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Purpose: Regional variations and temporal trends in the incidence of new-onset epilepsy are clinically important and may offer clues on how to prevent epilepsy.
Methods: We examined regional differences and secular trends in the incidence of new-onset epilepsy in the Finnish population based on the nationwide full-refundable antiepileptic drug registry and the population registry in the years 1986–2008.
Key Findings: The overall incidence of epilepsy was significantly higher in eastern Finland than in middle [risk ratio (RR) 1.08 (95% confidence interval, CI 1.05–1.12)), p < 0.0001] and western Finland [RR 1.32 (1.30–1.35), p < 0.0001] but it was declining from 1986 to 2008 in all regions [RR 0.83 (0.81–0.84), p < 0.0001]. The mean annual decline was 0.6%. Although the incidence of epilepsy was falling from 1986 to 2008 in childhood [annual decline 1.9%, RR 0.80 (0.75–0.86), p < 0.0001] and in middle age [annual decline 0.8%, RR 0.88 (0.84–0.93), p < 0.0001], it increased significantly in the elderly (age 65 years or older) in all of Finland [annual increase 3.5%, RR 1.25 (1.18–1.33), p < 0.0001], and particularly in east versus west Finland [RR 1.48 (1.42–1.55), p < 0.0001]. As a result, starting with the year 2000, the incidence rate of epilepsy was higher in the elderly than in children for all of Finland.
Significance: In view of the falling incidence of epilepsy in childhood and middle-age in all of Finland from 1986 to 2008, the significant increase in the incidence of epilepsy in the elderly is of concern. The regional increase of epilepsy may offer clues for allocating resources and, possibly, population epileptogenesis between west and east Finland and for strategies to prevent epilepsy in the elderly.
Although an increase in the incidence of new-onset epilepsy has been reported in the elderly (Hauser et al., 1993; Sillanpää et al., 2006), several studies suggest that the incidence of epilepsy is falling in the general population (Cockerell et al., 1995), particularly in the middle-aged (Sillanpää et al., 2006) and in children (Hauser et al., 1993; Annegers et al., 1995; Sillanpää et al., 2006). In a recent nationwide study from Finland (Sillanpää et al., 2006), a significant decline in the incidence of epilepsy was found in the total population, particularly in children and the middle-aged, but an increase in the elderly. This study did not examine regional differences and covered a follow-up of only 17 years. However, there are no nationwide long-term studies to examine temporal changes in the incidence of new-onset epilepsy over >20 years for each age group. Although a prevalence study based on the hospital discharge registries suggested that the epilepsy incidence is highest in eastern Finland and lowest in western Finland, with middle Finland in between (Sillanpää & Koivusilta, 1986), we found no nationwide reports from Finland or elsewhere that examined regional differences in the incidence of new-onset epilepsy over an extended observation period.
Finding regional differences in the incidence of epilepsy would not only be clinically important for public health planning but may also provide clues for research on epileptogenic mechanisms that either expose to or protect from the development of epilepsy. Because the age-related incidence of epilepsy seems to subject to secular trends, as reviewed above, we undertook a large nation-wide long-term study of geographic differences in the incidence of new epilepsy in Finland in different age groups.
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Our nationwide registry study has three main results. One, during the follow-up period of 23 years, the overall incidence of epilepsy significantly decreased 14% in the Finnish total population. The decrease in the incidence could be seen in western, middle, and eastern Finland.
Although the incidence of epilepsy decreased from 1986 to 2008 by 45% in the young and by 19% in the middle-aged, it increased in the elderly by 80%. Two, the incidence of epilepsy was throughout the observation period 1.2-fold higher in men than women in all age groups and all regions, with the most marked difference in eastern Finland. Three, we found substantial regional differences in the incidence of epilepsy. A significant 1.5-fold increase of epilepsy could be demonstrated in elderly men and women (65+ years) in eastern versus western Finland, whereas the increase was not significant for either men in middle versus western Finland or for women in eastern versus middle Finland. Therefore, middle Finland constitutes a kind of an intermediate zone between western and eastern Finland in terms of significant changes in the incidence of epilepsy. Starting with the year 2000, the incidence rate of epilepsy is higher in the elderly than in children for all of Finland. In the following section we discuss our finding of regional differences in the incidence of epilepsy in more detail.
Regional differences in the incidence of epilepsy
Compared with western Finland, eastern Finland had a significantly higher prevalence of and mortality from cardiovascular diseases (Keys et al., 1958; Pyörälä et al., 1985) as well as their risk factors (Juonala et al., 2004, 2005). Therefore, it seems possible that the higher rate of overt cardiovascular disease as well as risk factors for cardiovascular disease in eastern versus western Finland may have contributed to the higher incidence of epilepsy in eastern Finland. Although we have no evidence for a birth cohort effect, it is noteworthy that the risk factors for cardiovascular diseases were more common and more severe in eastern than western Finland in the 1960s and early 1970s until, in 1972, an intervention program against cardiovascular risk factors was started in eastern Finland (Puska et al., 1976; Puska, 2010). This program may have reduced the incidence of cerebrovascular events and of subsequent epilepsy in the middle-aged but may have come too late for the elderly.
In that respect it may be worthwhile to note that vascular factors have been suggested to contribute to epileptogenesis in symptomatic epilepsy, at least in experimental models of epilepsy (Ndode-Ekane et al., 2010). Furthermore, recessive diseases, typical of the Finnish population (Finnish Disease Heritage) are significantly more common in eastern than western Finland (Norio, 2003).
There is only one study on the regional differences of the occurrence of epilepsy in Finland (Sillanpää & Koivusilta, 1986). Based on nationwide hospital discharge registry data from the years 1977 and 1982, the proportion of the same-age people hospitalized for primary epileptic seizures was shown greater in eastern than in western Finland (120–168/100,000 vs. 79–100/100,000). Several confounding factors of the study include lower population density and longer distances from hospitals in eastern Finland, which are likely to have increased the hospitalization rate and worsened the discharge rate. The mean number of hospitalization days varied between 10.0 and 27.2 days in western Finland, but between 12.9 and 99.6 days in eastern Finland.
Secular trends in the incidence of epilepsy
As noted briefly in the introduction, there are few studies on secular trends in the incidence of epilepsy in the general population. Cockerell et al.(1995) reported a prevalence of active epilepsy in a small population of 6,000 persons to have significantly declined from 5.3/1,000 in 1983 to 4.3/1,000 in 1993. In the Rochester study (Annegers et al., 1995; Hauser et al., 1993), the incidence of one or more unprovoked cryptogenic epileptic seizures declined particularly in the childhood age group 0–9 years from 85/100,000 in 1935–1944 to 60/100,000 in 1975–84. A random sample study of the year 1986 birth cohort (M. Sillanpää, unpublished data), followed for 15 years in southwestern Finland, obtained the cumulative incidence of 150 per 100,000 children aged 4–15 years. This rate is of the same order as the incidence of epilepsy (158/100,000) of the 5–15-year-olds of the present study. As noted in the introduction, a recent nationwide study (Sillanpää et al., 2006) reported a significant decline in the incidence of epilepsy in the total population, particularly in children and the middle-aged, but an increase in the elderly. The novelty of the present study is that we examined the secular trends of the incidence over all age groups and in different regions of one country over 23 years.
The reasons for the decline of the incidence of childhood epilepsy are unknown but may include better obstetric and neonatal care (Hull & Dodd, 1992) and widespread national vaccination programs that prevent encephalitic brain injuries. Although mortality of very preterm infants is declining, there may be an increase in morbidity. During a 10-year period, in very preterm infants (below 25 gestational weeks), no changes in the rates of cerebral haemorrhages or seizures could be found (Lundqvist et al., 2009). Severe postnatal injuries, often followed by epilepsy (Annegers et al., 1998; Christensen et al., 2009), have been decreasing over the time period studied. In Finland, the annual incidence of head injuries decreased from 250–120 per 100,000 in boys and from 150–100 per 100,000 in girls (Parkkari et al., 2000).
Changes in treatment practices might also have contributed to the decline shown in the present registry data. The previous practice of regarding cases with a single seizure, particularly status epilepticus, as epilepsy and in need of drug therapy, may have evolved into a more restrictive use of long-term AED treatment in these cases. The number of pediatric neurologists who currently take care of most children with epilepsy in Finland prefer to have a longer follow-up of the patient with seizures than before to ascertain the diagnosis of epilepsy warranting full-refundable drugs. Some patients may then be left unmedicated. There is also a greater awareness of certain benign epileptic syndromes in infancy and childhood not necessarily needing long-term AED treatment at all. In few cases, some patients may have been administered a novel antiepileptic drug as a first-line drug without reimbursement. Although each of these particular factors may play a marginal role, they may jointly affect the incidence rate.
Incidence of epilepsy in the elderly
According to our study, the elderly are now at higher risk of epilepsy than 20 years ago. Although some studies still report lower rates in the elderly than in children (Forsgren, 1992), the increased rate of epilepsy is now widely recognized (Keränen et al., 1989; Hauser et al., 1993). An increasing trend in the elderly has been reported from France (Loiseau et al., 1990), the United States (Hauser et al., 1993; Annegers et al., 1995), Iceland (Olafsson et al., 1996), and Estonia (Oun et al., 2003).
Reasons for the rising incidence rate of epilepsy in the elderly are largely unclear. In all industrialized countries including Finland aging of people and increasing survival of people with underlying medical conditions such as stroke place them at higher risk than before. Stroke and other vascular catastrophies are the most common risk factor for epilepsy in the elderly (Camilo & Goldstein, 2004). Annegers et al. (1995) attributed an increased incidence in the elderly of longer survival after stroke. In accordance, reports from several Scandinavian countries indicate decreasing incidence, mortality and case fatality rates of stroke (Sivenius et al., 2004). According to the Finnish nationwide registry data (Pajunen et al., 2005b), the incidence of first-ever stroke declined from 1991 to 2002 both in men and in women aged 75–84 years and in those 85 years and older. Municipal health care, responsible for institutionalized patients with epilepsy (who are not included in the SII files), has increasingly moved these patients to open care, in part, to become eligible for fully refundable antiepileptic medication from the SII system. Although no data are available, that may possibly have, to a minor extent, contributed to the increase in the incidence of epilepsy in the elderly in registry-based data.
Cerebral tumors are another major cause of epilepsy in the elderly occurring in 11% (Sander et al., 1990; Forsgren et al., 1996). Similarly, a severe brain injury is associated with late seizures in 12% of adults (Annegers et al., 1998). The incidence of dementing diseases is increasing with aging and with time. A diagnosis of Alzheimer’s disease and a diagnosis of other dementia, classified according to the criteria of DSM-III, were associated with at least sixfold risk for epilepsy (Hesdorffer et al., 1996). Improving skills in identification and ascertainment of epilepsy due to an increased awareness by neurologists about the condition in the elderly may be an additional factor for the increase.
Finally, it is worthwhile to note that the age-specific incidences for different birth cohorts (Fig. 4) are similar in all the three regions, indicating no specific birth cohort effect on the incidence, with one exception. The exception is the oldest age group in the birth cohort of 1897–1930. The 1897–1930 birth cohort showed either a decline or a flat incidence rate in those beyond 80 years of age. In the light of other findings of our study, the most obvious explanation is a shorter life time of that cohort. Consequently, the patients in the oldest cohort at risk did not survive long enough to get epilepsy in their life time. The lower incidence of epilepsy in this subgroup, however, did not change the fact that the elderly people are at higher risk of epilepsy than other adults.
The SII data do not include a small minority of people (3% in 2003, data on the SII file) with epilepsy, who although eligible, elect not to utilize the fully refundable drug system. On the other hand, a small minority of patients with a misdiagnosis of epilepsy has been granted refundable medication (data on file). As an additional limitation of the registry, it does not cover people who are living in institutions for the mentally retarded or in nursing homes. Although there is uncertainty about the incidence of epilepsy among institutionalized patients or among residents of nursery homes, we estimate that the SII registry covers 97% of all persons with new-onset epilepsy (see Data S1).
Implications and conclusions
The two main outcomes of our study are that the incidence of epilepsy is much higher in east versus west Finland and that the incidence of epilepsy has increased in the elderly and declined in the young have implications for epilepsy research and for public health. We are not aware of publications of regional differences of the incidence of epilepsy elsewhere. Therefore, it is difficult as of now to extrapolate our findings to other countries. The increase in the incidence of epilepsy in the elderly is alarming and makes prevention of epilepsy in the aging population a top priority for experimental and clinical epilepsy research. On a more optimistic note, we found that pediatric epilepsy is declining. Identifying the cause(s) of the apparent increase in population epileptogenesis in one region versus another region is also a high priority for epilepsy research. Identifying the mechanism(s) for the decline in epilepsy may provide new tools for efforts to completely cure epilepsy. In conclusion, our study shows a janus-like view of epilepsy, with a decline of pediatric epilepsy and an increase in epilepsy for the rapidly increasing elderly population.