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Purpose: To determine the prevalence of epilepsy in a defined adult population and identify the frequency and principal features of pharmacoresistant epilepsy.
Methods: From a population over 15 years of age residing in a medium-sized French city, all patients with epilepsy on June 30, 1995 were identified from multiple sources. Pharmacoresistance was defined as failure to control epilepsy by at least two first-line antiepileptic drugs, with a seizure frequency of at least one per month for 18 months. Collected data were examined by experts in epileptology, and responding patients were reexamined using a standardized diagnostic questionnaire. ILAE definitions and classifications were used.
Results: The age-adjusted prevalence of active epilepsy was 5.4 per 1,000 (95% CI: 4.7–6.0) and was higher for males (7.8) than for females (5.2). For epilepsy in remission under treatment, this rate was 0.7 per 1,000 (95% CI: 0.5–0.95). Age-specific prevalence was highest in age groups 25–49 years and declined in the oldest age groups. Localization-related seizures represented 61.1% of cases and generalized seizures 30.9%. The proportion of noncontrolled epilepsy (seizure-frequency at least one per month for 18 months) was 15.6%, corresponding to a prevalence of 0.94 per 1,000. In this group, the mean age at onset was lower (p = 0.0007) and localization-related epilepsy more frequent (p = 0.01).
Conclusion: The findings support previous epidemiological estimates of the prevalence of epilepsy in developed countries. For approximately one patient in eight, epilepsy was not adequately controlled.
Prevalence studies provide pertinent epidemiological data for a rational approach to planning health-care provision, as well as providing a basis for hypothesis generation in clinical research or analytical epidemiological studies. Many studies have been performed in the past to determine the prevalence of epilepsy and these have yielded prevalence rates of active epilepsy varing from 4 to 10 in 1,000 (Crombie et al., 1960; Gudmundsson, 1966; Zielinski, 1974; Granieri et al., 1983; Haerer et al., 1986; Joensen, 1986; Keränen et al., 1989; Hauser et al., 1991; Maremmani et al., 1991; Forsgren, 1992; Giuliani et al., 1992; Cockerell et al., 1995; Nakashima et al., 1996; Reggio et al., 1996; Olafsson & Hauser, 1999; Oun et al., 2003). This variation can largely be explained by differences in case evaluation methods as well as in the definition of epileptic seizures and syndromes, since many of these studies date from several decades. In addition, improvements over time in diagnosis, prevention, and management of epilepsy may influence prevalence rates (Berg et al., 1996).
The publication of guidelines for epidemiological studies by the International League Against Epilepsy (ILAE) in 1993 (Commission on Epidemiology and Prognosis and International League Against Epilepsy, 1993) provided standardized definitions of epilepsy. However, there have been very few population-based prevalence studies performed since these guidelines were introduced. In Western Europe, no such population-based studies have been performed since then. The last major study was an incidence study of nonprovoked first epileptic seizures in South-West France (Loiseau et al., 1990).
The proportion of patients with pharmacoresistant epilepsy in the general population is currently unknown. Some studies have examined the proportion of patients with a high frequency of seizures but without specifying explicit criteria for pharmacoresistance (Haerer et al., 1986; Juul-Jensen, 1986; Keränen & Riekkinen, 1988; Hauser & Hesdorffer, 1990; Forsgren, 1992, 1995; Hart & Shorvon, 1995). Patients with pharmacoresistant epilepsy are the target for new antiepileptic drugs (AEDs) and, in case of failure, epilepsy surgery may be considered in certain circumstances. Therefore, it is important to determine the prevalence of pharmacoresistant epilepsy in order to plan resource allocations for epilepsy surgery centres.
The objectives of this study were, first, to assess the prevalence of epilepsy in a Western European country using a population-based sampling method and the ILAE guidelines and, second, to determine the frequency and features of pharmacoresistant epilepsy.
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This study is the first population-based study on the prevalence of epilepsy in Western Europe, and the only epidemiological study to have used the current classification criteria for seizures and syndromes, together with the ILAE guidelines for epidemiological studies published in 1993. We obtained an adjusted prevalence of 5.39 per 1,000 for active epilepsy in adults. The study's second goal was to determine the prevalence of pharmacoresistant epilepsy in the general population, for which there is no specific data. This prevalence was 1.4 per 1,000, corresponding to a proportion of 22.1% if lack of control is defined by a seizure frequency of at least one seizure per year. With a more restrictive definition, a seizure frequency of at least one per month, this rate is 0.9 per 1,000 and the proportion is 15.3%.
The principal limitations of the study include the retrospective nature of the study, which meant that information on epilepsy type could not always be ascertained, the use of operational definitions of pharmacoresistance, in the absence of an agreed definition, and difficulties related to diagnosis and classification of seizures, in particular in the elderly, which may have biased the observed age-distribution of seizure prevalence (see below).
The two main difficulties encountered with prevalence studies are ensuring complete ascertainment and diagnostic accuracy. We used every possible means to ensure that few cases went undiagnosed and those patients ascertained did indeed have epilepsy. A U.S. study conducted in the general population using a screening questionnaire found that around 7% of subjects with apparent epilepsy had not been diagnosed (Haerer et al., 1986). Considering the current provision of medical care in France and improved awareness of epilepsy, the rate here is probably lower. Furthermore, such cases remain insufficient to be taken into account when planning healthcare resources.
The prevalence of 4–10 per 1,000 obtained is comparable with results from studies carried out in industrialized countries, in particular two Northern European studies carried out on adults in Finland (Keränen et al., 1989) and Sweden (Forsgren, 1992), which used a similar methodology. The definitions of active epilepsy were somewhat different; at least one seizure or ongoing treatment for epilepsy over the previous 5 years in the Finnish study, and at least one unprovoked seizure during the last 5 years or ongoing treatment for epilepsy over the previous year in the Swedish study. The prevalence obtained in these studies was 6.3 per 1,000 (Sweden) and 5.6 per 1,000 (Finland). Unlike these two Scandinavian studies, our study included patients with isolated treated seizures, although their contribution to overall prevalence (0.3%) was minimal.
In our study, epilepsy was most prevalent in 20- to 50-year-olds, with a secondary peak for subjects aged 70- to 74-year-old. Similar age distributions are reported in other prevalence studies (Beran et al., 1982; Granieri et al., 1983; Keränen et al., 1989; Maremmani et al., 1991; Forsgren, 1992; Oun et al., 2003). Although the notion that the prevalence of epilepsy rises with increasing age is a common finding for epidemiological studies (Brodie & Kwan, 2005), the extent of that rise is unclear. Hauser et al. (1991) reported a prevalence of 14.8 per 1,000 for subjects over 75 in Rochester, U.S.A. in 1980. A prospective study carried out in The Netherlands (de la Court et al., 1996) yielded a prevalence of 9.9 to 12.1 per 1,000 in subjects aged 65–74 to 85–94 years, but provoked seizures were included. The lower prevalence for the elderly reported in our study is mainly due to the way seizures following a cerebrovascular event were classified, this event being a major risk factor for seizures in the elderly (Cloyd et al., 2006). Such seizures, generally occurring soon after an ischemic episode and immediately treated, were considered as provoked seizures in our study and were thus excluded. The prevalence of provoked seizures in subjects aged 70–74 was around 3 per 1,000; including these yielded a prevalence which is consistent with the findings of the Netherlands study.
When classified by syndrome, 64% of epilepsies were focal, again in agreement with the Finnish and Swedish studies (56% and 60%, respectively). These results were obtained with the use of the SISC and validated by epileptologists. Half of epilepsies initially considered as generalized were reclassified as localization-related epilepsies with secondary generalization. In addition, we observed a high prevalence of symptomatic epilepsies in men, mainly attributable to head injuries, which might explain the higher epilepsy prevalence in men with an overall sex ratio of 1.5.
The second objective of this study was to determine the proportion of pharmacoresistant epilepsies in adults in the general population. Previous studies indicate that 20–30% of patients who suffer from epilepsy will go through at least one phase of pharmacoresistance (Sander, 1993). The variations observed in the literature are mainly due to the absence of a consensus on the definition of pharmacoresistance. In the proceedings of a workshop on “Prevention of refractory epilepsy” (Arroyo et al., 2002), the authors consider that it would be more appropriate to separate patients into “easily controlled” and “difficult to control” according to their response to the first-line AED.
At the time of our study, only 20% of patients with uncontrolled seizures were taking new AEDs. Only vigabatrin was generally available and widely used, although some patients received lamotrigine or gabapentin. Nonetheless, the introduction of the newer drugs has clearly not resolved the problem of pharmacoresistant epilepsy. Response rates to these drugs (i.e., the proportion of patients whose seizure frequency is reduced by at least 50%) are typically lower than 50% (LaRoche & Helmers, 2004). In practice, the proportion of patients with pharmacoresistant epilepsy who become seizure-free with the new AEDs is around 10% (Forsgren et al., 2005; Gazzola & French, 2005). Furthermore, Mohanraj and Brodie have shown that overall response rates with the third treatment schedules and further drug trials is 3.1% (Mohanraj & Brodie, 2006).
Many patients with pharmacoresistant localization-related epilepsies may benefit from surgery. Given a prevalence of 0.71 cases per thousand (Definition 1), we can estimate that there are around 34,000 such cases in France. This represents an upper limit to the estimation, since only one-third of these patients, about 11,000 adult patients, would be eligible for surgery (Engel & Shewmon, 1993). Currently, such surgery is proposed in 12 hospital departments in France with about 300 patients operated on each year, which is probably less than the potential demand.
In conclusion, this study has identified the prevalence of adult epilepsy in Western Europe and found that one-eighth of subjects with epilepsy could be considered pharmacoresistant, principally those with localization-related epilepsies. These results could be used to estimate the target population for new AEDs or healthcare provision for surgery or alternative therapies in pharmacoresistant epilepsy.