a grant from the National Society for Epilepsy.