Understanding death in children with epilepsy

Donner EJ, Camfield P, Brooks L, Buchhalter J, Camfield C, Loddenkemper T, Wirrell E. Understanding Death in Children With Epilepsy. Pediatr Neurol. 2017 May;70:7-15.

Abstract

Death in children with epilepsy is profoundly disturbing, with lasting effects on the family, community, and health care providers. The overall risk of death for children with epilepsy is about ten times that of the general population. However, the risk of premature death for children without associated neurological comorbidities is similar to that of the general population, and most deaths are related to the cause of the epilepsy or associated neurological disability, not seizures. The most common cause of seizure-related death in children with epilepsy is sudden unexpected death in epilepsy (SUDEP). SUDEP is relatively uncommon in childhood, but the risk increases if epilepsy persists into adulthood. Although the direct cause of SUDEP remains unknown, most often death follows a generalized convulsive seizure and the risk of SUDEP is strongly related to drug-resistant epilepsy and frequent generalized tonic-clonic seizures. The most effective SUDEP prevention strategy is to reduce the frequency of seizures, although a number of seizure detection devices are under development and in the future may prove to be useful for seizure detection for those at particularly high risk. There are distinct benefits for health care professionals to discuss mortality with the family soon after the diagnosis of epilepsy. An individual approach is appropriate. When a child with epilepsy dies, particularly if the death was unexpected, family grief may be profound. Physicians and other health care professionals have a critical role in supporting families that lose a child to epilepsy. This review will provide health care providers with information needed to discuss the risk of death in children with epilepsy and support families following a loss.

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From the article

How common is death in pediatric epilepsy?

Mortality in children with epilepsy has been well described by several prospective and retrospective, population-based and regional cohorts.  A combined analysis of four large cohorts of children with new-onset epilepsy  has consolidated information about risk factors and causes of death for children with epilepsy who have been followed into early adult life.  The analysis included 2239 subjects with more than 30,000 person-years of follow-up and found an overall mortality rate of 228 per 100,000 person-years, five to ten times greater than the age-matched death rate in the general population. Throughout this article, we refer to this study as the “combined cohort study.”

What are the causes of death?

Mortality in children with epilepsy may be unrelated or related to the seizure disorder.  Non–epilepsy-related causes of death include natural and non-natural causes, the latter including accidents, suicide, and homicide. Specific natural causes can be associated with epilepsy such as brain tumors or neurometabolic diseases, but more commonly are related to severe, underlying neurological disability associated with diffuse brain pathology. Death during childhood occurs predominantly in those with “complicated” epilepsy, defined as epilepsy associated with an abnormal neurological examination, intellectual disability, or a known structural cause,  and is due to natural causes resulting from the underlying neurological disability.

Epilepsy-related causes of death include status epilepticus, aspiration due to a seizure, an accident during a seizure, a complication of therapy such as valproate-induced hepatotoxicity or anti-epileptic drug (AED)-induced Stevens-Johnson syndrome, and SUDEP. SUDEP is defined as the sudden and unexpected, nontraumatic and nondrowning death of a person with epilepsy, witnessed or unwitnessed, occurring in benign circumstances, with or without evidence of a seizure and excluding documented status epilepticus. To meet the criteria for definite SUDEP, a postmortem examination must be performed and it should fail to identify the cause of death.

In the combined cohort study, 70% of seizure-related deaths were due to nonepilepsy natural causes, and of these, pneumonia accounted for 35 of 48 (73%) deaths.  Sepsis and ventriculoperitoneal shunt malfunction each accounted for an additional 6% of natural deaths. Non-natural causes accounted for five of 69 (7%) deaths (two suicides, one homicide, and two non–seizure-related accidents). The very-long-term, Finnish study followed children with epilepsy into midadulthood and found that cardiovascular disease was also an important cause of natural death, accounting for approximately 13% of deaths. 

Epilepsy-related deaths accounted for 19% of deaths in the combined cohort study.  With longer-term follow-up into midadulthood, up to 55% of deaths were epilepsy related.  Of the seizure-related deaths, SUDEP is by far the most common cause, accounting for 10 of 13 (77%) individuals in the combined cohort study  and 18 of 33 (55%) seizure-related deaths in the Finnish cohort.  Less commonly, seizure-related deaths are the result of status epilepticus, drowning, aspiration, or adverse effects of treatment.

What are the risk factors for increased all-cause mortality in children with epilepsy?

Children with typical development and without a known cause for their epilepsy have a risk of death that is similar to that of the general population.  The strongest risk factor for mortality is “ complicated ” epilepsy. In fact, the vast majority of deaths in children with epilepsy are in those with “ complicated ” epilepsy, more than 20 times higher than the rate in those with “ uncomplicated ” epilepsy (743 versus 36 per 100,000 person-years)  6 regardless of the cause of death. See an example in Box 1 . Compared with the uncomplicated group, those with complicated epilepsy had markedly higher rates of death due to natural causes (561 versus 9 per 100,000 person-years), any seizure-related death (122 versus 14 per 100,000 person-years), and SUDEP (98 versus 9 per 100,000 person-years). The Finnish study also noted a markedly increased mortality rate in persons with a remote symptomatic cause for their epilepsy (defined as epilepsy associated with a major neurological abnormality or insult) compared with those with idiopathic or cryptogenic causes. 

 Another important risk factor for premature mortality is lack of seizure remission. In the Finnish cohort, the highest rate of death was in those without a five-year terminal remission (1590 per 100,000 person-years). Those with terminal remission but still receiving antiepileptic medication had a lower risk (1180 per 100,000 person-years), while those with a terminal remission and who no longer received AED treatment had a strikingly lower risk of death (150 per 100,000 person-years).  8  Similar findings were noted in the combined cohort study in which seizures in the preceding year were present in 74% of subjects dying of any cause, 92% of those dying of an epilepsy-related cause, and 70% of those dying of nonepilepsy causes.  In a large cohort of children identified through an epilepsy clinic, 95% who died had intractable epilepsy. 

Prior status epilepticus was a significant predictor of death on univariate analysis in the Finnish cohort but did not maintain significance on multivariable analysis.  The combined cohort study noted a history of prior status epilepticus in 62% of children dying of an epilepsy-related cause and in 47% of those dying from non–epilepsy-related reasons…

The literature supports that SUDEP may be less common in childhood because children have a shorter duration of epilepsy. When epilepsy begins in childhood and persists into adulthood, the risk of SUDEP increases. It also remains a possibility that children are more resistant to SUDEP. The role of environmental factors, including improved adherence to treatment; closer supervision, including nocturnal monitoring by parents and caregivers; and the more robust physiological state of youth should also be considered…

Epilepsy-related deaths are predominantly due to SUDEP. The clearest way to reduce SUDEP risk is to improve seizure control, particularly frequent convulsive seizures through better medical treatments, improved treatment adherence, and earlier epilepsy surgery. It is possible that increased nocturnal supervision and more vigorous interaction with the patient in the postictal period may decrease the risk of SUDEP.  Infrequently, epilepsy-related deaths are due to status epilepticus or aspiration, which may be preventable by improved seizure control, early administration of rescue medication, utilization of formal status protocols, and education regarding proper positioning during a seizure. Although drowning is believed to be a rare cause of seizure-related death in areas of the world with a water safety culture, it is preventable. A shower is likely safer than the bathtub, and persons with epilepsy should be closely supervised whenever they are swimming or are around water.