Death and epilepsy

Of all the chronic neurological disorders, epilepsy is the most common, affecting approximately 1 in 100 adults [1]. Recently, the risk of death associated with seizure disorders has received greater attention in the press. Numerous studies have shown that individuals with epilepsy have an increased rate of premature death compared with the general population. This is multifactorial, and can be attributed to accidental death, suicide, status epilepticus and sudden unexpected death in epilepsy (SUDEP).

Types of mortality associated with epilepsy

Accidental death

Accidental death can be secondary to seizure activity whilst a person with epilepsy is, for example, driving, swimming or eating. Epidemiological studies demonstrate that patients with epilepsy have a higher mortality rate due to accidents than the rest of the general population [2]. Avoidance, when possible, is effective, but results in decreased quality of life, social stigma and generalized morbidity. The risk of accidental death is, of course, the basis for placing limitations on activities that patients with epilepsy carry out, including driving.

Suicide

Patients with epilepsy have an increased risk of suicide than those without, with a relative risk (RR) of approximately three. The highest risk is found in those with concomitant psychiatric disease (RR: 13.7), especially in the first 6 months after the diagnosis of epilepsy (RR: 29.2). Even when excluding psychiatric disease and socioeconomic factors, patients with epilepsy have an overall suicide rate twice that of the general population [3]. Interestingly, although the risk of suicide in the general population increases with age, it decreases with age in the epileptic population. This may be because the highest morbidity of epilepsy is incurred in the period immediately following diagnosis (e.g., loss of job or driver’s license). After reviewing 199 studies that compared 11 antiepileptic drugs (AEDs) with placebo, the US FDA released a warning and found that patients on AEDs had twice the risk of suicidal ideation or behavior (0.43%) versus placebo (0.22%), observed as early as 1 week after commencing AED therapy [101]. The FDA is working with AED manufacturers to include this information on their labeling, and is encouraging physicians, patients and their caretakers to consider these risks before implementing therapy. Most experts, however, feel that this warning was misleading, out of context and may do more harm than good if patients unduly discontinue their AEDs. Certainly, epilepsy in itself raises the risk of suicide much more than the minute increase noted in a meta-analysis of AED studies.

SUDEP

Sudden unexpected death in epilepsy is defined as the sudden, unexpected, nontraumatic and nonaccidental death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in whom post-mortem examination does not reveal a structural or toxicological cause of death. SUDEP causes up to 18% of all epilepsy-related deaths [4], with an occurrence rate of up to 1% per year in those with medically intractable epilepsy [5]. Although the mechanism is unknown, seizure-induced asystole or central (ictal or postictal) apnea leading to cardiopulmonary arrest are suspected. Risk factors for SUDEP include generalized seizures, intractability, long duration of epilepsy (>30 years) and age of 20–40 years. A recent case series of 56 patients with localization-related epilepsy undergoing video EEG monitoring found that ictal hypoxemia and hypercapnea may contribute to SUDEP [6]. Whether the risk of SUDEP should be discussed with patients, including issues such as emotional distress, medico–legal ramifications, lack of preventability and right to (not) know are controversial; a task force recently convened to assess the state of knowledge of SUDEP and will relay its findings and recommendations to the public, researchers and clinicians [7]. Probably, SUDEP should be discussed in weighing the pros and cons of epilepsy surgery for the treatment of intractable epilepsy (see later).

Status epilepticus

Status epilepticus was traditionally defined as seizure persisting or recurring without return to consciousness for greater than 30 min. However, a more clinically realistic time frame is in the order of 5 min. With good medication and relatively standardized treatment protocols, the overall mortality of status epilepticus nowadays is approximately 10%, and most deaths are due to the underlying cause rather than the status epilepticus per se. Greater mortality is associated with increasing age, female sex, subsequent mechanical ventilation and longer duration of episode. However, death from status epilepticus secondary to intractable epilepsy is also not uncommon. Rhabdomyolysis, lactic acidosis, cardiac injury, neurogenic pulmonary edema, aspiration and respiratory failure are consequences of status epilepticus and contribute to mortality [8].

Intractable versus well-controlled epilepsy

Regardless of the mechanism, the overall increase in mortality is essentially accounted for by the subpopulation with medically intractable epilepsy. Several studies confirm that most deaths, whether it be SUDEP, suicides, accident or status epilepticus, are much more frequent in intractable or uncontrolled epilepsy [9,10].

Similarly, AED noncompliance is an important factor. A recent multistate, restrospective, open-cohort study [11] including over 33,000 patients found, over any given 3-month period, a 26% noncompliance rate. Periods of noncompliance were associated with an increased risk in mortality (hazard ratio: 3.32), emergency department visits (incidence rate ratio [IRR]: 1.50), hospitalizations (IRR: 1.86), motor vehicle accident injuries (IRR: 2.08) and fractures (IRR: 1.21).

Weighing the risks: what is more dangerous, intractable epilepsy or epilepsy surgery?

Aside from increased mortality, medically intractable epilepsy also carries significant morbidity, including accidental injury, cognitive decline, depression, anxiety, and social and vocational impairment. This presents a challenge to both the patient and physician, and both parties frequently harbor misconceptions concerning epilepsy surgery and the standard of care for medically intractable epilepsy. This results in a very long delay before a referral is made for possible surgery [12]. Thus, a legitimate question is whether the risk of death is higher with continued medical therapy or resective surgery.

We reviewed our own comprehensive epilepsy center’s experience in order to compare the number of deaths due to epilepsy surgery, versus unexpected deaths of other causes [13]. Over a 7-year period (2000–2006), we performed 282 resective epilepsy surgeries. During this time period, zero patients died of their neurosurgical procedure, however, 13 patients had unexpected death. Of these 13 patients, 11 had a localization-related epilepsy and two had a primary generalized epilepsy. Of the 13 patients who died, four had unsuccessful epilepsy surgery and three had vagus nerve stimulation. An unnecessary statistical analysis demonstrates that patients with intractable seizures are much more likely to die of seizures than of epilepsy surgery. Interestingly, and similarly, in the only controlled trial of medical treatment versus surgery for patients with intractable seizures [14], the only death was in the medical arm. This is also consistent with other series [15]. In addition, serious complications of epilepsy surgery are rare, occurring in less than 4% of patients. These include hemiparesis, superior quadrantanopsia cranial nerve palsies that typically resolve, bone flap infections and mild verbal memory problems. Computer simulations predict that, on average, a 35-year-old patient with medically intractable seizures who chooses to undergo surgery increases his survival by 5.0 years and his quality-adjusted life-years by 7.5 years [16].

Information resources

• • Pompili M, Girardi P, Tatarelli R. Death from suicide versus mortality from epilepsy in the epilepsies: a meta-analysis. Epilepsy Behav. 9(4), 641–648 (2006).

  A large meta-analysis that emphasizes the importance of suicide as a cause of death in patients with epilepsy.

• • Lhatoo SD, Sander JW. Cause-specific mortality in epilepsy. Epilepsia 46(Suppl. 11) 36–39 (2005).

  A good review of the causes of death depending on the type of populations studied.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.