Mortality In Epilepsy (SUDEP)
Feature Article by Joseph Bruni, B.Sc., M.D., F.R.C.P.(C).; Neurology, The Wellesley Hospital, Toronto, Ontario
In the context of the presentation epilepsy refers to a chronic condition characterized by recurrent epileptic seizures which are either idiopathic, cryptogenic or secondary to some recognizable cause. Epileptic seizures vary widely in clinical presentation and duration and the international classification of epileptic seizures classifies seizures into partial and generalized seizures. Seizure classification and the classification of epilepsy syndromes give some indication as to the possible underlying causes of epilepsy. It helps the physician develop a plan of investigations, and finally forms the basis of drug therapy.
The incidence of epilepsy varies from a range of 0.1% to 0.7% with the highest incidence of epilepsy occurring amongst the age groups of less than 1 to 4 years of age. Of all new cases of seizure disorders 75% occur before the age of 20. The incidence of epilepsy plateaux in adult life and middle age and then there is an increase in the incidence of seizures in elderly patients.
Since the initial introduction of bromides in the treatment of epilepsy in the 1850's until 1991 only several major antiepileptic drugs were available for the treatment of epilepsy. These included phenobarbital, primidone, phenytoin, carbamazepine, ethosuximide and valproate. In 1991 clobazam was introduced and in 1994 two new compounds vigabatrin and gabapentin were introduced. In 1995 lamotrigine therapy became available for general use. Antiepileptic drugs have a specific spectrum of activity and the probability of patients becoming completely seizure free will depend on the type of epilepsy syndrome. In general the primary generalized idiopathic seizure disorders and the benign partial seizure disorders of childhood have a more favourable response to antiepileptic drug therapy than partial seizure disorders. The overall probability of the patient becoming seizure free on antiepileptic drug therapy is generally in the range of 30-50%. The introduction of new antiepileptic drugs has improved seizure control in 30-50% of patients with refractory epilepsy.
Although antiepileptic drug therapy has improved overall seizure control the mortality of patients with epilepsy has generally remained consistent. Different population studies that have examined the mortality of patients with epilepsy have an increased mortality rate with the exception of patients with idiopathic absence and idiopathic complex partial seizures. The increased mortality is greatest in the younger age groups and more pronounced in men than in women.
Mortality studies in epilepsy have been studied using a number of techniques including life insurance policy holders, general populations, clinical studies, and the information derived from death certificates. All of these studies have certain biases and inadequacies.
When all forms of epilepsy are considered the standardized mortality ratio exceeds in various patients with various seizure types excluding absence and idiopathic complex partial seizures. Relative mortality is higher in individuals with epilepsy at all ages but standardized mortality ratios are highest in the younger age groups. The increased mortality in epilepsy generally relates to the underlying cause of epilepsy. In younger patients epilepsy is frequently associated with neurological deficits such as cerebral palsy and congenital malformations. In adults epilepsy is frequently related to head trauma and neoplasms. In elderly patients stroke, tumours and degenerative diseases are common causes of epilepsy.
Most clinical studies have shown higher standardized mortality ratios in men than in women. Mortality generally remains increased in patients with epilepsy for at least ten years after diagnosis. There generally is a correlation between the severity and frequency of seizures and mortality. Higher mortality rates for non-whites of either sex both for deaths due to and related to epilepsy have been reported in the USA. This might, however, be due to socio-economic factors rather than race.
Common causes of death in patients with epilepsy include epilepsy related death and accidents, infections and neoplasia. Bronchopneumonia is an important cause of death in people with epilepsy especially in the elderly age group. Predisposing factors to this increase in death rates may be partly related to aspiration during seizures. The mortality rates in patients with epilepsy are elevated for cancer whether or not primary brain tumours are included and death due to cancer is more frequent in people with epilepsy than in the general population.
Epilepsy as a direct cause of death can be subdivided in different categories. These include seizure related death, death due to prolonged status epilepticus accidents and sudden unexpected death.
Sudden unexpected death is defined as a non-traumatic death occurring in patient with epilepsy who was otherwise previously healthy and for whom no cause of death can be determined after a complete postmortem examination. This phenomenon has been recognized as early as 1910 although the explanation for the mechanism of sudden death is still poorly understood. This may be related to automatic disturbances during seizures which may result in fatal cardiac arrhythmias. 10-17% of deaths in patients with epilepsy are related to sudden unexpected and unexplained death. Most cases involve young patients with a long history of generalized tonic-clonic seizures. Frequently the patients are found dead in bed and the postmortem examinations may revealed focal brain lesions causing the epilepsy but anatomic cause of death cannot be established. In most patients antiepileptic drug serum levels are generally sub-therapeutic. Whether neurogenic pulmonary edema plays a role in sudden unexpected death in unclear. Sudden unexpected death is less common in other patients with epilepsy in whom cardiac disease and sudden cardiac death are the most common causes of mortality.
Patients with epilepsy may die because of accident secondary to a seizure or as a consequence of a seizure. There is a higher risk of patients being involved in accidents and standardized mortality ratios are uniformly elevated. Drowning remains a common cause of death. Patients with complex partial seizures have a higher risk of suicide.
It is difficult to prove any relationship between death and long term use of antiepileptic drugs. Rarely antiepileptic drugs, however, may cause fatal idiosyncratic reactions. Generally these occur during early stages of treatment. Rarely patients with epilepsy may take intentional or non-intentional fatal overdoses of antiepileptic drugs.
Some studies have suggested that long term use of antiepileptic drugs could be associated with oncogenic potential and the drugs that have been most frequently implicated are phenytoin and the barbiturates. Sporadic reports of an association with malignant lymphomeus have been published but before definite conclusions can be reached further long term studies are required.
