Tonic-Clonic Seizures Linked to Sudden Death in Epilepsy

SAN ANTONIO – Frequent generalized tonic-clonic seizures, the use of multiple antiepileptic drugs, a 15-year or longer duration of epilepsy, and an epilepsy diagnosis before age 16 were among the statistically significant risk factors for sudden unexplained death in epilepsy.

The associations were detected in a pooled analysis of four published case-control studies presented at the annual meeting of the American Epilepsy Society.

In patients with idiopathic generalized epilepsy, lamotrigine therapy also was associated with an increased risk of death. In addition, male gender was associated with increased mortality, as were stroke, infection, traumatic brain injury, and brain tumor, reported epidemiologist Dale Hesdorffer, Ph.D., of Columbia University in New York.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in chronic epilepsy. Yet most studies that have attempted to identify risk factors have been limited by the small number of cases in each study. To address this deficiency, Dr. Hesdorffer and her colleagues in the Epidemiology Task Force of the International League Against Epilepsy combined data from four similarly designed case-control studies conducted in the United States, Sweden, Scotland, and England. The number of cases of sudden death ranged from 20-149 cases in each study. All cases had a history of epilepsy with at least one seizure during a 5-year period and unexpected death that occurred suddenly and remained unexplained after further investigation, including autopsy.

"Across the studies, statistically significant risk factors for sudden unexplained death in epilepsy were a high number of generalized tonic-clonic seizures, poly-antiepileptic drug therapy, high seizure frequency, and young age at epilepsy onset," she said.

Using logistic regression analysis to identify risk factors, the researchers employed the largest study (149 cases, 602 controls) as the reference initially and then controlled for the largest study to eliminate the possibility that its size would bias the results, Dr. Hesdorffer explained. The investigators adjusted multivariate analyses for study, age of death, gender, and duration of epilepsy.

The analyses revealed that individuals with one or two generalized tonic-clonic seizures per year had a fivefold increased risk of sudden death compared with epilepsy patients with no history of generalized tonic-clonic seizures. "This risk was increased to 15-fold in patients who had three or more of these seizures per year," Dr. Hesdorffer reported. Male gender, onset of epilepsy before age 16, epilepsy duration of more than 15 years, and polytherapy also were associated with a significantly increased risk of sudden death, she said.

In patients with no history of generalized tonic-clonic seizures, polytherapy was associated with a 2.5-fold increased risk of sudden death. Those with a history of one or two generalized tonic-clonic seizures and polytherapy had a 10-fold increased risk. Three or more such seizures and polytherapy were associated with a 27-fold increased risk, Dr. Hesdorffer reported.

In patients on monotherapy, the sudden death risk for patients with one or two generalized tonic-clonic seizures was six times higher than that of controls; for those with three or more seizures, it was 12 times higher.

Idiopathic generalized epilepsy was associated with a decreased risk of sudden death. The exception was seen in patients taking lamotrigine, Dr. Hesdorffer said. Factors that were not significantly associated with SUDEP included levels of carbamazepine, valproate, or phenytoin, as well as age at death, epilepsy surgery, comorbid mental health disorders, learning difficulty, alcohol abuse, and comorbid pulmonary disease, she said.

The results provide an "emerging profile" of epilepsy patients who are at increased risk of SUDEP, said Dr. Hesdorffer. "The contribution of antiepileptic drug therapy – particularly that of lamotrigine therapy – should be further examined."

Dr. Hesdorffer reported having no financial conflicts of interest.

SAN ANTONIO – Frequent generalized tonic-clonic seizures, the use of multiple antiepileptic drugs, a 15-year or longer duration of epilepsy, and an epilepsy diagnosis before age 16 were among the statistically significant risk factors for sudden unexplained death in epilepsy.

The associations were detected in a pooled analysis of four published case-control studies presented at the annual meeting of the American Epilepsy Society.

In patients with idiopathic generalized epilepsy, lamotrigine therapy also was associated with an increased risk of death. In addition, male gender was associated with increased mortality, as were stroke, infection, traumatic brain injury, and brain tumor, reported epidemiologist Dale Hesdorffer, Ph.D., of Columbia University in New York.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in chronic epilepsy. Yet most studies that have attempted to identify risk factors have been limited by the small number of cases in each study. To address this deficiency, Dr. Hesdorffer and her colleagues in the Epidemiology Task Force of the International League Against Epilepsy combined data from four similarly designed case-control studies conducted in the United States, Sweden, Scotland, and England. The number of cases of sudden death ranged from 20-149 cases in each study. All cases had a history of epilepsy with at least one seizure during a 5-year period and unexpected death that occurred suddenly and remained unexplained after further investigation, including autopsy.

"Across the studies, statistically significant risk factors for sudden unexplained death in epilepsy were a high number of generalized tonic-clonic seizures, poly-antiepileptic drug therapy, high seizure frequency, and young age at epilepsy onset," she said.

Using logistic regression analysis to identify risk factors, the researchers employed the largest study (149 cases, 602 controls) as the reference initially and then controlled for the largest study to eliminate the possibility that its size would bias the results, Dr. Hesdorffer explained. The investigators adjusted multivariate analyses for study, age of death, gender, and duration of epilepsy.

The analyses revealed that individuals with one or two generalized tonic-clonic seizures per year had a fivefold increased risk of sudden death compared with epilepsy patients with no history of generalized tonic-clonic seizures. "This risk was increased to 15-fold in patients who had three or more of these seizures per year," Dr. Hesdorffer reported. Male gender, onset of epilepsy before age 16, epilepsy duration of more than 15 years, and polytherapy also were associated with a significantly increased risk of sudden death, she said.

In patients with no history of generalized tonic-clonic seizures, polytherapy was associated with a 2.5-fold increased risk of sudden death. Those with a history of one or two generalized tonic-clonic seizures and polytherapy had a 10-fold increased risk. Three or more such seizures and polytherapy were associated with a 27-fold increased risk, Dr. Hesdorffer reported.

In patients on monotherapy, the sudden death risk for patients with one or two generalized tonic-clonic seizures was six times higher than that of controls; for those with three or more seizures, it was 12 times higher.

Idiopathic generalized epilepsy was associated with a decreased risk of sudden death. The exception was seen in patients taking lamotrigine, Dr. Hesdorffer said. Factors that were not significantly associated with SUDEP included levels of carbamazepine, valproate, or phenytoin, as well as age at death, epilepsy surgery, comorbid mental health disorders, learning difficulty, alcohol abuse, and comorbid pulmonary disease, she said.

The results provide an "emerging profile" of epilepsy patients who are at increased risk of SUDEP, said Dr. Hesdorffer. "The contribution of antiepileptic drug therapy – particularly that of lamotrigine therapy – should be further examined."

Dr. Hesdorffer reported having no financial conflicts of interest.

SAN ANTONIO – Frequent generalized tonic-clonic seizures, the use of multiple antiepileptic drugs, a 15-year or longer duration of epilepsy, and an epilepsy diagnosis before age 16 were among the statistically significant risk factors for sudden unexplained death in epilepsy.

The associations were detected in a pooled analysis of four published case-control studies presented at the annual meeting of the American Epilepsy Society.

In patients with idiopathic generalized epilepsy, lamotrigine therapy also was associated with an increased risk of death. In addition, male gender was associated with increased mortality, as were stroke, infection, traumatic brain injury, and brain tumor, reported epidemiologist Dale Hesdorffer, Ph.D., of Columbia University in New York.

Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in chronic epilepsy. Yet most studies that have attempted to identify risk factors have been limited by the small number of cases in each study. To address this deficiency, Dr. Hesdorffer and her colleagues in the Epidemiology Task Force of the International League Against Epilepsy combined data from four similarly designed case-control studies conducted in the United States, Sweden, Scotland, and England. The number of cases of sudden death ranged from 20-149 cases in each study. All cases had a history of epilepsy with at least one seizure during a 5-year period and unexpected death that occurred suddenly and remained unexplained after further investigation, including autopsy.

"Across the studies, statistically significant risk factors for sudden unexplained death in epilepsy were a high number of generalized tonic-clonic seizures, poly-antiepileptic drug therapy, high seizure frequency, and young age at epilepsy onset," she said.

Using logistic regression analysis to identify risk factors, the researchers employed the largest study (149 cases, 602 controls) as the reference initially and then controlled for the largest study to eliminate the possibility that its size would bias the results, Dr. Hesdorffer explained. The investigators adjusted multivariate analyses for study, age of death, gender, and duration of epilepsy.

The analyses revealed that individuals with one or two generalized tonic-clonic seizures per year had a fivefold increased risk of sudden death compared with epilepsy patients with no history of generalized tonic-clonic seizures. "This risk was increased to 15-fold in patients who had three or more of these seizures per year," Dr. Hesdorffer reported. Male gender, onset of epilepsy before age 16, epilepsy duration of more than 15 years, and polytherapy also were associated with a significantly increased risk of sudden death, she said.

In patients with no history of generalized tonic-clonic seizures, polytherapy was associated with a 2.5-fold increased risk of sudden death. Those with a history of one or two generalized tonic-clonic seizures and polytherapy had a 10-fold increased risk. Three or more such seizures and polytherapy were associated with a 27-fold increased risk, Dr. Hesdorffer reported.

In patients on monotherapy, the sudden death risk for patients with one or two generalized tonic-clonic seizures was six times higher than that of controls; for those with three or more seizures, it was 12 times higher.

Idiopathic generalized epilepsy was associated with a decreased risk of sudden death. The exception was seen in patients taking lamotrigine, Dr. Hesdorffer said. Factors that were not significantly associated with SUDEP included levels of carbamazepine, valproate, or phenytoin, as well as age at death, epilepsy surgery, comorbid mental health disorders, learning difficulty, alcohol abuse, and comorbid pulmonary disease, she said.

The results provide an "emerging profile" of epilepsy patients who are at increased risk of SUDEP, said Dr. Hesdorffer. "The contribution of antiepileptic drug therapy – particularly that of lamotrigine therapy – should be further examined."

Dr. Hesdorffer reported having no financial conflicts of interest.