Epilepsy & Behavior 31 (2014) 291–294
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Longitudinal association between epilepsy and schizophrenia: A population-based study Eyal Fruchter a, Ori Kapara b, Avi Reichenberg c, Rinat Yoffe d, Oshrat Fono-Yativ a, Yitshak Kreiss a, Michael Davidson a,e, Mark Weiser a,b,e,⁎ a
IDF Medical Corps, Israel Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel Institute of Psychiatry, King's College London, London, England, UK d Department of Mental Health, Ministry of Health, Israel e Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel b c
a r t i c l e
i n f o
Article history: Received 10 July 2013 Revised 21 October 2013 Accepted 23 October 2013 Available online 19 November 2013 Keywords: Epilepsy Schizophrenia Epidemiology
a b s t r a c t A large number of studies have reported an association between epilepsy and major psychiatric conditions. This study investigated the association between epilepsy and later schizophrenia, utilizing a historical-prospective, population-based design. Of the 861,062 17-year-old male adolescents consecutively screened by the Israeli Draft Board and found free of major mental illness, 0.06% suffered from severe, treatment-refractory epilepsy, 0.25% had treated, controlled epilepsy, and 0.16% had a history of seizures which had abated 5 or more years prior to screening. Hospitalization for schizophrenia was ascertained through the Israeli National Psychiatric Hospitalization Case Registry, with an average follow-up of 9.6 ± 1.0 years (range: 1.0–10.0 years). Risk of hospitalization was calculated using Cox regression analyses, compared to socioeconomic-adjusted risk of hospitalization in the general population of male adolescents. Among adolescents whose epilepsy was nonresponsive to medication, the adjusted risk of hospitalization was significantly increased for schizophrenia (HR = 3.89, 95% CI = 1.75–89.67). Male adolescents with successfully treated epilepsy were not at increased risk for schizophrenia. Male adolescents with severe, treatment-refractory epilepsy are at increased risk of later schizophrenia. Future studies attempting to understand the biology of this association might focus on this subset of patients, and these patients should be monitored for the appearance of psychosis. © 2013 Elsevier Inc. All rights reserved.
1. Introduction There is considerable evidence demonstrating an association between epilepsy and schizophrenia [1]; patients with epilepsy were found to be 2–11 times more likely to have schizophrenia in comparison to people not diagnosed with epilepsy [2,3]. Much of the research that examined the association between epilepsy and schizophrenia was done on small samples and/or did not use standardized definitions that separate confusional postictal psychosis from interictal schizophreniform psychosis, for example [4]. Three more recent, population-based studies replicated this association between epilepsy and schizophrenia [2,3,5]. In a Finnish sample of 23,404 hospital visitors, the 208 patients with epilepsy were 8.5 times more likely to have schizophrenia [5]. In a registrybased study on a Finnish population-based birth cohort composed of
⁎ Corresponding author at: Department of Psychiatry, Sheba Medical Center, TelHashomer, Ramat Gan 52621, Israel. Fax: +972 3 6358599. E-mail addresses: [email protected] (E. Fruchter), [email protected] (O. Kapara), [email protected] (A. Reichenberg), [email protected] (R. Yoffe), [email protected] (O. Fono-Yativ), [email protected] (Y. Kreiss), [email protected] (M. Davidson), [email protected] (M. Weiser). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.10.026
11,017 persons, hospitalization for epilepsy was strongly associated with hospitalization for schizophrenia (OR = 11.1) [2]. We undertook further understanding of the association between epilepsy and schizophrenia by following adolescents with epilepsy, without any sign of psychosis at baseline, for later hospitalization for schizophrenia, utilizing a historical-prospective design. We hypothesized that patients with more severe, treatment-refractory epilepsy would have increased risk for later schizophrenia, while patients with only a history of epilepsy but no active disease will not be at increased risk. 2. Method 2.1. Measures 2.1.1. Israeli Draft Board assessment Adolescents in Israel undergo a mandatory pre-draft screening at ages 16–17 designed to ascertain their intellectual, medical, and psychiatric eligibility to serve in the military. This assessment is administered to the entire unselected population of Israeli adolescents through regional draft board centers located throughout the country. The screening procedure includes medical and psychiatric history conducted by a
292
E. Fruchter et al. / Epilepsy & Behavior 31 (2014) 291–294
physician and intelligence testing, consisting of 4 multiple-choice subtests testing arithmetic ability, verbal abstraction and concept formation, visuospatial abilities, and the ability to understand written instructions. It includes individuals who are eligible for military service as well as those who will be excused from service for medical, psychiatric, or social reasons. Adolescents have to present a letter from the treating pediatrician to the draft board physician. If suspected of having a medical (including neurological or psychiatric) illness, the adolescent is referred to a board-certified physician of the appropriate specialty in the draft board. Hence, based on the letter from the pediatricians' and physicians' clinical examination, if the adolescent is suspected of having epilepsy, he is referred to a board-certified neurologist, who examines the adolescent and, when warranted, assigns a clinical diagnosis of epilepsy. The diagnosis of epilepsy is categorized into 3 groups: (1) a history of epilepsy — seizures which occurred at least 5 years prior to screening and are no longer active; (2) epilepsy successfully treated by medication; and (3) treatment-refractory epilepsy, with many seizures for at least two years despite optimal treatment, medicinal or otherwise (Table 1). In addition to the screening by the physician in the draft board, all male recruits undergo an interview assessing personality and behavioral traits administered by trained college-age individuals who have completed a 4-month training course on administration of the interview. The test–retest reliability of the behavioral assessment for inductees interviewed after several days by different interviewers is above 0.8, and population-based norms are available [16]. On the basis of the interview and a physician's examination, adolescents who might be suffering from behavioral disturbances or mental illness are referred for an in-depth assessment by a mental health professional, and if the adolescent warrants a psychiatric diagnosis, a board-certified psychiatrist will examine him. Criteria for referral for an in-depth mental health assessment are having the lowest score on the prediction subscale (which reflects the interviewer's assessment of the adolescent's ability to succeed in the military), a history of psychological or psychiatric treatment, current complaints, or manifestation of behavioral abnormalities during the assessment procedure. The mental health assessment is done using a semistructured interview administered by a clinical social worker or psychologist, who inquires about personal and family history, previous psychological and psychiatric treatments, interpersonal relationships, self-esteem, self-injurious and antisocial acts, and functioning within the family and in school. If the clinician suspects that the adolescent has psychopathological symptoms, the adolescent is referred to a board-certified psychiatrist for evaluation and a clinical ICD-10 diagnosis. In cases of comorbidity, the examining psychiatrist decides which clinical diagnosis is most clinically significant, and only that clinical diagnosis is recorded without the comorbid condition. For a more detailed description of the draft board assessment procedure, see Gal (1986) [16] and Tubiana & Ben-Shachar (1982) [17]. This structured, in-depth assessment minimizes the possibility of an adolescent having an undiagnosed psychiatric illness [6–8], and relevant to the current study, this procedure minimizes the possibility that in this longitudinal study, patients with epilepsy had psychosis
or an affective disorder at baseline. Although females are also assessed by the draft board, they do not undergo the interview assessing personality and behavioral traits; hence, this paper refers only to males. 2.1.2. Israeli National Psychiatric Hospitalization Case Registry The Israeli National Psychiatric Hospitalization Case Registry is a complete listing of all psychiatric hospitalizations in Israel. By law, all inpatient psychiatric facilities in the country, including psychiatric hospitals, day hospitals, and psychiatric units in general hospitals, are required to report all admissions and discharges to the registry. These data include the diagnosis assigned and coded on admission and discharge by a board-certified psychiatrist at the facility. During the time periods covered by this study, ICD-9 and ICD-10 diagnoses were used by the registry. Registry diagnoses of schizophrenia (ICD-10: F20.0–F20.9) have a sensitivity of 0.89 [9], and the Israeli National Psychiatric Hospitalization Case Registry captures 93.1% of patients with schizophrenia in the community [10]. In this current study, the last discharge diagnosis of patients was used to assess for schizophrenia. We used the Israeli National Psychiatric Hospitalization Case Registry to follow-up persons assessed in the draft board and later hospitalized with a diagnosis of schizophrenia (ICD-10: 20.0–20.9). 2.1.3. Socioeconomic status (SES) Socioeconomic status (SES) is significantly associated with risk for schizophrenia in this and other datasets [11]; hence, it was added as a covariate in the analyses as a continuous measure. The SES measure is based on census data collected by the Israeli Central Bureau of Statistics and divides the country into ‘geographical units’, which are areas with 3000–4000 residents. The division is performed so that the population in each area is as homogeneous as possible in terms of ethnic background, culture, and income. Information about socioeconomic status is based on the number of persons per room in the home, number of computers per household, number of motor vehicles per household, and per capita income [12]. 2.2. Procedure After receiving approval from the local IRB, the draft board data were linked with the psychiatric hospitalization data from the Israeli National Psychiatric Hospitalization Case Registry using the national identification number (equivalent to the US Social Security number) as the linking variable. Before the linked file was transferred to the investigators for analysis, the national identification number was removed to preserve patient confidentiality. 2.3. Statistical analyses Since the follow-up period varied among the sample, the association between epilepsy and later hospitalization for schizophrenia was examined using Cox regression analyses. The follow-up period was defined as the age at first admission for schizophrenia or, among individuals
Table 1 Characteristics of the three groups with epilepsy.
History of epilepsy (1) Controlled, treated epilepsy (2)
Treatment-refractory epilepsy (3) a
Description
N
Mean time observed in years (SD)
Mean age of hospitalization for schizophrenia (SD)
Mean SESa (SD)
Last seizure at least 5 years ago and without medicinal treatment for at least 2 years (a) Cases receiving medicinal treatment for at least 2 years and showing no seizures during therapy, (b) last seizure at least 1 year ago and currently medicinally treated or without treatment for less than 2 years, or (c) condition requiring antiepileptic prophylactic treatment, last seizure 1–2 to 5 years ago, and treated or without treatment for at least 2 years Epilepsy with many seizures for at least 2 years despite optimal treatment, medicinal and otherwise
1383 2120
9.47 (1.15) 9.47 (1.19)
21.43 (3.36) 21.50 (4.95)
11.37 (4.01) 11.57 (4.17)
489
9.14 (1.46)
22.67 (5.68)
10.57 (4.12)
Score ranges from 1 to 20 (1 = lowest SES to 20 = highest SES).
E. Fruchter et al. / Epilepsy & Behavior 31 (2014) 291–294
without schizophrenia, as the date when the draft board data were merged with the data from the Israeli National Psychiatric Hospitalization Case Registry. In addition, in order to limit bias caused by disparate follow-up periods, the analysis was limited to psychiatric hospitalizations occurring up to 10 years after the draft board screening. All analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA).
293
refractory epilepsy. The validity of these data is supported by the prevalence of epilepsy in this study, 4.6 cases per 1000, which is congruent with the reported prevalence of epilepsy in developed countries [13]. In addition, the finding that patients with treatment-refractory schizophrenia are most likely to come from lower socioeconomic strata has also been described [14,15]. 4.1. Limitations
3. Results Of the 868,208 male adolescents consecutively screened by the Israeli Draft Board, 3996 were diagnosed with epilepsy, giving a prevalence of 4.6 cases per 1000. When analyzing risk for schizophrenia in adolescents diagnosed with epilepsy in the draft board, adolescents who had been hospitalized prior to the draft board screening with a diagnosis of schizophrenia or other psychiatric disorders or were diagnosed with a psychotic or major affective disorder in the draft board screening process were excluded from the analyses (N = 7146, 0.82%). Adolescents were followed up in an average of 9.6 ± 1.0 years (range: 1.0–10.0 years). Compared with the general population of male adolescents and controlling for SES, risk of hospitalization for schizophrenia was significantly higher among male adolescents with treatmentrefractory epilepsy (HR = 3.89, 95% CI = 1.75–89.67, p b 0.001). Neither patients with controlled, treated epilepsy nor patients with a history of epileptic seizures 5 or more years prior to screening had increased risk of hospitalization for schizophrenia (Table 2). Socioeconomic status differed among the three groups with epilepsy, with the group with treatment-refractory epilepsy having lower mean SES ratings compared to those with controlled, treated epilepsy or those with a history of epilepsy (p b 0.001, Table 1). Mean time observed, mean age at hospitalization for schizophrenia, and mean SES are presented separately for each group with epilepsy in Table 1. 4. Discussion To the best of our knowledge, this is the first report on the association between epilepsy and schizophrenia utilizing data on severity of the epilepsy. As hypothesized, adolescents with severe, treatmentrefractory epilepsy, but not epilepsy controlled by medication, were at increased risk for later schizophrenia. Other population-based studies have shown an overrepresentation of epilepsy among patients with schizophrenia [2], a higher risk of schizophrenia or schizophrenia-like psychosis among patients with epilepsy [3], and evidence of overlapping etiological factors, especially genetic, between epilepsy and schizophrenia [5]. Our data expand on those findings in that we were able to separate the patients according to their clinical and treatment status, and we were able to observe that not all patients with epilepsy have increased risk for schizophrenia but only those with severe, treatment-
Table 2 Risk of hospitalization for schizophrenia among male adolescents with epilepsy compared to adolescents without epilepsy. N
Risk of later hospitalization for schizophrenia (adjusted for SES)
Group
Total
Hospitalizations for schizophrenia
HR (95% CI)
p
History of epilepsy (1) Controlled, treated epilepsy (2) Treatment-refractory epilepsy (3)
1383 2120
7 2
1.77 (0.85–3.72) 0.34 (0.85–1.37)
0.130 0.129
489
2
3.89 (1.75–89.67)
0.001
HR, hazard ratio; CI, confidence interval; significance level of p b 0.01 is shown with bold emphasis.
Adolescents who had been hospitalized prior to the draft board screening with a diagnosis of schizophrenia or other psychiatric disorders as well as adolescents who were diagnosed with psychotic or major affecting disorders by draft board specialists were removed from this analysis. This might explain the somewhat lower risk for schizophrenia among patients with epilepsy in this study compared to other studies [2,3]. This design allows us to address the sequence of events, namely, the extent to which psychiatric illness follows the onset of epilepsy, and not vice versa. To our knowledge, this design has not been previously implemented in population-based studies of the association between epilepsy and schizophrenia. A limitation of this design is the lack of data on change in status of epilepsy throughout the follow-up period. It is likely that some individuals with a history of epilepsy or whose epilepsy was treated and controlled at the time of the draft board assessment had a relapse, while some patients with treatment-refractory epilepsy later responded to treatment during the follow-up period. Other limitations of this study include the use of clinical rather than research criteria for diagnosing epilepsy and schizophrenia. However, by law, adolescents in Israel come to the draft board with a note from a treating pediatrician who has treated the adolescent for his entire life and are then examined by a GP and then by a board-certified neurologist. The utility of this rigorous process is reflected by the finding that the prevalence of epilepsy in this study is congruent with the reported rate of epilepsy in this age group [13]. Given the heterogeneity of epilepsy, other important limitations include lack of data on the type of epilepsy, seizure frequency, and severity. Also, the Israeli National Psychiatric Hospitalization Case Registry utilizes clinical, not research, diagnoses, and both ICD-9 and ICD-10 diagnoses were used; however, the change in coding is unlikely to affect the findings substantially, and all diagnoses used were made by board-certified psychiatrists who see the patient over several admissions, including 93.1% of all patients hospitalized with schizophrenia in the country [10] at a sensitivity level of 0.89 [9]. In conclusion, in this population-based dataset of male adolescents, severe, treatment-refractory epilepsy was associated with increased risk of later hospitalization for schizophrenia. Future studies attempting to elucidate the association between epilepsy and schizophrenia might focus on this subset of patients when attempting to understand the biology of this association, and these patients should be monitored for the appearance of psychosis. Patients and families of patients with treated, controlled epilepsy might be assured that they do not appear to be at increased risk for schizophrenia. Conflict of interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Ettinger AB, Copeland LA, Zeber JE, Van Cott AC, Pugh MJ. Are psychiatric disorders independent risk factors for new-onset epilepsy in older individuals? Epilepsy Behav 2010;17:70–4. [2] Makikyro T, Karvonen JT, Hakko H, Nieminen P, Joukamaa M, Isohanni M, et al. Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort. Public Health 1998;112:221–8.
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[3] Qin P, Xu H, Laursen TM, Vestergaard M, Mortensen PB. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ 2005;331:23. [4] Sachdev P. Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry 1998;155:325–36. [5] Clarke MC, Tanskanen A, Huttunen MO, Clancy M, Cotter DR, Cannon M. Evidence for shared susceptibility to epilepsy and psychosis: a population-based family study. Biol Psychiatry 2012;71:836–9. [6] Davidson M, Reichenberg A, Rabinowitz J, Weiser M, Kaplan Z, Mark M. Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry 1999;156:1328–35. [7] Rabinowitz J, Reichenberg A, Weiser M, Mark M, Kaplan Z, Davidson M. Cognitive and behavioural functioning in men with schizophrenia both before and shortly after first admission to hospital. Cross-sectional analysis. Br J Psychiatry 2000;177:26–32. [8] Weiser M, Reichenberg A, Rabinowitz J, Kaplan Z, Mark M, Bodner E, et al. Association between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onset of schizophrenia. Arch Gen Psychiatry 2001;58:959–64. [9] Weiser M, Kanyas K, Malaspina D, Harvey PD, Glick I, Goetz D, et al. Sensitivity of ICD-10 diagnosis of psychotic disorders in the Israeli National Hospitalization Registry compared with RDC diagnoses based on SADS-L. Compr Psychiatry 2005;46:38–42.
[10] Weiser M, Werbeloff N, Dohrenwend BP, Levav I, Yoffe R, Davidson M. Do psychiatric registries include all persons with schizophrenia in the general population? A population-based longitudinal study. Schizophr Res 2012;135:187–91. [11] Goldberg S, Fruchter E, Davidson M, Reichenberg A, Yoffe R, Weiser M. The relationship between risk of hospitalization for schizophrenia, SES, and cognitive functioning. Schizophr Bull 2011;37:664–70. [12] Characterization and classification of geographical units by the socio-economic level of the population. Jerusalem: Ministry of the Units; 1995. [13] Tellez-Zenteno JF, Hernandez-Ronquillo L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res Treat 2012;2012:630853. [14] Collings JA, Chappell B. Correlates of employment history and employability in a British epilepsy sample. Seizure 1994;3:255–62. [15] Jacoby A, Baker GA, Steen N, Potts P, Chadwick DW. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. community study. Epilepsia 1996;37:148–61. [16] Gal R. The selection, classification and placement process: A portrait of the Israeli soldier. Westport, Conn: Greenwood Press; 1986. [17] Tubiana JH, Ben-Shachar G. An objective group questionnaire as a substitute for a personal interview in the prediction of success in military training in Israel. Pers Psychol 1982;35:349–57.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Longitudinal association between epilepsy and schizophrenia: A population-based study Eyal Fruchter a, Ori Kapara b, Avi Reichenberg c, Rinat Yoffe d, Oshrat Fono-Yativ a, Yitshak Kreiss a, Michael Davidson a,e, Mark Weiser a,b,e,⁎ a
IDF Medical Corps, Israel Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel Institute of Psychiatry, King's College London, London, England, UK d Department of Mental Health, Ministry of Health, Israel e Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel b c
a r t i c l e
i n f o
Article history: Received 10 July 2013 Revised 21 October 2013 Accepted 23 October 2013 Available online 19 November 2013 Keywords: Epilepsy Schizophrenia Epidemiology
a b s t r a c t A large number of studies have reported an association between epilepsy and major psychiatric conditions. This study investigated the association between epilepsy and later schizophrenia, utilizing a historical-prospective, population-based design. Of the 861,062 17-year-old male adolescents consecutively screened by the Israeli Draft Board and found free of major mental illness, 0.06% suffered from severe, treatment-refractory epilepsy, 0.25% had treated, controlled epilepsy, and 0.16% had a history of seizures which had abated 5 or more years prior to screening. Hospitalization for schizophrenia was ascertained through the Israeli National Psychiatric Hospitalization Case Registry, with an average follow-up of 9.6 ± 1.0 years (range: 1.0–10.0 years). Risk of hospitalization was calculated using Cox regression analyses, compared to socioeconomic-adjusted risk of hospitalization in the general population of male adolescents. Among adolescents whose epilepsy was nonresponsive to medication, the adjusted risk of hospitalization was significantly increased for schizophrenia (HR = 3.89, 95% CI = 1.75–89.67). Male adolescents with successfully treated epilepsy were not at increased risk for schizophrenia. Male adolescents with severe, treatment-refractory epilepsy are at increased risk of later schizophrenia. Future studies attempting to understand the biology of this association might focus on this subset of patients, and these patients should be monitored for the appearance of psychosis. © 2013 Elsevier Inc. All rights reserved.
1. Introduction There is considerable evidence demonstrating an association between epilepsy and schizophrenia [1]; patients with epilepsy were found to be 2–11 times more likely to have schizophrenia in comparison to people not diagnosed with epilepsy [2,3]. Much of the research that examined the association between epilepsy and schizophrenia was done on small samples and/or did not use standardized definitions that separate confusional postictal psychosis from interictal schizophreniform psychosis, for example [4]. Three more recent, population-based studies replicated this association between epilepsy and schizophrenia [2,3,5]. In a Finnish sample of 23,404 hospital visitors, the 208 patients with epilepsy were 8.5 times more likely to have schizophrenia [5]. In a registrybased study on a Finnish population-based birth cohort composed of
⁎ Corresponding author at: Department of Psychiatry, Sheba Medical Center, TelHashomer, Ramat Gan 52621, Israel. Fax: +972 3 6358599. E-mail addresses: [email protected] (E. Fruchter), [email protected] (O. Kapara), [email protected] (A. Reichenberg), [email protected] (R. Yoffe), [email protected] (O. Fono-Yativ), [email protected] (Y. Kreiss), [email protected] (M. Davidson), [email protected] (M. Weiser). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.10.026
11,017 persons, hospitalization for epilepsy was strongly associated with hospitalization for schizophrenia (OR = 11.1) [2]. We undertook further understanding of the association between epilepsy and schizophrenia by following adolescents with epilepsy, without any sign of psychosis at baseline, for later hospitalization for schizophrenia, utilizing a historical-prospective design. We hypothesized that patients with more severe, treatment-refractory epilepsy would have increased risk for later schizophrenia, while patients with only a history of epilepsy but no active disease will not be at increased risk. 2. Method 2.1. Measures 2.1.1. Israeli Draft Board assessment Adolescents in Israel undergo a mandatory pre-draft screening at ages 16–17 designed to ascertain their intellectual, medical, and psychiatric eligibility to serve in the military. This assessment is administered to the entire unselected population of Israeli adolescents through regional draft board centers located throughout the country. The screening procedure includes medical and psychiatric history conducted by a
292
E. Fruchter et al. / Epilepsy & Behavior 31 (2014) 291–294
physician and intelligence testing, consisting of 4 multiple-choice subtests testing arithmetic ability, verbal abstraction and concept formation, visuospatial abilities, and the ability to understand written instructions. It includes individuals who are eligible for military service as well as those who will be excused from service for medical, psychiatric, or social reasons. Adolescents have to present a letter from the treating pediatrician to the draft board physician. If suspected of having a medical (including neurological or psychiatric) illness, the adolescent is referred to a board-certified physician of the appropriate specialty in the draft board. Hence, based on the letter from the pediatricians' and physicians' clinical examination, if the adolescent is suspected of having epilepsy, he is referred to a board-certified neurologist, who examines the adolescent and, when warranted, assigns a clinical diagnosis of epilepsy. The diagnosis of epilepsy is categorized into 3 groups: (1) a history of epilepsy — seizures which occurred at least 5 years prior to screening and are no longer active; (2) epilepsy successfully treated by medication; and (3) treatment-refractory epilepsy, with many seizures for at least two years despite optimal treatment, medicinal or otherwise (Table 1). In addition to the screening by the physician in the draft board, all male recruits undergo an interview assessing personality and behavioral traits administered by trained college-age individuals who have completed a 4-month training course on administration of the interview. The test–retest reliability of the behavioral assessment for inductees interviewed after several days by different interviewers is above 0.8, and population-based norms are available [16]. On the basis of the interview and a physician's examination, adolescents who might be suffering from behavioral disturbances or mental illness are referred for an in-depth assessment by a mental health professional, and if the adolescent warrants a psychiatric diagnosis, a board-certified psychiatrist will examine him. Criteria for referral for an in-depth mental health assessment are having the lowest score on the prediction subscale (which reflects the interviewer's assessment of the adolescent's ability to succeed in the military), a history of psychological or psychiatric treatment, current complaints, or manifestation of behavioral abnormalities during the assessment procedure. The mental health assessment is done using a semistructured interview administered by a clinical social worker or psychologist, who inquires about personal and family history, previous psychological and psychiatric treatments, interpersonal relationships, self-esteem, self-injurious and antisocial acts, and functioning within the family and in school. If the clinician suspects that the adolescent has psychopathological symptoms, the adolescent is referred to a board-certified psychiatrist for evaluation and a clinical ICD-10 diagnosis. In cases of comorbidity, the examining psychiatrist decides which clinical diagnosis is most clinically significant, and only that clinical diagnosis is recorded without the comorbid condition. For a more detailed description of the draft board assessment procedure, see Gal (1986) [16] and Tubiana & Ben-Shachar (1982) [17]. This structured, in-depth assessment minimizes the possibility of an adolescent having an undiagnosed psychiatric illness [6–8], and relevant to the current study, this procedure minimizes the possibility that in this longitudinal study, patients with epilepsy had psychosis
or an affective disorder at baseline. Although females are also assessed by the draft board, they do not undergo the interview assessing personality and behavioral traits; hence, this paper refers only to males. 2.1.2. Israeli National Psychiatric Hospitalization Case Registry The Israeli National Psychiatric Hospitalization Case Registry is a complete listing of all psychiatric hospitalizations in Israel. By law, all inpatient psychiatric facilities in the country, including psychiatric hospitals, day hospitals, and psychiatric units in general hospitals, are required to report all admissions and discharges to the registry. These data include the diagnosis assigned and coded on admission and discharge by a board-certified psychiatrist at the facility. During the time periods covered by this study, ICD-9 and ICD-10 diagnoses were used by the registry. Registry diagnoses of schizophrenia (ICD-10: F20.0–F20.9) have a sensitivity of 0.89 [9], and the Israeli National Psychiatric Hospitalization Case Registry captures 93.1% of patients with schizophrenia in the community [10]. In this current study, the last discharge diagnosis of patients was used to assess for schizophrenia. We used the Israeli National Psychiatric Hospitalization Case Registry to follow-up persons assessed in the draft board and later hospitalized with a diagnosis of schizophrenia (ICD-10: 20.0–20.9). 2.1.3. Socioeconomic status (SES) Socioeconomic status (SES) is significantly associated with risk for schizophrenia in this and other datasets [11]; hence, it was added as a covariate in the analyses as a continuous measure. The SES measure is based on census data collected by the Israeli Central Bureau of Statistics and divides the country into ‘geographical units’, which are areas with 3000–4000 residents. The division is performed so that the population in each area is as homogeneous as possible in terms of ethnic background, culture, and income. Information about socioeconomic status is based on the number of persons per room in the home, number of computers per household, number of motor vehicles per household, and per capita income [12]. 2.2. Procedure After receiving approval from the local IRB, the draft board data were linked with the psychiatric hospitalization data from the Israeli National Psychiatric Hospitalization Case Registry using the national identification number (equivalent to the US Social Security number) as the linking variable. Before the linked file was transferred to the investigators for analysis, the national identification number was removed to preserve patient confidentiality. 2.3. Statistical analyses Since the follow-up period varied among the sample, the association between epilepsy and later hospitalization for schizophrenia was examined using Cox regression analyses. The follow-up period was defined as the age at first admission for schizophrenia or, among individuals
Table 1 Characteristics of the three groups with epilepsy.
History of epilepsy (1) Controlled, treated epilepsy (2)
Treatment-refractory epilepsy (3) a
Description
N
Mean time observed in years (SD)
Mean age of hospitalization for schizophrenia (SD)
Mean SESa (SD)
Last seizure at least 5 years ago and without medicinal treatment for at least 2 years (a) Cases receiving medicinal treatment for at least 2 years and showing no seizures during therapy, (b) last seizure at least 1 year ago and currently medicinally treated or without treatment for less than 2 years, or (c) condition requiring antiepileptic prophylactic treatment, last seizure 1–2 to 5 years ago, and treated or without treatment for at least 2 years Epilepsy with many seizures for at least 2 years despite optimal treatment, medicinal and otherwise
1383 2120
9.47 (1.15) 9.47 (1.19)
21.43 (3.36) 21.50 (4.95)
11.37 (4.01) 11.57 (4.17)
489
9.14 (1.46)
22.67 (5.68)
10.57 (4.12)
Score ranges from 1 to 20 (1 = lowest SES to 20 = highest SES).
E. Fruchter et al. / Epilepsy & Behavior 31 (2014) 291–294
without schizophrenia, as the date when the draft board data were merged with the data from the Israeli National Psychiatric Hospitalization Case Registry. In addition, in order to limit bias caused by disparate follow-up periods, the analysis was limited to psychiatric hospitalizations occurring up to 10 years after the draft board screening. All analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA).
293
refractory epilepsy. The validity of these data is supported by the prevalence of epilepsy in this study, 4.6 cases per 1000, which is congruent with the reported prevalence of epilepsy in developed countries [13]. In addition, the finding that patients with treatment-refractory schizophrenia are most likely to come from lower socioeconomic strata has also been described [14,15]. 4.1. Limitations
3. Results Of the 868,208 male adolescents consecutively screened by the Israeli Draft Board, 3996 were diagnosed with epilepsy, giving a prevalence of 4.6 cases per 1000. When analyzing risk for schizophrenia in adolescents diagnosed with epilepsy in the draft board, adolescents who had been hospitalized prior to the draft board screening with a diagnosis of schizophrenia or other psychiatric disorders or were diagnosed with a psychotic or major affective disorder in the draft board screening process were excluded from the analyses (N = 7146, 0.82%). Adolescents were followed up in an average of 9.6 ± 1.0 years (range: 1.0–10.0 years). Compared with the general population of male adolescents and controlling for SES, risk of hospitalization for schizophrenia was significantly higher among male adolescents with treatmentrefractory epilepsy (HR = 3.89, 95% CI = 1.75–89.67, p b 0.001). Neither patients with controlled, treated epilepsy nor patients with a history of epileptic seizures 5 or more years prior to screening had increased risk of hospitalization for schizophrenia (Table 2). Socioeconomic status differed among the three groups with epilepsy, with the group with treatment-refractory epilepsy having lower mean SES ratings compared to those with controlled, treated epilepsy or those with a history of epilepsy (p b 0.001, Table 1). Mean time observed, mean age at hospitalization for schizophrenia, and mean SES are presented separately for each group with epilepsy in Table 1. 4. Discussion To the best of our knowledge, this is the first report on the association between epilepsy and schizophrenia utilizing data on severity of the epilepsy. As hypothesized, adolescents with severe, treatmentrefractory epilepsy, but not epilepsy controlled by medication, were at increased risk for later schizophrenia. Other population-based studies have shown an overrepresentation of epilepsy among patients with schizophrenia [2], a higher risk of schizophrenia or schizophrenia-like psychosis among patients with epilepsy [3], and evidence of overlapping etiological factors, especially genetic, between epilepsy and schizophrenia [5]. Our data expand on those findings in that we were able to separate the patients according to their clinical and treatment status, and we were able to observe that not all patients with epilepsy have increased risk for schizophrenia but only those with severe, treatment-
Table 2 Risk of hospitalization for schizophrenia among male adolescents with epilepsy compared to adolescents without epilepsy. N
Risk of later hospitalization for schizophrenia (adjusted for SES)
Group
Total
Hospitalizations for schizophrenia
HR (95% CI)
p
History of epilepsy (1) Controlled, treated epilepsy (2) Treatment-refractory epilepsy (3)
1383 2120
7 2
1.77 (0.85–3.72) 0.34 (0.85–1.37)
0.130 0.129
489
2
3.89 (1.75–89.67)
0.001
HR, hazard ratio; CI, confidence interval; significance level of p b 0.01 is shown with bold emphasis.
Adolescents who had been hospitalized prior to the draft board screening with a diagnosis of schizophrenia or other psychiatric disorders as well as adolescents who were diagnosed with psychotic or major affecting disorders by draft board specialists were removed from this analysis. This might explain the somewhat lower risk for schizophrenia among patients with epilepsy in this study compared to other studies [2,3]. This design allows us to address the sequence of events, namely, the extent to which psychiatric illness follows the onset of epilepsy, and not vice versa. To our knowledge, this design has not been previously implemented in population-based studies of the association between epilepsy and schizophrenia. A limitation of this design is the lack of data on change in status of epilepsy throughout the follow-up period. It is likely that some individuals with a history of epilepsy or whose epilepsy was treated and controlled at the time of the draft board assessment had a relapse, while some patients with treatment-refractory epilepsy later responded to treatment during the follow-up period. Other limitations of this study include the use of clinical rather than research criteria for diagnosing epilepsy and schizophrenia. However, by law, adolescents in Israel come to the draft board with a note from a treating pediatrician who has treated the adolescent for his entire life and are then examined by a GP and then by a board-certified neurologist. The utility of this rigorous process is reflected by the finding that the prevalence of epilepsy in this study is congruent with the reported rate of epilepsy in this age group [13]. Given the heterogeneity of epilepsy, other important limitations include lack of data on the type of epilepsy, seizure frequency, and severity. Also, the Israeli National Psychiatric Hospitalization Case Registry utilizes clinical, not research, diagnoses, and both ICD-9 and ICD-10 diagnoses were used; however, the change in coding is unlikely to affect the findings substantially, and all diagnoses used were made by board-certified psychiatrists who see the patient over several admissions, including 93.1% of all patients hospitalized with schizophrenia in the country [10] at a sensitivity level of 0.89 [9]. In conclusion, in this population-based dataset of male adolescents, severe, treatment-refractory epilepsy was associated with increased risk of later hospitalization for schizophrenia. Future studies attempting to elucidate the association between epilepsy and schizophrenia might focus on this subset of patients when attempting to understand the biology of this association, and these patients should be monitored for the appearance of psychosis. Patients and families of patients with treated, controlled epilepsy might be assured that they do not appear to be at increased risk for schizophrenia. Conflict of interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Ettinger AB, Copeland LA, Zeber JE, Van Cott AC, Pugh MJ. Are psychiatric disorders independent risk factors for new-onset epilepsy in older individuals? Epilepsy Behav 2010;17:70–4. [2] Makikyro T, Karvonen JT, Hakko H, Nieminen P, Joukamaa M, Isohanni M, et al. Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort. Public Health 1998;112:221–8.
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