6
CHAPTER
Epidemiology
Sanjeev V. Kothare
The epidemiology of epilepsies across ages is described, with specific emphasis on incidence and prevalence for age, gender, type of seizures and epilepsy syndromes, etiology, efficacy of surgery and effect of medications and their withdrawal during remission, recurrent risks, prognosis, and mortality. The epidemiology of status epilepticus (SE) is also discussed. A short description on the epidemiology of sudden unexpected death in epilepsy (SUDEP) has also been provided. Appropriate definitions of epidemiological terms have been discussed. A list of appropriate references for additional reading is provided at the end.
DEFINITIONS
Epidemiology is the study of the distribution and determinants of a disease in human populations; the study of the dynamics of a medical condition in the community. It can be classified into three aspects: descriptive, analytical, and experimental (1).
Descriptive epidemiology concerns the incidence and prevalence, and the natural history (prognosis and mortality) of a condition. It may be thought of as observational, with no designed control group (2). Analytical epidemiology compares those with a disease or risk factor with those without, for example, in cross-sectional, cohort, and case–control studies. Experimental epidemiology includes studies under conditions that allow an investigator to control relevant factors. The epidemiology of epilepsy is largely based on descriptive and analytical studies (3).
The incidence rate of a condition is the number of persons who become diseased during a defined period divided by the total person-time at risk during that period. It is generally expressed as the number of cases per 100,000 people in the population per year. The point prevalence rate is the number of diseased persons in a defined population at one point in time, divided by the number of persons in that population and time.
Despite epilepsy being among the most common serious neurological conditions, the reported incidence and prevalence figures vary widely. This may be due to differences in case ascertainment, differences in age groups studied, and differences in location of the study (4).
Before 1960, most studies of epilepsy were based on patients seen in tertiary care centers. These tended to show that epilepsy was a chronic, progressive and incurable disease. Underreporting, inaccurate assessment, and diagnosis of seizures, and inappropriate and inaccurate coding are important examples of ascertainment bias. Appropriate inclusion criteria such as inclusion of neonatal seizure, febrile seizures, and acute symptomatic seizures may further confound this bias.
The incidence of epilepsy is higher in children and the elderly (5,6). About 50% of cases of epilepsy start in the two extremes of life, with half of those being under 1 year.
In general, higher incidences of epilepsy have been reported from developing countries, especially Latin American, African, and many Asian countries (7,8). This may be related to a higher prevalence of parasitic infections, intracranial infections, perinatal brain damage, head trauma, and hereditary factors. Racial differences have also been found, including higher incidence and prevalence among African Americans in the United States.
INCIDENCE AND PREVALENCE
The overall incidence of epilepsy, excluding febrile seizures and single seizures, is generally estimated to be about 50 cases per 100,000 persons per year (range 40–70) in developed countries and 100–190 per 100,000 cases per year in developing countries (4). The cumulative incidence of epilepsy (proportion of a fixed population that develops epilepsy in a certain time) is between 2% and 5%, with 1 out of 15 people experiencing an unprovoked seizure at some stage.
The prevalence of epilepsy is usually estimated to be between 4–7 and 7–30 cases per 1,000 persons in developing countries, excluding febrile seizures, single seizures, and inactive seizures. The lifetime prevalence of developing seizures is between 2% and 5%. Over one-third enter long-term remission and subsequent relapse is uncommon (4).
Gender and Age
Most studies have cited a slightly higher incidence of epilepsy in males than in females. There is a bimodal age distribution of the incidence of epilepsy, with the highest incidence being reported at 168.5 per 100,000 person-years between ages 75 and 84 years, 110 for age over 65 years, and 130 for infants (1). In contrast, the prevalence of epilepsy increases with age, with the highest prevalence between 10 and 15 cases per 1000 persons above 75 years of age. The prevalence may be lower in the developing countries because of lower life expectancy and quality of care available (9).
Classification
Seizure Type
The National General Practice Study of Epilepsy (NGPSE), a prospective population-based cohort of 564 subjects with various seizure types, found that 11% were classified as having complex partial seizures, 3% with simple partial seizures, 27% with secondarily generalized seizures, 35% with primarily generalized tonic–clonic seizures, and less than 1% each with generalized absences and myoclonus. Fourteen percent were mixed (partial and generalized), and 9% were unclassified (1). Generalized seizures are more common in children, while partial seizures are twice as common in adults over 24 years. Similar figures are also seen for the prevalence rates. Misdiagnosing partial from generalized seizures may be an issue in developing countries because of lack of easy access to EEG (8).
Epilepsy Syndrome
Localization-related epilepsies are the most frequent form of epilepsy in most studies, with 47% having localization-related epilepsy and 34% having generalized epilepsy (9). Between 15% and 20% of epilepsies lack clear focal versus generalized features. In general, the syndrome classification is better suited for classifying childhood-onset epilepsy. In one study from Iceland, incidence rates for various epilepsy syndromes were calculated as follows: nearly 1 per 100,000 for juvenile myoclonic epilepsy and childhood absence epilepsy, nearly 3 per 100,000 for benign rolandic epilepsy, 0.007 per 100,000 for West syndrome, and less than 0.5 per 100,000 for benign occipital lobe epilepsy, benign familial infantile convulsions, and Landau-Kleffner syndrome (4).
ETIOLOGY
A recent community-based magnetic resonance imaging (MRI) study found that in newly diagnosed patients, a relevant putative etiology could be found in 70% of those with partial-onset seizures and 30% of those with generalized seizures. Improvement in better imaging and genetic/metabolic testing will lead to an improved yield for finding an etiology in the future.
PROGNOSIS
Recurrence After Single Seizure
The overall risk of seizure recurrence is 40% in prospective studies and 52% in retrospective studies. Two-thirds of the cases have their recurrence within a year, and about 80% within 3 years. The overall risk of seizure recurrence decreases with time.
Recurrence After Second Seizure
After the second seizure in a patient, the cumulative risk of a further seizure recurrence is 32% at 3 months, 41% at 6 months, 57% at 1 year, and 74% at 4 years. The risk is reduced significantly if there were no recurrence beyond 4 years.
Short- to Long-Term Prognosis
The short-/medium-term prognosis is favorable, with 60% to 70% of patients achieving remission. About 60% to 70% of cases achieve remission in the long term with or without treatment. Remission is more likely with childhood epilepsies.
Prognostic Factors
Remote symptomatic epilepsy, presence of a neurologic birth defect, and learning disability have consistently been shown to be associated with a poor prognosis (4). The number of seizures in the first 6 months after seizure onset is a strong determinant of the probability of subsequent remission. More than 10 seizures in 6 months after seizure onset are associated with a lower chance of going into remission on or off treatment. Similarly, seizure freedom within 3 months of initiating therapy seems to be a strong predictor of subsequent remission. Seizure clusters are a poor prognostic factor.
Among patients who have not received any antiepileptic drug (AED), 47% become seizure free on their first AED, and an additional 14% on a second or third drug (10). In addition, only 3% are controlled with a combination of two AEDs. Eleven percent of those who did not achieve seizure control on using the first appropriate AED respond to the second drug. Approximately 4% to 5% of patients with refractory epilepsy will achieve seizure control eventually on a combination of multiple AEDs. There is no significant difference in the seizure-free rates between patients taking an established AED and those taking a newer AED. Primary generalized epilepsy has the best prognosis for seizure control and hippocampal sclerosis the worst for seizure control on AEDs. Immediate treatment with AEDs delays the early recurrence of seizures but does not affect the medium- or long-term prognosis.
Prognosis Following AED Withdrawal
After two or more years of seizure freedom, the chance of recurrence of seizures is 41% for those in whom AEDs have been discontinued. When AEDs are continued, the recurrence rate is 22% (4). On reinstating the AED for seizure recurrence, the chance of achieving seizure freedom again is 80%. Thus, the long-term prognosis for both groups is similar.
Prognosis Following Epilepsy Surgery
In appropriately selected patients with refractory partial epilepsy, surgery is 4 times more likely to render patients seizure free (42%) as compared to medical treatment alone (8%).
MORTALITY
People with epilepsy have a two- to threefold increased risk of premature death compared with the general population. This is more so in patients with neurological deficits and symptomatic seizures, while the risk in idiopathic generalized epilepsy is the same as in the general population.
Mortality in Epilepsy
Standardized mortality rate (SMR) is defined as the ratio of observed deaths in a cohort divided by the number of expected deaths in the age-/sex-specific population. The SMR in patients with a newly diagnosed, unprovoked seizure ranges from 2.5 to 4. In young children and those with remote symptomatic epilepsy, the SMR is higher (1). Reported SMRs for epilepsy from developed countries range from 1.6 to 4.1, more so in males than in females for unclear reasons and in children due to the underlying etiology of the epilepsy syndrome.
Cause of Death
The cause of death can be divided into epilepsy-related and non-epilepsy-related. Common non-epilepsy-related causes include pneumonia, cerebrovascular disease, malignancy, and heart disease. Deaths directly related to epilepsy include sudden unexpected death in epilepsy (SUDEP), SE, and accidents, as a consequence of the seizures including drowning, drug toxicity, and suicide (4).
Sudden Unexpected Death in Epilepsy
The incidence of SUDEP is 1 in 1000 persons with epilepsy (in the general population it is 1 in 40,000). In patients with refractory epilepsy, it is 1 in 100 to 200, but is four times less likely in children. Identified risk factors for SUDEP include younger age of onset of epilepsy, higher seizure frequency, refractory epilepsy, longer duration of epilepsy, occurrence of tonic–clonic seizures (especially at night during sleep), use of two or more AEDs, noncompliance with AEDs, substance abuse, mental retardation, neurological deficits, and remote symptomatic etiology for the epilepsy. SUDEP is discussed in more detail elsewhere in this text.
STATUS EPILEPTICUS
The epidemiology of SE has a bimodal distribution with peaks in children aged less than a year and the elderly (11–14). Most SE cases have an acute symptomatic etiology. The overall incidence rates for SE ranges from 10 to 41 per 100,000 cases per year (median 20). The incidence is higher in children at 10 to 38 per 100,000 cases per year, more so in ages less than 1 year (50 per 100,000 cases per year). Similarly, the cumulative incidence of developing SE in patients above 65 years is significantly higher at 86 per 100,000. In patients older than 75 years, it is even more at about 400 per 100,000 cases (14). The large variability in the incidence of SE may be due to ascertainment bias, including cases of convulsive versus nonconvulsive SE and prolonged febrile seizures. Gender may also affect incidence. Males are twice more likely to develop SE than females.
Recurrence of SE occurs in less than 20% cases, with the greatest risk of recurrence in the first 2 years after the first episode. The short-term mortality ranges between 7.6% and 22%, while the long-term mortality is around 43%. Age and underlying etiology are the major determinants of mortality. An acute symptomatic etiology is the most common cause precipitating SE. The hospital mortality following SE in childhood is around 3% (range 2.7%–5.2%). Continuous EEG monitoring and early aggressive treatment, especially with adequate doses of benzodiazepines, improves outcomes.
