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Purpose: Epilepsy is a common childhood neurologic disorder, affecting 0.5–1% of children. Increased mortality occurs due to progression of underlying disease, seizure-related accidents, suicide, status epilepticus, aspiration during seizures, and sudden unexplained death in epilepsy (SUDEP). Previous studies show mortality rates of 2.7–6.9 per 1,000 person-years. Potential risk factors include poor seizure control, intractable epilepsy, status epilepticus, tonic–clonic seizures, mental retardation, and remote symptomatic cause of epilepsy. Few population-based studies of mortality and SUDEP in childhood-onset epilepsy have been published. The purpose of this study is to report mortality and SUDEP from a 30-year population-based cohort of children with epilepsy.
Methods: The Medical Diagnostic Index of the Rochester Epidemiology Project was searched for all codes related to seizure and convulsion in children living in Olmsted County, Minnesota and of ages birth through 17 years from 1980 through 2009. The medical records of these children were reviewed to identify all those with new-onset epilepsy, and to abstract other baseline and follow-up information. Potential risk factors including seizure type, epilepsy syndrome, history of status epilepticus, the presence and severity of neurologic impairment, and epilepsy outcome was reviewed. Epilepsy outcome was characterized by seizure frequency, number of antiseizure medications (antiepileptic drugs, AEDs) used, and number of AEDs failed due to lack of efficacy, and epilepsy intractability at 1 year and 2, 3, 5, 10, 15, and 20 years after epilepsy onset. We followed all children through their most recent visit to determine vital status, cause of death, and whether autopsy was performed.
Key Findings: From 1980 to 2009, there were 467 children age birth through 17 years diagnosed with epilepsy while residents of Olmsted County, Minnesota, and who had follow-up beyond the time of epilepsy diagnosis. Children were followed for a median of 7.87 years after the time of diagnosis (range 0.04–29.49 years) for a total of 4558.5 person-years. Sixteen (3.4%) of the children died, or 3.51 deaths per 1,000 person-years. Two deaths were epilepsy related (12.5%) for a rate of 0.44 per 1,000 person-years. One of these children died of probable SUDEP and one died of aspiration during a seizure. The remaining 14 deaths (87.5%) were caused by other complications of underlying disease. Several risk factors for mortality were found, including abnormal cognition, abnormal neurologic examination, structural/metabolic etiology for epilepsy, and poorly controlled epilepsy.
Significance: Although mortality in children with epilepsy was higher than what would be expected in the general pediatric population, death occurred significantly more in children with neurologic impairment and poorly controlled epilepsy. Epilepsy-related death, including SUDEP, was rare and mortality due to epilepsy alone was similar to the expected mortality in the general population (observed deaths = 2, expected deaths = 1.77; standardized mortality ratio 1.13, 95% confidence interval 0.19–3.73, p = 0.86). By contrast, most children died of complications of the underlying neurologic disease or unrelated disease rather than the epilepsy.
Epilepsy is a common neurologic disorder in childhood; it affects 0.5–1% of children (Shinnar & Pellock, 2002). Increased mortality is seen in those with epilepsy due to progression of underlying disease, seizure-related accidents, suicide, status epilepticus, aspiration during seizures, and sudden unexplained death in epilepsy (SUDEP) (Ficker, 2000). The standardized mortality ratio (SMR) in adults with epilepsy has been reported to be 2.5–3.6 when compared to the general population, suggesting that adults with epilepsy have significantly higher mortality rates (Cockerell et al., 1994; Nilsson et al., 1997).
SUDEP is a common cause of death in adults with epilepsy, accounting for 2–18% of deaths in patients with epilepsy, with an incidence of 0.35–1.5 deaths per 1,000 person-years (Ficker et al., 1998; Annegers & Coan, 1999; Walczak et al., 2001; Vlooswijk et al., 2007). A previous population-based study of SUDEP in all patients with epilepsy in Rochester, Minnesota, reported the incidence of SUDEP to be 0.35 deaths per 1,000 person-years, with a standardized mortality ratio of 23.7 when compared to the general population. Although SUDEP was responsible for 1.7% of deaths in the cohort, 8.6% of deaths in the 15–44 year age group were due to SUDEP (Ficker et al., 1998). However, the incidence of seizure-related death and SUDEP in children has been reported to be much lower.
Previous population- and community-based studies of epilepsy in children have shown overall mortality rates of between 2.7 and 6.9 deaths per 1,000 person-years (Sillanpaa et al., 1998; Callenbach et al., 2001; Berg et al., 2004; Camfield & Camfield, 2005). The incidence of death due to SUDEP in children has been reported to be 1.1–2 deaths per 10,000 person-years (Donner et al., 2001; Camfield & Camfield, 2005). A recently published cohort of children with epilepsy (including both prevalent and incident cases) reported an overall mortality rate of 6.9 deaths per 1,000 person-years (Sillanpaa & Shinnar, 2010). Epilepsy-related deaths accounted for 55% of all deaths, and 30% of all deaths were due to SUDEP (Sillanpaa & Shinnar, 2010). This rate of SUDEP is much higher than previously reported. Risk factors in that study included remote symptomatic etiology of epilepsy, lack of 5-year terminal remission, and severe cognitive impairment (Sillanpaa & Shinnar, 2010). Other previously cited risk factors for increased mortality in epilepsy include poor seizure control, intractable epilepsy, status epilepticus at the time of initial diagnosis, history of tonic–clonic seizures, mental retardation/neurologic deficit, and remote symptomatic cause of epilepsy (Walczak et al., 2001; Camfield et al., 2002; Berg et al., 2004).
Few population-based studies of mortality and SUDEP in childhood-onset epilepsy have been published. Those studies that have been published have yielded variable results, with the most recent study demonstrating higher mortality rates than previously reported. Therefore, the aim of this study is to report mortality and SUDEP from a 30-year population-based incidence cohort of children with epilepsy.
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This was a large population-based study of 467 children over a 30-year period, with >4,500 person-years of follow-up. We found an increased mortality rate in children with epilepsy, 3.5 per 1,000 person years, which is higher than expected in the Olmsted County population (SMR 9.04) and 10 times the national mortality rate for children in 2005 of 0.32 per 1,000 person-years (Martin et al., 2008). The results of this study are within the wide range of previously reported population- and community-based studies of childhood-onset epilepsy that demonstrated mortality rates of 2.7–6.9 per 1,000 person-years (Berg et al., 2004; Sillanpaa & Shinnar, 2010). However, this is much lower than the 21.5 deaths per 1,000 person years reported in a prospective population based study of mortality in children and adults with epilepsy (Cockerell et al., 1994). This is also lower than the 6.90 per 1,000 person years in a recently reported population-based study of children with epilepsy (Sillanpaa & Shinnar, 2010).
The higher mortality rate seen in the recent population-based study by Shinnar and Sillanpaa is likely related to the increased severity of disease in this cohort, as well as the longer duration of follow-up (40 years) in that study. Remote symptomatic epilepsy and poorly controlled epilepsy have been shown previously to be associated with increased risk for death in children with epilepsy. This is supported by the higher mortality in children with symptomatic epilepsy, compared to those with cryptogenic or idiopathic epilepsy, 11.1 versus 3.23 per 1,000 person-years, seen in the recent population-based study (Sillanpaa & Shinnar, 2010). This was also seen in our study, with mortality in those with structural/metabolic cause being 10.1 per 1,000 person years, compared to 0.9 per 1,000 person-years in children with epilepsy due to genetic or unknown cause.
Furthermore, 50% of the subjects in the previous study had remote symptomatic epilepsy, defined as “epilepsy associated with a major neurologic abnormality or insult” (Sillanpaa & Shinnar, 2010). By contrast, 27% of the children in our study had epilepsy due to structural or metabolic abnormalities, and 29% were diagnosed with intractable epilepsy at some time during follow-up, which is similar to the other population- and community-based studies (Berg et al., 2004; Camfield & Camfield, 2005). Previous population-based studies of mortality in children with developmental disabilities have also demonstrated increased mortality, with increasing mortality reflecting increased disability (Strauss et al., 1998; Decoufle & Autry, 2002).
Finally, although the length of follow-up in our study was shorter, a previous population-based study of SUDEP in adults demonstrated that SUDEP was responsible for 8.6% of deaths and another population based study in children demonstrated SUDEP was the cause of death in 3.8% (Ficker et al., 1998; Camfield et al., 2002). Therefore, the lower mortality rate, and especially SUDEP, in our study is not explained by the shorter follow-up. Therefore, the lower mortality rate in this population-based study, like that seen in previous population-based studies, most likely reflects the expected mortality rate in children with epilepsy.
This study identified multiple significant risk factors for mortality in children with epilepsy, including abnormal cognition, abnormal neurologic examination, structural/metabolic etiology for epilepsy, history of status epilepticus, and poorly controlled epilepsy (the use of more than one AED at last follow-up, continued frequent seizures at follow-up, and diagnosis of intractable epilepsy). These findings are similar to those of previous studies, which demonstrated developmental delay, refractory epilepsy, and AED polypharmacy to be risk factors for increased mortality (Brorson & Wranne, 1987; Cockerell et al., 1994; Callenbach et al., 2001; Decoufle & Autry, 2002; Berg et al., 2004; Weber et al., 2005). However, the majority of deaths (87.5%) were not directly related to the underlying epilepsy, but rather due to complications—primarily respiratory—of the underlying neurologic disease. Therefore, there were multiple epilepsy-related risk factors for mortality present in these children, and this is likely due to poor seizure control being more common in children with neurologic impairment.
Epilepsy-related death in our study occurred in only two of the children (12.5%), or 0.44 per 1,000 person-years. SUDEP occurred in only one of these children, or 0.22 per 1,000 person years. This is significantly lower than the recent study of mortality in children with epilepsy, in which 55% of deaths were due to epilepsy and 30% of deaths were related to SUDEP (Sillanpaa & Shinnar, 2010). However, our findings are consistent with previous studies of SUDEP in children reported as 0–4% (Cockerell et al., 1994; Camfield & Camfield, 2005; Weber et al., 2005). Therefore, the higher prevalence of SUDEP in the recent study is likely due to the high proportion of patients with profound neurologic impairment in that cohort.
There may be several potential limitations of this study. First, this study was historical, and it is possible that we failed to find all children with epilepsy or that treatment and epilepsy outcome was incompletely documented in the medical records. However, our incidence rates were similar to those of previously published population-based studies of childhood onset epilepsy, suggesting a complete cohort was obtained. Furthermore, we did not directly examine or interview all children to verify syndrome classification. However, we screened the complete Medical Diagnostic Index of the Rochester Epidemiology Project for children diagnosed at any time with seizure or convulsion. All identified charts were then reviewed by a pediatric epileptologist. Furthermore, complete medical records, including neuroimaging, laboratory results, electroencephalography, and all documentation from both the inpatient and outpatient settings was available for each child, minimizing the possibility that information was missed.
Mortality in children with epilepsy was higher than would be expected in the general pediatric population. However, death occurred significantly more in children with neurologic impairment and poorly controlled epilepsy. Furthermore, death related to epilepsy, including SUDEP, occurred in only two patients. The remaining deaths were due to complications of the underlying neurologic disease or unrelated disease. Mortality due to epilepsy alone was similar to the expected mortality in children.
Although the findings of this study demonstrated significantly lower rates of mortality and SUDEP when compared to the most recent population-based study of mortality in children with epilepsy, this is likely due to different population demographics. In addition, we feel our study is more consistent with other population-based studies. Therefore, although mortality in children with epilepsy is significantly higher than expected, a large proportion of this excess is likely related to the underlying neurologic disease, rather than the epilepsy. Furthermore, children with epilepsy who are not medically intractable and are otherwise neurologically normal have an exceedingly low risk of seizure-related death. Therefore, although it is important to counsel patients and families about the risk of seizure-related death and SUDEP, we can be reassured that this risk is low. However, it is also important to understand that seizure-related death and SUDEP do occur in children, and the risk factors for this— primarily the underlying neurologic disease—are not preventable.