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Psychiatric comorbidity in refractory focal epilepsy: A study of 490 patients
Epilepsy & Behavior 25 (2012) 593–597
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Psychiatric comorbidity in refractory focal epilepsy: A study of 490 patients Charles L. Dalmagro a, Tonicarlo R. Velasco a, Marino M. Bianchin c, Ana Paula P. Martins a, Ricardo Guarnieri d, Maria P. Cescato b, Carlos G. Carlotti Jr. b, João A. Assirati Jr. b, David Araújo Jr. a, Antonio C. Santos a, Jaime E. Hallak a, Américo C. Sakamoto a,⁎ a
Department of Neuroscience and Behavioral Science, Ribeirão Preto School of Medicine, University of São Paulo, Brazil Department of Neurosurgery, Ribeirão Preto School of Medicine, University of São Paulo, Brazil B.R.A.I.N., Division of Neurology, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil d Division of Psychiatry, Federal University of Santa Catarina, Brazil b c
a r t i c l e
i n f o
Article history: Received 13 July 2012 Revised 24 August 2012 Accepted 17 September 2012 Available online 14 November 2012 Keywords: Psychiatric comorbidities Temporal lobe epilepsy Frontal lobe epilepsy Limbic system Neocortical epilepsy
a b s t r a c t We studied the prevalence and associated factors of psychiatric comorbidities in 490 patients with refractory focal epilepsy. Of these, 198 (40.4%) patients had psychiatric comorbidity. An Axis I diagnosis was made in 154 patients (31.4%) and an Axis II diagnosis (personality disorder) in another 44 (8.97%) patients. After logistic regression, positive family history of psychiatric comorbidities (O.R. = 1.98; 95% CI = 1.10–3.58; p = 0.023), the presence of Axis II psychiatric comorbidities (O.R. = 3.25; 95% CI = 1.70–6.22; p b 0.0001), and the epileptogenic zone located in mesial temporal lobe structures (O.R. = 1.94; 95% CI = 1.25–3.03; p = 0.003) remained associated with Axis I psychiatric comorbidities. We concluded that a combination of clinical variables and selected structural abnormalities of the central nervous system contributes to the development of psychiatric comorbidities in patients with focal epilepsy. © 2012 Published by Elsevier Inc.
1. Introduction Epilepsy is a chronic brain disorder that affects approximately 50 million people worldwide. Patients with epilepsy have significant physical, social, neuropsychological, and psychiatric comorbidities that impact their health-related quality of life (HRQOL). Due to a combination of this high prevalence of comorbidities and the presence of long-term seizures, patients with refractory epilepsy experience even more deleterious effects on their individual health when compared to those with controlled seizures [1–7]. Population-based studies have shown that epilepsy is associated with an increased prevalence of mental health disorders when compared to the general population. In one study, the lifetime prevalence of suicidal ideation in people with epilepsy was almost double than that in individuals without epilepsy [6]. In another study, it was shown that up to 58% of patients with refractory epilepsy had a current or past history of psychiatric disorders [8]. These comorbidities are frequently associated with a significant decrease in HRQOL in such patients [9,10]. To reduce the burden of the disease, considerable efforts have been spent to develop effective and safe therapies to treat patients with
⁎ Corresponding author at: CIREP (Centro de Cirurgia de Epilepsia), Hospital das Clínicas de Ribeirão Preto, Ribeirão Preto, CEP 14048-900, Brazil. E-mail address: [email protected] (A.C. Sakamoto). 1525-5050/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.yebeh.2012.09.026
epilepsy. With the increasing recognition that such comorbidities represent a significant challenge to achieve this goal, one of the top priorities in epilepsy research is to prevent, limit, and reverse the occurrence of comorbidities associated with the epilepsies, such as cognitive impairment and psychiatric disorders. Regarding the last ones, approaches to understand the natural history of psychiatric comorbidities associated with epilepsy constitute a reasonable first step to achieve the above-mentioned goal. Although the prevalence and characteristics of psychiatric disorders have been extensively studied in patients with temporal lobe epilepsy (TLE), supporting the view that TLE and psychiatric illness are closely related [1,6,11–17], the natural history of psychiatric comorbidities in extratemporal lobe epilepsy (ExTLE) is much less understood. More importantly, the identification of all factors that are independently associated with psychiatric comorbidities in epilepsy remains to be fully elucidated. Here, we report a large series of 490 patients with refractory epilepsy as defined by the ILAE criteria [18], submitted to a comprehensive and multidisciplinary pre-surgical evaluation. Our goal was to identify the relationship between psychiatric comorbidities and location of the epileptogenic zone (EZ). In addition, we aimed to assess whether or not specific features of the epileptic syndrome, such as gender, etiology, age at seizure onset, seizure frequency, epilepsy duration, and seizure clinical characteristics, were factors associated with psychiatric comorbidities in some forms of refractory focal epilepsy.
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2. Methods 2.1. Subjects We retrospectively reviewed clinical, neuroimaging, video-EEG monitoring, and psychiatric data of patients with refractory epilepsy evaluated at the CIREP (Center for Epilepsy Surgery), Ribeirão Preto School of Medicine, University of Sao Paulo, Brazil, from 1995 to 2005. Inclusion criteria were adult patients older than 18 years, with refractory epilepsy, and with well-defined focal epilepsy. During this period, five hundred and twenty-four patients fulfilled the inclusion criteria. From these, thirty-four patients were excluded because of incomplete data at the time of the study. The remaining four hundred and ninety patients were included in this study. The mean (±standard deviation) age at evaluation was 41± 9.9 years (range: 18 to 66 years), the mean age of epilepsy onset was 12.2± 8.6 years (range: 0 to 43 years), and the mean epilepsy duration was 29.12 ±11.76 years (range: 1 to 58 years). Medically refractory epilepsy was defined according to the ILAE criteria [18]. Patients whose epileptogenic zone could not be determined during presurgical evaluation and those with incomplete clinical, electrophysiological, or neuroimaging data were excluded. This study was approved by the Ethics Committee of our institution and followed the ethical standards defined by the Declaration of Helsinki. All persons included in the study gave written informed consent prior to their inclusion in the study. 2.2. Clinical variables Clinical variables were abstracted from the medical records. These included age at evaluation, age at seizure onset, epilepsy duration, seizure frequency per month, frequency of generalized tonic-clonic seizures per year, gender, family history of epilepsy, family history of psychiatric disease, years of education, intelligence quotient (IQ), and side of MRI lesion. Epilepsy duration was calculated as the interval (in years) from age at seizure onset to age at evaluation. During the neurological interview, patients and their family members were questioned about the presence of a family history of epilepsy in first- or second-degree relatives. During the psychiatric interview, a family history of psychiatric disorders was considered positive if a first- or second-degree relative had a confirmed diagnosis of a psychiatric disorder. 2.3. Psychiatric evaluation All patients were submitted to an extensive, formal, and standardized psychiatric evaluation as part of the pre-surgical evaluation protocol. This evaluation was performed by psychiatrists dedicated to the assessment of patients with epilepsy in our center (J.H., R.G., and M.P.C). In these assessments, all patients were initially interviewed alone. Next, they were reevaluated when accompanied by a family member. During these evaluations, a complete family history of psychiatric disorders was recorded. Detailed Axis I and II diagnoses were made clinically during psychiatric evaluation based on the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition (DSM-IV and DSM-IV-RT). For the purpose of this study, a lifetime psychiatric diagnosis was used. In addition, Axis I psychiatric comorbidities were grouped into mood disorders (depression, mania, hypomania, bipolar, and dysthymic disorder), anxiety disorders (generalized anxiety disorder, panic, obsessive–compulsive disorder, post-traumatic stress disorders), and psychosis (interictal and post-ictal). The personality disorders were classified according to the groups A, B, and C of personality disorders of the DSM-IV. The “epileptic personality condition” was classified within “other personality disorders”. The presence of an Axis I diagnosis did not exclude the possibility of an overlapping personality disorder (Axis II). Because of the lack of psychiatric categories in the DSM-IV
classification specifically applied to epilepsy, we additionally considered three specific psychiatric comorbidities frequently associated with epilepsy: interictal dysphoric disorder, postictal psychosis, and interictal psychosis. Interictal dysphoric disorder has been classified by Blumer et al. [19] as an intermittent course of depressive somatoform and affective symptoms. Depressive somatoform symptoms include depressive mood, anergia, pain, and insomnia. Affective symptoms include irritability, euphoric mood, fear, and anxiety [19,20]. The postictal psychosis group was defined according to Logsdail and Toone's criteria: a psychotic state characterized by hallucinations, delusions or disorders of thought, and eventually mood changes, occurring within 24 h to 7 days after the last epileptic seizure. During the psychotic state (ranging from a few days to 90 days), consciousness is often preserved [21]. The interictal psychosis group was defined as a prolonged psychotic state not temporally related to the epileptic seizures. Features include hallucinations, preoccupation with religious themes, and Schneider's first-rank symptoms, i.e., certain symptoms as being characteristic of schizophrenia and, therefore, exhibiting a “first-rank” status in the hierarchy of potentially diagnostic symptoms [22]. Ictal psychosis or psychosis associated with changes in AED regimen, status epilepticus, and delirium were not included. 2.4. Definition of the epileptogenic zone The gold standard to determine the localization of the EZ was a combination of diagnostic tests. The standard presurgical evaluation included a detailed clinical interview and neurological examination, interictal and ictal scalp EEG-video recordings, structural highresolution MRI, ictal and interictal SPECT, and neuropsychological and social assessments. If the standard protocol failed to localize the EZ unequivocally, patients were submitted to semi-invasive (foramen ovale) or invasive investigations with subdural grids and strips. Patients were then categorized according to the localization of the EZ as having mesial temporal lobe epilepsy (MTLE), neocortical temporal lobe epilepsy (NeoTLE), and extratemporal epilepsy (ExTLE). 2.5. Study design and statistical analysis All data were analyzed with SPSS 15.0 for Windows (SPSS, Inc.). The chi-square test was used for categorical variables, and results are expressed as odds ratios (OR) and 95% confidence interval (95% CI). The Kolmogorov–Smirnov test was applied to test normality of the data. When variables presented a normal distribution, a parametric test such as the Student's t-test or analysis of variance (ANOVA) was used. When variables did not present a normal distribution, the non-parametric Mann–Whitney or Kruskal–Wallis test was used. Binary logistic regression was used to control for confounding variables for Axis I psychiatric comorbidities when p ≤ 0.10. Additionally, we forced these same variables in a multinomial logistic regression model to study independent effects and their relationship with each and with Axis I psychiatric comorbidities (mood, anxiety, or psychotic disorders). Results were considered significant if p b 0.05. 3. Results 3.1. Clinical and demographic characteristics of study participants The clinical and demographic characteristics of our series are presented in Table 1. Of the 490 patients included in the study, 328 (66%) had MTLE, 47 (10%) had NeoTLE, and 115 (24%) had ExTLE. The natural history of patients with refractory focal epilepsies differed depending on the location of the EZ. For example, patients with MTLE had a lower frequency of secondarily generalized tonicclonic seizures (p b 0.001) and better seizure outcomes after surgery (p b 0.001) compared to patients with NeoTLE and ExTLE. In addition, patients with NeoTLE had a slightly higher IQ (p = 0.006) and a lower
C.L. Dalmagro et al. / Epilepsy & Behavior 25 (2012) 593–597 Table 1 Clinical and demographic characteristics of the cohort. Variables
Mesial TLE n=328
Mean age at evaluation, 43.7 (8.7) years (SD) Mean age of seizure 10.8 (7.8) onset, years (SD) Epilepsy duration, 27.4 (10.1) years (SD) Seizure frequency/month, 9.0 (7.5) mean (SD) Generalized seizures/year, 2.7 (4.8) mean (SD) Mean years of education, 7.2 (0.1) mean (SD) Mean IQ (SD) 83.0 (7.8) Female, n (%) 176 (53.7%) Family history of 39(11.8%) psychiatric dis., n (%) Risk factor for epilepsy, 185 (56.4%) n (%) Submitted to surgery, 264 (80.4%) n (%) Etiology, n (%) HS 328 (100%) MCD 0 (0%) Tumor 0 (0%) Gliosis 0 (0%) Others 0 (0%) Seizure free after 213 (80.7%) surgery, n (%)
595
Table 2 Psychiatric comorbidities according to epileptogenic zone in refractory focal epilepsy.
Neocortical TLE n=47
Extra-temporal p-Value n=115
40.4 (11.4)
35.5 (10.0)
b0.0001#
13.8 (7.4)
16.0 (10.1)
#
b0.0001
21.8 (12.2)
17.2 (11.2)
b0.0001#
10.5 (16.8)
20.1 (22.5)
b0.0001‡
4.1 (3.9)
35.5 (24.1)
b0.0001‡
8.9 (3.2)
7.9 (2.9)
0.0020‡
88.7(12.7) 21 (44.7%) 2 (4.2%)
84.8 (8.1) 48 (41.7%) 12 (10.4%)
0.0060‡ 0.0660† 0.2860†
8 (17.0%)
50 (43.5%)
b0.0001†
30 (63.8%)
58 (50.4%)
b0.0001†
0 (0%) 11 (23.40%) 17 (36.17%) 6 (12.77%) 13 (27.66%) 18 (60%)
0 (0%) 9 (7.8%) 39 (33.9%) 38 (33.0%) 29 (25.1%) 23 (39.6%)
b0.0001†
b0.0001†
IQ refers to intelligence quotient; HS, hippocampal sclerosis, MCD, malformations of cortical development, and SD, standard deviation. # = ANOVA; ‡ = Kruskal–Wallis; † = chi-square test. Significant p-values are shown in bold.
prevalence of risk factors for epilepsy (p b 0.0001) when compared to the other groups. Finally, patients with ExTLE had a higher seizure frequency (p b 0.001) and the poorest seizure outcome after surgery. Hippocampal sclerosis (HS) was the etiology for all patients with MTLE. Low-grade tumors were the most frequent etiology for both the NeoTLE (36.2%) and ExTLE groups (33.9%).
Mesial TLE n = 328
Neocortical TLE n= 47
Extra-temporal n=115
p-Value
Axis I, n (%) Mood Anxiety Psychosis Axis II, n (%) PD paranoid PD schizoid PD borderline PD histrionic PD obsessive–compulsive Others Total (Axis I plus Axis II)
116 (35.4%) 69 (21.0%) 16 (4.9%) 31 (9.5%) 23 (7.0%) 0 (0%) 2 (0.6%) 3 (0.9%) 7 (2.1%) 0 (0%) 11 (3.3%) 139 (42.4%)
9 (19.1%) 5 (10.6%) 3 (6.4%) 1 (2.1%) 6 (12.8%) 0 (0%) 1 (2.1%) 0 (0%) 1 (2.1%) 0 (0%) 4 (8.5%) 15 (31.9%)
29 (25.2%) 20 (17.3%) 2 (1.7%) 7 (6.1%) 15 (13.0%) 1 (0.8%) 1 (0.8%) 3 (2.6%) 5 (4.3%) 1 (0.8%) 4 (3.4%) 44 (38.3%)
0.021 0.204 0.272 0.155 0.095 0.380 0.528 0.479 0.744 0.380 0.200 0.339
TLE refers to temporal lobe epilepsy; PD, personality disorder. Chi-square test (significant p-values are shown in bold).
seizures, mean IQ, and presence of associated factors for epilepsy were similar in groups of patients with Axis I psychiatric abnormalities and without these comorbidities. In this cohort, a positive family history of psychiatric disorders, EZ located in the mesial temporal lobe, and presence of Axis II disorders were associated with Axis I psychiatric comorbidities in univariate analysis. In Table 4, we present the results of binary logistic regression showing independent associated factors for the presence of Axis I psychiatric comorbidities. In this model, we included all variables with p b 0.30. Although HS was highly correlated with the presence of Axis I psychiatric disorders, this variable was not included in the model because it was completely correlated with the mesial temporal EZ, leading to multicollinearity in the logistic regression model. The analysis showed that positive family history of
Table 3 Factors associated with psychiatric Axis I comorbidities in focal refractory epilepsy. Variables
Axis I absent 336 (68.6%)
Axis I present 154 (31.4%)
Mean age seizure 11.9 (8.1) 13.0 (9.8) onset (SD) Epilepsy duration, 23.9 (11.4) 25.7 (11.5) mean (SD) Female, n (%) 161 (47.92%) 84 (54.55%) Psychiatric familial 28 (8.3%) 25 (16.2%) history, n (%) Seizure frequency/month, 11.90(14.97) 11.48 (12.70) mean (SD) Number of SGS/year, 10.5 (18.3) 10.8 (19.2) mean (SD) Presence of SGS 266 (79.2%) 114 (74.0%) Mean IQ (SD) 84.2 (8.8) 83.5 (8.2) Axis II diagnosis, n (%) 20 (5.95%) 24 (15.59%) Risk factors for 158 (47.02%) 70 (45.45%) epilepsy, n (%) Mesial temporal 212 (63.09%) 116 (75.32%) location, n (%) Etiology, n (%) HS 212 (63.09%) 116 (75.32%) Tumor 20 (5.95%) 06 (3.89%) Gliosis 30 (8.93%) 14 (9.09%) Cortical dysplasia 30 (8.93%) 10 (6.5%) Side of MRI lesion, n (%) Left 153 (45.53%) 82 (53.24%) Right 151 (44.94%) 61 (39.62%) Bilateral 29 (8.63%) 11 (7.14%) Normal 3 (0.90%) 0 (0%)
3.2. Prevalence of psychiatric comorbidities Psychiatric disorders were diagnosed in 198 of 490 patients (40.4%). In Table 2, psychiatric comorbidities are presented according to the localization of the EZ. An Axis I diagnosis was observed in 35.4% of MTLE patients, 19.1% of NeoTLE patients, and 25.2% of ExTLE patients. Although Axis I disorders were more frequently observed in patients with MTLE than in the other groups (p = 0.02), no specific Axis I psychiatric disorder was more prevalent in MTLE in our series. Axis II disorders were observed in 7% of MTLE patients, 12.8% of NeoTLE, and 13.0% of ExTLE patients (for details, see Table 2). When patients with neocortical epilepsy (NeoTLE and ExTLE) were pooled together in a post hoc analysis, an Axis II diagnosis was more prevalent in patients with neocortical epilepsy (NeoTLE plus ExTLE) than in those with MTLE (13% versus 7%; p = 0.045; OR = 2.00; 95% CI = 1.06 to 3.70). Personality disorders specifically related to epilepsy were observed in 19 patients. 3.3. Factors associated with Axis I psychiatric comorbidities #
Table 3 shows clinical and neuroimaging variables according to the presence or absence of Axis I psychiatric disorders. Age at epilepsy onset, gender, frequency of secondarily generalized tonic-clonic
Variables
†
‡
Odds ratio (95% CI)
p-Value
–
0.216#
–
0.110#
1.3 (0.9 to 1.9) 0.200† 0.5 (0.2 to 0.8) 0.009† –
0.651‡
–
0.557‡
0.7 (0.5 to 1.2) – 0.3 (0.2 to 0.6) 1.0 (0.7 to 1.5)
0.205† 0.497‡ 0.001† 0.770†
0.6 (0.3 to 0.8) 0.007†
– – – –
0.370†
– – – –
0.300†
= independent sample t-test; = chi-square test; = Mann–Whitney test; (significant p-values are shown in bold). IQ refers to intelligence quotient; HS, hippocampal sclerosis, SGS, secondary generalized seizures.
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Table 4 Binary logistic regression for factors associated with Axis I psychiatric comorbidities in focal refractory epilepsy. Variables
Crude odds ratio p-Value (95%CI)
Positive psychiatric 2.1 (1.2 to 3.8) familial history Temporal mesial EZ 1.7 (1.1 to 2.5) Presence of an Axis II 2.9 (1.6 to 5.5) diagnosis
0.012
Adjusted odds ratio p-Value (95% CI) 1.98 (1.10 to 3.58)
0.007 1.94 (1.25 to 3.03) b0.0001 3.25 (1.70 to 6.22)
0.023 0.003 b0.0001
EZ refers to epileptogenic zone (significant p-values are shown in bold).
psychiatric comorbidities (O.R.= 1.98; 95% CI = 1.10 to 3.58; p = 0.023), presence of Axis II psychiatric comorbidities (O.R.= 3.25; 95% CI= 1.70 to 6.22; p b 0.0001), and EZ located in mesial temporal lobe structures (O.R.= 1.94; 95% CI = 1.25 to 3.03; p = 0.003) were all independent factors associated with Axis I psychiatric disorders in this cohort of patients with refractory focal epilepsies. These 3 variables were forced as factors in a multinomial logistic regression model with Axis I psychiatric comorbidities used as independent variables. By doing this procedure, we could control statistically what variables were independently associated with each one of the major Axis I specific psychiatric comorbidities. Results are presented in Table 5. Positive psychiatric family history, mesial temporal EZ and the presence of Axis II psychiatric comorbidity emerged as factors independently and significantly associated with mood disorders in refractory focal epilepsy. The presence of Axis II comorbidity was also independently associated with the presence of anxiety or psychosis comorbidity. Finally, temporal mesial EZ was also a factor independently associated with psychosis in refractory focal epilepsy. 4. Discussion In this study, we analyzed the prevalence of psychiatric comorbidities in a cohort of 490 patients with refractory focal epilepsy. We observed an overall prevalence of psychiatric comorbidity in 40.4% of all patients (in 42.4% of patients with mesial temporal lobe epilepsy, in 31.9% of patients with neocortical temporal lobe epilepsy, and in 38.3% of patients with extra-temporal lobe epilepsy), confirming the high rate encountered in previous studies [1,6,11–17,23]. Overall, Axis I psychiatric disorders were diagnosed in 31.4% of patients
Table 5 Multinomial logistic regression for individual factors associated with Axis I psychiatric comorbidities in focal refractory epilepsy. Variables Mood disorders Positive psychiatric familial history Temporal mesial EZ Presence of an Axis II diagnosis Anxiety disorders Positive psychiatric familial history Temporal mesial EZ Presence of an Axis II diagnosis Psychotic disorders Positive psychiatric familial history Temporal mesial EZ Presence of an Axis II diagnosis
Crude odds ratio (95%CI)
p-Value
Adjusted odds ratio (95% CI)
2.45 (1.31–4.54)
0.004
2.45 (1.28–4.71)
0.007
0.68 (0.41–1.13) 0.60 (0.30–1.22)
0.14 0.15
1.69 (1.00–2.85) 2.48 (1.14–5.40)
0.049 0.022
0.72 (0.20–2.52)
0.60
1.60 (0.43–5.93)
0.481
0.62 (0.22–1.73) 4.54 (1.66–12.3)
0.36 0.001
2.34 (0.81–6.82) 7.37 (2.50–21.7)
0.117 b0.0001
1.07 (0.36–3.13)
0.91
1.15 (0.38–3.50)
0.809
0.50 (0.22–1.11) 0.51 (0.20–1.28)
0.08 0.14
2.52 (1.11–5.75) 3.43 (1.26–9.38)
0.028 0.016
EZ refers to epileptogenic zone (significant p-values are shown in bold).
p-Value
and were more frequent in those with EZ localized in the limbic structures of the temporal lobe. Axis II psychiatric comorbidities were less frequent; observed in 9.0% of the patients. In contrast to Axis I disorders, Axis II psychiatric comorbidities were more prevalent in patients with EZ localized in neocortical structures (NeoTLE plus ExTLE) than in patients with limbic epilepsy. We also found that positive family history of psychiatric comorbidities, the presence of Axis II psychiatric comorbidities, and EZ in mesial temporal lobe structures were ndependent factors associated with Axis I psychiatric comorbidities in our group of patients with refractory focal epilepsies. The higher prevalence of Axis I disorders in MTLE in our series results from a combination of patients with mood and psychotic disorders. This association is in line with evidence suggesting that limbic structures play a critical role in the etiopathology of mood disorders and psychosis. In fact, some authors have suggested the existence of a bidirectional relationship between epilepsy and psychiatric disorders, especially with mood disorders [17,24,25]. These authors do not suggest that depression causes epilepsy or vice versa but rather suggest they share common pathophysiological mechanisms that facilitate the development of both disorders [17,24,25]. We found an unexpected low prevalence of anxiety disorders in our patients (4.3%) in contrast to previous studies that observed a high prevalence of anxiety disorders associated with epilepsy [3,6,13,15,23]. One possible explanation for this low prevalence of anxiety disorders in our series might be the frequent use of high doses of benzodiazepines (e.g., clobazam and clonazepam) as adjunctive therapy for seizure control. Although our study was not designed to assess this possibility, we observed that benzodiazepines were chronically used by 92.8% of our patients, suggesting that further studies are necessary to address it. Nevertheless, if this possibility holds true, the adjunctive use of benzodiazepines for seizure control might have an additional beneficial effect in terms of reducing anxiety levels in patients with refractory epilepsies. An important point that deserves further discussion is the observation of a higher prevalence of Axis II personality disorders in patients with neocortical epilepsies (NeoTLE plus ExTLE) when compared to MTLE. Historically, personality disorders have been associated with temporal lobe epilepsy, and especially with limbic system abnormalities [26]. The higher prevalence of Axis II disorders in patients with extra-mesial epilepsies was, therefore, somehow unexpected. It is well-known that patients with frontal lobe lesions tend to exhibit abnormal impulsivity, socially inappropriate behaviors, and executive dysfunction, features also frequently found in patients with Axis II diagnosis. Moreover, a possible involvement of prefrontal and cingulate areas in Axis II psychopathologies has also been described, at least for borderline personality disorder [27,28]. Thus, in our view, extratemporal limbic involvement and/or other frontal lobe dysfunctions might well explain our findings, and these possibilities deserve further studies. Associated factors for psychiatric comorbidities in patients with epilepsy are still controversial, varying according to the population analyzed, to the methodologies utilized for the categorization of the distinct groups with epilepsy, and to the tools used for the evaluation and classification of the psychiatric comorbidities. Some studies have described an association between EZ in the temporal lobe and psychiatric comorbidities [11,13,15,23,29–31]. However, other authors have failed to find such associations [8,32–34]. Mood disorders and depression are the most common psychiatric comorbidities observed in association with epilepsy and are also the most studied [9,35–38]. When depression is considered alone, female gender, specific neurological conditions associated with epilepsy, sinistrality, family history of psychiatric illness, structural changes in the medial temporal lobe, learning disabilities or low IQ, and seizure type were all considered to be risk factors for depression in patients with epilepsy according to several authors [11,13,15,23,29,35,39–42]. However, few studies
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have been carried out using modern statistical tools that are able to identify isolated risk factors or associated factors. In this large series of patients with refractory focal epilepsies with a well-defined EZ and using modern statistical methods that controlled for confounding factors, we observed that mesial temporal lobe EZ (MTLE-HS), family history of psychiatric disorders, and the presence of Axis II psychiatric comorbidities were all independent factors associated with Axis I psychiatric comorbidities, mainly mood or psychosis disorders. On the other hand, gender, presence or frequency of secondarily generalized seizures, mean IQ, neuropathological category, and side of brain lesion were not found to be associated with psychiatric comorbidities. More specifically, we observed that positive psychiatric family history, EZ in mesial temporal structures and the presence of an Axis II psychiatric comorbidity were independently and significantly associated with mood disorders in refractory focal epilepsy. Anxiety or psychosis comorbidity was also associated with the presence of Axis II comorbidity, and temporal mesial EZ was also independently associated with psychosis in refractory focal epilepsy. We recognize that our study has limitations. We were not able to establish risk factors for psychiatric comorbidities in epilepsy due to the cross-sectional design of the study. Also, in spite of the comprehensive investigation, we included patients who were not seizure free and some patients still waiting for surgery. Thus, in spite of very good accuracy of our study for most patients, the delimitation of the EZ might not be one hundred percent accurate for some patients. However, our study has strengths that need to be recognized as well. We studied a large group of patients with diverse forms of focal epilepsy using detailed, accurate and homogeneous investigations. Also, we used modern statistical analysis to establish the independence of the associations encountered. Thus, in spite of possible limitations, we believe that our study adds relevant information regarding psychiatric comorbidities in focal refractory epilepsy. Taken together, our results support the concept that a combination of selected clinical variables associated with the presence of specific structural abnormalities of the central nervous system contributes to the development of Axis I psychiatric comorbidities in patients with refractory focal epilepsies. More studies specifically designed to assess a cause–effect relationship between these variables are needed for a better understanding of how these factors merge together leading to psychiatric comorbidity in patients with focal epilepsy. Acknowledgments This study was fully supported by grants from the Brazilian Government agencies. The authors receive financial support from FAPESP/CINAPCE, Project #04/14004-9. Dr. Hallak, Dr. Velasco, and Dr. Araujo were also supported by CNPq. Dr. Bianchin is supported by CNPq (#306644/2010-0 and #483108/2010-3) and FAPERGS/PRONEM. References [1] Kanner AM. The complex epilepsy patient: intricacies of assessment and treatment. Epilepsia 2003;44(Suppl. 5):S3-8. [2] Devinsky O. Psychiatric comorbidity in patients with epilepsy: implications for diagnosis and treatment. Epilepsy Behav 2003;4(Suppl. 4):S2–S10. [3] Johnson EK, Jones JE, Seidenberg M, Hermann BP. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia 2004;45:544-50. [4] Brodie MJ. Diagnosing and predicting refractory epilepsy. Acta Neurol Scand Suppl 2005;181:36-9. [5] Wiebe S, Hesdorffer DC. Epilepsy: being ill in more ways than one. Epilepsy Curr 2007;7:145-8. [6] Tellez-Zenteno JF, Patten SB, Jette N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007;48:2336-44. [7] Hermann B, Seidenberg M, Jones J. The neurobehavioural comorbidities of epilepsy: can a natural history be developed? Lancet Neurol 2008;7:151-60.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Psychiatric comorbidity in refractory focal epilepsy: A study of 490 patients Charles L. Dalmagro a, Tonicarlo R. Velasco a, Marino M. Bianchin c, Ana Paula P. Martins a, Ricardo Guarnieri d, Maria P. Cescato b, Carlos G. Carlotti Jr. b, João A. Assirati Jr. b, David Araújo Jr. a, Antonio C. Santos a, Jaime E. Hallak a, Américo C. Sakamoto a,⁎ a
Department of Neuroscience and Behavioral Science, Ribeirão Preto School of Medicine, University of São Paulo, Brazil Department of Neurosurgery, Ribeirão Preto School of Medicine, University of São Paulo, Brazil B.R.A.I.N., Division of Neurology, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil d Division of Psychiatry, Federal University of Santa Catarina, Brazil b c
a r t i c l e
i n f o
Article history: Received 13 July 2012 Revised 24 August 2012 Accepted 17 September 2012 Available online 14 November 2012 Keywords: Psychiatric comorbidities Temporal lobe epilepsy Frontal lobe epilepsy Limbic system Neocortical epilepsy
a b s t r a c t We studied the prevalence and associated factors of psychiatric comorbidities in 490 patients with refractory focal epilepsy. Of these, 198 (40.4%) patients had psychiatric comorbidity. An Axis I diagnosis was made in 154 patients (31.4%) and an Axis II diagnosis (personality disorder) in another 44 (8.97%) patients. After logistic regression, positive family history of psychiatric comorbidities (O.R. = 1.98; 95% CI = 1.10–3.58; p = 0.023), the presence of Axis II psychiatric comorbidities (O.R. = 3.25; 95% CI = 1.70–6.22; p b 0.0001), and the epileptogenic zone located in mesial temporal lobe structures (O.R. = 1.94; 95% CI = 1.25–3.03; p = 0.003) remained associated with Axis I psychiatric comorbidities. We concluded that a combination of clinical variables and selected structural abnormalities of the central nervous system contributes to the development of psychiatric comorbidities in patients with focal epilepsy. © 2012 Published by Elsevier Inc.
1. Introduction Epilepsy is a chronic brain disorder that affects approximately 50 million people worldwide. Patients with epilepsy have significant physical, social, neuropsychological, and psychiatric comorbidities that impact their health-related quality of life (HRQOL). Due to a combination of this high prevalence of comorbidities and the presence of long-term seizures, patients with refractory epilepsy experience even more deleterious effects on their individual health when compared to those with controlled seizures [1–7]. Population-based studies have shown that epilepsy is associated with an increased prevalence of mental health disorders when compared to the general population. In one study, the lifetime prevalence of suicidal ideation in people with epilepsy was almost double than that in individuals without epilepsy [6]. In another study, it was shown that up to 58% of patients with refractory epilepsy had a current or past history of psychiatric disorders [8]. These comorbidities are frequently associated with a significant decrease in HRQOL in such patients [9,10]. To reduce the burden of the disease, considerable efforts have been spent to develop effective and safe therapies to treat patients with
⁎ Corresponding author at: CIREP (Centro de Cirurgia de Epilepsia), Hospital das Clínicas de Ribeirão Preto, Ribeirão Preto, CEP 14048-900, Brazil. E-mail address: [email protected] (A.C. Sakamoto). 1525-5050/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.yebeh.2012.09.026
epilepsy. With the increasing recognition that such comorbidities represent a significant challenge to achieve this goal, one of the top priorities in epilepsy research is to prevent, limit, and reverse the occurrence of comorbidities associated with the epilepsies, such as cognitive impairment and psychiatric disorders. Regarding the last ones, approaches to understand the natural history of psychiatric comorbidities associated with epilepsy constitute a reasonable first step to achieve the above-mentioned goal. Although the prevalence and characteristics of psychiatric disorders have been extensively studied in patients with temporal lobe epilepsy (TLE), supporting the view that TLE and psychiatric illness are closely related [1,6,11–17], the natural history of psychiatric comorbidities in extratemporal lobe epilepsy (ExTLE) is much less understood. More importantly, the identification of all factors that are independently associated with psychiatric comorbidities in epilepsy remains to be fully elucidated. Here, we report a large series of 490 patients with refractory epilepsy as defined by the ILAE criteria [18], submitted to a comprehensive and multidisciplinary pre-surgical evaluation. Our goal was to identify the relationship between psychiatric comorbidities and location of the epileptogenic zone (EZ). In addition, we aimed to assess whether or not specific features of the epileptic syndrome, such as gender, etiology, age at seizure onset, seizure frequency, epilepsy duration, and seizure clinical characteristics, were factors associated with psychiatric comorbidities in some forms of refractory focal epilepsy.
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2. Methods 2.1. Subjects We retrospectively reviewed clinical, neuroimaging, video-EEG monitoring, and psychiatric data of patients with refractory epilepsy evaluated at the CIREP (Center for Epilepsy Surgery), Ribeirão Preto School of Medicine, University of Sao Paulo, Brazil, from 1995 to 2005. Inclusion criteria were adult patients older than 18 years, with refractory epilepsy, and with well-defined focal epilepsy. During this period, five hundred and twenty-four patients fulfilled the inclusion criteria. From these, thirty-four patients were excluded because of incomplete data at the time of the study. The remaining four hundred and ninety patients were included in this study. The mean (±standard deviation) age at evaluation was 41± 9.9 years (range: 18 to 66 years), the mean age of epilepsy onset was 12.2± 8.6 years (range: 0 to 43 years), and the mean epilepsy duration was 29.12 ±11.76 years (range: 1 to 58 years). Medically refractory epilepsy was defined according to the ILAE criteria [18]. Patients whose epileptogenic zone could not be determined during presurgical evaluation and those with incomplete clinical, electrophysiological, or neuroimaging data were excluded. This study was approved by the Ethics Committee of our institution and followed the ethical standards defined by the Declaration of Helsinki. All persons included in the study gave written informed consent prior to their inclusion in the study. 2.2. Clinical variables Clinical variables were abstracted from the medical records. These included age at evaluation, age at seizure onset, epilepsy duration, seizure frequency per month, frequency of generalized tonic-clonic seizures per year, gender, family history of epilepsy, family history of psychiatric disease, years of education, intelligence quotient (IQ), and side of MRI lesion. Epilepsy duration was calculated as the interval (in years) from age at seizure onset to age at evaluation. During the neurological interview, patients and their family members were questioned about the presence of a family history of epilepsy in first- or second-degree relatives. During the psychiatric interview, a family history of psychiatric disorders was considered positive if a first- or second-degree relative had a confirmed diagnosis of a psychiatric disorder. 2.3. Psychiatric evaluation All patients were submitted to an extensive, formal, and standardized psychiatric evaluation as part of the pre-surgical evaluation protocol. This evaluation was performed by psychiatrists dedicated to the assessment of patients with epilepsy in our center (J.H., R.G., and M.P.C). In these assessments, all patients were initially interviewed alone. Next, they were reevaluated when accompanied by a family member. During these evaluations, a complete family history of psychiatric disorders was recorded. Detailed Axis I and II diagnoses were made clinically during psychiatric evaluation based on the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition (DSM-IV and DSM-IV-RT). For the purpose of this study, a lifetime psychiatric diagnosis was used. In addition, Axis I psychiatric comorbidities were grouped into mood disorders (depression, mania, hypomania, bipolar, and dysthymic disorder), anxiety disorders (generalized anxiety disorder, panic, obsessive–compulsive disorder, post-traumatic stress disorders), and psychosis (interictal and post-ictal). The personality disorders were classified according to the groups A, B, and C of personality disorders of the DSM-IV. The “epileptic personality condition” was classified within “other personality disorders”. The presence of an Axis I diagnosis did not exclude the possibility of an overlapping personality disorder (Axis II). Because of the lack of psychiatric categories in the DSM-IV
classification specifically applied to epilepsy, we additionally considered three specific psychiatric comorbidities frequently associated with epilepsy: interictal dysphoric disorder, postictal psychosis, and interictal psychosis. Interictal dysphoric disorder has been classified by Blumer et al. [19] as an intermittent course of depressive somatoform and affective symptoms. Depressive somatoform symptoms include depressive mood, anergia, pain, and insomnia. Affective symptoms include irritability, euphoric mood, fear, and anxiety [19,20]. The postictal psychosis group was defined according to Logsdail and Toone's criteria: a psychotic state characterized by hallucinations, delusions or disorders of thought, and eventually mood changes, occurring within 24 h to 7 days after the last epileptic seizure. During the psychotic state (ranging from a few days to 90 days), consciousness is often preserved [21]. The interictal psychosis group was defined as a prolonged psychotic state not temporally related to the epileptic seizures. Features include hallucinations, preoccupation with religious themes, and Schneider's first-rank symptoms, i.e., certain symptoms as being characteristic of schizophrenia and, therefore, exhibiting a “first-rank” status in the hierarchy of potentially diagnostic symptoms [22]. Ictal psychosis or psychosis associated with changes in AED regimen, status epilepticus, and delirium were not included. 2.4. Definition of the epileptogenic zone The gold standard to determine the localization of the EZ was a combination of diagnostic tests. The standard presurgical evaluation included a detailed clinical interview and neurological examination, interictal and ictal scalp EEG-video recordings, structural highresolution MRI, ictal and interictal SPECT, and neuropsychological and social assessments. If the standard protocol failed to localize the EZ unequivocally, patients were submitted to semi-invasive (foramen ovale) or invasive investigations with subdural grids and strips. Patients were then categorized according to the localization of the EZ as having mesial temporal lobe epilepsy (MTLE), neocortical temporal lobe epilepsy (NeoTLE), and extratemporal epilepsy (ExTLE). 2.5. Study design and statistical analysis All data were analyzed with SPSS 15.0 for Windows (SPSS, Inc.). The chi-square test was used for categorical variables, and results are expressed as odds ratios (OR) and 95% confidence interval (95% CI). The Kolmogorov–Smirnov test was applied to test normality of the data. When variables presented a normal distribution, a parametric test such as the Student's t-test or analysis of variance (ANOVA) was used. When variables did not present a normal distribution, the non-parametric Mann–Whitney or Kruskal–Wallis test was used. Binary logistic regression was used to control for confounding variables for Axis I psychiatric comorbidities when p ≤ 0.10. Additionally, we forced these same variables in a multinomial logistic regression model to study independent effects and their relationship with each and with Axis I psychiatric comorbidities (mood, anxiety, or psychotic disorders). Results were considered significant if p b 0.05. 3. Results 3.1. Clinical and demographic characteristics of study participants The clinical and demographic characteristics of our series are presented in Table 1. Of the 490 patients included in the study, 328 (66%) had MTLE, 47 (10%) had NeoTLE, and 115 (24%) had ExTLE. The natural history of patients with refractory focal epilepsies differed depending on the location of the EZ. For example, patients with MTLE had a lower frequency of secondarily generalized tonicclonic seizures (p b 0.001) and better seizure outcomes after surgery (p b 0.001) compared to patients with NeoTLE and ExTLE. In addition, patients with NeoTLE had a slightly higher IQ (p = 0.006) and a lower
C.L. Dalmagro et al. / Epilepsy & Behavior 25 (2012) 593–597 Table 1 Clinical and demographic characteristics of the cohort. Variables
Mesial TLE n=328
Mean age at evaluation, 43.7 (8.7) years (SD) Mean age of seizure 10.8 (7.8) onset, years (SD) Epilepsy duration, 27.4 (10.1) years (SD) Seizure frequency/month, 9.0 (7.5) mean (SD) Generalized seizures/year, 2.7 (4.8) mean (SD) Mean years of education, 7.2 (0.1) mean (SD) Mean IQ (SD) 83.0 (7.8) Female, n (%) 176 (53.7%) Family history of 39(11.8%) psychiatric dis., n (%) Risk factor for epilepsy, 185 (56.4%) n (%) Submitted to surgery, 264 (80.4%) n (%) Etiology, n (%) HS 328 (100%) MCD 0 (0%) Tumor 0 (0%) Gliosis 0 (0%) Others 0 (0%) Seizure free after 213 (80.7%) surgery, n (%)
595
Table 2 Psychiatric comorbidities according to epileptogenic zone in refractory focal epilepsy.
Neocortical TLE n=47
Extra-temporal p-Value n=115
40.4 (11.4)
35.5 (10.0)
b0.0001#
13.8 (7.4)
16.0 (10.1)
#
b0.0001
21.8 (12.2)
17.2 (11.2)
b0.0001#
10.5 (16.8)
20.1 (22.5)
b0.0001‡
4.1 (3.9)
35.5 (24.1)
b0.0001‡
8.9 (3.2)
7.9 (2.9)
0.0020‡
88.7(12.7) 21 (44.7%) 2 (4.2%)
84.8 (8.1) 48 (41.7%) 12 (10.4%)
0.0060‡ 0.0660† 0.2860†
8 (17.0%)
50 (43.5%)
b0.0001†
30 (63.8%)
58 (50.4%)
b0.0001†
0 (0%) 11 (23.40%) 17 (36.17%) 6 (12.77%) 13 (27.66%) 18 (60%)
0 (0%) 9 (7.8%) 39 (33.9%) 38 (33.0%) 29 (25.1%) 23 (39.6%)
b0.0001†
b0.0001†
IQ refers to intelligence quotient; HS, hippocampal sclerosis, MCD, malformations of cortical development, and SD, standard deviation. # = ANOVA; ‡ = Kruskal–Wallis; † = chi-square test. Significant p-values are shown in bold.
prevalence of risk factors for epilepsy (p b 0.0001) when compared to the other groups. Finally, patients with ExTLE had a higher seizure frequency (p b 0.001) and the poorest seizure outcome after surgery. Hippocampal sclerosis (HS) was the etiology for all patients with MTLE. Low-grade tumors were the most frequent etiology for both the NeoTLE (36.2%) and ExTLE groups (33.9%).
Mesial TLE n = 328
Neocortical TLE n= 47
Extra-temporal n=115
p-Value
Axis I, n (%) Mood Anxiety Psychosis Axis II, n (%) PD paranoid PD schizoid PD borderline PD histrionic PD obsessive–compulsive Others Total (Axis I plus Axis II)
116 (35.4%) 69 (21.0%) 16 (4.9%) 31 (9.5%) 23 (7.0%) 0 (0%) 2 (0.6%) 3 (0.9%) 7 (2.1%) 0 (0%) 11 (3.3%) 139 (42.4%)
9 (19.1%) 5 (10.6%) 3 (6.4%) 1 (2.1%) 6 (12.8%) 0 (0%) 1 (2.1%) 0 (0%) 1 (2.1%) 0 (0%) 4 (8.5%) 15 (31.9%)
29 (25.2%) 20 (17.3%) 2 (1.7%) 7 (6.1%) 15 (13.0%) 1 (0.8%) 1 (0.8%) 3 (2.6%) 5 (4.3%) 1 (0.8%) 4 (3.4%) 44 (38.3%)
0.021 0.204 0.272 0.155 0.095 0.380 0.528 0.479 0.744 0.380 0.200 0.339
TLE refers to temporal lobe epilepsy; PD, personality disorder. Chi-square test (significant p-values are shown in bold).
seizures, mean IQ, and presence of associated factors for epilepsy were similar in groups of patients with Axis I psychiatric abnormalities and without these comorbidities. In this cohort, a positive family history of psychiatric disorders, EZ located in the mesial temporal lobe, and presence of Axis II disorders were associated with Axis I psychiatric comorbidities in univariate analysis. In Table 4, we present the results of binary logistic regression showing independent associated factors for the presence of Axis I psychiatric comorbidities. In this model, we included all variables with p b 0.30. Although HS was highly correlated with the presence of Axis I psychiatric disorders, this variable was not included in the model because it was completely correlated with the mesial temporal EZ, leading to multicollinearity in the logistic regression model. The analysis showed that positive family history of
Table 3 Factors associated with psychiatric Axis I comorbidities in focal refractory epilepsy. Variables
Axis I absent 336 (68.6%)
Axis I present 154 (31.4%)
Mean age seizure 11.9 (8.1) 13.0 (9.8) onset (SD) Epilepsy duration, 23.9 (11.4) 25.7 (11.5) mean (SD) Female, n (%) 161 (47.92%) 84 (54.55%) Psychiatric familial 28 (8.3%) 25 (16.2%) history, n (%) Seizure frequency/month, 11.90(14.97) 11.48 (12.70) mean (SD) Number of SGS/year, 10.5 (18.3) 10.8 (19.2) mean (SD) Presence of SGS 266 (79.2%) 114 (74.0%) Mean IQ (SD) 84.2 (8.8) 83.5 (8.2) Axis II diagnosis, n (%) 20 (5.95%) 24 (15.59%) Risk factors for 158 (47.02%) 70 (45.45%) epilepsy, n (%) Mesial temporal 212 (63.09%) 116 (75.32%) location, n (%) Etiology, n (%) HS 212 (63.09%) 116 (75.32%) Tumor 20 (5.95%) 06 (3.89%) Gliosis 30 (8.93%) 14 (9.09%) Cortical dysplasia 30 (8.93%) 10 (6.5%) Side of MRI lesion, n (%) Left 153 (45.53%) 82 (53.24%) Right 151 (44.94%) 61 (39.62%) Bilateral 29 (8.63%) 11 (7.14%) Normal 3 (0.90%) 0 (0%)
3.2. Prevalence of psychiatric comorbidities Psychiatric disorders were diagnosed in 198 of 490 patients (40.4%). In Table 2, psychiatric comorbidities are presented according to the localization of the EZ. An Axis I diagnosis was observed in 35.4% of MTLE patients, 19.1% of NeoTLE patients, and 25.2% of ExTLE patients. Although Axis I disorders were more frequently observed in patients with MTLE than in the other groups (p = 0.02), no specific Axis I psychiatric disorder was more prevalent in MTLE in our series. Axis II disorders were observed in 7% of MTLE patients, 12.8% of NeoTLE, and 13.0% of ExTLE patients (for details, see Table 2). When patients with neocortical epilepsy (NeoTLE and ExTLE) were pooled together in a post hoc analysis, an Axis II diagnosis was more prevalent in patients with neocortical epilepsy (NeoTLE plus ExTLE) than in those with MTLE (13% versus 7%; p = 0.045; OR = 2.00; 95% CI = 1.06 to 3.70). Personality disorders specifically related to epilepsy were observed in 19 patients. 3.3. Factors associated with Axis I psychiatric comorbidities #
Table 3 shows clinical and neuroimaging variables according to the presence or absence of Axis I psychiatric disorders. Age at epilepsy onset, gender, frequency of secondarily generalized tonic-clonic
Variables
†
‡
Odds ratio (95% CI)
p-Value
–
0.216#
–
0.110#
1.3 (0.9 to 1.9) 0.200† 0.5 (0.2 to 0.8) 0.009† –
0.651‡
–
0.557‡
0.7 (0.5 to 1.2) – 0.3 (0.2 to 0.6) 1.0 (0.7 to 1.5)
0.205† 0.497‡ 0.001† 0.770†
0.6 (0.3 to 0.8) 0.007†
– – – –
0.370†
– – – –
0.300†
= independent sample t-test; = chi-square test; = Mann–Whitney test; (significant p-values are shown in bold). IQ refers to intelligence quotient; HS, hippocampal sclerosis, SGS, secondary generalized seizures.
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Table 4 Binary logistic regression for factors associated with Axis I psychiatric comorbidities in focal refractory epilepsy. Variables
Crude odds ratio p-Value (95%CI)
Positive psychiatric 2.1 (1.2 to 3.8) familial history Temporal mesial EZ 1.7 (1.1 to 2.5) Presence of an Axis II 2.9 (1.6 to 5.5) diagnosis
0.012
Adjusted odds ratio p-Value (95% CI) 1.98 (1.10 to 3.58)
0.007 1.94 (1.25 to 3.03) b0.0001 3.25 (1.70 to 6.22)
0.023 0.003 b0.0001
EZ refers to epileptogenic zone (significant p-values are shown in bold).
psychiatric comorbidities (O.R.= 1.98; 95% CI = 1.10 to 3.58; p = 0.023), presence of Axis II psychiatric comorbidities (O.R.= 3.25; 95% CI= 1.70 to 6.22; p b 0.0001), and EZ located in mesial temporal lobe structures (O.R.= 1.94; 95% CI = 1.25 to 3.03; p = 0.003) were all independent factors associated with Axis I psychiatric disorders in this cohort of patients with refractory focal epilepsies. These 3 variables were forced as factors in a multinomial logistic regression model with Axis I psychiatric comorbidities used as independent variables. By doing this procedure, we could control statistically what variables were independently associated with each one of the major Axis I specific psychiatric comorbidities. Results are presented in Table 5. Positive psychiatric family history, mesial temporal EZ and the presence of Axis II psychiatric comorbidity emerged as factors independently and significantly associated with mood disorders in refractory focal epilepsy. The presence of Axis II comorbidity was also independently associated with the presence of anxiety or psychosis comorbidity. Finally, temporal mesial EZ was also a factor independently associated with psychosis in refractory focal epilepsy. 4. Discussion In this study, we analyzed the prevalence of psychiatric comorbidities in a cohort of 490 patients with refractory focal epilepsy. We observed an overall prevalence of psychiatric comorbidity in 40.4% of all patients (in 42.4% of patients with mesial temporal lobe epilepsy, in 31.9% of patients with neocortical temporal lobe epilepsy, and in 38.3% of patients with extra-temporal lobe epilepsy), confirming the high rate encountered in previous studies [1,6,11–17,23]. Overall, Axis I psychiatric disorders were diagnosed in 31.4% of patients
Table 5 Multinomial logistic regression for individual factors associated with Axis I psychiatric comorbidities in focal refractory epilepsy. Variables Mood disorders Positive psychiatric familial history Temporal mesial EZ Presence of an Axis II diagnosis Anxiety disorders Positive psychiatric familial history Temporal mesial EZ Presence of an Axis II diagnosis Psychotic disorders Positive psychiatric familial history Temporal mesial EZ Presence of an Axis II diagnosis
Crude odds ratio (95%CI)
p-Value
Adjusted odds ratio (95% CI)
2.45 (1.31–4.54)
0.004
2.45 (1.28–4.71)
0.007
0.68 (0.41–1.13) 0.60 (0.30–1.22)
0.14 0.15
1.69 (1.00–2.85) 2.48 (1.14–5.40)
0.049 0.022
0.72 (0.20–2.52)
0.60
1.60 (0.43–5.93)
0.481
0.62 (0.22–1.73) 4.54 (1.66–12.3)
0.36 0.001
2.34 (0.81–6.82) 7.37 (2.50–21.7)
0.117 b0.0001
1.07 (0.36–3.13)
0.91
1.15 (0.38–3.50)
0.809
0.50 (0.22–1.11) 0.51 (0.20–1.28)
0.08 0.14
2.52 (1.11–5.75) 3.43 (1.26–9.38)
0.028 0.016
EZ refers to epileptogenic zone (significant p-values are shown in bold).
p-Value
and were more frequent in those with EZ localized in the limbic structures of the temporal lobe. Axis II psychiatric comorbidities were less frequent; observed in 9.0% of the patients. In contrast to Axis I disorders, Axis II psychiatric comorbidities were more prevalent in patients with EZ localized in neocortical structures (NeoTLE plus ExTLE) than in patients with limbic epilepsy. We also found that positive family history of psychiatric comorbidities, the presence of Axis II psychiatric comorbidities, and EZ in mesial temporal lobe structures were ndependent factors associated with Axis I psychiatric comorbidities in our group of patients with refractory focal epilepsies. The higher prevalence of Axis I disorders in MTLE in our series results from a combination of patients with mood and psychotic disorders. This association is in line with evidence suggesting that limbic structures play a critical role in the etiopathology of mood disorders and psychosis. In fact, some authors have suggested the existence of a bidirectional relationship between epilepsy and psychiatric disorders, especially with mood disorders [17,24,25]. These authors do not suggest that depression causes epilepsy or vice versa but rather suggest they share common pathophysiological mechanisms that facilitate the development of both disorders [17,24,25]. We found an unexpected low prevalence of anxiety disorders in our patients (4.3%) in contrast to previous studies that observed a high prevalence of anxiety disorders associated with epilepsy [3,6,13,15,23]. One possible explanation for this low prevalence of anxiety disorders in our series might be the frequent use of high doses of benzodiazepines (e.g., clobazam and clonazepam) as adjunctive therapy for seizure control. Although our study was not designed to assess this possibility, we observed that benzodiazepines were chronically used by 92.8% of our patients, suggesting that further studies are necessary to address it. Nevertheless, if this possibility holds true, the adjunctive use of benzodiazepines for seizure control might have an additional beneficial effect in terms of reducing anxiety levels in patients with refractory epilepsies. An important point that deserves further discussion is the observation of a higher prevalence of Axis II personality disorders in patients with neocortical epilepsies (NeoTLE plus ExTLE) when compared to MTLE. Historically, personality disorders have been associated with temporal lobe epilepsy, and especially with limbic system abnormalities [26]. The higher prevalence of Axis II disorders in patients with extra-mesial epilepsies was, therefore, somehow unexpected. It is well-known that patients with frontal lobe lesions tend to exhibit abnormal impulsivity, socially inappropriate behaviors, and executive dysfunction, features also frequently found in patients with Axis II diagnosis. Moreover, a possible involvement of prefrontal and cingulate areas in Axis II psychopathologies has also been described, at least for borderline personality disorder [27,28]. Thus, in our view, extratemporal limbic involvement and/or other frontal lobe dysfunctions might well explain our findings, and these possibilities deserve further studies. Associated factors for psychiatric comorbidities in patients with epilepsy are still controversial, varying according to the population analyzed, to the methodologies utilized for the categorization of the distinct groups with epilepsy, and to the tools used for the evaluation and classification of the psychiatric comorbidities. Some studies have described an association between EZ in the temporal lobe and psychiatric comorbidities [11,13,15,23,29–31]. However, other authors have failed to find such associations [8,32–34]. Mood disorders and depression are the most common psychiatric comorbidities observed in association with epilepsy and are also the most studied [9,35–38]. When depression is considered alone, female gender, specific neurological conditions associated with epilepsy, sinistrality, family history of psychiatric illness, structural changes in the medial temporal lobe, learning disabilities or low IQ, and seizure type were all considered to be risk factors for depression in patients with epilepsy according to several authors [11,13,15,23,29,35,39–42]. However, few studies
C.L. Dalmagro et al. / Epilepsy & Behavior 25 (2012) 593–597
have been carried out using modern statistical tools that are able to identify isolated risk factors or associated factors. In this large series of patients with refractory focal epilepsies with a well-defined EZ and using modern statistical methods that controlled for confounding factors, we observed that mesial temporal lobe EZ (MTLE-HS), family history of psychiatric disorders, and the presence of Axis II psychiatric comorbidities were all independent factors associated with Axis I psychiatric comorbidities, mainly mood or psychosis disorders. On the other hand, gender, presence or frequency of secondarily generalized seizures, mean IQ, neuropathological category, and side of brain lesion were not found to be associated with psychiatric comorbidities. More specifically, we observed that positive psychiatric family history, EZ in mesial temporal structures and the presence of an Axis II psychiatric comorbidity were independently and significantly associated with mood disorders in refractory focal epilepsy. Anxiety or psychosis comorbidity was also associated with the presence of Axis II comorbidity, and temporal mesial EZ was also independently associated with psychosis in refractory focal epilepsy. We recognize that our study has limitations. We were not able to establish risk factors for psychiatric comorbidities in epilepsy due to the cross-sectional design of the study. Also, in spite of the comprehensive investigation, we included patients who were not seizure free and some patients still waiting for surgery. Thus, in spite of very good accuracy of our study for most patients, the delimitation of the EZ might not be one hundred percent accurate for some patients. However, our study has strengths that need to be recognized as well. We studied a large group of patients with diverse forms of focal epilepsy using detailed, accurate and homogeneous investigations. Also, we used modern statistical analysis to establish the independence of the associations encountered. Thus, in spite of possible limitations, we believe that our study adds relevant information regarding psychiatric comorbidities in focal refractory epilepsy. Taken together, our results support the concept that a combination of selected clinical variables associated with the presence of specific structural abnormalities of the central nervous system contributes to the development of Axis I psychiatric comorbidities in patients with refractory focal epilepsies. More studies specifically designed to assess a cause–effect relationship between these variables are needed for a better understanding of how these factors merge together leading to psychiatric comorbidity in patients with focal epilepsy. Acknowledgments This study was fully supported by grants from the Brazilian Government agencies. The authors receive financial support from FAPESP/CINAPCE, Project #04/14004-9. Dr. Hallak, Dr. Velasco, and Dr. Araujo were also supported by CNPq. Dr. Bianchin is supported by CNPq (#306644/2010-0 and #483108/2010-3) and FAPERGS/PRONEM. References [1] Kanner AM. The complex epilepsy patient: intricacies of assessment and treatment. Epilepsia 2003;44(Suppl. 5):S3-8. [2] Devinsky O. Psychiatric comorbidity in patients with epilepsy: implications for diagnosis and treatment. Epilepsy Behav 2003;4(Suppl. 4):S2–S10. [3] Johnson EK, Jones JE, Seidenberg M, Hermann BP. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia 2004;45:544-50. [4] Brodie MJ. Diagnosing and predicting refractory epilepsy. Acta Neurol Scand Suppl 2005;181:36-9. [5] Wiebe S, Hesdorffer DC. Epilepsy: being ill in more ways than one. Epilepsy Curr 2007;7:145-8. [6] Tellez-Zenteno JF, Patten SB, Jette N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007;48:2336-44. [7] Hermann B, Seidenberg M, Jones J. The neurobehavioural comorbidities of epilepsy: can a natural history be developed? Lancet Neurol 2008;7:151-60.
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