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Epilepsy Across the Spectrum: Promoting Health and Understanding (2012)

Chapter: 3 Epidemiology and Prevention

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Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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3

Epidemiology and Prevention

Epidemiologic research assesses epilepsy’s risk factors, burden, comorbidities, and outcomes to identify opportunities for prevention efforts. Although data are incomplete, it is clear that epilepsy is one of the most common brain disorders and is likely to increase in prevalence with the aging population. Most cases of epilepsy result from unknown causes, but some cases with known causes—such as neurocysticercosis and other brain infections, traumatic brain injury, and stroke—could be avoided. Epilepsy is linked to numerous physical, neurological, mental health, and cognitive comorbidities, including heart disease, autism spectrum disorders, Alzheimer’s disease, depression, anxiety, and learning and memory problems. People with epilepsy are also more likely than others to have injuries, primarily seizure-related (e.g., fractures, burns, concussion), and to commit suicide. In addition to experiencing prejudice and discrimination, many people with epilepsy internalize feelings of stigma. Overall death rates, including from sudden unexpected death, are higher among people with epilepsy than in the general population. Actions needed to prevent epilepsy and its consequences include interventions to reduce the occurrence of epilepsy’s known risk factors, to eliminate seizures in people with epilepsy and mental health comorbidities, and to decrease felt stigma and epilepsy-related causes of death.

Epidemiologic research in epilepsy aims to assess the risk factors for developing the disorder; to evaluate its burden, comorbidities, and outcomes; and to identify opportunities for preventing epilepsy and its consequences. Chapter 2 explores the various methodological and

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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measurement issues associated with epilepsy surveillance and describes sources for data collection. This chapter focuses on the gaps in epilepsy research in terms of what is known and not known related to incidence, prevalence, risk factors, comorbidities, and outcomes. These gaps suggest opportunities for prioritizing future epidemiologic studies in order to guide preventive and early intervention strategies. Improved epilepsy data collection and measurement, as described in Chapter 2, are necessary for better epidemiologic research, along with well-designed and targeted studies to illuminate significant trends and inform health care providers, policy makers, and the public.

To improve knowledge regarding preventing epilepsy and its outcomes, the committee’s vision is for well-designed epidemiologic studies that highlight areas ripe for preventive efforts. Some, but by no means all, key focus areas are discussed here, including prevention of epilepsy, its comorbidities, and its consequences, including death. Before discussing these research areas, the continuum of public health prevention is described as background.

PUBLIC HEALTH AND PREVENTION

In the context of public health, there are traditionally three levels of prevention: primary, secondary, and tertiary. Each aims to intervene at a different point along the continuum of a disease or disorder and involves different types of actions to ameliorate the condition or its impact.

“Primary prevention” is the prevention of a disease or disorder before it begins, with the goal of decreasing its incidence in a population. For example, public health agencies, policy makers, and others work to eliminate environmental hazards (e.g., through sanitary measures such as ensuring clean drinking water), to improve disease resistance (e.g., through immunization), and to decrease high-risk behavior (e.g., tobacco use) and promote healthy behavior (e.g., seatbelt use). In looking forward, future advances in biomedical research hold the promise of greater understanding of epileptogenesis or possibly a cure; meanwhile, it may be possible to prevent some known causes of epilepsy, such as neurocysticercosis through education and sanitary measures, other brain infections through vaccines, traumatic brain injury (TBI) through seatbelt and helmet use, and stroke through reduction of known risk factors.

“Secondary prevention” is the early identification and mitigation of a disease or disorder once it is present in the body but before it is symptomatic. For example, public health agencies collaborate with health professionals to screen a population (e.g., blood glucose or blood pressure screenings) and follow up to manage early symptoms and forestall the development of full-blown disease. Secondary prevention of epilepsy may be possible in the future, if biomarkers of epileptogenesis are identified and early intervention measures are developed.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

“Tertiary prevention” is the prevention of the progression of a disease or disorder and its outcomes after it has become symptomatic, in order to decrease the degree of resulting disability or impacts on health (i.e., to improve quality of life). For example, health professionals, together with public health agencies, work to minimize or eliminate exposures that make a disease or disorder worse (e.g., air pollution for people with asthma) and to screen for early detection of adverse outcomes (e.g., vision changes for people with diabetes). For chronic diseases and disorders, tertiary prevention is sometimes called disease management, although it should not be confused with medical treatment, and it may involve rehabilitation therapy, as after stroke. Some tertiary prevention efforts target the consequences of epilepsy (e.g., early identification of those who do not respond to seizure medications in order to identify options to prevent seizure recurrence), whereas others focus on its comorbidities (e.g., screening and interventions to identify and manage depression in people with epilepsy, described in Chapter 4). Future population health studies on comorbidities, including mental health conditions, and important outcomes (e.g., sudden unexpected death in epilepsy [SUDEP], injuries) may provide opportunities for successful interventions to promote optimal quality of life and avoid preventable deaths.

INCIDENCE AND PREVALENCE

Incidence

Studies of the incidence of epilepsy describe the rate of new-onset epilepsy and the characteristics of newly diagnosed epilepsy. The annual incidence of epilepsy in the United States is estimated at approximately 48/100,000 people (Hirtz et al., 2007). This estimate represents the median of a range of incidence estimates across all age groups. The hallmark longitudinal study of the epilepsies in the United States is the Rochester Epidemiology Project (described in Chapter 2), in which the incidence of epilepsy was examined in more than 2 million residents of Rochester, Minnesota, across 5 decades from 1935 to 1984. The Rochester study found an age-adjusted incidence of 44/100,000 (Hauser et al., 1993). Based on the Rochester project, Hesdorffer and colleagues (2011a) estimated that 1 in 26 people (3.8 percent of people born today) will develop epilepsy over the course of their lifetime. However, this estimate is based on a nonrepresentative population from one community in the United States. Furthermore, diagnostic data from this study are out of date, given the advances in imaging and other medical technologies (e.g., none of the Rochester participants had available MRI [magnetic resonance imaging] data).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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More recent studies have arrived at varying estimates of epilepsy incidence:

•  A population study in northern Manhattan reported an incidence of 41/100,000 (Benn et al., 2008).

•  Holden and colleagues (2005) looked at managed care organizations and found an incidence of 47/100,000 for those who were continuously enrolled for 3 years and 71/100,000 for those enrolled for 5 years.

•  In a health maintenance organization population, incidence for enrollees under age 65 was 35.5/100,000 (Annegers et al., 1999), although this age group would be expected to have a lower incidence than adults 65 years old or older, who have a high incidence of epilepsy (Thurman, 2011).

Existing trend information suggests that the incidence of epilepsy may be declining in children and increasing among older adults (Hauser et al., 1993; Kotsopoulos et al., 2002; Sillanpää et al., 2011). However, it is not known whether these trends will continue or if changes in the distribution of risk factors for epilepsy (discussed later) are driving them.

Research Gaps

Epidemiologic research is needed in large, representative U.S. populations to monitor trends in epilepsy incidence and related mortality and to track outcomes. Studies need to be conducted among the general population and in subpopulations at higher risk: children, for whom prognosis is a major concern; older adults, who have greater mortality associated with epilepsy; women, to track outcomes, including reproductive outcomes; as well as veterans and diverse racial/ethnic and socioeconomic groups, in order to assess any disparities in incidence, prognosis, and mortality and to determine opportunities for intervention. Within these subpopulations, sufficient numbers are needed to compare incidence by etiology, seizure type, syndrome, and the presence of comorbid conditions. With respect to treatment, these surveillance data could be used to monitor the outcomes of epilepsy care and provide feedback to health care providers (Box et al., 2010; Trevathan, 2011). As examples, specific populations for whom further research is needed—older adults, veterans, children, and people with epilepsy and associated comorbidities—are described below.

Older adults The incidence of epilepsy is highest in children and older adults (Faught et al., 2012; Hauser et al., 1993; Kotsopoulos et al., 2002; Stephen and Brodie, 2000). By 2030, about 20 percent of the U.S. popula-

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

tion will be age 65 or older, an increase from approximately 13 percent in 2010 (Census Bureau, 2011; IOM, 2008). Due to the aging of the population and increases in life expectancy, the number of older adults who develop or have epilepsy will increase. Some of the increase will be from known causes, such as stroke, dementia, and TBI, which is often due to falls. Better medical management of stroke has increased survival rates and, thus, the number of survivors at risk for epilepsy; the number of people with aging-related dementia also is increasing; and the incidence of fall-induced TBI is rising in older adults (Annegers et al., 1995; Broderick et al., 1989; Fuster and Bansilal, 2010; Kannus et al., 2007; Ramanathan et al., 2012; Tartaglia et al., 2011; Watson and Mitchell, 2011). Older adults with epilepsy may experience greater disability because of deteriorations in health due to advanced age, comorbid conditions, and greater likelihood of side effects from seizure medications due to altered pharmacokinetics and interactions with other medications (Faught, 1999). The resultant impairments can decrease quality of life and increase the need for health services and long-term care (Guralnik et al., 1996). In anticipation of a growing number of older adults with epilepsy, additional research is needed that focuses on concerns specific to this population, including preventing adverse medication interactions and disability and maintaining independent living.

Epilepsy takes freedom from those who suffer from it. We cannot allow our citizens who have fought for freedom to lose their own freedom.

-Kevin Malone

Veterans Returning service members from Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) are a specific population in which research on epilepsy incidence is needed, because TBI, the most common injury of OEF-OIF (U.S. Army Traumatic Brain Injury Task Force, 2007), is associated with up to a 53-percent risk for posttraumatic epilepsy, depending on the severity of the injury (Salazar et al., 1985). The number of service members who survive after sustaining a serious injury is higher now than for any previous war (Goldberg, 2010; Lowenstein, 2009). Between 2001 and 2007, an estimated 1.6 million U.S. military personnel were deployed to Afghanistan and Iraq (Tanielian et al., 2008). Among a study population of approximately 868,000 service members, approximately 1,300 were hospitalized with a severe TBI, 1,550 with a moderate TBI, and 133 with a mild TBI (Wojcik et al., 2010). However, most people who sustain a mild TBI are not hospitalized, and many do not go to the emergency department (U.S. Army Traumatic Brain Injury Task Force, 2007), and mild TBIs comprise approximately three-quarters of all TBI cases in OEF-OIF service members (Armed Forces Health Surveillance Center, 2012). A report of the Armed Forces Epidemiological Board (2006) found that the Department of Defense (DOD) did not have a system-wide

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

approach for identifying, treating, and monitoring TBIs, especially mild cases. Since that report, the DOD has established and is working to implement guidelines for the identification and treatment of mild TBI (U.S. Army Traumatic Brain Injury Task Force, 2007). Similarly, the Department of Veterans Affairs has also dedicated efforts to recognizing and managing mild TBI in OEF-OIF veterans (GAO, 2008). The emphasis on improved surveillance and care of mild TBI in today’s conflicts contrasts with earlier eras, when attention focused on more severe, penetrating TBI (Evans, 1962; Salazar et al., 1985).

Studies of returning veterans require validated diagnosis of the severity of TBI and follow-up to monitor a range of potential outcomes, including the onset of epilepsy. Questions about the validity of the diagnosis of mild TBI have arisen in connection with a study of 2,525 service members answering a questionnaire after 1 year of deployment in Iraq, where symptoms of mild TBI were reported by 15.2 percent (Hoge et al., 2008). An accompanying New England Journal of Medicine editorial highlighted the difficulty of separating symptoms of mild TBI from posttraumatic stress disorder (PTSD) and other psychological reactions due to the emotional trauma of wartime (Bryant, 2008). Because TBI among returning veterans may be associated with an increased risk for developing epilepsy, work to distinguish mild TBI from PTSD is crucial. PTSD itself is associated with the occurrence of seizure-like events that are not epilepsy (D’Alessio et al., 2006). Recently, Salinsky and colleagues (2011) found that there is a significant delay in the diagnosis of seizure-like events with a psychological basis in veterans treated with seizure medications, suggesting a presumptive diagnosis of epilepsy. Among veterans with seizure-like events with a psychological basis, the delay in diagnosis was nearly five times as long as for civilians, and the cumulative treatment with seizure medications was four times higher. Progress in distinguishing between mild TBI and PTSD as well as between epilepsy and seizure-like events with a psychological basis is needed to determine the incidence and prevalence of TBI-related epilepsy among veterans and to provide optimal care.

Children The most catastrophic forms of epilepsy occur in children, particularly young children. Previous incidence studies have not assembled a sufficiently large incidence cohort of children with epilepsy to study the prognosis of most individual syndromes. However, it has been possible to study risk factors for poor seizure prognosis in childhood onset epilepsy overall, the risk for status epilepticus (SE), and the risk for early refractory epilepsy1 in different etiologic categories (Arts et al., 2004; Berg et al.,

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1As noted in Chapter 1, refractory epilepsy is defined as the failure to control seizures after two seizure medications (whether as monotherapies or in combination) have been appropriately chosen and used (Kwan et al., 2010) (see also Chapter 4).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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2001a,b; Camfield et al., 2002; Sillanpää and Shinnar, 2002, 2010). However, studies have focused on common syndromes, and studies that have elucidated risk factors for poor prognosis within specific syndromes have been rare (Wirrell et al., 1996). Future studies of unselected incident cohorts of children with epilepsy are needed to assemble large enough cohorts with rare syndromes to study factors affecting prognosis.

Epilepsy accompanied by comorbidities There is some evidence (see the discussion below on comorbidities) that the prognosis for epilepsy is worse in the presence of comorbidities that predate the diagnosis of epilepsy. Because comorbidities may influence epilepsy prognosis and are known to affect quality of life, studies of the incidence of epilepsy in people with comorbidities at or before the onset of epilepsy will permit greater understanding of the consequences of the disorder when it is accompanied by comorbidities. For example, case-control studies of people with newly diagnosed epilepsy could be conducted retrospectively to identify preexisting comorbidities, or prospective cohort studies of individuals with depression or migraine could look at the incidence of epilepsy in these groups. These studies may provide a greater understanding of how the timing of epilepsy onset in relation to its comorbidities affects prognosis.

Prevalence

Studies of the prevalence of epilepsy provide information on its burden in the population. Prevalence data encompass the number of newly diagnosed cases of epilepsy as well as cases of epilepsy that persist over time, which includes people with continued seizures and people who are in remission but who take seizure medications. Except for rapidly fatal conditions, prevalence is greater than incidence, because it accounts for the accumulation of cases over time. Prevalence thus reflects the incidence, chronicity, and related mortality of epilepsy.

Similar to incidence, there is a range of estimates of prevalence of epilepsy in the United States:

•  Hirtz and colleagues (2007) estimate annual prevalence at 7.1/ 1,000 people.

•  The Rochester Epidemiology Project found that prevalence in-creased from 2.7/1,000 in 1940 to 6.8/1,000 in 1980 (Hauser et al., 1991).

•  Kelvin and colleagues (2007) found a 5/1,000 prevalence in New York City.

•  The Centers for Disease Control and Prevention’s (CDC’s) Behavioral Risk Factor Surveillance System (BRFSS), which depends on

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

  self-reporting, estimated 8.4/1,000 cases of active epilepsy2 (Kobau et al., 2008). If lifetime prevalence (i.e., ever having epilepsy) is considered, the BRFSS estimate increases to 16.5/1,000 (1.7 percent of respondents) (Kobau et al., 2008).

Research Gaps

More studies have been done on the prevalence of epilepsy than on its incidence because prevalence studies are easier and faster to conduct. Prevalence data are used to inform planning for resources and services to meet the health care and social needs of people with epilepsy. To obtain a complete picture of epilepsy, prevalence studies should be conducted using the same data sources as those in which long-term studies of epilepsy incidence are conducted. Socioeconomic status (SES) and race/ethnicity are discussed below as examples of two areas in which further research on incidence and prevalence is needed.

Socioeconomic status Low SES is associated with a higher incidence of epilepsy (Heaney et al., 2002). Hesdorffer and colleagues (2005) studied adults in Iceland and found that people with epilepsy are more likely to have low SES in comparison to age- and gender-matched controls without epilepsy. This association exists in a society with universal health care where everyone has health insurance, and it also persists in adults with epilepsy of unknown etiology, even after adjustment for cumulative alcohol consumption, which could be a confounding factor. Furthermore, low SES is also associated with an increased prevalence of epilepsy (Morgan et al., 2000; Shamansky and Glaser, 1979). Reasons for this are not well understood because these studies did not distinguish between epilepsy of unknown etiology and epilepsy of known etiology, which is problematic because some known etiologies of epilepsy (e.g., TBI, stroke) may themselves be associated with low SES (Chang et al., 2002; Cubbin et al., 2000). While associations between SES and the etiology of epilepsy is one possible explanation for the association between SES and prevalence, existing treatment gaps may play a role as well, since people of lower SES are less likely to obtain seizure medications or to be under the care of a neurologist than people of higher SES (Begley et al., 2009), making them more likely to experience persistent seizures (Chapter 4).

Race/ethnicity A study in the Harlem neighborhood of New York City found epilepsy prevalence to be higher in Hispanics than in non-Hispanics

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2Defined as “a history of epilepsy and currently taking medication or reporting one or more seizures during the past 3 months” (Kobau et al., 2008, p. 1).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

and a higher prevalence of active epilepsy3 in whites than in blacks, although the prevalence of lifetime epilepsy4 was higher in blacks compared to whites (Kelvin et al., 2007). In this community, there were racial/ethnic disparities in care; blacks were more likely to receive care in the emergency department compared to whites and Hispanics. Similarly, Hope and colleagues (2009) found that blacks and Hispanics were more likely than whites to be diagnosed in an emergency department, and blacks were more likely to receive a suboptimal seizure medication. Differences in care for prevalent epilepsy were also observed in residents of Alabama and surrounding states, where blacks were 60 percent less likely than non-Hispanic whites to undergo epilepsy surgery after receiving electroencephalograph (EEG) monitoring as part of a surgical evaluation, an association that persisted after controlling for factors such as SES and medical insurance coverage (Burneo et al., 2005). The degree to which differences in epilepsy incidence and prevalence in different racial/ethnic groups reflect differences in socioeconomic status is unknown. Also unknown is the degree to which treatment gaps contribute to the higher epilepsy prevalence in some subgroups.

Next Steps for Incidence and Prevalence Studies

As described in Chapter 2, none of the recent estimates of incidence and prevalence are based on active and ongoing surveillance of epilepsy in the U.S. population over time. Updated and longitudinal data are needed from large, representative populations throughout the country to generate population-wide estimates of incidence and prevalence and allow subgroup analysis by severity and type of epilepsy, age, gender, race/ethnicity, geography, and SES. This information is necessary to have a complete understanding of the burden of epilepsy in the United States compared to other diseases and conditions, to show trends over time, and to learn whether specific populations carry a disproportionate amount of the epilepsy burden so that actions can be taken to provide needed health care and support services.

Future studies of time trends in the incidence and prevalence of epilepsy conducted in large, representative cohorts will also be able to assess trends in remission, relapse, and refractory epilepsy. Although previous and ongoing prospective studies have examined these outcomes, the studies are mostly short term, outdated, and too small to enable subgroup analysis. A major contribution of the types of surveillance and population-based studies suggested in this report would be the ability not only to report incidence and prevalence but also to examine the course of epilepsy overall and in

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3In this study, active epilepsy was defined as having ongoing seizures or taking a seizure medication within the previous 5 years.

4In this study, lifetime epilepsy was defined as having a history of two or more unprovoked seizures.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

subpopulations. Such data may allow assessment of how risk factors influence the prevalence of epilepsy over time. Specific subgroups of interest include older adults, veterans, children, people with epilepsy accompanied by comorbidities, and diverse racial/ethnic and socioeconomic populations. These data are needed to know where and how to better focus epilepsy prevention and treatment efforts.

RISK FACTORS

Epilepsy Due to a Known Cause

Cases of epilepsy that have a known etiology have a worse overall prognosis, more commonly involve persistent seizures, and have a higher mortality rate than cases in which the cause is unknown (Forsgren et al., 2005b; Hauser et al., 1998). Less than half of all newly diagnosed cases of epilepsy have a known structural or metabolic cause (Adelöw et al., 2009; Forsgren et al., 2005a; Hauser et al., 1993). Among people with newly diagnosed epilepsy, the predominant known causes are stroke, neurodegenerative diseases such as dementia and multiple sclerosis, primary brain tumors or the spread of cancer from another site to the brain, and TBI (Annegers and Coan, 2000; Hauser et al., 1993; Herman, 2002; Hesdorffer et al., 1996a; Kelley and Rodriguez, 2009). Other known causes are rarer but confer a strong risk for developing epilepsy: brain infections, such as meningitis, encephalitis, and neurocysticercosis; pre- and perinatal injury; intellectual disability; cerebral palsy; and autism spectrum disorders (Annegers et al., 1988; Bergamasco et al., 1984; Carpio et al., 1998; Nelson and Ellenberg, 1987; Rocca et al., 1987; Tuchman and Rapin, 2002; Van der Berg and Yerushalmy, 1969). A recent study by Crump and colleagues (2011) found that preterm birth is associated with an increased risk of epilepsy in adulthood.

Identifying causes of epilepsy is the first step in primary prevention. Prevention of posttraumatic epilepsy has been attempted through indirect means and planned interventions. Efforts to prevent epilepsy from developing after TBI have involved randomized clinical trials of drug therapies; regrettably, these have not been successful (Temkin et al., 1990, 1999, 2007). Prevention of epilepsy after TBI is a complex problem, because the types, location, and extent of brain injury vary widely, and the process of epileptogenesis after TBI is not well understood. The heterogeneity of TBI has hindered the development of effective interventions to prevent poor functional outcomes in general. A systematic review of the literature found that only a third of randomized clinical trials of interventions to prevent negative health outcomes after TBI have been successful, underscoring the complexity of this injury (Hernández et al., 2005). Currently, the prevention of TBI itself allows the best opportunity to prevent posttraumatic epilepsy.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

Significant public health efforts have successfully increased the use of helmets and seatbelts to prevent TBI (Coronado et al., 2011). These measures to reduce the occurrence of TBI have likely led to a decrease in new cases of epilepsy associated with TBI, although this is undocumented. However, motor vehicle accidents are still among the leading causes of TBI (Bruns and Hauser, 2003; Coronado et al., 2011; Labi et al., 2003; Tagliaferri et al., 2006). Furthermore, in some populations, the incidence of TBI appears to be rising. For example, the number of visits to the emergency department because of TBI due to sports and recreational activities, in particular bicycling and football, increased from approximately 150,000 to 250,000 between 2001 and 2009 (Gilchrist et al., 2011). Therefore, TBI remains a significant public health problem, where people who participate in sports, especially children and adolescents, and members of the military and older adults (discussed earlier in the chapter) are at particularly high risk (Armed Forces Health Surveillance Center, 2012; Gilchrist et al., 2011; Ramanathan et al., 2012).

The prevention of other risk factors for epilepsy could decrease the incidence of epilepsy as well. Prevention efforts for stroke often target its established risk factors, which include hypertension, cigarette smoking, and insufficient physical activity (Sacco et al., 1999). Results from the 2005 BRFSS found disparities in stroke prevalence among categories such as race/ ethnicity, age, and educational level (Neyer et al., 2007), indicating a need for targeted prevention programs. Prevention of brain infections such as meningitis through the use of childhood vaccines has proven to be effective (Robbins et al., 1996; Tsai et al., 2008) and should be continued.

Among the known infectious etiologies of epilepsy, primary prevention associated with neurocysticercosis5 may be most likely to succeed. Neurocysticercosis is caused by infection of the nervous system by a type of tapeworm, Taenia solium, and is a major cause of epilepsy in many developing countries throughout the world, including Latin America. Like other parasites that are transmitted through the digestive tract, tapeworms are spread to others through the consumption of food contaminated with the feces of an infected carrier, primarily due to poor sanitation, improper food handling practices, and inadequate hand washing. Neurocysticercosis is increasingly diagnosed in areas of the United States, especially the Southwest and other areas with large populations who travel to or immigrate from countries where the parasite is endemic (Del Brutto, 2012; Ong et al., 2002; White, 2000). For people who develop epilepsy from neurocysticercosis,

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5Cysticercosis is a parasitic infection with Taenia solium, an adult tapeworm, resulting from ingestion of the eggs of the tapeworm through consuming undercooked food (e.g., vegetables, pork) or water contaminated with the feces of a carrier of T. solium larvae. Cysticercosis that involves the central nervous system is termed neurocysticercosis and is the most common parasitic brain infection (DeGiorgio et al., 2004).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

treatment of the infection has not been shown to reduce seizures (Carpio and Hauser, 2002; Carpio et al., 1998, 2008).

A study in a farming community in California found the sero-prevalence of T. solium was associated with decreased frequency of hand washing (DeGiorgio et al., 2005), suggesting a feasible intervention for primary prevention. The annual economic burden of neurocysticercosis infection due to hospitalizations was estimated to be $7.9 million per year in Los Angeles County from 1991 to 2008 (Croker et al., 2010).

Although the risk for developing epilepsy following infection with the T. solium parasite is unknown, neurocysticercosis has been associated with premature death (Sorvillo et al., 2007). In an effort to identify new diseases or epidemics and mount a rapid response, the CDC has assembled a network of 11 U.S. emergency departments. One focus of this network is neurocysticercosis (Talan et al., 1998). In a study of patients who visited the network’s emergency departments with seizures, 2.1 percent had seizures attributable to neurocysticercosis, and among the Hispanic patients, approximately 9 percent had seizures attributable to it (Ong et al., 2002). Hispanic ethnicity, uninsured status, being born outside the United States, and visiting an endemic country are all risk factors for neurocysticercosis.

In the few mortality studies conducted, few deaths are attributed to cysticercosis on death certificates (Santo, 2007; Sorvillo et al., 2007). The disease was identified as causing an estimated 221 deaths in the United States from 1990 to 2002; however, given the limited data on cysticercosis in the United States, this may be an underestimate due to a failure to diagnose or recognize the disease (Sorvillo et al., 2007).

In a Bolivian study of people with active epilepsy,6 26 percent were identified as having neurocysticercosis, based upon epidemiologic criteria and clinical manifestation. Additionally, neurocysticercosis was present in 83 percent of those with epilepsy of a known cause who died during the study (half of the total deaths in the study) (Nicoletti et al., 2009). Thus, neurocysticercosis represents a meaningful proportion of epilepsy cases in developing countries and increasingly in the United States, particularly among Hispanics.7 In the BRFSS, the prevalence of active epilepsy8 among U.S. Hispanics was 6.6/1,000 and the prevalence of inactive epilepsy was 9.0/1,000 (Kobau et al., 2008). Using the 2010 U.S. Census data (Ennis et al., 2011), this translates into 333,300 U.S. Hispanics with active epi-

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6Defined in this study as people who have ongoing seizures (within the last 5 years) or are currently taking seizure medications.

7Hispanics made up 16 percent of the U.S. population in the 2010 U.S. Census, which was an increase from 13 percent in the 2000 Census (Ennis et al., 2011).

8Active epilepsy in this study was defined as “a history of epilepsy and currently taking medication or reporting one or more seizures during the past 3 months” (Kobau et al., 2008, p. 1).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

lepsy and 454,500 with inactive epilepsy, among whom approximately 10 percent may have epilepsy caused by neurocysticercosis (Ong et al., 2002).

Next Steps for Prevention: TBI, Stroke, and Brain Infections, Including Neurocysticercosis

Continued efforts are needed to prevent the occurrence of TBI, including from motor vehicle accidents and in sports and the military. Research assessing risk factors for sports-related TBI and effectiveness of helmet design in preventing TBI should be part of these efforts in addition to the promotion of helmet use. Additional work is needed in the prevention of stroke, including interventions to decrease risk factors in disproportionately affected populations, and the continued use of vaccines is needed to prevent brain infections such as meningitis.

With growing numbers of people being diagnosed, neurocysticercosis is an important public health problem in the United States (Del Brutto, 2012; Ong et al., 2002; Serpa et al., 2011; Sorvillo et al., 2011; Wallin and Kurtzke, 2004; White, 2000). Recently, cysticercosis was highlighted as a “neglected infection of poverty in the United States” (Hotez, 2008). There are opportunities for prevention of this disease; in fact, in 1992, the International Task Force for Disease Eradication determined that cysticercosis is one of ten potentially eradicable diseases (CDC, 1992). Public education and sanitary measures should be used to decrease the occurrence of infection with the T. solium parasite (Sotelo, 2011). If these primary prevention measures are successfully implemented, it may be possible to track their effects on the development of epilepsy in different populations and geographic areas. Interventions to decrease the prevalence of neurocysticercosis in high-risk populations who travel to or immigrate from endemic countries could significantly reduce the percentage of those populations who will develop epilepsy.

Epilepsy Due to Unknown Causes

In this chapter epilepsy due to unknown, genetic,9 or presumed genetic causes is called “epilepsy of unknown etiology” for simplicity. The majority of new-onset cases of epilepsy are of unknown etiology (Adelöw et al., 2009; Forsgren et al., 2005a; Hauser et al., 1993). The assumption is that etiologies exist but have not yet been detected. While the risk for continued seizures is relatively lower in epilepsy of unknown etiology than in epilepsy due to structural or metabolic causes and early mortality is lower (Forsgren

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9For example, identified genes, such as SCN1A, are rare but confer a strong risk for developing epilepsy (Ferraro et al., 2006).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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et al., 2005b; Hauser et al., 1998), there are risk factors for continued seizures and for increased mortality long after the diagnosis of epilepsy, suggesting that such cases are not benign. Moreover, increasing numbers of genetic mutations are being discovered that result in catastrophic epilepsies such as Dravet syndrome and other severe epilepsy syndromes with onset in infancy (Carranza Rojo et al., 2011), or in congential syndromes such as tuberous sclerosis complex that may result in epilepsy (Holmes et al., 2007). Although several risk factors for developing epilepsy of unknown etiology have been elucidated recently, including mental health conditions and migraine (Hesdorffer et al., 2004, 2006; Ludvigsson et al., 2006; Ottman and Lipton, 1994), evidence that would support causality is lacking. It is possible that genes may be discovered to explain the occurrence of some of these epilepsies or that other factors common to both epilepsy and the risk factors may be found that contribute to the occurrence of these disorders.

Research Gaps

The potential array of risk factors for epilepsy of unknown etiology is incompletely understood and elucidated. This is a significant gap in knowledge pertaining to more than half of all new cases of epilepsy. Further epidemiologic studies can help to close this gap by examining other potential risk factors for developing epilepsy in the absence of established causes and can examine factors such as stress that may contribute to the association between low SES and risk for developing epilepsy. As knowledge accumulates, it may be possible to consider ways to prevent some of these cases, but this is a hope for the future.

COMORBIDITIES

Comorbidity is defined as the “co-occurrence of two supposedly separate conditions at above chance levels” (Rutter, 1994, p. 100). Common comorbidities among people with prevalent epilepsy include somatic,10 neurological, and mental health conditions (e.g., Beghi et al., 2002; Boylan et al., 2004; Gaitatzis et al., 2004a; Jacoby et al., 1996; O’Donoghue et al., 1999; Ottman et al., 2011; Téllez-Zenteno et al., 2007b). Only a subset of these comorbidities has been examined in incidence and prevalence studies. Having additional information from studies in new-onset epilepsy is important, because studies of comorbidities in prevalent epilepsy do not permit identification of the sequence in which the conditions occur, which can be vital in understanding the reasons why comorbidities co-occur with epilepsy. In addition, little is known about the best strategies for prevent-

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10Related to the body.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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ing these comorbidities in people with epilepsy or minimizing their adverse effects. The additional cost and burden on the health care system of epilepsy’s comorbidities are likely to be significant, but at this point no cost or utilization studies have been done. Further, changing trends in the incidence and prevalence of comorbidities may affect the prevalence of epilepsy, as described previously with respect to stroke, dementia, and TBI.

Many of the risk factors for epilepsy are also comorbidities, because they are chronic or episodic conditions that continue to affect the individual’s health after the onset of epilepsy. Table 3-1 lists common comorbid conditions associated with epilepsy. Recently, Berg (2011) proposed a conceptualization of epilepsy as linked to a spectrum of disorders and highlighted potential shared mechanisms that may cause both epilepsy and some of its comorbidities as well as affect health and quality-of-life outcomes. However, the mechanisms that underlie these associations and the impact of comorbidities on the prognosis of epilepsy itself are not well understood currently, including whether specific populations (e.g., older adults, people of low SES) are more likely to have a higher comorbidity burden (Thurman et al., 2011). Improved data on epilepsy’s comorbidities and their impact on the course of epilepsy and quality of life are needed. This chapter discusses comorbidities in terms of opportunities in epidemiologic research and prevention efforts, Chapter 4 analyzes the impact of comorbidities on health care, and Chapter 6 explores the consequences of comorbidities for quality of life.

Somatic Disorders

A number of somatic disorders have been associated with epilepsy in cross-sectional studies. In a population-based, cross-sectional study, the most common somatic comorbid conditions among adults with prevalent epilepsy were fractures, asthma, diabetes, ischemic heart disease, and heart failure (Gaitatzis et al., 2004a). Another large, cross-sectional study of prevalent epilepsy reported an increased prevalence of fibromyalgia and asthma among people with epilepsy compared to those without epilepsy (Ottman et al., 2011). In addition to the comorbidities already mentioned, another population-based study identified anemia and nonischemic heart disease as comorbidities (Nuyen et al., 2006). Conversely, one case-control study of people with congenital heart disease identified epilepsy as an associated disorder (Billett et al., 2008).

Fractures are likely consequences of epilepsy or its treatment, discussed later in the chapter. Neoplasia likely precedes the onset of epilepsy, since primary brain tumors and cancer metastases from another site to the brain are known epilepsy risk factors. Some somatic conditions, such as ischemic heart disease, diabetes, and heart failure, may be related to epilepsy through

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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TABLE 3-1
Comorbid Conditions Associated with Epilepsy

Category Condition Sources
Somatic disorders

•  Fractures

•  Asthma and other pulmonary conditions

•  Diabetes

•  Heart disease and heart failure

•  Osteoarthritis, osteopenia, and osteoporosis

•  Fibromyalgia

•  High blood pressure

•  Anemia

Babu et al., 2009; Coppola et al., 2009; Gaitatzis et al., 2004a; Hesdorffer et al., 1996b; Nuyen et al., 2006; Ottman et al., 2011
Neurological disorders

•  Stroke

•  Alzheimer′s disease

•  Brain neoplasm

•  Autism spectrum disorders

•  Cerebral palsy

•  Migraine

•  Chronic pain and neuropathic pain


Berg et al., 2011; Bolton et al., 2011; Gaitatzis et al., 2004a; Hauser et al., 1993; Ottman et al., 2011; Wallace, 2001
Mental health conditions

•  Mood disorders (e.g., depression)

•  Anxiety disorders

•  Alcohol-related disorders

•  Attention deficit hyperactivity disorders

•  Schizophrenia and psychotic disorders

•  Personality disorders

•  Suicidality

•  Seizure-like events with a psychological basis

Berg et al., 2011; D’Alessio et al., 2006; Davies et al., 2003; Gaitatzis et al., 2004a,c; Hesdorffer et al., 2000, 2004, 2006, 2007; Qin et al., 2005; Rodenburg et al., 2005
Cognitive disorders

•  Cognitive impairment

•  Intellectual disability

•  Learning disability

•  Memory dysfunction

Elger et al., 2004; Hermann and Seidenberg, 2007; Sillanpää, 2004
Infectious disease

•  Neurocysticercosis

•  Meningitis

•  Encephalitis

Annegers et al., 1988; Carpio et al., 1998; Rocca et al., 1987
Infestations

•  Possibly onchocerciasis and toxocariasis

Kabore et al., 1996; Nicoletti et al., 2002, 2007, 2008; Pion et al., 2009
Physical disabilities

•  Hearing and vision loss

Murphy et al., 1995
Injuries

•  Accidents and injuries

Tomson et al., 2004
Nutritional problems

•  Malnutrition

•  Gastrointestinal bleeding

•  Obesity

Crepin et al., 2007; Daniels et al., 2009; Gaitatzis et al., 2004a

SOURCE: Adapted from Thurman et al., 2011. Reprinted with permission from John Wiley and Sons.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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their association with stroke. Little is understood about the relationship between the remaining somatic comorbidities and epilepsy (Gaitatzis et al., 2004a).

Research Gaps

Gaps in knowledge include

•  the identification of risk factors for somatic comorbidities related to epilepsy, which could provide insights into whether these comorbidities are currently unrecognized risk factors for developing epilepsy of unknown etiology; and

•  the extent to which increased identification of somatic comorbidities in prevalent epilepsy is due to more frequent medical visits by people with epilepsy, compared to those without.

Neurological Comorbidities

Many of the neurological comorbidities identified in people with epilepsy are themselves causal factors for developing epilepsy, such as Alzheimer’s disease and stroke in adults, brain neoplasms in children and adults, and autism spectrum disorders and cerebral palsy in children (Gaitatzis et al., 2004a; Hauser et al., 1993; Hesdorffer et al., 1996a; Tuchman and Rapin, 2002; Wallace, 2001). Several pain disorders are associated with prevalent epilepsy, including migraine, chronic pain, and neuropathic pain (Ottman et al., 2011); however, none of these are known causal factors.

Among children, there is a bidirectional relationship between autism spectrum disorders and epilepsy, particularly for children with a low IQ (Amiet et al., 2008; Berg et al., 2011; Tuchman and Rapin, 2002) (see also the discussion of cognitive dysfunction).

•  A study in a cohort of children with epilepsy found that 5 percent of the children also had autism spectrum disorders (Berg et al., 2011), compared to the estimate of 0.9 percent in the general population of children aged 8 years (CDC, 2009). Both West syndrome11 and intellectual impairment were associated with the autism spectrum. Among children with epilepsy and without cognitive impairment, autism spectrum disorders occurred in 2.2 percent and being male was the only associated risk factor (Berg et al., 2011).

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11West syndrome (i.e., infantile spasms) is an epilepsy disorder in children usually accompanied by severe and multiple comorbidities.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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•  In a prospective study, the risk for autism spectrum disorders in children with epilepsy diagnosed within the first year of life was 14 percent. Among those with autism spectrum disorders and seizures, 69 percent had symptomatic seizures, generally due to brain injury, and 46 percent had West syndrome (Saemundsen et al., 2008).

These studies suggest that at least part of the increased risk for epilepsy in autism spectrum disorders may reflect increasing brain damage, some of which may have a genetic basis.

Two of the neurological disorders mentioned above, migraine and stroke, bear specific mention because they offer an opportunity to understand ways to prevent epilepsy or ameliorate its outcomes. There is a bidirectional relationship between migraine and epilepsy, where having a history of one condition is associated with an increased risk for the other (Ludvigsson et al., 2006; Ottman and Lipton, 1994). Velioglu and colleagues (2005) found that people with both epilepsy and migraine had poorer seizure control than people with epilepsy but without migraine. The latter finding is important, because it suggests that the drugs used to treat epilepsy, some of which are also used in migraine, may not work to the same degree in people with both conditions. There may be a common risk factor for both disorders or a common underlying genetic susceptibility that may, in the future, suggest novel therapies in epilepsy accompanied by migraine.

Among older adults, the occurrence of either stroke or epilepsy is associated with an increased risk for the other condition (Cleary et al., 2004; Hauser et al., 1993; Kotila and Waltimo, 1992; Shinton et al., 1987). This bidirectional relationship may be explained by hypertension or, in epilepsy of unknown cause, by untreated left ventricular hypertrophy, a marker of severe hypertension, both of which are associated with an increased risk for developing seizures, even in the absence of stroke (Hesdorffer et al., 1996b; Ng et al., 1993). In this context, it is interesting to note that diuretics, a first-line treatment for hypertension, are protective for the development of epilepsy of unknown cause (Hesdorffer et al., 2001), a finding supported by animal studies (Hochman et al., 1995; Maa et al., 2011). Epidemiologic studies have stimulated the development of novel diuretics as treatments for seizures and the use of carbonic anhydrase inhibitors (which can act as diuretics), previously used in childhood epilepsy, in adult epilepsy (Edwards et al., 2010; Haglund and Hochman, 2005; Kozinska et al., 2009; Lim et al., 2001).

Mental Health Comorbidities

Mental health comorbidities have been recognized in people with epilepsy since the time of the ancient Greeks (Temkin, 1971), yet even today a

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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significant percentage of people with epilepsy may have mental health conditions that remain undiagnosed and untreated. The term “mental health conditions” is used here to reflect a range of conditions (e.g., depression, anxiety, attention deficit hyperactivity disorder [ADHD], psychosis) described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

In the 1970s, studies of mental health conditions in people with prevalent epilepsy became a topic of interest for researchers exploring the adverse effects of seizure medications (Trimble and Reynolds, 1976). Many studies subsequently examined the frequency of these disorders and conditions in people with prevalent epilepsy (e.g., Beghi et al., 2002; Boylan et al., 2004; Jacoby et al., 1996; O’Donoghue et al., 1999; Téllez-Zenteno et al., 2007b). These studies, which included population-based studies and studies in referral centers, found that many mental health comorbidities were attributable to the challenges of living with epilepsy, an unpredictable and stigmatizing disorder. As a group, the cross-sectional studies did not assess the sequence of the conditions, and some lacked a comparison group. Despite these methodological weaknesses, some people with epilepsy clearly experience adverse psychosocial outcomes associated with mental health conditions that affect their quality of life (Gilliam et al., 2003).

Longitudinal epidemiologic studies have established a more complex relationship between mental health conditions and epilepsy than revealed by cross-sectional studies. For example, behavioral problems and ADHD have been found to have a bidirectional relationship with epilepsy, with either condition increasing the risk for the other (Austin et al., 2001; Dunn et al., 1997; Hesdorffer et al., 2004; Holtmann et al., 2003; Jones et al., 2007; Williams et al., 1998). In two case-control studies of children with their first recognized, unprovoked seizure, behavioral disturbances before the onset of the first seizure were more frequent among children who developed epilepsy than among controls (siblings without epilepsy or children with no additional seizures) (Austin et al., 2001; Dunn et al., 1997). A population-based, case-control study conducted among Icelandic children found that those with an unprovoked seizure were 2.5 times more likely than age- and gender-matched controls to have a prior history of ADHD (95 percent CI = 1.1-5.5) that met DSM-IV criteria (Hesdorffer et al., 2004). The association was restricted to ADHD-predominantly inattentive type (Hesdorffer et al., 2004). When the occurrence of new-onset seizures is examined in people with ADHD (Holtmann et al., 2003; Williams et al., 2001), the percentage developing unprovoked seizures is 4 to 40 times greater than expected (Hauser et al., 1993; Hesdorffer et al., 2004). Recent research suggests that the co-occurrence of ADHD and epilepsy is due to frontal lobe dysfunction (Hermann et al., 2008a).

The incidence of psychosis increased following the diagnosis of epilepsy in two population-based registry studies in Denmark. In the earlier study,

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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the incidence of nonorganic, nonaffective psychoses was significantly increased for people with epilepsy, even after those diagnosed with learning disabilities or substance abuse were excluded (both of which increase the risk for developing epilepsy) (Bredkjaer et al., 1998). In the second study, epilepsy was associated with a 2.5-fold increased risk for schizophrenia, even for people without a family history of psychosis—an important exclusion, because positive family history might be expected to explain the increased risk (Qin et al., 2005). The risk was dependent on age at onset of epilepsy, with a significantly increased likelihood of schizophrenia observed with increasing age of epilepsy onset, suggesting that the peak age of schizophrenia incidence among people with epilepsy is greater than the peak incidence of 22 years reported for the general population (Thorup et al., 2007). The risk of developing schizophrenia is also increased in individuals with a history of febrile seizures, particularly when febrile seizures are followed by the development of epilepsy (Vestergaard et al., 2005). Recently, Chang and colleagues (2011) found that the association between schizophrenia and epilepsy is bidirectional.

Next Steps for Prevention: Depression

A history of depression is associated with an increased risk for developing epilepsy (Forsgren and Nystrom, 1990; Hesdorffer et al., 2000, 2006). Depression is also associated with a worse prognosis of seizures (Hitiris et al., 2007a), and a lifetime psychiatric history is associated with poor seizure control after surgery (Kanner et al., 2009). This latter finding implies that a worse seizure outcome could exist even after surgical removal of the lesion presumed to cause the seizures. Given current knowledge, it is possible that interventions can be developed for the comorbidity of depression and epilepsy.

Rather than the burden associated with having epilepsy increasing the risk for depression, the above findings suggest that depression may lower the seizure threshold, leading to an increased risk for epilepsy and an increased risk for continued seizures. This possibility is further supported by data from phase II and III clinical trials of psychotropic drugs conducted in the United States between 1985 and 2004, which found that the incidence of seizures was 52 percent lower in people who received antidepressants than in people receiving placebo (Alper et al., 2007). This result suggests that serotonergic mechanisms (i.e., those related to the neurotransmitter serotonin) underpin the occurrence of seizures in people with depression. Serotonergic mechanisms also may be associated with continued seizures in people with a history of depression and epilepsy; this possibility is supported by animal studies (Mazarati et al., 2008). Thus, it may be possible to decrease the occurrence of seizures in people with epilepsy and depres-

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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sion through the use of antidepressants that affect serotonin activity. This approach has been taken in interventions for people with stroke, in which placebo-controlled randomized clinical trials of antidepressants within 6 months of a stroke showed significant decreases in mortality (67.9 percent of people receiving antidepressants were alive at 9-year follow-up compared with 35.7 percent of those receiving the placebo treatment), whether they had depression or not (Jorge et al., 2003).

Research Gaps

As described in Chapter 4, standard screening protocols are needed to identify people with epilepsy who have mental health comorbidities. Studies are needed in populations of people with epilepsy and diagnosed mental health comorbidities to determine whether treatment of these comorbidities improves overall health outcomes for people with epilepsy. Further, additional research is needed to identify effective public health interventions for epilepsy and mental health comorbidities. Few studies have examined interventions for mental health conditions in people with epilepsy. In one of the only studies of children or youth, Martinovic and colleagues (2006) observed that a cognitive-behavioral intervention reduced depressive symptoms in adolescents with epilepsy and improved quality of life, but the results were not statistically significant, perhaps due to small sample size. Future studies of behavioral and other types of interventions for people with epilepsy and comorbid mental health conditions require adequate sample sizes to demonstrate effectiveness.

The Managing Epilepsy Well (MEW) Network12 is an important effort in the development of behavioral interventions for people with epilepsy and comorbid mental health conditions (see also Chapters 4 and 7). The CDC Prevention Research Centers and Epilepsy Program formed the MEW Network in 2007 to encourage research focused on the self-management of epilepsy, with the ultimate goal of improving quality of life. The MEW Network conducts research on interventions aimed at the broad area of self-management support, defined by the Institute of Medicine as “the systematic provision of education and supportive interventions [by health professionals] to increase patients’ skills and confidence in managing their health problems, including regular assessment of progress and problems, goal setting, and problem-solving support” (IOM, 2003, p. 52). Self-management for epilepsy includes the information and resources that people

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12Currently four academic universities participate in the MEW Network, in collaboration with community partners (e.g., state and local Epilepsy Foundation affiliates), state and federal agencies (e.g., the CDC), and others. For more information, see www.sph.emory.edu/ManagingEpilepsyWell/.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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with epilepsy and their families need to develop skills and behaviors that enable them to actively participate in patient-centered care. Studies conducted by the MEW Network seek to identify and better understand what epilepsy self-management needs are and evaluate programs that are designed to improve self-management skills in a variety of contexts. Since mental health comorbidities are common in epilepsy, the MEW Network is testing interventions such as Project UPLIFT (Chapter 4), which is designed to help people with epilepsy and co-occurring depression through a combination of cognitive-behavioral therapy and mindfulness techniques (Thompson et al., 2010; Walker et al., 2010). Broadening the scope of comorbidities covered by MEW Network interventions—for example to look at anxiety disorders—would be beneficial.

Cognitive Dysfunction

Cognitive dysfunction is a major concern for people with epilepsy, particularly at both ends of the age spectrum. Many people with epilepsy experience declines in cognitive function, which will become increasingly important as the population with epilepsy ages. In addition, the impact of having intellectual disability on the risk for developing epilepsy is profound in children and young adults as well.

In a study of children with intellectual disabilities (98 percent had an IQ less than 70), approximately 15 percent developed epilepsy13 by 22 years of age (Goulden et al., 1991), reflecting a 43-fold increased risk in comparison to children without intellectual disability (Hauser et al., 1993). When adjustment is made for age, SES, and gender, among children with intellectual disabilities a 9-fold increased risk to have one or more seizures was found when compared to matched comparisons (Richardson et al., 1980). Furthermore, the presence of disabilities associated with intellectual disability strongly increases the risk for developing epilepsy. The risk is 38 percent for those with intellectual disability and cerebral palsy, compared with 5.2 percent risk in the absence of associated disabilities (Goulden et al., 1991). In addition to the 43-fold increased risk for epilepsy in children with intellectual disability, there is a 123-fold increased risk in children with cerebral palsy (Carlsson et al., 2003). Results are similar for autism spectrum disorders with or without intellectual disability and cerebral palsy. By 10 years of age, the cumulative probability of developing epilepsy is 8 percent for children with autism spectrum disorders only, compared to 27 percent for children with autism spectrum disorders and severe intellectual disability and 67 percent for children with autism spectrum disorders, severe intellectual disability, and cerebral palsy (Tuchman and Rapin, 2002).

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13In this study, defined as two or more nonfebrile seizures.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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Common epilepsy-associated cognitive impairments affect several domains, especially memory and psychomotor speed. Executive dysfunction, such as deficits in working memory and planning abilities, has been noted in many children and adolescents with epilepsy (MacAllister et al., 2011). As noted by Bhise and colleagues (2010), these problems have been attributed to an interplay of genetic susceptibility, uncontrolled seizures, subclinical epileptiform discharges,14 postictal states,15 psychosocial factors, underlying abnormalities of the brain, and use of seizure medications. A variety of factors—many of which are not intrinsically associated with having seizures or treatment—impact the neurobehavioral status of people with epilepsy (Hermann and Seidenberg, 2007). For example, even people with newly diagnosed epilepsy who have not yet begun treatment—and who do not have other neurological disorders—have significantly worse results than healthy volunteers in several cognitive domains (Taylor et al., 2010). Similarly, Hermann and colleagues (2006a) found that children with new-onset epilepsy demonstrate cognitive impairment and academic under-achievement in comparison to children without epilepsy.

The presence of neurobehavioral comorbidities, particularly ADHD or academic problems, at the time of epilepsy onset is an important marker of impaired cognitive development before and after epilepsy onset (Hermann et al., 2008c). Clinically significant declines in intellectual or cognitive abilities are seen in a subgroup of about 10 to 25 percent of children after the onset of epilepsy. This subgroup includes children who have frequent seizures, those who take multiple seizure medications, and those whose epilepsy began at an early age, although the role of psychosocial factors may be important as well (Vingerhoets, 2006). An increased risk for SE appears to be associated with severe cognitive impairments, rather than SE being the cause of cognitive decline (Helmstaedter, 2007). Furthermore, even if seizures are controlled, cognitive impairments may remain, some of which may be due to the side effects of seizure medications (Loring and Meador, 2001).

Long-term epilepsy in adults is commonly associated with significant impairments in cognition, and in some people these become worse by middle age (Hermann et al., 2008b). In people with chronic temporal lobe epilepsy, adverse cognitive outcomes are seen in approximately 20 percent, including deficits in memory, psychomotor or motor abilities, naming, and some executive functions (Hermann et al., 2006b). The cognitive decline often seen in refractory epilepsy can be stopped or reversed to some degree by successful epilepsy surgery (Téllez-Zenteno et al., 2007a); however,

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14Subclinical epileptiform discharges refer to EEG abnormalities without clinical correlates.

15Postictal states follow a seizure and are characterized by a range of responses, including confusion, drowsiness, and unresponsiveness.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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many people who undergo epilepsy surgery have low memory functioning on presurgery tests, and further decline below presurgery levels may not be possible in some people (Baxendale et al., 2012).

Research Gaps

Currently, there is insufficient knowledge about cognitive impairment in epilepsy, including its timing, its prognosis, and to what extent refractory epilepsy causes cognitive decline over time (Hermann and Seidenberg, 2007). Much of the published work is cross-sectional; such studies have several methodological problems that preclude them from clearly elucidating the cognitive course of people with epilepsy. These shortcomings include the studies’ inability to evaluate cognitive status over time and to account for cohort effects. Further, research on epilepsy and cognitive disorders has, for the most part, been descriptive rather than explanatory (Hermann and Seidenberg, 2007). The few prospective studies that have sought to identify the etiology of cognitive impairment in people with epilepsy also have methodological shortcomings, such as evaluating cognitive status only through assessments of IQ, use of cohorts that have a mixture of seizure types, lack of appropriate control groups, absence of baseline data, polypharmacy, varying test-retest intervals, and relatively short follow-up periods (Bhise et al., 2010).

Analysis of cognitive decline in children with epilepsy is particularly difficult given the extremely small number of studies that have used comprehensive neuropsychological test batteries (Vingerhoets, 2006). The course of cognition in middle-aged and older adults with chronic epilepsy has been even less studied (Hermann et al., 2008b). Limitations in the few long-term studies of outcomes after epilepsy surgery include failure to include an adequate control group; not reporting on outcomes beyond seizure-related measures, such as cognitive outcomes over a period longer than 5 years; and a focus on temporal lobe epilepsy (Téllez-Zenteno et al., 2007a).

For these reasons, a large-scale, well-designed epidemiologic study on cognitive impairment in epilepsy is a research priority. This might be achieved though the addition of questions on cognitive impairment in surveys such as the CDC’s BRFSS. In addition, people with epilepsy who are already experiencing cognitive decline need to be identified and referred to specialists in order to try to halt additional impairment (Chapter 4). School performance can be used to identify children at high risk for attention and behavior problems early on, allowing appropriate management to begin (Bhise et al., 2010).

Future longitudinal prospective investigations are needed to accurately describe seizure type and frequency and compare cognitive effects in groups

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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of people with different epilepsy syndromes (Vingerhoets, 2006). Studying middle-aged people with epilepsy, who may face later neurocognitive declines typical of aging, is another important area for future research (Hermann et al., 2006b). Neuropsychological evaluation can provide essential information for maximal sparing of functional tissues if epilepsy surgery is undertaken and for monitoring surgery outcomes (Helmstaedter, 2004). Longer-term, prospective, controlled studies of the effects of epilepsy surgery on cognitive functioning also are warranted (Téllez-Zenteno et al., 2007a).

OUTCOMES

In addition to the seizures themselves, a number of negative health outcomes are possible for people with epilepsy, including poorer overall health status, impaired intellectual and physical functioning, a greater risk for accidents and injuries, and side effects from seizure medications and other treatments (Camfield and Camfield, 2007; Kobau et al., 2008; Tomson et al., 2004). According to data collected by the BRFSS surveys and the California Health Interview Survey, adults with epilepsy are more likely than adults without epilepsy to report poor quality of life (Kobau et al., 2007, 2008). They are more likely to be unemployed or unable to work; to have low annual household incomes; to be obese and physically inactive; and to currently smoke. Further, people with poorly controlled epilepsy report worse quality of life than people with well-controlled epilepsy; and they report more mentally and physically unhealthy days per month compared to people without epilepsy (Baker et al., 1997; Kobau et al., 2007) (Chapter 6).

The focus in this chapter is on potentially preventable outcomes in epilepsy, including accidental injury and epilepsy-related mortality, specifically accidents and injuries, suicide, and SUDEP. First, the course of epilepsy is discussed briefly to provide some context.

Remission, Relapse, and Refractory Epilepsy

As discussed in Chapter 1, with the appropriate diagnosis and treatment, many people with epilepsy can be free of seizures. Using data from the Rochester Epidemiology Project, Annegers and colleagues (1979) found that at 20 years after diagnosis with epilepsy, 70 percent of people with epilepsy were in remission with at least 5 consecutive seizure-free years. Similarly, 63 percent of people with epilepsy achieved remission in a study by Kwan and Brodie (2000), who noted that people who did not respond to their first seizure medication and those who had numerous seizures before beginning a medication regimen were more likely to have refractory

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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epilepsy. Among adults, the cumulative probability of early remission16 is 56.3 percent, and the cumulative probability of a 2-year remission by the time an individual has had epilepsy for a decade is 79.5 percent (Del Felice et al., 2010).

In a prospective study of newly diagnosed children with epilepsy, 74 percent achieved 2 seizure-free years (Berg et al., 2001c). This early remission was less likely if the epilepsy had a structural or metabolic etiology17 or in cases where there was an increased baseline seizure frequency, family history of epilepsy, and slowing of brain function as measured by an EEG. When children with epilepsy of genetic cause18 were excluded and remission in those with epilepsy of unknown etiology19 was compared to those with epilepsy of structural or metabolic causes, remission was markedly higher for epilepsy of unknown etiology, and the only predictor of lack of seizure remission was perinatal complications (Wirrell et al., 2011). A study examining long-term outcomes of childhood epilepsy found that children were more likely to achieve at least 5 years of remission if they had epilepsy of unknown etiology, no previous febrile seizures, a 3-month remission in the first 6 months, and a fast response to seizure medications (Geerts et al., 2010). Refractory epilepsy20 occurred in 9 percent of children who were followed for almost 15 years (Geerts et al., 2010).

Periods of remission and relapse cycle back and forth in adults and children who have continued seizures despite treatment. Cycling of remission and relapse is seen in adults with refractory epilepsy, with 13 to 24 percent entering at least a 12-month remission; of those who achieved this remission, 60 to 71 percent subsequently relapsed (Callaghan et al., 2011; Choi et al., 2011). In adjusted analysis, the only factor associated with lack of remission was the number of drugs that had failed to help (Callaghan et al., 2011). For those who did achieve remission, only focal epilepsy21 predicted seizure relapse. Repeated remissions and relapses also are common among children whose seizures do not respond to two drugs, with structural or metabolic causes of epilepsy being the only predictors of lack of remission (Berg et al., 2009). Risk factors for lack of remission in children with a

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16In this study, early remission is defined as beginning immediately after the initiation of treatment and lasting at least 2 years.

17The most recent terminology, structural or metabolic etiology, is used here in place of the previous terminology, remote symptomatic etiology.

18The most recent terminology, genetic etiology, is used here in place of the previous terminology, idiopathic etiology.

19The most recent terminology, unknown etiology, is used here in place of the previous terminology, cryptogenic etiology.

20In this study, refractory epilepsy is defined as continued seizures for at least 3 months in a single year despite adequate treatment for at least 2 years.

21In focal epilepsy, seizures originate in a network of neurons limited to one hemisphere of the brain (Chapter 1).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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period of continued seizures despite treatment include seizure etiology and family history of epilepsy, which are not amenable to intervention.

Among people with continued seizures for whom medications do not work and who then receive surgery, 66 percent experienced at least 2 seizure-free years, and 25 percent subsequently relapsed (Spencer et al., 2005). Predictors of remission in the group with medial temporal lobe surgery included absence of generalized tonic-clonic seizures and presence of hippocampal atrophy. In a meta-analysis, predictors of remission included febrile seizures, mesial temporal sclerosis, tumors, abnormal MRI, concordance between MRI and EEG, and extensive surgery (Tonini et al., 2004). These results suggest that surgery is most likely to be effective for mesial temporal sclerosis, compared to other types of epilepsy.

Research Gaps

Accurate estimates of the number of people with refractory epilepsy and its severity are not available, nor are estimates of the number of people who could be in remission if they received the appropriate treatment at the appropriate time. Improved data on the number of people who could be seizure-free would suggest opportunities to mitigate the current burden of disease and improve health outcomes and quality of life associated with epilepsy.

Nonfatal Accidents and Injuries

Accidents and injuries are common among people with epilepsy.22 Severity of epilepsy affects the risk for injury, with injury rates being higher in people with poorly controlled epilepsy, particularly those with generalized tonic-clonic seizures (Asadi-Pooya et al., 2012; Tomson et al., 2004). This risk factor has been confirmed in a large multicenter European cohort study, where the risk of injury in children (ages 5 and older) and adults with epilepsy of less than 10 years’ duration (without any progressive neurological condition) were compared to age- and gender-matched controls (Beghi and Cornaggia, 2002). After 2 years of follow-up, the cumulative risk for accidents among people with epilepsy was 17 percent at 12 months and 27 percent at 24 months, compared to 12 and 17 percent in the control group—a significant difference. For study participants, the probability of accidents not related to seizures was 14 percent by 12 months and 22 percent by 24 months. Wounds, abrasions, and concussions were each more common among people with epilepsy than in the control group.

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22Accidents are used in this report to refer to unexpected and unintended events that lead to physical injury or death (also see Epilepsy-Related Death section).

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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Complications after the injury also were more common, with people with epilepsy spending more days in the hospital than the control group (Beghi and Cornaggia, 1997).

Across studies, seizure type, severity, and frequency were found to be predictors of accidents and injuries in people with epilepsy as was having more than three treatment-related adverse effects (Tomson et al., 2004). Seizure severity is associated with an increased risk for any injury and for specific injury types—burns or scalding, head injury, dental injury, and fractures. Having at least one seizure per month is associated with an increased risk for injuries, including burns or scalding and seizures while bathing or swimming; and a number of adverse events are associated with fractures and seizures while bathing or swimming (Tomson et al., 2004).

Scant data exist on injury in children with epilepsy. Among children with newly diagnosed epilepsy, 12.6 percent experienced an injury before diagnosis, most of which were presumed to be seizure related (Appleton, 2002). In a comparison of children with epilepsy who had no cognitive impairment and their peer controls, there was no difference in injury rates, and only the presence of ADHD was associated with a higher injury rate—in children both with and without epilepsy (Kirsch and Wirrell, 2001). Since children with cognitive impairment experience more seizures than those without (Aicardi, 1990; Berg et al., 2007), the absence of an increased risk for injury in this population of children with epilepsy but without cognitive impairment may reflect less severe and less frequent seizures.

Next Steps for Prevention: Accidents and Injuries

In combination, these studies suggest that prevention of accidents and injuries among people with epilepsy will be related to improving seizure control and avoiding, if possible, adverse effects of seizure medications, such as dizziness, which may themselves lead to injury. Once seizure-related accidents are eliminated from consideration, the excess accident and injury risk for people with epilepsy decreases (Beghi and Cornaggia, 2002). This finding underscores the importance of controlling risk factors for seizures. To date there have been no accident and injury prevention trials in people with epilepsy, although they are clearly needed. Such trials should focus on those at high risk for injury and build on injury prevention efforts in the general population.

The risk for fractures in epilepsy is a special case because of the possible relationship between seizure medications and impaired bone health, including changes in bone turnover and osteoporosis (Pack, 2008). This is particularly important among children with disorders that cause vitamin D deficiency (Vestergaard, 2008). A large population-based study docu-

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
×

mented increased hip-fracture risk associated with ever taking a seizure medication, particularly liver enzyme-inducing medications (Tsiropoulos et al., 2008). Other epidemiologic studies also have found an increased fracture incidence associated with the use of seizure medications and an association between seizure medications and falls, themselves a common cause of fractures (Bohannon et al., 1999; Cummings et al., 1995; Ensrud et al., 2002).

However, the association between fractures and seizure medications remains uncertain, and fractures in people with epilepsy also may be caused by the seizures themselves (Vestergaard et al., 1999). Still, given the potential role of seizure medications in the development of osteoporosis, routine screening for bone disease in epilepsy is advisable. Currently, only 41 percent of pediatric neurologists and 28 percent of adult neurologists evaluate patients with epilepsy for bone mineral disease (Valmadrid et al., 2001). Of those who screen, only 40 percent of pediatric neurologists and 37 percent of adult neurologists reported that they prescribe calcium or vitamin D supplements to patients with detected bone disease and approximately half referred patients to specialists (Valmadrid et al., 2001). Thus, a gap in practice for the prevention of fractures in people with epilepsy is screening for bone disease and treating it when it is found.

Mortality

Overall mortality is 1.6- to 3.0-fold greater in people with epilepsy than in the general population (Forsgren et al., 2005b). Among children, the increased risk of death associated with epilepsy is greater than among adults, because the usual mortality rate among U.S. children in the general population is low, whereas the expected mortality among adults increases with advancing age. Between 1950 and 1994, epilepsy-related mortality decreased among people under age 20; in adults age 70 years and older, the mortality rate first declined and then increased (O’Callaghan et al., 2000). In epilepsy of unknown cause, mortality is increased 1.1- to 1.8-fold (Forsgren et al., 2005b), with only one study showing a statistically significant mortality increase 25 to 29 years after diagnosis (Hauser et al., 1980). In epilepsy of known etiology, by contrast, mortality is increased 2.2- to 6.5-fold (Forsgren et al., 2005b). Gaitatzis and colleagues (2004b) estimated that 2 years of life are lost in people with epilepsy of unknown etiology, and 10 years in people with epilepsy of known etiology.

As noted above, among children and adults with epilepsy with known etiologies of structural or metabolic disorders, studies consistently demonstrate a statistically significant increased mortality. Mortality is highest when epilepsy is accompanied by neurodeficits, such as cerebral palsy, with mortality increasing 3- to 12-fold above that of the general population

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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(Forsgren et al., 1996). Most deaths in people with a known underlying cause of their epilepsy occur due to the underlying cause, such as brain tumor or stroke (which are themselves associated with an increased risk for death) (Benn et al., 2009). Many challenges remain to identify effective strategies for decreasing the risk of epilepsy-related deaths.

Status Epilepticus

SE is a common neurological emergency associated with high mortality (DeLorenzo et al., 1996; Hesdorffer et al., 1998; Logroscino et al., 1997, 2001). Most cases of SE (54 percent) are not associated with epilepsy; however, when SE is associated with epilepsy, it is usually either the first or the second time that an unprovoked seizure has been diagnosed; thus, an epilepsy diagnosis does not often exist prior to the occurrence of SE (Hesdorffer et al., 1998). Less than 20 percent of unprovoked cases of SE occur in people with an established diagnosis of epilepsy (Hesdorffer et al., 1998).

Mortality is high in the first 30 days after SE, with almost 90 percent of deaths occurring in people with acute symptomatic SE and no deaths in those with SE of unknown etiology (Logroscino et al., 1997). A 10-year follow-up study of people who initially survived more than 30 days after SE found that, of those who died, 43.5 percent of deaths occurred in acute symptomatic SE and 56.5 percent in unprovoked SE; overall, the study population had a mortality rate three times that of the general population (Logroscino et al., 2002). In people surviving who had unprovoked SE, long-term mortality over a 10-year period occurred in 43 percent of people whose seizures had a structural or metabolic cause, in 75 percent whose seizures were progressive, and in 29 percent whose seizures were of unknown cause (Logroscino et al., 2002). Risk factors for long-term mortality in SE include SE lasting 24 hours or longer, acute symptomatic etiology, and myoclonic SE (Logroscino et al., 2002).

An important question is whether SE itself is associated with death or whether death is due to an underlying etiology. This has been examined in unprovoked seizures of unknown cause, comparing mortality of people with SE to those with a brief seizure (Logroscino et al., 2008). Compared to people with brief seizure, those with SE had a 2.4-fold increased risk of death over 10 years, and increased risk was found in the group over age 65 and among those who later developed epilepsy, where there was a 5- and 6-fold increased risk for death, respectively. This suggests a specific vulnerability of older adults who experience SE of unknown etiology. Currently, the only prevention measure available for SE is early identification or recognition and treatment of a seizure lasting more than 5 minutes.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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Epilepsy-Related Deaths

Causes of epilepsy-related deaths include accidents and injuries, SUDEP, and suicide. These deaths may be preventable and are the focus of the rest of this section.

Fatal accidents and injuries In population-based studies, accidents and injuries accounted for between 6 and 20 percent of all deaths of people with epilepsy (Cockerell et al., 1994; Hauser et al., 1980; Rafnsson et al., 2001; Shackleton et al., 1999). Among institutionalized people with severe epilepsy, 3 to 16 percent of deaths were due to accidents and injuries (Iivanainen and Lehtinen, 1979; Klenerman et al., 1993; Krohn, 1963), and in a hospital-based cohort, 7 percent of deaths were due to accidents and injuries (Nilsson et al., 1997). Compared to the general population, people with epilepsy have more than twice the risk of death due to accidents and injuries (Hauser et al., 1980; Rafnsson et al., 2001) and nearly six times the risk in a hospital-based cohort (Nilsson et al., 1997). Prevention measures to reduce the occurrence of deaths due to accidents and injuries in epilepsy should rely on the same interventions proposed for prevention of nonfatal accidents and injuries.

All of us have recollections of our first exposure to epilepsy. The stigma, the fear of the tonic-clonic episodes, the restrictions, but not death. People don’t die from epilepsy. But Carei did—her death certificate reads “cause of death: SUDEP” … This can’t be, no one told me she could die, no one ever mentioned SUDEP…. Research in this field has been limited, but the small amount of available literature consistently identifies risk factors. There is a significant underappreciation of mortality in epilepsy.

-Linda Coughlin Brooks

Sudden unexpected death in epilepsy As noted in Chapter 2, deaths categorized as SUDEP encompass nontraumatic, non-drowning-related deaths in people with epilepsy that may or may not be associated with a recent seizure, but are not due to SE (Nashef et al., 2012). In definite SUDEP, an autopsy reveals no evidence of an anatomical or toxicological cause of death (Nashef et al., 2012).

SUDEP is the most common of the epilepsy-related causes of death (Tomson et al., 2004). The risk of sudden death in people with epilepsy is more than 20 times greater than in the general population (Ficker et al., 1998), making efforts to prevent SUDEP of paramount importance. Current estimates suggest that the incidence of SUDEP is 0.1 to 2.3 per 1,000 person-years23 in community samples; 1.1 to 5.9 for people treated in

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23“Person-years” is calculated by multiplying each person being followed by the time that he or she is observed and then adding across all of the study subjects being followed. A person followed for 1 year contributes 1 person-year.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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epilepsy centers, many of whom have refractory epilepsy; and 6.3 to 9.3 among those who are candidates for epilepsy surgery or who have seizures after surgery (Tomson et al., 2008). People with cognitive impairment and refractory epilepsy are particularly vulnerable populations in which the cumulative risk of SUDEP can exceed 10 percent (Sillanpää and Shinnar, 2010).

Risk factors for SUDEP have been identified in case-control studies (Hesdorffer et al., 2011b; Hitiris et al., 2007b; Langan et al., 2005; Nilsson et al., 1999; Walczak et al., 2001). A recent 40-year follow-up of childhood-onset epilepsy found recurrent seizures to be the strongest SUDEP risk factor (Sillanpää and Shinnar, 2010). Seizure-related risk factors include onset of epilepsy at an early age, ongoing frequent seizures, frequent generalized tonic-clonic seizures, and long duration of epilepsy. Neurological status, such as IQ less than 70, and the presence of a major neurological insult (e.g., stroke) also have been identified as risk factors; these are factors associated with recurrent seizures, as well. Studies have suggested that an increased risk for SUDEP is associated with frequent changes in dosing of seizure medication, use at subtherapeutic levels, polytherapy, use of lamotrigine, and nocturnal seizures (Aurlien et al., 2012; Berg et al., 2001a; George and Davis, 1998; Hesdorffer et al., 2011b; Lamberts et al., 2012; Langan et al., 2005; Nilsson et al., 1999; Walczak et al., 2001). Some authors have suggested that sleep-related disorders, such as obstructive sleep apnea, may contribute to SUDEP (Nobili et al., 2011; Surges et al., 2009). Among surgical patients in whom the seizure focus in the brain was removed, there were no cases of SUDEP, compared to 3 percent among people whose seizures continued (Sperling et al., 1999).

Although some studies have identified seizure medication polytherapy as a risk for SUDEP (Hesdorffer et al., 2011b), the strongest evidence from a meta-analysis of randomized placebo-controlled clinical trials suggests that it is the occurrence of seizures that drives an increased risk for SUDEP (Ryvlin et al., 2011), not polytherapy as suggested in previous studies (Hesdorffer et al., 2011b; Nilsson et al., 1999; Walczak et al., 2001). In this analysis, the risk for SUDEP in the group treated with polytherapy at efficacious doses was seven times less than that of the group receiving addon placebo. This provides strong evidence that polytherapy at efficacious doses actually protects against SUDEP (Ryvlin et al., 2011). Additionally, since the risk for SUDEP is higher in people with recurring seizures, these findings suggest that trial designs are needed in epilepsy that minimize the time spent on adjunctive placebo or ineffective adjunctive seizure medications. A reanalysis of the combined case-control studies supports this argument (Hesdorffer et al., 2012); after simultaneous adjustment for the number of seizure medications and the number of generalized tonic-clonic

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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seizures, the latter had a strong effect on SUDEP risk, whereas the number of medications did not affect SUDEP risk.

The role of continued seizures in SUDEP is further implicated by reports of witnessed SUDEP. In one study, 15 of 135 instances of SUDEP were witnessed (Langan et al., 2000), 12 of which occurred in conjunction with a generalized tonic-clonic seizure. One person shouted, “I’m going to have a seizure” and collapsed without a generalized seizure; one recovered consciousness after a seizure and collapsed; and one likely died during the postictal period. Case reports of patients who were monitored in epilepsy monitoring units when they died or nearly died from SUDEP show that all experienced a secondary generalized tonic-clonic seizure; most of these were accompanied by a flat or diffusely suppressed EEG and changes in the electrocardiogram, including asystole and premature heart beats (Bateman et al., 2010; Bird et al., 1997; Lee, 1998; McLean and Wimalaratna, 2007; So et al., 2000).

Next steps for prevention: SUDEP These and other data are very important for considering potential prevention strategies for these sudden deaths. One study has found a decreased risk for SUDEP associated with supervision at night (Langan et al., 2005), suggesting that sleeping in the same room as another adult or installing monitoring devices may offer the opportunity to help someone having a seizure during sleep. If SUDEP is related to continued seizures as suggested above, then it would be important to aggressively treat people with continued seizures and to optimize compliance with seizure medications (Chapter 7), as is done in randomized clinical trials. While it is also possible that SUDEP is associated with more severe epilepsy and that treating the seizures will not alter SUDEP risk, prevention trials should be undertaken in high-risk individuals (e.g., people with continued seizures, people with known causes of seizures) to determine whether SUDEP risk declines.

Suicide Deaths due to suicide accounted for 1.3 percent of deaths in a hospital-based cohort of people with epilepsy (Nilsson et al., 1997) and 1.6 to 9.1 percent in a population-based cohort (Hauser et al., 1980; Rafnsson et al., 2001). While one study failed to find a significantly increased risk of death due to suicide (Hauser et al., 1980), other studies have found a risk of suicide in epilepsy that is 3.5 to 5.8 times that of the general population (Nilsson et al., 1997; Rafnsson et al., 2001).

An increased risk for developing epilepsy is associated with both suicide attempt and major depression (Hesdorffer et al., 2006); these also are strong risk factors for later completed suicide (Harris and Barraclough, 1997). In people with epilepsy, the prevalence of suicidal ideation is 12.2 percent, with increased prevalence associated with current or past history

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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of major depression and generalized anxiety disorder (Jones et al., 2003). A Food and Drug Administration report implicated seizure medications in suicidality generally and in people with epilepsy in particular (FDA, 2008). Controversy exists concerning whether adverse event reporting to identify suicidality is complete and whether it may reflect reporting bias because adverse events tend to be reported more frequently by people on the active drug in comparison to those using the placebo (Hesdorffer and Kanner, 2009). Additionally, only two seizure medications had a statistically significant increased risk for suicidality, and small protective effects were observed for two others. Further observational studies have failed to clarify these associations (Hesdorffer et al., 2010).

Next steps for prevention: Suicide Suicide prevention strategies have been systematically reviewed, and those with greatest efficacy include education of physicians, restriction of the means to commit suicide, and gatekeeper education24 (Mann et al., 2005).

•  Clinicians need to know how to inform patients with epilepsy and their families about the risk for suicidal ideation when they take seizure medications, how to screen these patients for increased suicide risk, and also how to implement the screening and make referrals for mental health treatment when appropriate.

•  Restricting access to highly lethal means of suicide—through fire-arms control, detoxification of natural gas, restrictions on pesticides, control of drugs used for intentional overdose, mandatory use of catalytic converters in cars, and barriers at jumping sites— are all ways to reduce suicide risk at the population level that can have an impact on suicide in epilepsy.

•  Education of gatekeepers is needed to increase their awareness of what constitutes increased risk for suicidality and their knowledge of how to encourage at-risk individuals to seek help.

As yet, no systematic interventions have been reported that focus on preventing suicide in people with epilepsy who are at high risk. Early detection of suicidal ideation is needed for all people with epilepsy, including children (Caplan et al., 2005). Targeted interventions are needed for those who have a past or current history of suicidality, depression, anxiety, bipolar disorder, or schizophrenia. Broad-based interventions are also needed for people with

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24In the field of suicide prevention, gatekeepers are professionals who spend time with people who may be vulnerable to suicidal ideation. Gatekeepers include a range of people, such as health professionals, teachers, coaches, law enforcement officers, and members of the clergy.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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epilepsy generally because epilepsy itself is associated with an increased risk for suicide (Christensen et al., 2007).

Stigma

As described in Chapter 1, over time people with epilepsy have been subject to stigma based on misinformation and misconceptions about epilepsy. Historically, the legal system was used to limit the rights of people with epilepsy (Alström, 1950; Jacoby, 2002). Recent research comparing attitudes of lay people regarding acquired immune deficiency syndrome (AIDS), epilepsy, and diabetes demonstrated that prejudice scores for epilepsy were just below those for AIDS and noticeably higher than those for diabetes (Fernandes et al., 2007). In the United States, two important studies, one of adults and another of adolescents, reported on institutional and interpersonal stigma (Austin et al., 2002; DiIorio et al., 2004). They found that lower levels of knowledge about epilepsy were associated with these types of stigma, they identified negative stereotypes, and they described personal and social avoidance. Interventions to reduce stigma in the general public require public education and awareness campaigns (Chapter 8). Negative attitudes are reflected in the internal experience of “difference” and fear of prejudice experienced by people with epilepsy, called “felt” or internalized stigma (Jacoby, 1994; Jacoby and Austin, 2007). This section focuses on the internalized experience of stigma.

Stigma is related to continued seizures and therefore is less likely to be experienced by people whose seizures are in remission than by those with ongoing seizures (Jacoby, 2002). Among people with prevalent epilepsy, who by definition have ongoing seizures or are taking seizure medications, the perception of stigma has been associated with increased depression and poor health status, as well as poor quality of life (Baker, 2002; Jacoby and Baker, 2008; Kumari et al., 2009; Reisinger and DiIorio, 2009). Furthermore, results from a study conducted by DiIorio and colleagues (2003) suggest that felt stigma negatively affects self-management skills. Felt stigma is present in one-fifth of people with newly diagnosed epilepsy, with more newly diagnosed people reporting felt stigma if they also had a lifetime history of major depression; this association remained a year later (Leaffer et al., 2011). The relationship among felt stigma, negative outlook on life, and increased levels of worry has been described in populations with prevalent epilepsy (Baker et al., 2000).

Next Steps for Prevention: Stigma

Interventions to reduce depression or negative outlook on life in people with prevalent epilepsy may also reduce felt stigma. Additionally, interven-

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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tions to decrease a negative outlook and foster self-esteem may prevent the development of felt stigma for people with newly diagnosed epilepsy who have a past history of depression.

CONCLUSION

There are a number of opportunities for the public health community to improve efforts to prevent epilepsy and its consequences. Throughout this chapter, the committee has provided the basis for its research priorities and recommendations regarding improvements needed to achieve this goal in Chapter 9. Further research is needed to improve knowledge about epilepsy’s incidence, prevalence, risk factors, comorbidities, and outcomes, which will inform future prevention efforts. For example, research is needed to determine if treatment of mental health comorbidities and behavioral interventions improve health outcomes for people with epilepsy, including reduction in seizure frequency.

Actions are needed to prevent risk factors for epilepsy. Neurocysticercosis, which is a growing concern in the United States, represents a known risk factor for epilepsy where education and sanitary measures could decrease infections and resulting cases of epilepsy. Continued intervention efforts are needed to prevent the occurrence of TBI, through mechanisms such as the use of seatbelts, to prevent TBI associated with motor vehicle accidents, as well as helmets, including improved helmet design, to reduce the occurrence and severity of TBI in sports and military combat. In addition, progress in the prevention of other risk factors—such as stroke, through targeted efforts to reduce risk factors, and brain infections such as meningitis, through sustained vaccination programs—will likely result in fewer new cases of epilepsy. Further opportunities for primary prevention may come to light if epidemiologic studies identify other risk factors for epilepsies whose etiologies are currently unknown. Secondary prevention of seizures may be possible through the use of antidepressants.

While risk factors for accidents, injuries, and suicide are generally known, there is less information on risk factors specific to people with the epilepsies. This information is needed in order to design tertiary prevention efforts. Additionally, risk factors for SUDEP have been described, but interventions to reduce the occurrence of this devastating outcome have not been tested in those at highest risk. Interventions to promote seizure control may decrease rates of preventable deaths. Further, the implementation of screening for bone disease, mental health comorbidities, suicidality, and felt stigma will identify populations for whom tertiary prevention measures are needed.

Suggested Citation:"3 Epidemiology and Prevention." Institute of Medicine. 2012. Epilepsy Across the Spectrum: Promoting Health and Understanding. Washington, DC: The National Academies Press. doi: 10.17226/13379.
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Although epilepsy is one of the nation's most common neurological disorders, public understanding of it is limited. Many people do not know the causes of epilepsy or what they should do if they see someone having a seizure. Epilepsy is a complex spectrum of disorders that affects an estimated 2.2 million Americans in a variety of ways, and is characterized by unpredictable seizures that differ in type, cause, and severity. Yet living with epilepsy is about much more than just seizures; the disorder is often defined in practical terms, such as challenges in school, uncertainties about social situations and employment, limitations on driving, and questions about independent living.

The Institute of Medicine was asked to examine the public health dimensions of the epilepsies, focusing on public health surveillance and data collection; population and public health research; health policy, health care, and human services; and education for people with the disorder and their families, health care providers, and the public. In Epilepsy Across the Spectrum, the IOM makes recommendations ranging from the expansion of collaborative epilepsy surveillance efforts, to the coordination of public awareness efforts, to the engagement of people with epilepsy and their families in education, dissemination, and advocacy for improved care and services. Taking action across multiple dimensions will improve the lives of people with epilepsy and their families. The realistic, feasible, and action-oriented recommendations in this report can help enable short- and long-term improvements for people with epilepsy. For all epilepsy organizations and advocates, local, state, and federal agencies, researchers, health care professionals, people with epilepsy, as well as the public, Epilepsy Across the Spectrum is an essential resource.

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