Growing old with epilepsy

Summary

The purpose of this review is to examine what is known about cognitive and brain aging in elders with chronic epilepsy. We contend that much remains to be learned about the ultimate course of cognition and brain structure in persons with chronic epilepsy and concern appears warranted. Individuals with chronic epilepsy are exposed to many risk factors demonstrated to be associated with abnormal cognitive and brain aging in the general population, with many of these risk factors present in persons with chronic epilepsy as early as midlife. We suggest that a research agenda be developed to systematically identify and treat known modifiable risk factors in order to protect and promote cognitive and brain health in aging and elder persons with chronic epilepsy.

Although epilepsy is a prevalent neurological disorder with known cognitive consequences, in the review to follow we will contend that the course of cognition and brain structure in aging (age 50+) and elder (age 65+) persons with chronic epilepsy is very poorly understood. Virtually no literature addresses this important issue, but we will present data to suggest that there are several reasons for concern. Numerous cognitive deficits, neuroimaging abnormalities, and psychiatric comorbidities have been well characterized in younger persons with chronic epilepsy, with evidence of progression of these problems in some patients by middle age. In that context, people with chronic epilepsy have been exposed to several factors that may place them at increased risk for accelerated cognitive and brain aging, including treatment with medications now known to adversely affect cholesterol, folate and glucose metabolism; increased rates of vascular disease risk factors; altered lifestyles that include decreased social interaction and physical inactivity; and elevated inflammatory markers. In the general aging literature, prospective studies have confirmed the association of these factors with abnormal cognitive and brain aging as well as the risk of dementia including vascular dementia (VaD) and Alzheimer’s disease (AD). We will argue that for aging and elder persons with chronic epilepsy these risk factors have never been comprehensively characterized, never thoroughly examined in relation to major dimensions of physical health (e.g., vascular, pulmonary, cerebral blood flow), and never directly related to cognitive function or brain structure.

At the present time, unprecedented efforts are under way to understand the causes of abnormal cognitive and brain aging in the general population, but similar research in epilepsy is virtually nonexistent. For persons with chronic epilepsy, little is known about the impact of aging on the course of cognitive and brain health, the prevalence of clinical disorders of aging (mild cognitive impairment, dementia), or the disease burdens and modifiable risk factors associated with abnormal cognitive and brain aging. In the material to follow we will review existing studies to address these points. While recent attention regarding epilepsy in aging individuals has centered on elders with new-onset epilepsy (Collins et al., 2006; Cloyd et al., 2006), the focus here is on persons who have lived with epilepsy for long periods of time (15+ years) and are now middle-aged and older.

Chronic Epilepsy is a Prevalent Disorder That May be Associated with Significant Abnormalities in Cognition, Brain Structure, and Psychiatric Health That Progress in Some Patients by Middle Age

An extensive body of cross-sectional neuropsychological research documents impairments in general intellectual ability (IQ) and specific cognitive functions (e.g., memory) in persons with chronic epilepsy and the association of these impairments with disease variables such as early age of onset and seizure frequency (Jones-Gotman, 2000; Aldenkamp & Arends, 2004; Elger et al., 2004). A long-standing concern has been whether chronic pharmacoresistent epilepsy causes progressive cognitive decline over time (Helmstaedter & Elger, 1999; Jokeit & Ebner, 1999; Pitkanen & Sutula, 2002). The number of controlled prospective investigations is modest but the findings suggest progressive cognitive impairment in a subset of patients (cf, Helmstaedter et al., 2003; Dodrill, 2004; Seidenberg et al., in press). Our own controlled prospective cohort study documented an abnormal cognitive trajectory, including memory, among patients with chronic temporal lobe epilepsy compared to healthy controls, a trajectory that was associated with chronicity of disorder. The extent of abnormality was poorly predicted by traditional specific disease-related factors (e.g., seizure frequency), suggesting that other important causes are involved and remain to be identified (Hermann et al., 2006). Importantly, these individuals were middle-aged at follow-up (mean age approximately 40) and yet to face the effects of normal aging on cognition and brain structure, cognitive changes (Dixon et al., 2004) that will be superimposed on an already compromised substrate.

Similarly, a growing neuroimaging literature, best characterized in patients with chronic temporal lobe epilepsy, has demonstrated distributed abnormalities in the hippocampus, temporal and extratemporal regions (e.g., frontal lobe, cerebellum), and subcortical structures (e.g., caudate, thalamus), as well as reduction in cerebral white matter and thinning of the cortical mantle with abnormal gyral/sulcal curvature, with reported progression of some of these abnormalities in a subset of patients (Sisodiya et al., 1997; Sandok et al., 2000; Liu et al., 2001, 2003; Duncan, 2002; Keller et al., 2002; Hermann et al., 2003, 2004; Bernasconi et al., 2004; McMillan et al., 2004; Oyegbile et al., 2004; Bonilha et al., 2006; Lin et al., 2007; Pulsipher et al., in press; Yu et al., in press). Not only are some of these volumetric abnormalities associated with cognitive status in cross-sectional research (Trenerry et al., 1995; Baxendale et al., 1998; Martin et al., 1999; Sawrie et al., 2001; Pegna et al., 2002; Alessio et al., 2004; Bonilha et al., In press), but volumetric abnormalities have also been found to be predictive of adverse cognitive change in short-term (4-year) prospective studies of middle-aged patients with chronic epilepsy (e.g., Hermann et al., 2006).

Brain imaging studies of normal aging have revealed age-related reductions in cerebral blood flow and cerebral metabolic rate of oxygen consumption (Pantano et al., 1984), glucose metabolism in the frontal and temporal lobes (De Santi et al., 1995), white matter integrity measured using diffusion tensor imaging (DTI) (Ardekani et al., 2007; Malloy et al., 2007), and volume reductions in distributed brain regions including medial temporal lobes and prefrontal cortex (Raz et al., 2007). Recent evidence from functional MRI studies suggest that increasing age is also associated with changes in brain activity across the lifespan on several tasks including both episodic and working memory paradigms (Persson & Nyberg, 2006). Among patients with chronic epilepsy, these normal age related changes may then be superimposed on an already adversely affected neural substrate as summarized above. To date there is no information addressing the course and ultimate status of brain structure in aging and elder persons with chronic epilepsy.

Psychiatric comorbidites are overrepresented in the epilepsies (Jones et al., 2005; Swinkels et al., 2005; Tellez-Zenteno et al., in press). There has been little investigation of the natural history and risk of progression of these disorders in medically managed patients with chronic epilepsy. Recent evidence has documented higher prospective rates of DSM-IV Axis I disorders and especially mood disorders in persons with chronic temporal lobe epilepsy compared to controls, even after adjustment for prior psychiatric history (Jones et al., in press). We are not aware of any data addressing the psychiatric status of elders with chronic epilepsy.

The findings reviewed above raise concern regarding the risk for abnormal/accelerated cognitive, brain, and psychiatric aging in elder persons with chronic epilepsy. At this time of major interest and investigation of cognitive and brain aging in the general population, there has been no systematic investigation of cognition, brain structure, or psychiatric health in aging persons and elders with chronic epilepsy, a significant oversight given the accumulating evidence of risk factor exposure in this population. In addition, other evidence potentially suggestive of an increased risk for abnormal cognitive and brain aging comes from other sources in the epilepsy literature and it is to those factors that we now turn.

Potential Risk Factors for Abnormal Cognitive and Brain Aging in Epilepsy and Mental Status in Elders with Epilepsy

Neuropathological studies in temporal lobe epilepsy, mental status screening in elders with established epilepsy, and studies of association between epilepsy and cognitive disorders in elders with epilepsy raise concern regarding cognitive and brain aging in persons with chronic epilepsy.

Up-regulated amyloid precursor protein, senile plaque deposition, and corpora amylacea in chronic epilepsy

Examining brain tissue from middle-aged patients with epilepsy undergoing anterior temporal lobectomy (n = 8), immunoreactive β-amyloid precursor protein levels were found to be higher compared to age-matched postmortem controls (n = 8) (Sheng et al., 1994). Mackenzie and Miller (1994) examined Aβ deposition in resected human temporal lobe cortex obtained during anterior temporal lobectomy (n = 101) compared to autopsy controls (n = 406). Senile plaques were found in 10% of epilepsy patients, some of whom were aged <40, with a reported age-accelerated rate of senile plaque formation compared to controls that was especially prominent in the presence of the epsilon4 (e4) allele (Gouras et al., 1997), a known susceptibility factor for AD. Premature accumulation of corpora amylacea in middle age patients with mesial temporal lobe epilepsy has been reported (34.5% of 373 patients) and noted to be associated with older age and longer duration of epilepsy (Radhakrishnan et al., 2007). Whether these neuropathologies are associated with age-accelerated cognitive changes and risk of dementia in aging persons and elders with chronic epilepsy remains to be determined.

Abnormal cognition in elders with chronic epilepsy

We are aware of only four published studies that have directly assessed cognitive status in elders with chronic epilepsy (Martin et al., 2005; Griffith et al., 2006, 2007; Piazzini et al., 2006). Compared to healthy controls (n = 27), community-dwelling elders with chronic partial epilepsy (n = 25) exhibited significantly poorer performance across all scales of a dementia screening test (Dementia Rating Scale) (Martin et al., 2005). A related investigation (Griffith et al., 2006) compared matched groups of community-dwelling elders with chronic partial epilepsy (n = 26), healthy control elders (n = 26) and healthy elders with amnestic mild cognitive impairment, a known precursor to AD (n = 26). Compared to patients with amnestic MCI, community-dwelling elders with epilepsy exhibited a comparable degree of memory impairment and even greater impairment in executive function than this clinical group (Griffith et al., 2006), with significant worsening of the deficit in executive function in prospective follow-up of elders with chronic epilepsy (Griffith et al., 2007).

Association between epilepsy and dementia

Two population-based investigations of medical comorbidities (U.K., Canada) demonstrate a significantly higher association between dementia and AD in persons with epilepsy compared to controls (Gaitatzis et al., 2004; Tellez-Zenteno et al., 2005). It is widely appreciated that seizures are part of the natural history of AD. Population-based studies demonstrate that unprovoked seizures occur with increased incidence in persons with AD compared to nondemented elderly controls (Hauser et al., 1986; Romanelli et al., 1990; Hesdorffer et al., 1996; Amatniek et al., 2006). However, less appreciated is evidence suggesting that dementia may develop with greater frequency in aging and elder persons with chronic and established epilepsy compared to controls. Breteler et al. (1991), in the EURODEM project, reanalyzed eight case-control studies and reported that the risk for AD was significantly elevated in persons with established epilepsy (duration ≥10 years). In a later study, Breteler et al. (1995) demonstrated an age-accelerated risk of dementia in 4,505 persons with epilepsy, aged 50-75, compared to age-matched persons with other medical disorders over an 8-year observation period.

In addition to this evidence from the field of epilepsy, there is a large general population literature that has identified risk factors for abnormal cognitive and brain aging and it is to that literature that we now turn. Numerous risk factors for abnormal cognitive aging and dementia have been identified in prospective population-based research. Many of these factors are overrepresented in epilepsy but their relationships to cognitive and brain aging have never been examined.

Prospective research in nonepilepsy populations has identified a variety of risk factors associated with accelerated cognitive and brain aging and dementia including AD. In the material to follow, prospective data from community- and population-based cohort studies will be reviewed to characterize three classes of risk factors (vascular disease, inflammatory markers, and lifestyle factors) for dementia, followed by review of evidence demonstrating that these risk factors appear to be elevated in persons with chronic epilepsy, but never related to cognition in epilepsy.

Vascular disease risk factors

Hypertension (Knopman et al., 2001), hyperhomocysteinemia (Troen & Rosenberg, 2005), abnormal glucose metabolism (Greenwood & Winocur, 2005; Watson & Craft, 2006), hypercholesterolemia (Solfrizzi et al., 2006), and obesity/metabolic syndrome (Cournot et al., 2006; Gustafson, 2006) have been demonstrated in prospective investigations to be predictive of cognitive decline and dementia including VaD and AD in the general population. An emerging view is that vascular risk factors and vascular disease are responsible for accelerated cognitive and brain aging in the general population and may even represent a fundamental factor in provoking the neurodegenerative processes of AD (de la Torre, 2002, 2004, 2005). One of these risk factors, elevated plasma homocysteine, is associated with increased risk of heart disease, stroke, cerebrovascular disease and peripheral vascular disease (Clarke et al., 1991, 1998; Eikelboom et al., 1999; Hankey & Eikelboom, 1999; Wald et al., 2002; Refsum et al., 2006), and prospective research has demonstrated its association with cognitive decline (McCaddon et al., 2001; Dufouil et al., 2003) and dementia (Seshadri et al., 2002; Luchsinger et al., 2004; Ravaglia et al., 2005). Vascular risk factors contribute to atherosclerotic progression and endothelial dysfunction, key factors in the maintenance of cerebral blood flow, but also adversely affecting Aβ metabolism (Sparks et al., 1994; Fewlass et al., 2004).

Persons with chronic epilepsy may be at increased risk of abnormal cognitive and brain aging because of an increased prevalence of vascular risk factors that may result at least in part from treatment with antiepilepsy drugs (AEDs). Valproic acid (VPA) treatment has been associated with several metabolic disorders including hyperinsulinemia and insulin resistance (Isojarvi et al., 1998; Luef et al., 2004) and substantial weight gain/increased body mass index (BMI) (Pylvanen et al., 2003; Sheth, 2004). In addition to alterations in insulin sensitivity and body mass, commonly prescribed enzyme inducing medications (e.g., phenytoin [PHT], carbamazepine [CBZ]) disturb folate metabolism leading to significantly increased levels of homocysteine (Ono et al., 1997; Schwaninger et al., 1999; Yoo & Hong, 1999; Apeland et al., 2000; 2001a, b; Tamura et al., 2000; Verrotti et al., 2000; Tümer et al., 2002; Karabiber et al., 2003; Attilakos et al., 2006). Especially troubling are reports of elevated insulin resistance and hyperhomocysteinemia in children with epilepsy caused by AEDs (Verrotti et al., 2000; Tümer et al., 2002; Karabiber et al. 2003; Attilakos et al., 2006) since early exposure to vascular risk factors predict cerebrovascular disease in adults in the general population (Berenson et al., 1998; Berenson, 2002; Berenson & Srnivasan, 2005). Adults with chronic epilepsy have been found to have significantly increased carotid artery intima media thickness (IMT) (Schwaninger et al., 2000; Hamed et al., 2007) and early death from ischemic heart disease has been reported (Annegers et al., 1984). Population-based surveys of medical comorbidities document higher rates of hypertension, ischemic heart disease, heart failure, diabetes, and cerebrovascular disease in persons with epilepsy (Gaitatzis et al., 2004; Tellez-Zenteno et al., 2005). Prospective studies are needed to characterize directions of causality in these comorbidity studies as well as the specific relationships between abnormalities in cognitive and brain health that may be associated with these medical comorbidities in aging and elder persons with chronic epilepsy.

Epidemiological, clinical, and experimental investigations demonstrate that serum lipids and apolipoproteins are intimately related to atherosclerotic cardiovascular and cerebrovascular disease, cognitive disorder and dementia (Castro-Gago et al., 2006; Panza et al., 2006). In chronic epilepsy, AED-induced abnormalities in cholesterol and lipoprotein homeostasis have been reported. Reliable findings include (1) increased risk of dyslipidemia with enzyme-inducing medications, including CBZ, PHY, PB leading to elevations of total cholesterol and triglicerides (Hamed & Nabeshima, 2005), and (2) elevation of lipoprotein (a) in chronically treated children (Aynaci et al., 2001; Tümer et al. 2002; Sonmez et al. 2006; Voudris et al., 2006) and adults with epilepsy (Schwaninger et al., 2000; Voudris et al., 2006) as well as healthy volunteers exposed to AEDs (Brämswig et al., 2003). These disruptions in lipid and lipoprotein metabolism have been demonstrated in both cross-sectional and longitudinal epilepsy investigations. These important potentially modifiable vascular disease risk factors are elevated in persons with chronic epilepsy but have never been examined in relation to cognitive and brain aging.

Two examples of the possible significance of these factors for cognitive and brain aging will be briefly presented.

Carotid artery intima media thickness

Hamed et al. (2007) examined carotid artery intima media thickness (CIMT), vascular risk biomarkers, and oxidative stress in 225 adult epilepsy patients and 60 controls with a mean age of 30. Compared to controls, for epilepsy subjects the IMT of common carotid artery, bifurcation, and internal carotid arteries, respectively, was thickened in 51.1%, 73.3%, and 43.6% of epilepsy patients. Furthermore, a significantly greater proportion of epilepsy patients (14.2%) were found to have plaques compared to controls (2%). The majority of epilepsy patients (80%) had multiple risk factors, including significantly lower levels of high-density lipoprotein cholesterol, and significantly higher levels of homocysteine, fibrinogen, and von Willbrand factor. That “subclinical” atherosclerosis can have important long-term implications has been reported recently by the Rotterdam group. Following 6,647 participants, van Oijen et al. (2007) reported that atherosclerosis, predominantly carotid atherosclerosis, was associated with an increased risk of dementia. Critically, the relationship of atherosclerosis and its complications (e.g., decreased brain perfusion) to cognitive and brain change and dementia has been demonstrated in the general population, but never investigated in chronic epilepsy.

APOE epsilon4

Previous research has documented that epilepsy patients do not show an increased rate of the e4 allele (Kilpatrick et al., 1996; Gambardella et al., 1999; Cavalleri et al., 2005; Yeni et al., 2005) and there is no reliable relationship between the e4 allele and clinical seizure features (onset age, seizure frequency) (Kilpatrick et al., 1996; Blumcke et al., 1997; Gambardella et al., 1999; Briellmann et al., 2000; Cavalleri et al., 2005; Sporis et al., 2005; Yeni et al., 2005) with the exception of Diaz-Arrastia et al. (2003), who reported increased relative risk of late posttraumatic seizures with e4 allele. There is, however, evidence of age-accelerated senile plaque formation in chronic temporal lobe epilepsy (Gouras et al., 1997) and cross-sectional evidence of age-accelerated memory impairment in persons with chronic temporal lobe epilepsy in the presence of e4 (Gambardella et al., 2005; Busch et al., 2007).

Inflammation

Increasing evidence suggests that inflammation plays an integral role in the pathogenesis of cognitive decline and dementing disorders including AD (Dik et al., 2005). High-sensitivity C-reactive protein (hs-CRP) is an indicator of systemic inflammation and a novel plasma marker for atherosclerosis (Kuo et al., 2005). Five of six prospective community-based investigations showed elevated hs-CRP to be associated with cognitive decline and increased risk for dementia (Schmidt et al., 2002; Teunissen et al., 2003; Yaffe et al., 2003; Engelhart et al., 2004; Tilvis et al., 2004; Dik et al., 2005). Other markers of chronic inflammation include interleukin-6 (IL-6) and fibrinogen. IL-6 predicted cognitive decline in four of five prospective investigations (Weaver et al., 2002; Yaffe et al., 2003; Engelhart et al., 2004; Rafnsson et al., 2007, but not Dik et al., 2005), and fibrinogen predicted 4-year cognitive decline in the Edinbergh Artery Study (Rafnsson et al., 2007). Overall, prospective studies suggest that inflammatory markers (hs-CRP, IL-6, fibrinogen) are important predictors of adverse cognitive outcomes and recent reports link inflammatory biomarkers to age-accelerated cerebral atrophy as well (Jefferson et al., 2007).

Chronic epilepsy appears associated with an increased risk of exposure to inflammatory risk factors linked with abnormal cognitive aging and dementia. Evidence that persons with epilepsy may be particularly vulnerable to inflammation comes from both human and animal studies. For example, experimentally induced seizures trigger a prominent inflammatory response in neural areas involved in the onset and propagation of seizures (Vezzani, 2005; Vezzani & Granata, 2005). Increased inflammatory markers have been detected in serum, CSF, and brain in persons with epilepsy. Pertinent are findings of increased IL-6 following recent tonic-clonic seizures (Peltola et al., 2002; Lehtimaki et al., 2004). IL-6 has also been reported to be elevated secondary to CBZ but not VPA treatment (Verrotti et al., 2001) and elevated levels of fibrinogen have been reported in chronic epilepsy (Hamed et al., 2007). These important serum inflammatory markers that may be elevated in persons with chronic epilepsy have never been examined in relation to cognitive and brain aging.

Lifestyle factors

Lifestyle factors are associated with the risk of cognitive decline and dementia in the general population. Fratiglioni et al. (2004) reviewed 28 community-based prospective studies examining relationships between extent of social networks, physical activity, and leisure-time mental stimulation with the risk of cognitive decline, dementia, and AD. Evidence that lifestyle factors may influence cognitive aging is persuasive. In regard to the risk of prospective cognitive decline, 18 of 22 studies reported positive relationships. Specifically, seven of eight prospective investigations demonstrated a significant association between physical activity and cognitive health, six of seven prospective studies showed increased mental activity to be associated with preservation of cognitive health, and five of seven prospective studies demonstrated that the range and frequency of interaction with social networks were associated with better cognitive function.

Chronic epilepsy is associated with an increased prevalence of lifestyle factors associated with abnormal cognitive aging and dementia. Compared to healthy controls, epilepsy patients are less likely to participate in regular physical exercise/activity (Nakken, 1999; Wong & Wirrell, 2006) and demonstrate poorer aerobic capacity and diminished muscle strength and endurance (Bjorholt et al., 1990; Steinhoff et al., 1996; Jalava & Sillanpää, 1997). These lifestyle differences probably contribute to reports of elevated BMI in both adults (Steinhoff et al., 1996) and children (Wong & Wirrell, 2006). Persons with epilepsy have also been shown to have decreased contacts with available social networks (Bjorholt et al., 1990; Steinhoff et al., 1996), consistent with the known psychosocial consequences and felt stigma associated with epilepsy (Jacoby et al., 2005). These important potentially modifiable lifestyle risk factors are elevated in persons with chronic epilepsy but have never been examined in relation to cognitive and brain aging.

Vascular, lifestyle, inflammatory, and cognitive abnormalities in midlife are critical predictors of eventual cognitive and brain aging. A important body of research in the general population with direct implications for cognitive and brain aging in these individuals demonstrates that the presence of midlife risk factors including vascular (hypertension, dyslipidemia, obesity, diabetes mellitus), health habits (smoking, diet, physical activity), inflammatory markers (hs-CRP), and pulmonary function (forced expiratory volume) predict (1) the adequacy of late-life cognition; (2) the risk of developing mild cognitive impairment, dementia, and AD; (3) brain atrophy; and (4) the degree of neuropathological abnormalities at autopsy (Chyou et al., 1996; Launer et al., 2000; Petrovitch et al. 2000; Kivipelto et al., 2001a, b, 2002, 2005; Schmidt et al., 2002; Tyas et al., 2003; Rovio et al., 2005; Whitmer et al., 2005; Gustafson, 2006; Laitinen et al., 2006). In addition, midlife cognitive and especially memory impairments have prognostic significance for compromised mental status in later life (Zonderman et al., 1995; Kawas et al., 2003). The relationship between cognitive and brain health with vascular, lifestyle, and inflammatory risk factors is an important issue for people with epilepsy of any age, presenting an opportunity for early intervention and treatment. However, the long-term implications of these findings for cognitive and brain aging in there individuals must not be underestimated since increased exposure to these risk factors in midlife may be common for persons with chronic epilepsy. Because chronic epilepsy may be associated with progression of preexisting impairments in memory and other cognitive abilities as well as significant abnormalities in brain structure in midlife, there is a compelling argument to not only carefully examine the ultimate status of cognitive and brain aging in persons with chronic epilepsy but to identify cumulative risk factor exposure in younger years and determine the prognostic significance of this exposure to adverse cognitive outcomes as has been done in the general aging literature. The outcomes of such research would offer the opportunity to alter the trajectory of cognitive function in aging and elder years. While comorbidity studies raise the possibility of an association between chronic epilepsy and adverse cognitive outcomes, issues of causality need to be addressed by prospective investigations.

Why is it critical to characterize the pattern of cognitive and brain aging in elder persons with chronic epilepsy?

The expected increase in age-related cognitive disabilities including AD and associated disorders will exert a significant impact on the health and social well-being of this country. These projections and their fiscal and social implications have led multiple federal and private agencies to conduct clinical and research initiatives to promote cognitive and brain health in aging populations. Examples include the NIA/NINDS/NIMH Cognitive and Emotional Health Project: The Healthy Brain (http://trans.nih.gov/cehp/); the CDC Healthy Brain Initiative: A National Public Health Road Map to Maintaining Cognitive Health (http://www.cdc.gov/aging/roadmap/); and the Maintain Your Brain initiative of the Alzheimer’s Association (http://www.alz.org/we_can_help_brain_health_maintain_your_brain.asp). These initiatives have yet to be recognized or embraced by the epilepsy community but they provide a template for clinical and research action for the future as well as an opportunity for collaborative research efforts.

Interestingly, it seems that more attention and concern was paid to the relationship between chronic epilepsy and dementia in the older literature (c.f., Friedlander (2001, pages 217-220). However, much of this work derived from special centers where patients with chronic, severe, and incapacitating epilepsy were cared for, with older and less precise characterizations of dementia and cognitive decline. Factors reported to be predictive of dementia included early-onset, poor seizure control, and long duration of epilepsy. Greater attention to the cognitive and brain health of aging and elder persons with chronic epilepsy would seem important, and natural partners in these research endeavors would be colleagues from the fields of aging and dementia. Finally, important related concerns and areas of research include the differential adverse cognitive outcomes (if any) associated with standard treatments such as AEDs and epilepsy surgery including anterior temporal lobectomy in elder persons with epilepsy, as well as the ultimate cognitive outcomes of persons who underwent anterior temporal lobectomy with hippocampectomy and are now approaching their elder years.

Conclusion

Evidence has been assembled to suggest that chronic epilepsy may be associated with significant abnormalities in cognition, brain structure, and psychiatric health that may progress by middle age in some patients, changes that are weakly predicted by traditional epilepsy factors. Additional evidence includes upregulated amyloid precursor protein, increased rates of senile plaque deposition and other neuropathologies, direct but limited evidence of particularly impaired mentation/dementia screening in elders with chronic epilepsy, and association of dementia with established epilepsy in medical record linkage studies. Prospective population-based research has identified numerous risk factors for abnormal cognitive aging and dementia in the general population, including vascular, inflammatory, and lifestyle factors, many of which we have shown to be overrepresented in epilepsy, but not examined in relationship to cognitive and brain aging in epilepsy. These are important oversights given the epidemiological evidence that risk exposure and cognitive abnormalities in midlife represent critical predictors of eventual abnormal cognitive and brain aging. If these factors exert comparable effects in people with chronic epilepsy, the management of epilepsy must be expanded to aggressively address critical risk factors in order to protect and promote cognitive and brain health. Identification of salient modifiable risk factors would open the opportunity to address these factors in order to improve both short-term and long-term cognitive and brain health.