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Purpose: In a nationally representative population-based study in England, we estimated the burden of psychiatric and neurodevelopmental comorbidities in people with epilepsy. We investigated whether any overrepresentation of comorbidities could be explained by epilepsy being a chronic medical or neurologic condition, or by the confounding effect of demographic and socioeconomic factors or other health conditions.
Methods: The Adult Psychiatric Morbidity Survey 2007 comprised detailed interviews with 7,403 individuals living in private households in England. Doctor-diagnosed epilepsy (and asthma, diabetes, and migraine, chronic conditions for comparison) was ascertained by self-report, and extensive diagnostic and screening interviews were used to assess psychiatric and neurodevelopmental conditions.
Key Findings: The estimated lifetime prevalence of epilepsy in the adult (≥16 years old) population of England was 1.2% (95% confidence interval [CI] 1.0–1.5). Almost one-third of the people with epilepsy had an International Classification of Diseases, Tenth Revision (ICD-10) anxiety or depressive disorder (compared with one in six people without epilepsy). Among these, social phobia and agoraphobia, generalized anxiety disorder, depression, and measures of suicidality had strong associations with epilepsy, which remained robust after accounting for potential confounders. These associations were consistently stronger than those in people with asthma or diabetes, and similar to those in people reporting migraine or chronic headaches. Epilepsy was also strongly associated with autism spectrum disorders (odds ratio [OR] 7.4, 95% CI 1.5–35.5) and possible eating disorders, and these associations were not evident in people with asthma, diabetes, or migraine.
Significance: Psychiatric and neurodevelopmental conditions were overrepresented in people with epilepsy. These associations were stronger than with other nonneurologic chronic conditions, and not explained by confounding. Some overlap in the psychopathology observed in epilepsy and migraine cannot rule out the presence of common pathways of psychiatric comorbidity in neurologic conditions. However, associations of epilepsy with conditions such as autism spectrum disorders point to comorbidities specific to epilepsy that may not be shared by other neurologic conditions.
Epilepsy is the most common serious neurologic disorder, and it affects >50 million people worldwide (World Health Organization 2005; Ngugi et al., 2010). Psychiatric disorders are commonly encountered in people with epilepsy, and these may negatively influence the course of epilepsy, lead to inadequate response to treatment, and contribute to a poor quality of life as well as increased mortality (Christensen et al., 2007; Thapar et al., 2009). However, psychopathology is frequently unrecognized and untreated in people with epilepsy (Hermann et al., 2000), and many questions remain about both the extent and the nature of the relationships between epilepsy and specific psychiatric conditions. A good understanding of the burden of these comorbidities is essential for better recognition and treatment, and to inform the training needs of clinicians. This has the potential to translate into improved care of people with epilepsy. In addition, observed associations may illuminate understanding of common mechanisms behind epilepsy and specific forms of psychopathology.
Population-based studies in adults have often focused on comorbid depression in epilepsy (reviewed in Tellez-Zenteno et al., 2007), but potentially important relationships with other conditions such as anxiety (Beyenburg et al., 2005) and neurodevelopmental disorders (Garcia-Morales et al., 2008; Bolton et al., 2011) have not been adequately examined. The reported prevalence of comorbid psychopathology in epilepsy also varies widely across studies, reflecting methodologic limitations including possible selection (due to recruitment of epilepsy cases from unrepresentative clinical populations) (Swinkels et al., 2005; Tellez-Zenteno et al., 2007; Garcia-Morales et al., 2008) or measurement (lack of diagnostic assessment tools to ascertain psychopathology) (Gilliam et al., 2003; Gaitatzis et al., 2004b; Lacey et al., 2009; Ottman et al., 2011) biases. Furthermore, studies without adequate control populations (Gilliam et al., 2003; Gaitatzis et al., 2004b) may have led to inaccurate estimates of the risk of psychopathology in people with epilepsy compared with the general population.
Two other important issues remain unexplored. First, because socioeconomic disadvantage and health problems are common in people with epilepsy (Scambler & Hopkins, 1980; Gaitatzis et al., 2004a) as well as psychiatric disorders (Muntaner et al., 2004; Prince et al., 2007), confounding by these factors may explain the observed relationships, but this has not been previously considered. Second, depression and anxiety disorders are commonly associated with many chronic conditions (Prince et al., 2007). Depressive symptoms (assessed by a screening instrument) appeared to be more common among people with epilepsy than among people with asthma in one previous study (Ettinger et al., 2004), but this issue has not been explored in studies using diagnostic instruments, or for disorders other than depression. Specifically, no study has investigated how comorbid psychopathology in epilepsy compares with that in people with chronic neurologic presentations such as migraines or chronic headaches. Therefore, it is largely unknown whether epilepsy is associated with an increased risk of psychopathology in addition to the effect of having a chronic medical or neurologic condition.
We hypothesized that epilepsy would be associated with psychiatric and neurodevelopmental disorders, even after adjusting for potential confounders. We also hypothesized that epilepsy would have stronger associations with depressive and anxiety disorders than similar associations in people with other chronic conditions such as asthma, diabetes, and migraine. We tested these hypotheses using face-to-face interview data from a large nationally representative population-based study in England, which used validated diagnostic and screening measures to ascertain a range of psychiatric and neurodevelopmental conditions.
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Doctor-diagnosed epilepsy, present since age 16, was reported by 101 people corresponding to a weighted prevalence of 1.2% (95% CI 1.0–1.5) in the general population of England. About 3% of our original sample had missing data in covariates, and we included 94 people with epilepsy and 7,071 people without epilepsy with complete data in our analysis. People with epilepsy were more likely to be divorced or separated (as compared to being married), have lower educational qualifications, live in rented accommodation, and be economically inactive compared with people without epilepsy (Table 1).
Table 1. Characteristics of people with epilepsy as compared to the general populationwithout epilepsy in England.
| ||Epilepsy (n = 94) %||No epilepsy (n = 7,071)a %||OR (95% CI)|
| 35–54||45.1||35.7||1.2 (0.7–2.2)|
| 55 or more||22.9||33.5||0.7 (0.3–1.3)|
| Female||52.4||51.6||1.0 (0.7–1.6)|
| Single/widowed||34.1||29.6||1.3 (0.8–2.3)|
| Divorced/separated||11.2||7.3||1.8 (1.0–3.2)|
| Tertile 1 (highest)||33.0||36.1||Ref|
| Tertile 2||25.6||32.7||0.9 (0.5–1.6)|
| Tertile 3 (lowest)||41.4||31.2||1.5 (0.9–2.5)|
| Economically inactive||49.5||38.7||1.6 (1.0–2.4)|
|Occupational social classb|
| III||45.8||40.6||1.2 (0.7–2.0)|
| IV/V||16.9||20.7||0.8 (0.4–1.7)|
|Highest educational qualification|
| Degree level||21.8||27.9||Ref|
| A/0 Level||45.9||46.1||1.3 (0.7–2.4)|
| No qualifications||32.3||26.1||1.6 (0.9–2.9)|
|Tenure of accommodation|
| Rented accommodation||43.5||29.4||1.9 (1.2–3.0)|
|Comorbid physical illness|
| 1||25.1||25.3||1.0 (0.6–1.6)|
| 2 or more||19.2||17.6||1.1 (0.6–1.9)|
Generalized anxiety disorder (12.5%), nonspecific psychiatric morbidity (12.2%), and depressive disorders (9.6%) were the most common psychiatric comorbidities in people with epilepsy (Table 2). When compared with the rest of the population without epilepsy—and after adjusting for potential confounders—social phobias, agoraphobia, generalized anxiety disorder, and depression were the common mental disorders with the strongest independent associations with epilepsy (Table 2). People with epilepsy also had strong relationships with all measures of lifetime and recent suicidal thoughts and behavior. These associations were largely similar with those observed in the group of people reporting migraines, or chronic headaches, bar some differences, although the CIs overlapped. Specifically, the association with social phobias appeared to be much stronger, and nonspecific psychiatric morbidity, panic disorder and specific phobias appeared to be weaker in people with epilepsy as compared to those reporting migraines or chronic headaches (Table 3). In contrast, similar associations were either absent or much weaker in people with asthma and diabetes (Table 3). The associations between epilepsy and all measures of suicidality were attenuated after adjusting for concurrent depression or anxiety disorders (Table 4).
Table 2. Prevalence of psychiatric conditions in people with epilepsy, and results of logistic regression analysis comparing psychopathology in people with epilepsy with the general population of England without epilepsy.
|Mental disorder||Prevalence in people with epilepsy % (95% CI)||Crude OR (95% CI)||Adjusted OR (95% CI)|
|Any depressive or anxiety disorder||30.6 (21.5–41.4)||2.3 (1.4–3.8)**||1.9 (1.2–3.2)*|
|Depression and an anxiety disorder||4.2 (2.2–7.2)||4.1 (2.1–8.2)***||3.1 (1.5–6.3)**|
|Depression||9.6 (5.3–16.9)||3.7 (1.9–7.1)***||2.7 (1.4–5.4)**|
|Generalized anxiety disorder||12.5 (7.6–20.1)||3.3 (1.8–5.9)***||2.6 (1.5–4.7)**|
|Social phobia||6.0 (2.7–12.8)||7.1 (3.0–16.7)***||5.2 (2.1–13.1)***|
|Specific phobias||1.8 (0.6–5.7)||2.0 (0.6–6.7)||1.2 (0.3–4.5)|
|Panic disorder||No observation||–||–|
|Agoraphobia||4.9 (2.7–11.4)||4.7 (1.8–12.5)**||3.2 (1.2–8.7)*|
|Obsessive compulsive disorder||3.1 (1.5–6.3)||2.9 (1.3–6.4)**||1.8 (0.8–4.4)|
|Nonspecific psychiatric morbidity||12.2 (6.4–21.9)||1.5 (0.8–3.1)||1.3 (0.6–2.6)|
|Suicide and self-harm|
| Suicidal thoughts lifetime||26.5 (18.0–37.1)||2.3 (1.4–3.8)**||2.0 (1.2–3.2)**|
| Suicidal thoughts in last year||12.2 (6.9–20.8)||3.3 (1.7–6.2)***||2.5 (1.3–4.8)**|
| Suicide attempts lifetime||12.5 (6.7–21.2)||3.0 (1.5–5.9)**||2.3 (1.1–4.6)*|
| Suicide attempts last year||4.1 (1.5–10.5)||7.3 (2.4–21.9)***||4.6 (1.6–13.6)*|
| Deliberate self-harm||12.7 (7.2–21.5)||2.9 (1.5–5.5)**||2.3 (1.2–4.5)*|
| Autism spectrum disorder||8.1 (2.2–25.9)||9.3 (2.0–42.4)**||7.4 (1.8–30.6)*|
| Psychotic disorder||1.1 (0.1–7.2)||2.7 (0.4–20.8)||1.7 (0.2–15.8)|
| Eating disorder (SCREEN)||5.0 (1.9–12.6)||3.4 (1.2–9.7)*||2.9 (1.1–7.7)*|
| Posttraumatic stress disorder (SCREEN) ||4.9 (2.0–11.4)||1.8 (0.7–4.4)||1.2 (0.5–2.9)|
| Attention deficit disorder (SCREEN) ||15.4 (9.2–24.7)||2.0 (1.1–3.7)*||1.6 (0.9–3.0)|
Table 3. Logistic regression analysis of associations of anxiety, depression, and suicidality in people with asthma, diabetes, and migraine or chronic headaches as compared to the general population of England (without these respective conditions).
|Mental disorder||Asthma (n = 886) Adjusted OR (95% CI)||Diabetes (n = 406) Adjusted OR (95% CI)||Migraine (n = 936) Adjusted OR (95% CI)|
|Any depressive or anxiety disorder||1.7 (1.3–1.9)***||1.0 (0.7–1.3)||2.3 (1.9–2.8)***|
|Depression and an anxiety disorder||1.6 (1.1–2.3)*||0.8 (0.5–1.4)||3.1 (2.1–4.7)***|
|Depression||1.4 (1.0–2.0)||0.9 (0.5–1.5)||2.5 (1.7–3.8)***|
|Generalized anxiety disorder||1.2 (0.9–1.6)||1.0 (0.6–1.7)||2.1 (1.6–2.9)***|
|Social phobia||0.8 (0.4–1.6)||–||1.9 (1.0–3.5)|
|Specific phobias||1.5 (0.8–2.9)||0.1 (0.0–1.0)||2.7 (1.5–5.0)**|
|Panic disorder||1.3 (0.7–2.4)||2.2 (1.0–5.0)||1.9 (1.0–3.4)*|
|Agoraphobia||1.1 (0.6–2.2)||0.4 (0.1–1.3)||2.3 (1.3–3.9)**|
|Obsessive compulsive disorder||1.7 (0.9–3.2)||1.0 (0.4–2.6)||1.8 (1.0–3.2)|
|Nonspecific psychiatric morbidity||1.7 (1.3–2.1)***||0.9 (0.6–1.3)||1.8 (1.4–2.2)***|
|Suicide and self-harm|
|Suicidal thoughts lifetime||1.5 (1.2–1.8)***||1.0 (0.7–1.4)||2.2 (1.8–2.6)***|
|Suicidal thoughts in last year||1.5 (1.1–2.1)*||1.1 (0.7–1.8)||2.5 (1.8–3.5)***|
|Suicide attempts lifetime||1.5 (1.1–2.1)**||1.1 (0.6–1.9)||1.9 (1.3–2.6)**|
|Suicide attempts last year||3.5 (1.6–7.7)**||1.3 (0.3–6.8)||4.3 (1.8–10.1)**|
|Deliberate self-harm||1.5 (1.1–2.0)*||0.5 (0.2–1.1)||1.5 (1.0–2.2)*|
Table 4. Evidence of mediation of the relationship between epilepsy and suicidality by anxiety and depressive disorders (model 2) and symptoms (model 3).
|Measure of suicidality||Model 1 OR (95% CI)||Model 2 OR (95% CI)||Model 3 OR (95% CI)|
|Suicidal thoughts lifetime||2.3 (1.1–4.6)**||1.6 (0.9–2.8)||1.5 (0.9–2.8)|
|Suicidal thoughts in last year||2.5 (1.3–4.9)**||1.9 (0.9–3.8)||1.7 (0.8–3.5)|
|Suicide attempts lifetime||2.2 (1.1–4.6)*||1.8 (0.8–4.0)||1.7 (0.8–3.8)|
|Suicide attempts last year||4.3 (1.4–13.5)*||3.2 (1.0–10.4)||2.7 (0.8–9.1)|
|Deliberate self-harm||2.2 (1.1–4.2)*||1.8 (0.9–3.5)||1.6 (0.8–3.3)|
A strong association between epilepsy and autism spectrum disorders was observed even after accounting for sociodemographic and health covariates (OR 6.2) and increased further after adjusting for verbal IQ (OR 7.4, 95% CI 1.5–35.5). Epilepsy was also associated with a 70% increase in odds of a psychotic disorder, although CIs were wide (adjusted OR 1.7, 95% CI 0.2–14.2). The associations with screen-positive adult ADHD were attenuated when covariates were introduced in the models. Finally, epilepsy was associated with an almost threefold increase in odds of screen-positive eating disorder. None of these conditions appeared to have significant associations in people with asthma, diabetes, or migraine.
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In this comprehensive, nationally representative population-based study, we examined the burden and relationships of a range of comorbid psychiatric conditions in epilepsy, including several that have never been investigated previously in adult populations. Almost one third of the people with epilepsy met ICD-10 diagnostic criteria for an anxiety or depressive disorder in this study, compared with about one in six people in the general population without epilepsy. After adjustment for confounders, people with epilepsy had significantly elevated odds of having social phobias, agoraphobia, generalized anxiety disorder, and depression and all measures of suicidality. These associations were consistently stronger than similar relationships in people with asthma or diabetes, and comparable to people reporting migraines or chronic headaches. People with epilepsy had a more than sevenfold increase in odds of having an autism spectrum disorder and an almost threefold increase in the odds of being screen positive for eating disorder, compared with people without epilepsy. These associations were not observed in people with asthma, diabetes, or migraine.
To our knowledge, this nationally representative population-based study represents the most detailed examination of the psychiatric and neurodevelopmental comorbidities of epilepsy ascertained by face-to-face interviews using standardized validated measures of psychopathology. In addition, our ability to control for appropriate confounders, and compare our results with similar associations in people with asthma, diabetes, and migraines offers a significant advantage in comparison to previous literature.
Some limitations of our study should be noted. The ascertainment of epilepsy in this household survey was by self-report; therefore, the possibility of some reporting bias cannot be excluded. In addition, we had no information on the nature of the diagnostic process, seizure type, frequency, or treatment of epilepsy. However, these limitations are common to almost all previous population-based studies on this topic (Ettinger et al., 2004; Gaitatzis et al., 2004b; Tellez-Zenteno et al., 2007; Ottman et al., 2011), and yielded an internationally comparable prevalence of epilepsy. Furthermore, due to the recognized challenges in the diagnosis of epilepsy it is possible that a proportion of our sample classified as epilepsy actually have an alternative diagnosis such as non–epileptic attack disorder; however, this potential misclassification is common to all population-identified epilepsy samples. Population-based studies with more robust measures of epilepsy and detailed information on the various types of epilepsy are required to overcome this limitation (Berg et al., 2010; Thurman et al., 2011). Similarly, the comparison conditions included in this study were ascertained by self-report, although an effort was made to ascertain if these had been diagnosed by a doctor. Despite the large sample, as expected, the number of people with epilepsy was relatively low, which limited our statistical power, particularly evident through wide CIs of associations with other rare conditions. Response rates in national surveys are falling throughout the world (Groves, 2002), and the 7,461 individuals interviewed in the APMS constituted 57% of the eligible sample, comparable to other population-based studies on this topic (Ettinger et al., 2004). We used detailed weighting procedures to minimize the likelihood of nonresponse bias (McManus et al., 2009). Finally, the cross-sectional design, although important to estimate the burden of comorbidities, does not allow for directional inferences. For instance, the relationship between epilepsy and depression may be bidirectional (Kanner, 2008), and longitudinal studies are required to clarify causal pathways of our observations.
The prevalence estimates of depression and anxiety disorders in people with epilepsy in our study are consistent with the relatively sparse population-based literature on this topic (Ettinger et al., 2004; Gaitatzis et al., 2004b; Tellez-Zenteno et al., 2007; Garcia-Morales et al., 2008). In addition, our study clarifies several issues not adequately addressed previously. First, it is notable, that anxiety disorders, particularly phobias and GAD, are common comorbidities in epilepsy. This is important, since these may be as disabling as depression (Rai et al., 2010), and are potentially treatable. Second, the associations of epilepsy with depression, anxiety disorders, and suicidality were consistently stronger than similar estimates in asthma and diabetes, indicating that epilepsy has specific and stronger relationships with these comorbidities than other chronic physical conditions. Similarly, although people reporting migraines or chronic headaches may actually represent the presence of neurotic psychopathology rather than a primary neurologic condition, (Antonaci et al., 2011) comparing the rates of psychopathology in people with epilepsy with this group only reinforce our results that depression, anxiety disorders, and suicidality are significant issues in people with epilepsy. Our observation that apart from depression, anxiety, and suicidality, no other conditions we studied had significant relationships with asthma, diabetes, or migraine suggests that epilepsy has unique associations with psychopathology that are not simply explained due to it being a chronic (neurologic) condition.
The associations between suicidality and epilepsy in our study were largely mediated by comorbid depression or anxiety disorder. This contrasts with findings from a Danish study (Christensen et al., 2007), where secondary-care diagnosis (ascertained mostly from inpatient records) of psychiatric conditions did not fully explain the risk of suicide in people with epilepsy. Two important issues may explain this discrepancy. First, depressive and anxiety disorders are mostly managed in primary care, and second, psychopathology is often undiagnosed in people with epilepsy (Hermann et al., 2000). Hence our comprehensive face-to-face assessment of psychopathology was an inherent advantage as compared to the use of a registered secondary-care diagnosis.
Another notable contribution of our study is in relation to the relatively high prevalence of nonspecific psychiatric morbidity in people with epilepsy, but without a significant increase in odds ratios as compared to the general population (Table 2). These presentations, where significant anxiety or depressive symptoms do not meet diagnostic criteria for specific disorders, are reminiscent of the “atypical” presentations of depression and anxiety that epileptologists have previously termed as “dysthymic like disorders” or “dysphoric disorder of epilepsy” (Kanner, 2003; Blumer et al., 2004). These presentations were among the most common psychiatric morbidities in the general population, and were no more common in people with epilepsy than those without.
Our data also allowed us to estimate associations between epilepsy and several conditions that are relatively uncommon in the general population. Noteworthy among these was the strong association between adult autism spectrum disorders and epilepsy. This relationship is widely noted in children, although pediatric population-based studies on this topic are also limited (Tuchman & Rapin, 2002). Furthermore, a recent study suggests seizures may, in fact, arise in late adolescence or adulthood in people with ASD (Bolton et al., 2011), reinforcing our confidence in our results. In addition, in keeping with some previous literature, we found a 70% increase in odds of a psychotic disorder in people with epilepsy, albeit with wide CIs. Clinical studies have reported a higher prevalence (2–9%) of psychotic disorders (Garcia-Morales et al., 2008) in people with epilepsy (particularly temporal lobe epilepsy) than our modest 1% prevalence. However, it has been noted that previous reports may have overestimated this association by studying highly selected clinical populations (Swinkels et al., 2005).
Although questions covering adult ADHD, eating disorders, and PTSD were administered using screening instruments, our study represents the first population-based estimates of their possible relationship with epilepsy in adults. It has previously been suggested that the prevalence of ADHD in adults with epilepsy may be underestimated (Garcia-Morales et al., 2008), the rationale being that 25–30% of the pediatric population with epilepsy have comorbid ADHD, and that 50–75% of these children may continue to have ADHD in adulthood (Garcia-Morales et al., 2008). We found partial support for this assertion. More than 15% of adults with epilepsy in our sample with epilepsy screened positive for adult ADHD, representing an over twofold increase in odds when compared with the general population without epilepsy. This association, however, was largely explained after adjustment for confounders. We also found a significant association between epilepsy and screen-positive eating disorders, which has not been previously investigated. We did not find evidence of a relationship between screen-positive PTSD and epilepsy in contrast with findings from one small study (Rosenberg et al., 2000) of 35 patients with intractable seizures. Further exploration of the relationships between epilepsy and these conditions, using diagnostic instruments are obvious questions for future research.
Epilepsy has been a stigmatized condition throughout history, and negative societal (mis)perceptions, stereotyping, and discrimination against people with epilepsy continues to be common (Scambler & Hopkins, 1980; Baxendale & O’Toole, 2007; de Boer et al., 2008; de Boer, 2010; The Lancet Neurology, 2010), and is known to propagate social isolation and low self-esteem (Jacoby, 1994; Krauss et al., 2000). People with epilepsy often live in uncertainty and in fear of having further seizures (Fisher et al., 2000). These issues could explain our results, and conditions associated with worry (GAD and other anxiety disorders), avoidance (phobias, particularly social phobia), stigma (depression, phobias), and low self-esteem (depression and suicidality, eating disorders) all had strong relationships with epilepsy.
The understanding of a common neurobiology between epilepsy and psychiatric comorbidities is also emerging (Tecott et al., 1995; Cowan & Kandel, 2001; Martin, 2002; Tuchman & Rapin, 2002; Jobe, 2003; Kanner, 2005), although most evidence is based on animal models or observed indirectly (e.g., through efficacy of anticonvulsants on mood disorders) (Grunze, 2008). Some overlap in the psychopathology observed in epilepsy and migraine cannot rule out the presence of common pathways of comorbidity in neurologic conditions. However, associations of epilepsy with conditions such as autism spectrum disorders point to comorbidities specific to epilepsy that may not be shared by other neurologic conditions. Furthermore, advances in the neurosciences hold potential for elucidation of pathways between seizures, other neurologic conditions, and psychopathology (Cowan & Kandel, 2001; Martin, 2002).