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Validation of the Generalized Anxiety Disorder-7 (GAD-7) among Chinese people with epilepsy
Epilepsy Research 120 (2016) 31–36
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Validation of the Generalized Anxiety Disorder-7 (GAD-7) among Chinese people with epilepsy Xin Tong a,1 , Dongmei An a,∗,1 , Aileen McGonigal b , Sung-Pa Park c , Dong Zhou a a
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China Aix Marseille Université, Inserm, INS UMR S 1106, CHU Timone, Service de Neurophysiologie Clinique, Assistance Publique des Hôpitaux de Marseille, Marseille 13005, France c Department of Neurology, School of Medicine, Kyungpook National University, Daegu, South Korea b
a r t i c l e
i n f o
Article history: Received 24 August 2015 Received in revised form 25 October 2015 Accepted 24 November 2015 Available online 28 November 2015 Keywords: Validation GAD-7 Epilepsy Anxiety Screening China
a b s t r a c t Objective: To validate the Chinese version of the Generalized Anxiety Disorder-7 (GAD-7) in Chinese people with epilepsy (PWE). Methods: A consecutive cohort of PWE from the West China Hospital was recruited. Each patient received a psychiatric evaluation comprising the Mini International Neuropsychiatric Interview (MINI) and the GAD-7. Demographic and clinical characteristics were collected. Cronbach’s ˛ coefficient was calculated and receiver operating curve (ROC) analysis was conducted. Results: A total of 213 PWE completed the psychiatric evaluation. The GAD-7 was easily understood and quickly completed by all participants. Fifty patients (23.5%) had GAD according to the MINI criteria. Cronbach’s ˛ coefficient for the GAD-7 was 0.888. ROC analysis showed an area under the curve of 0.974 (95% CI = 0.956–0.993). At a cut-off score of >6, the GAD-7 achieved the largest Youden index of 0.854 with a sensitivity of 94%, a specificity of 91.4%, a positive predictive value of 77% and a negative predictive value of 98%. Significance: The Chinese version of the GAD-7 is a valuable tool for screening for GAD in Chinese PWE. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Many epidemiological studies have found the prevalence of depression and anxiety to be higher in people with epilepsy (PWE) than in those without epilepsy (Kwon and Park, 2014). Comorbid anxiety in PWE has been highlighted because of its negative impact on quality of life (QOL), which has been shown to be equal to that of depression (Johnson et al., 2004; Kanner et al., 2010; Kwon and Park, 2013). The prevalence of anxiety in adult PWE ranges from 11% to 50%, depending on the population investigated and the anxiety measure instrument used (Munger Clary, 2014). Comorbid anxiety is associated with more side effects of antiepileptic drugs (AEDs) (Kanner et al., 2012), greater cognitive difficulties (Velissaris et al., 2009), poorer seizure outcome (Kanner et al., 2009; Petrovski et al., 2010), higher risk of suicide (Gandy et al., 2013), increased rate of hospital admission and heavier economic burden (Hamilton et al., 2014; Noble et al., 2012). Indeed anxiety was found to be
∗ Corresponding author. Tel.: +86 2885422549; fax: +86 2885422549. E-mail address: [email protected] (D. An). 1 These two authors contribute equally to this work. http://dx.doi.org/10.1016/j.eplepsyres.2015.11.019 0920-1211/© 2015 Elsevier B.V. All rights reserved.
the most important predictor of QOL in some studies (Huang et al., 2011; Kwan et al., 2009). Furthermore, comorbid occurrence of mixed depressive/anxiety disorders yielded an even greater negative impact on QOL than did anxiety disorders alone (Kanner et al., 2010; Kwon and Park, 2013). Early detection and appropriate management of depression and anxiety in PWE is crucial for achieving better QOL. From this perspective, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) (Gilliam et al., 2006) including its Chinese version (C-NDDI-E) (Tong et al., 2015) have been developed and proven to be valid screening tools for detecting major depressive disorder (MDD) in PWE. The Generalized Anxiety Disorder-7 (GAD-7) has been used as a screening tool for generalized anxiety disorder (GAD) in primary care patients (Kroenke et al., 2007; Spitzer et al., 2006). A score of >9 is considered indicative of likely presence of GAD. It was also suggested as a suitable screening tool for PWE, because it did not have items with somatic symptoms that could be confused with adverse effects of antiepileptic drugs (AEDs), or cognitive symptoms of the seizure disorder or underlying neurologic disorder associated with the epilepsy (Kanner, 2011). Recently, validation of the GAD-7 in PWE was performed in Korea (Seo et al., 2014). It was found that a score of >6 represented GAD in Korean
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PWE, this cut-off score being much lower than that found in studies of primary care patients. The authors explained the gap between the scores as possibly reflecting different composition of the groups of subjects (for example the proportion of men and women being different in the two studies); or ethnic and language differences between the different populations studied. For those reasons, they recommended that further validation studies for GAD-7 should be performed with respect to different disease categories and native languages. The GAD-7 has been translated into Chinese and validated in general hospital outpatients, with a cut-off score of >9 (He et al., 2010). However, we cannot presume that this cut-off score is likely to be same in Chinese PWE. The aim of the study is to validate the GAD-7 in Chinese PWE.
2.3. Statistical analysis Statistical analysis was performed with SPSS Version 19.0 (SPSS Inc., Chicago, IL, USA). Categorical demographic and clinical variables were analyzed by Chi-square test or Fisher’s exact test, and continuous variables were analyzed by Mann–Whitney U test. A significance level was set at p < 0.05 (two-tailed). Internal consistency was analyzed by Cronbach’s ˛ coefficient. Receiver operating curves (ROC) analysis was carried out to measure sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) for a range of cut-off scores of the GAD-7, with respect to the diagnoses of GAD by the MINI. The ideal cut-off score was settled by the largest Youden index. 3. Results
2. Method 2.1. Participants Participants were consecutively recruited from the epilepsy outpatient clinic of West China Hospital from March to May 2015. To be enrolled, they had to be ≥18 years old and currently diagnosed with epilepsy according to the International League Against Epilepsy (ILAE) criteria (Fisher et al., 2014). Second, they should be Chinese citizens and had to have received at least primary education so that they could properly understand the questionnaire and interview. Patients with psychogenic non-epileptic seizures or other significant neurological/psychiatric disorders, such as cognitive deficits, aphasia or schizophrenia, which might hamper appropriate understanding and completion of the questionnaire, were excluded. All patients gave written informed consent to state their willingness to participate. The study protocol and informed consent were approved by the ethics committee of West China Hospital, Sichuan University.
2.2. Psychiatric evaluation and the instruments used Each patient underwent psychiatric evaluation conducted by a qualified psychiatrist using the following instruments:
2.2.1. Mini International Neuropsychiatric Interview (MINI) The MINI is an internationally validated structured interview tested to be simple, effective and reliable. It is mainly used for screening and diagnosis of 16 axis I psychiatric disorders and one personality disorder in DSM-IV and ICD-10 (Sheehan et al., 1998). Only the module for GAD of the MINI (Chinese version 5.0.0) was administered. In the current study it was the gold standard for diagnosis of current GAD.
2.2.2. Chinese version of the Generalized Anxiety Disorder-7 (GAD-7) Spitzer et al. (2006) published the GAD-7 and proved it to be a valid and efficient tool for screening for GAD and assessing its severity. It was a seven-item self-rating instrument. Each item described one of the typical symptoms of GAD and was evaluated by the frequency in which that symptom emerged over the last two weeks: “Not at all” scored zero, “Several days” scored one, “More than half the days” scored two, and “Nearly every day” scored three. In 2010, the GAD-7 was translated into a Chinese version and validated in general hospital outpatients (He et al., 2010). In this study population the Chinese version, as the original GAD-7 study, adopts >9 as the cut-off score.
Two hundred and thirteen PWE completed the psychiatric evaluation and 50 (23.5%) had current GAD according to the MINI. The GAD-7 was fairly easy to understand and complete for the patients. No major difficulties were reported in the process of answering the questionnaire and no items of the scale were left blank. 3.1. Demographic and clinical characteristics The mean age was 29.86 ± 11.9 years old. There were 109 (51.2%) males and 104 (48.8%) females. In those 50 patients diagnosed as having GAD, gender was equally distributed. Two thirds of them lived in urban areas; 102 (47.9%) were married and 98 were single including the one widowed and two divorced patients who were classified as “unmarried”. There was no statistical difference in education level and employment status between the groups with and without GAD. There were more patients with complex partial seizures diagnosed with GAD (p = 0.046), while for other seizure types no such difference was found. Patients with idiopathic epilepsy had less GAD (p = 0.013). For the GAD group, their seizures occurred more frequently (p = 0.001) and more recently (p = 0.013), and they were also more likely to be taking multiple AEDs (p = 0.042). However, no particular kind of AED was found to be associated with higher anxiety levels. The age at seizure onset and course of disease did not differ between patients with and without GAD. For details see Table 1. 3.2. Patients’ response to the GAD-7 and Cronbach’s alpha coefficient The mean GAD-7 score was 4.86 for all the participants. The patients with GAD scored 11.46 in average, far higher than 2.83 scored by those without GAD (p < 0.001). For patients who were seizure free in the last six months (n = 61), their mean GAD-7 score was 3.75 (±3.8, range 0–15), lower than patients with uncontrolled seizures (n = 152) scored (5.30 ± 5.1, range 0–21) (p = 0.035). While the seven items responded in different frequencies as Table 2 demonstrates, the GAD-7 had a Cronbach’s ˛ coefficient of 0.888 and this coefficient would decrease if any item were deleted. Such details were displayed in Table 3 with corrected item–total correlations for each item. 3.3. ROC curve analysis As Table 4 and Fig. 1 showed, ROC analysis showed an area under the curve (AUC) of 0.974 (95%CI = 0.956–0.993). A cut-off score of >6, maximizing the Youden Index, yielded a sensitivity of 94%, a specificity of 91.4%, a PPV of 77% and a NPV of 98%.
X. Tong et al. / Epilepsy Research 120 (2016) 31–36
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Table 1 Demographic and clinical characteristics of the participants. Mean ± SD (range) or number (%) Total (n = 213)
Group with GAD (n = 50)
Group without GAD (n = 163)
109 (51.2) 104 (48.8)
25 (50.0) 25 (50.0)
84 (51.5) 79 (48.5)
30.90 ± 12.4 (18–69)
29.54 ± 11.8 (18–81)
p Value 0.849a
Sex Male Female
29.86 ± 11.9 (18–81)
Age (years)
0.594c 0.161a
Domicile Urban area Rural area
145 (68.1) 68 (31.9)
30 (60.0) 20 (40.0)
115 (70.6) 48 (29.4)
Marital status Unmarried Married
111 (52.1) 102 (47.9)
25 (50.0) 25 (50.0)
86 (52.8) 77 (47.2)
0.732a
Educated time (years)
12.42 ± 3.1 (4–19)
12.20 ± 3.3 (6–17)
12.48 ± 3.0 (4–19)
Employment status Unemployed Full-time student Employed temporarily Employed permanently Self-employed Retired
68 (31.9) 33 (15.5) 14 (6.6) 70 (32.9) 19 (8.9) 9 (4.2)
21 (42.0) 8 (16.0) 5 (10.0) 11 (22.0) 2 (4.0) 3 (6.0)
47 (28.8) 25 (15.3) 9 (5.5) 59 (36.2) 17 (10.4) 6 (3.7)
14 (6.6) 81 (38.0) 103 (48.4) 55 (25.8) 8 (3.8)
5 (3.3) 25 (50.0) 26 (52.0) 9 (18.0) 1 (1.9)
9 (5.5) 56 (34.4) 77 (47.2) 46 (28.2) 7 (4.3)
0.325b 0.046a 0.556a 0.149a 0.684b
Etiology Idiopathic Symptomatic Cryptogenic
69 (32.4) 54 (25.4) 90 (42.3)
9 (16.2) 16 (32.0) 25 (50.0)
60 (36.8) 38 (23.3) 65 (39.9)
0.013a 0.217a 0.205a
Onset age (years)
21.03 ± 12.8 (0.5–79)
20.41 ± 12.9 (0.5–67)
21.22 ± 12.8 (0.5–79)
0.411c
Years since onset of seizures
8.74 ± 8.2 (0.02–48)
10.32 ± 8.5 (0.34–32)
8.26 ± 8.1 (0.02–48)
0.099c
Seizure frequency (per month)
4.17 ± 12.8 (0–110)
8.77 ± 21.5 (0–110)
2.75 ± 8.1 (0–70)
0.001c
Time since last seizure (months)
6.94 ± 12.8 (0–72)
6.04 ± 13.4 (0–60)
7.22 ± 12.7 (0–72)
0.013c
0.646c 0.164a
Seizure type Simple partial Complex partial Partial with secondary General Unclassified
Seizure free for the last 6 months
61 (28.6)
9 (18.0)
52 (31.9)
24 (11.3) 103 (48.4) 67 (31.5) 19 (8.9)
2 (4.0) 20 (40.0) 21 (42.0) 7 (14.0)
22 (13.5) 83 (50.9) 46 (28.2) 12 (7.4)
0.057a 0.042a
AED therapy regimen None Mono-therapy Dual-therapy Poly-therapy (≥3 AEDs)
4.86 ± 4.8 (0–21)
Score of the GAD-7
11.46 ± 4.7 (4–21)
2.83 ± 2.4 (0–10)
<0.001c
Bold data show statistical significance <0.05. a Chi-square test. b Fisher’s exact test. c Mann–Whitney U test.
Table 2 Distribution of answers to the GAD-7 items and their respective mean scores. Items
Not At all
Several Days
More than Half the days
Nearly Every day
Mean Scores
Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7
83 (39.0%) 127 (59.6%) 90 (42.3%) 126 (59.2%) 153 (71.8%) 84 (39.4%) 138 (64.8%)
90 (42.3%) 55 (25.8%) 74 (34.7%) 60 (28.2%) 39 (18.3%) 92 (43.2) 53 (24.9%)
24 (11.3%) 12 (5.6%) 25 (11.7%) 14 (6.6%) 9 (4.2%) 22 (10.3%) 10 (4.7%)
16 (7.5%) 19 (8.9%) 24 (11.3%) 13 (6.1%) 12 (5.6%) 15 (7.0%) 12 (5.6%)
0.87 0.64 0.92 0.60 0.44 0.85 0.51
Data were expressed as number (%) or mean ± SD. GAD-7: Generalized Anxiety Disorder-7.
± ± ± ± ± ± ±
0.89 0.96 0.99 0.86 0.82 0.87 0.83
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Table 3 Corrected item—total correlations and Cronbach’s ˛ if an item was deleted from the GAD-7. Items
Corrected item–total correlation
Cronbach’s ˛ without this item
Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7
0.777 0.809 0.804 0.827 0.740 0.753 0.670
0.871 0.866 0.868 0.862 0.876 0.874 0.886
proportional to the disease that they have to cope with, instead of “too much”. Specifically for epilepsy, some side effects of AEDs cause overlapping symptoms with those of GAD, such as irritability, anxiety and panic (Beyenburg et al., 2005; Gomez-Arias et al., 2012), and some of the patients experiencing such feelings might have prepared themselves mentally as they started taking medication, with less tendency to report these as active symptoms. Additionally, PWE often hold negative feelings toward the disease or themselves, and more than half of them perceived stigma (Baker et al., 2000), which might lead to them disclosing their feelings less when answering the questionnaire. In any case, the high sensitivity and specificity when adopting the cut-off score of >6 in the present study proved its validity as a screening tool for GAD in PWE. Fifty of the 213 patients (23.5%) were diagnosed with GAD in the current study. This rate was close to the GAD prevalence of 21.0% in Korea PWE (Seo et al., 2014). On the other hand, European hospital-based studies reported lower prevalence of GAD in PWE, ranged from 3.1% to 12.0% (Brandt et al., 2010; Mula et al., 2008). Ethnic or cultural differences might be an important explanation. Different populations investigated and different measurements of GAD used could affect the result too, considering the study revealed a prevalence of 3.1% used the Structured Clinical Interview for DSMIV Axis I disorders (SCID-I) as the gold standard of GAD (Brandt et al., 2010), while the others used the MINI (Mula et al., 2008; Seo et al., 2014). However, since the frequency of GAD in Chinese primary care patients was 4.1% (Ying et al., 2010), GAD was far more prevalent in Chinese PWE. There were equal numbers of male and female PWE with GAD in the current study, which is different from some studies showing that GAD was more prevalent in females (Kimiskidis and Valeta, 2012; Mensah et al., 2007). Patients with complex partial seizures were more likely to develop GAD, which has previously been demonstrated (de Oliveira et al., 2010; Kimiskidis and Valeta, 2012). The relevance of complex partial seizures may be related to the negative effect of altered consciousness on quality of life (Blumenfeld, 2012). However we were not able to demonstrate an association with any specific sublobar epilepsy localization. It was also observed in our study that patients who had more frequent and/or more recent seizures were more anxious. And patients who were seizure free for the last six months were less likely to be diagnosed with GAD and scored lower in GAD-7 as well. Some previous studies also found such associations, and explained them from different perspectives (Gandy et al., 2012; Kwon and Park, 2014), although the causality relationship was not so clear. The present study found idiopathic epilepsy to have the lowest risk of associated GAD. Idiopathic epilepsy is usually considered to have a favorable prognosis with little intellectual or behavioral impairment (Cutting et al., 2001) and that might be one of the reasons why such patients were less anxious. However several works have reported a variably increased incidence of psychiatric symptoms in this category (Akanuma et al., 2008; Cutting et al., 2001). Last but not least, use of multiple AEDs, being indicative of a refractory process when seizures were usually poorly controlled, was more highly associated with GAD; of course use of more AEDs may also produce more side effects, which also contributes to anxiety (Gomez-Arias et al., 2012).
GAD-7: Generalized Anxiety Disorder-7.
Fig. 1. ROC curve of the GAD-7, with the MINI-defined current GAD. ROC: receiver operating characteristic; GAD-7: Generalized Anxiety Disorder-7; MINI: Mini International Neuropsychiatric Interview; GAD: generalized anxiety disorder.
4. Discussion The GAD-7 was readily understood and quickly completed by the patients. This scale showed good internal consistency with a Cronbach’s ˛ coefficient of 0.888, which is close to the Cronbach’s ˛ of 0.898 when this version was applied in general hospital outpatients of China (He et al., 2010), and comparable to other versions of the GAD-7 (Seo et al., 2014; Sousa et al., 2015; Spitzer et al., 2006). At the optimal cut-off score of >6, the same as that of the Korean version (Seo et al., 2014), the GAD-7 had a sensitivity of 94% and a specificity of 91.4% when applied in Chinese PWE. This cut-off score was lower than the value of >9 adopted in primary care patients or general populations (He et al., 2010; Löwe et al., 2008; Spitzer et al., 2006). However, it has been previously observed that for people with some specific medical conditions lower cut-off scores may be more appropriate, such as an optimal cut-off score of >8 in drug and alcohol users (Delgadillo et al., 2012), and >6 in pregnant women (Zhong et al., 2015); this appears likewise to be the case for epilepsy. We might presume that with certain medical conditions, people tend to view their worry or fear as being reasonable and Table 4 ROC and diagnostic efficiency of the GAD-7 for the diagnosis of current GAD. Cut-off scores
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
YI
>5 >6 >7 >8
98.0 94.0 86.0 60.0
84.0 91.4 95.1 98.8
65.3 77.0 84.3 93.8
99.3 98.0 95.7 88.0
0.820 0.854 0.811 0.588
AUC
95%CI
SE
p Value
0.974
0.956–0.993
0.009
<0.001
GAD-7: Generalized Anxiety Disorder-7; GAD: generalized anxiety disorder; ROC: receiver operating characteristic; PPV: positive predictive value; NPV: negative predictive value; YI: Youden index; AUC: area under the curve; 95%CI: 95% confidence interval; SE: standard error.
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There are several limitations to our study. First, although it has been reported that the GAD-7 could be used for detecting other anxiety disorders such as panic disorder and social phobia (Kroenke et al., 2007), it should be remembered that this scale was specifically designed to screen for GAD. It might not perform so well in detecting other anxiety disorders, which was a limitation of our study. Second, the GAD-7 provides only probable diagnoses that should be investigated by further evaluation. Third, a cut-off score of >6 in the Chinese version had a PPV of 77%, which may lead to false positive results. As we know, the GAD-7 asks about symptoms during the preceding two weeks. On the other hand, GAD assessed by the MINI takes into account symptoms over the past six months. The difference of the observation period between two tools may help to explain the low PPV of the GAD-7 for suggesting GAD. However, as GAD-7 was a screening tool, higher score indicated further evaluation rather than definite GAD diagnosis, we considered this PPV acceptable. And therefore using GAD-7 as a diagnosis tool might be inappropriate. Fourth, China is a big country with many different ethic populations and dialects, and there are many overseas Chinese as well. Thus not all Chinese people speak standard Chinese, known as Mandarin. Nevertheless, since many dialects don’t have written forms, the written language for majority of Chinese people is the same. And the government has greatly promoted application of Mandarin through education and official use. Therefore as long as a person had received primary education in Chinese mainland, he/she must have the ability to read standard Chinese more or less. Since this version is fairly simple and compulsory education has been popularized, we believe the GAD-7 would be easily understood for most Chinese people in mainland China. Although there already were Malaysia Chinese, Taiwanese Chinese and Hong Kong Chinese versions of GAD-7(He et al., 2010), those versions have not been tested in PWE. For PWE from such places, results from this version may not be applied and should be interpreted with caution. In conclusion, we proved the GAD-7 to be a reliable and valid screening tool for use in PWE. We recommend >6 as the optimal cut-off score when applying the GAD-7 in Chinese PWE. Wider usage of this scale could bring earlier detection of comorbid anxiety in PWE, promote appropriate intervention and ultimately achieve better outcome. 5. Disclosure 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 Akanuma, N., Hara, E., Adachi, N., Hara, K., Koutroumanidis, M., 2008. Psychiatric comorbidity in adult patients with idiopathic generalized epilepsy. Epilepsy Behav.: E&B 13, 248–251. Baker, G.A., Brooks, J., Buck, D., Jacoby, A., 2000. The stigma of epilepsy: a European perspective. Epilepsia 41, 98–104. Beyenburg, S., Mitchell, A.J., Schmidt, D., Elger, C.E., Reuber, M., 2005. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav.: E&B 7, 161–171. Blumenfeld, H., 2012. Impaired consciousness in epilepsy. Lancet Neurol. 11, 814–826. Brandt, C., Schoendienst, M., Trentowska, M., May, T.W., Pohlmann-Eden, B., Tuschen-Caffier, B., Schrecke, M., Fueratsch, N., Witte-Boelt, K., Ebner, A., 2010. Prevalence of anxiety disorders in patients with refractory focal epilepsy—a prospective clinic based survey. Epilepsy Behav.: E&B 17, 259–263. Cutting, S., Lauchheimer, A., Barr, W., Devinsky, O., 2001. Adult-onset idiopathic generalized epilepsy: clinical and behavioral features. Epilepsia 42, 1395–1398. de Oliveira, G.N., Kummer, A., Salgado, J.V., Portela, E.J., Sousa-Pereira, S.R., David, A.S., Teixeira, A.L., 2010. Psychiatric disorders in temporal lobe epilepsy: an overview from a tertiary service in Brazil. Seizure 19, 479–484. Delgadillo, J., Payne, S., Gilbody, S., Godfrey, C., Gore, S., Jessop, D., Dale, V., 2012. Brief case finding tools for anxiety disorders: validation of GAD-7 and GAD-2 in addictions treatment. Drug Alcohol Depend. 125, 37–42.
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Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology 75, 1015–1021. Seo, J.G., Cho, Y.W., Lee, S.J., Lee, J.J., Kim, J.E., Moon, H.J., Park, S.P., 2014. Validation of the Generalized Anxiety Disorder-7 in people with epilepsy: a MEPSY study. Epilepsy Behav.: E&B 35, 59–63. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59 (Suppl. 20), 22–33 [quiz 34–57]. Sousa, T.V., Viveiros, V., Chai, M.V., Vicente, F.L., Jesus, G., Carnot, M.J., Gordo, A.C., Ferreira, P.L., 2015. Reliability and validity of the Portuguese version of the
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Validation of the Generalized Anxiety Disorder-7 (GAD-7) among Chinese people with epilepsy Xin Tong a,1 , Dongmei An a,∗,1 , Aileen McGonigal b , Sung-Pa Park c , Dong Zhou a a
Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China Aix Marseille Université, Inserm, INS UMR S 1106, CHU Timone, Service de Neurophysiologie Clinique, Assistance Publique des Hôpitaux de Marseille, Marseille 13005, France c Department of Neurology, School of Medicine, Kyungpook National University, Daegu, South Korea b
a r t i c l e
i n f o
Article history: Received 24 August 2015 Received in revised form 25 October 2015 Accepted 24 November 2015 Available online 28 November 2015 Keywords: Validation GAD-7 Epilepsy Anxiety Screening China
a b s t r a c t Objective: To validate the Chinese version of the Generalized Anxiety Disorder-7 (GAD-7) in Chinese people with epilepsy (PWE). Methods: A consecutive cohort of PWE from the West China Hospital was recruited. Each patient received a psychiatric evaluation comprising the Mini International Neuropsychiatric Interview (MINI) and the GAD-7. Demographic and clinical characteristics were collected. Cronbach’s ˛ coefficient was calculated and receiver operating curve (ROC) analysis was conducted. Results: A total of 213 PWE completed the psychiatric evaluation. The GAD-7 was easily understood and quickly completed by all participants. Fifty patients (23.5%) had GAD according to the MINI criteria. Cronbach’s ˛ coefficient for the GAD-7 was 0.888. ROC analysis showed an area under the curve of 0.974 (95% CI = 0.956–0.993). At a cut-off score of >6, the GAD-7 achieved the largest Youden index of 0.854 with a sensitivity of 94%, a specificity of 91.4%, a positive predictive value of 77% and a negative predictive value of 98%. Significance: The Chinese version of the GAD-7 is a valuable tool for screening for GAD in Chinese PWE. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Many epidemiological studies have found the prevalence of depression and anxiety to be higher in people with epilepsy (PWE) than in those without epilepsy (Kwon and Park, 2014). Comorbid anxiety in PWE has been highlighted because of its negative impact on quality of life (QOL), which has been shown to be equal to that of depression (Johnson et al., 2004; Kanner et al., 2010; Kwon and Park, 2013). The prevalence of anxiety in adult PWE ranges from 11% to 50%, depending on the population investigated and the anxiety measure instrument used (Munger Clary, 2014). Comorbid anxiety is associated with more side effects of antiepileptic drugs (AEDs) (Kanner et al., 2012), greater cognitive difficulties (Velissaris et al., 2009), poorer seizure outcome (Kanner et al., 2009; Petrovski et al., 2010), higher risk of suicide (Gandy et al., 2013), increased rate of hospital admission and heavier economic burden (Hamilton et al., 2014; Noble et al., 2012). Indeed anxiety was found to be
∗ Corresponding author. Tel.: +86 2885422549; fax: +86 2885422549. E-mail address: [email protected] (D. An). 1 These two authors contribute equally to this work. http://dx.doi.org/10.1016/j.eplepsyres.2015.11.019 0920-1211/© 2015 Elsevier B.V. All rights reserved.
the most important predictor of QOL in some studies (Huang et al., 2011; Kwan et al., 2009). Furthermore, comorbid occurrence of mixed depressive/anxiety disorders yielded an even greater negative impact on QOL than did anxiety disorders alone (Kanner et al., 2010; Kwon and Park, 2013). Early detection and appropriate management of depression and anxiety in PWE is crucial for achieving better QOL. From this perspective, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) (Gilliam et al., 2006) including its Chinese version (C-NDDI-E) (Tong et al., 2015) have been developed and proven to be valid screening tools for detecting major depressive disorder (MDD) in PWE. The Generalized Anxiety Disorder-7 (GAD-7) has been used as a screening tool for generalized anxiety disorder (GAD) in primary care patients (Kroenke et al., 2007; Spitzer et al., 2006). A score of >9 is considered indicative of likely presence of GAD. It was also suggested as a suitable screening tool for PWE, because it did not have items with somatic symptoms that could be confused with adverse effects of antiepileptic drugs (AEDs), or cognitive symptoms of the seizure disorder or underlying neurologic disorder associated with the epilepsy (Kanner, 2011). Recently, validation of the GAD-7 in PWE was performed in Korea (Seo et al., 2014). It was found that a score of >6 represented GAD in Korean
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PWE, this cut-off score being much lower than that found in studies of primary care patients. The authors explained the gap between the scores as possibly reflecting different composition of the groups of subjects (for example the proportion of men and women being different in the two studies); or ethnic and language differences between the different populations studied. For those reasons, they recommended that further validation studies for GAD-7 should be performed with respect to different disease categories and native languages. The GAD-7 has been translated into Chinese and validated in general hospital outpatients, with a cut-off score of >9 (He et al., 2010). However, we cannot presume that this cut-off score is likely to be same in Chinese PWE. The aim of the study is to validate the GAD-7 in Chinese PWE.
2.3. Statistical analysis Statistical analysis was performed with SPSS Version 19.0 (SPSS Inc., Chicago, IL, USA). Categorical demographic and clinical variables were analyzed by Chi-square test or Fisher’s exact test, and continuous variables were analyzed by Mann–Whitney U test. A significance level was set at p < 0.05 (two-tailed). Internal consistency was analyzed by Cronbach’s ˛ coefficient. Receiver operating curves (ROC) analysis was carried out to measure sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) for a range of cut-off scores of the GAD-7, with respect to the diagnoses of GAD by the MINI. The ideal cut-off score was settled by the largest Youden index. 3. Results
2. Method 2.1. Participants Participants were consecutively recruited from the epilepsy outpatient clinic of West China Hospital from March to May 2015. To be enrolled, they had to be ≥18 years old and currently diagnosed with epilepsy according to the International League Against Epilepsy (ILAE) criteria (Fisher et al., 2014). Second, they should be Chinese citizens and had to have received at least primary education so that they could properly understand the questionnaire and interview. Patients with psychogenic non-epileptic seizures or other significant neurological/psychiatric disorders, such as cognitive deficits, aphasia or schizophrenia, which might hamper appropriate understanding and completion of the questionnaire, were excluded. All patients gave written informed consent to state their willingness to participate. The study protocol and informed consent were approved by the ethics committee of West China Hospital, Sichuan University.
2.2. Psychiatric evaluation and the instruments used Each patient underwent psychiatric evaluation conducted by a qualified psychiatrist using the following instruments:
2.2.1. Mini International Neuropsychiatric Interview (MINI) The MINI is an internationally validated structured interview tested to be simple, effective and reliable. It is mainly used for screening and diagnosis of 16 axis I psychiatric disorders and one personality disorder in DSM-IV and ICD-10 (Sheehan et al., 1998). Only the module for GAD of the MINI (Chinese version 5.0.0) was administered. In the current study it was the gold standard for diagnosis of current GAD.
2.2.2. Chinese version of the Generalized Anxiety Disorder-7 (GAD-7) Spitzer et al. (2006) published the GAD-7 and proved it to be a valid and efficient tool for screening for GAD and assessing its severity. It was a seven-item self-rating instrument. Each item described one of the typical symptoms of GAD and was evaluated by the frequency in which that symptom emerged over the last two weeks: “Not at all” scored zero, “Several days” scored one, “More than half the days” scored two, and “Nearly every day” scored three. In 2010, the GAD-7 was translated into a Chinese version and validated in general hospital outpatients (He et al., 2010). In this study population the Chinese version, as the original GAD-7 study, adopts >9 as the cut-off score.
Two hundred and thirteen PWE completed the psychiatric evaluation and 50 (23.5%) had current GAD according to the MINI. The GAD-7 was fairly easy to understand and complete for the patients. No major difficulties were reported in the process of answering the questionnaire and no items of the scale were left blank. 3.1. Demographic and clinical characteristics The mean age was 29.86 ± 11.9 years old. There were 109 (51.2%) males and 104 (48.8%) females. In those 50 patients diagnosed as having GAD, gender was equally distributed. Two thirds of them lived in urban areas; 102 (47.9%) were married and 98 were single including the one widowed and two divorced patients who were classified as “unmarried”. There was no statistical difference in education level and employment status between the groups with and without GAD. There were more patients with complex partial seizures diagnosed with GAD (p = 0.046), while for other seizure types no such difference was found. Patients with idiopathic epilepsy had less GAD (p = 0.013). For the GAD group, their seizures occurred more frequently (p = 0.001) and more recently (p = 0.013), and they were also more likely to be taking multiple AEDs (p = 0.042). However, no particular kind of AED was found to be associated with higher anxiety levels. The age at seizure onset and course of disease did not differ between patients with and without GAD. For details see Table 1. 3.2. Patients’ response to the GAD-7 and Cronbach’s alpha coefficient The mean GAD-7 score was 4.86 for all the participants. The patients with GAD scored 11.46 in average, far higher than 2.83 scored by those without GAD (p < 0.001). For patients who were seizure free in the last six months (n = 61), their mean GAD-7 score was 3.75 (±3.8, range 0–15), lower than patients with uncontrolled seizures (n = 152) scored (5.30 ± 5.1, range 0–21) (p = 0.035). While the seven items responded in different frequencies as Table 2 demonstrates, the GAD-7 had a Cronbach’s ˛ coefficient of 0.888 and this coefficient would decrease if any item were deleted. Such details were displayed in Table 3 with corrected item–total correlations for each item. 3.3. ROC curve analysis As Table 4 and Fig. 1 showed, ROC analysis showed an area under the curve (AUC) of 0.974 (95%CI = 0.956–0.993). A cut-off score of >6, maximizing the Youden Index, yielded a sensitivity of 94%, a specificity of 91.4%, a PPV of 77% and a NPV of 98%.
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Table 1 Demographic and clinical characteristics of the participants. Mean ± SD (range) or number (%) Total (n = 213)
Group with GAD (n = 50)
Group without GAD (n = 163)
109 (51.2) 104 (48.8)
25 (50.0) 25 (50.0)
84 (51.5) 79 (48.5)
30.90 ± 12.4 (18–69)
29.54 ± 11.8 (18–81)
p Value 0.849a
Sex Male Female
29.86 ± 11.9 (18–81)
Age (years)
0.594c 0.161a
Domicile Urban area Rural area
145 (68.1) 68 (31.9)
30 (60.0) 20 (40.0)
115 (70.6) 48 (29.4)
Marital status Unmarried Married
111 (52.1) 102 (47.9)
25 (50.0) 25 (50.0)
86 (52.8) 77 (47.2)
0.732a
Educated time (years)
12.42 ± 3.1 (4–19)
12.20 ± 3.3 (6–17)
12.48 ± 3.0 (4–19)
Employment status Unemployed Full-time student Employed temporarily Employed permanently Self-employed Retired
68 (31.9) 33 (15.5) 14 (6.6) 70 (32.9) 19 (8.9) 9 (4.2)
21 (42.0) 8 (16.0) 5 (10.0) 11 (22.0) 2 (4.0) 3 (6.0)
47 (28.8) 25 (15.3) 9 (5.5) 59 (36.2) 17 (10.4) 6 (3.7)
14 (6.6) 81 (38.0) 103 (48.4) 55 (25.8) 8 (3.8)
5 (3.3) 25 (50.0) 26 (52.0) 9 (18.0) 1 (1.9)
9 (5.5) 56 (34.4) 77 (47.2) 46 (28.2) 7 (4.3)
0.325b 0.046a 0.556a 0.149a 0.684b
Etiology Idiopathic Symptomatic Cryptogenic
69 (32.4) 54 (25.4) 90 (42.3)
9 (16.2) 16 (32.0) 25 (50.0)
60 (36.8) 38 (23.3) 65 (39.9)
0.013a 0.217a 0.205a
Onset age (years)
21.03 ± 12.8 (0.5–79)
20.41 ± 12.9 (0.5–67)
21.22 ± 12.8 (0.5–79)
0.411c
Years since onset of seizures
8.74 ± 8.2 (0.02–48)
10.32 ± 8.5 (0.34–32)
8.26 ± 8.1 (0.02–48)
0.099c
Seizure frequency (per month)
4.17 ± 12.8 (0–110)
8.77 ± 21.5 (0–110)
2.75 ± 8.1 (0–70)
0.001c
Time since last seizure (months)
6.94 ± 12.8 (0–72)
6.04 ± 13.4 (0–60)
7.22 ± 12.7 (0–72)
0.013c
0.646c 0.164a
Seizure type Simple partial Complex partial Partial with secondary General Unclassified
Seizure free for the last 6 months
61 (28.6)
9 (18.0)
52 (31.9)
24 (11.3) 103 (48.4) 67 (31.5) 19 (8.9)
2 (4.0) 20 (40.0) 21 (42.0) 7 (14.0)
22 (13.5) 83 (50.9) 46 (28.2) 12 (7.4)
0.057a 0.042a
AED therapy regimen None Mono-therapy Dual-therapy Poly-therapy (≥3 AEDs)
4.86 ± 4.8 (0–21)
Score of the GAD-7
11.46 ± 4.7 (4–21)
2.83 ± 2.4 (0–10)
<0.001c
Bold data show statistical significance <0.05. a Chi-square test. b Fisher’s exact test. c Mann–Whitney U test.
Table 2 Distribution of answers to the GAD-7 items and their respective mean scores. Items
Not At all
Several Days
More than Half the days
Nearly Every day
Mean Scores
Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7
83 (39.0%) 127 (59.6%) 90 (42.3%) 126 (59.2%) 153 (71.8%) 84 (39.4%) 138 (64.8%)
90 (42.3%) 55 (25.8%) 74 (34.7%) 60 (28.2%) 39 (18.3%) 92 (43.2) 53 (24.9%)
24 (11.3%) 12 (5.6%) 25 (11.7%) 14 (6.6%) 9 (4.2%) 22 (10.3%) 10 (4.7%)
16 (7.5%) 19 (8.9%) 24 (11.3%) 13 (6.1%) 12 (5.6%) 15 (7.0%) 12 (5.6%)
0.87 0.64 0.92 0.60 0.44 0.85 0.51
Data were expressed as number (%) or mean ± SD. GAD-7: Generalized Anxiety Disorder-7.
± ± ± ± ± ± ±
0.89 0.96 0.99 0.86 0.82 0.87 0.83
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Table 3 Corrected item—total correlations and Cronbach’s ˛ if an item was deleted from the GAD-7. Items
Corrected item–total correlation
Cronbach’s ˛ without this item
Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7
0.777 0.809 0.804 0.827 0.740 0.753 0.670
0.871 0.866 0.868 0.862 0.876 0.874 0.886
proportional to the disease that they have to cope with, instead of “too much”. Specifically for epilepsy, some side effects of AEDs cause overlapping symptoms with those of GAD, such as irritability, anxiety and panic (Beyenburg et al., 2005; Gomez-Arias et al., 2012), and some of the patients experiencing such feelings might have prepared themselves mentally as they started taking medication, with less tendency to report these as active symptoms. Additionally, PWE often hold negative feelings toward the disease or themselves, and more than half of them perceived stigma (Baker et al., 2000), which might lead to them disclosing their feelings less when answering the questionnaire. In any case, the high sensitivity and specificity when adopting the cut-off score of >6 in the present study proved its validity as a screening tool for GAD in PWE. Fifty of the 213 patients (23.5%) were diagnosed with GAD in the current study. This rate was close to the GAD prevalence of 21.0% in Korea PWE (Seo et al., 2014). On the other hand, European hospital-based studies reported lower prevalence of GAD in PWE, ranged from 3.1% to 12.0% (Brandt et al., 2010; Mula et al., 2008). Ethnic or cultural differences might be an important explanation. Different populations investigated and different measurements of GAD used could affect the result too, considering the study revealed a prevalence of 3.1% used the Structured Clinical Interview for DSMIV Axis I disorders (SCID-I) as the gold standard of GAD (Brandt et al., 2010), while the others used the MINI (Mula et al., 2008; Seo et al., 2014). However, since the frequency of GAD in Chinese primary care patients was 4.1% (Ying et al., 2010), GAD was far more prevalent in Chinese PWE. There were equal numbers of male and female PWE with GAD in the current study, which is different from some studies showing that GAD was more prevalent in females (Kimiskidis and Valeta, 2012; Mensah et al., 2007). Patients with complex partial seizures were more likely to develop GAD, which has previously been demonstrated (de Oliveira et al., 2010; Kimiskidis and Valeta, 2012). The relevance of complex partial seizures may be related to the negative effect of altered consciousness on quality of life (Blumenfeld, 2012). However we were not able to demonstrate an association with any specific sublobar epilepsy localization. It was also observed in our study that patients who had more frequent and/or more recent seizures were more anxious. And patients who were seizure free for the last six months were less likely to be diagnosed with GAD and scored lower in GAD-7 as well. Some previous studies also found such associations, and explained them from different perspectives (Gandy et al., 2012; Kwon and Park, 2014), although the causality relationship was not so clear. The present study found idiopathic epilepsy to have the lowest risk of associated GAD. Idiopathic epilepsy is usually considered to have a favorable prognosis with little intellectual or behavioral impairment (Cutting et al., 2001) and that might be one of the reasons why such patients were less anxious. However several works have reported a variably increased incidence of psychiatric symptoms in this category (Akanuma et al., 2008; Cutting et al., 2001). Last but not least, use of multiple AEDs, being indicative of a refractory process when seizures were usually poorly controlled, was more highly associated with GAD; of course use of more AEDs may also produce more side effects, which also contributes to anxiety (Gomez-Arias et al., 2012).
GAD-7: Generalized Anxiety Disorder-7.
Fig. 1. ROC curve of the GAD-7, with the MINI-defined current GAD. ROC: receiver operating characteristic; GAD-7: Generalized Anxiety Disorder-7; MINI: Mini International Neuropsychiatric Interview; GAD: generalized anxiety disorder.
4. Discussion The GAD-7 was readily understood and quickly completed by the patients. This scale showed good internal consistency with a Cronbach’s ˛ coefficient of 0.888, which is close to the Cronbach’s ˛ of 0.898 when this version was applied in general hospital outpatients of China (He et al., 2010), and comparable to other versions of the GAD-7 (Seo et al., 2014; Sousa et al., 2015; Spitzer et al., 2006). At the optimal cut-off score of >6, the same as that of the Korean version (Seo et al., 2014), the GAD-7 had a sensitivity of 94% and a specificity of 91.4% when applied in Chinese PWE. This cut-off score was lower than the value of >9 adopted in primary care patients or general populations (He et al., 2010; Löwe et al., 2008; Spitzer et al., 2006). However, it has been previously observed that for people with some specific medical conditions lower cut-off scores may be more appropriate, such as an optimal cut-off score of >8 in drug and alcohol users (Delgadillo et al., 2012), and >6 in pregnant women (Zhong et al., 2015); this appears likewise to be the case for epilepsy. We might presume that with certain medical conditions, people tend to view their worry or fear as being reasonable and Table 4 ROC and diagnostic efficiency of the GAD-7 for the diagnosis of current GAD. Cut-off scores
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
YI
>5 >6 >7 >8
98.0 94.0 86.0 60.0
84.0 91.4 95.1 98.8
65.3 77.0 84.3 93.8
99.3 98.0 95.7 88.0
0.820 0.854 0.811 0.588
AUC
95%CI
SE
p Value
0.974
0.956–0.993
0.009
<0.001
GAD-7: Generalized Anxiety Disorder-7; GAD: generalized anxiety disorder; ROC: receiver operating characteristic; PPV: positive predictive value; NPV: negative predictive value; YI: Youden index; AUC: area under the curve; 95%CI: 95% confidence interval; SE: standard error.
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There are several limitations to our study. First, although it has been reported that the GAD-7 could be used for detecting other anxiety disorders such as panic disorder and social phobia (Kroenke et al., 2007), it should be remembered that this scale was specifically designed to screen for GAD. It might not perform so well in detecting other anxiety disorders, which was a limitation of our study. Second, the GAD-7 provides only probable diagnoses that should be investigated by further evaluation. Third, a cut-off score of >6 in the Chinese version had a PPV of 77%, which may lead to false positive results. As we know, the GAD-7 asks about symptoms during the preceding two weeks. On the other hand, GAD assessed by the MINI takes into account symptoms over the past six months. The difference of the observation period between two tools may help to explain the low PPV of the GAD-7 for suggesting GAD. However, as GAD-7 was a screening tool, higher score indicated further evaluation rather than definite GAD diagnosis, we considered this PPV acceptable. And therefore using GAD-7 as a diagnosis tool might be inappropriate. Fourth, China is a big country with many different ethic populations and dialects, and there are many overseas Chinese as well. Thus not all Chinese people speak standard Chinese, known as Mandarin. Nevertheless, since many dialects don’t have written forms, the written language for majority of Chinese people is the same. And the government has greatly promoted application of Mandarin through education and official use. Therefore as long as a person had received primary education in Chinese mainland, he/she must have the ability to read standard Chinese more or less. Since this version is fairly simple and compulsory education has been popularized, we believe the GAD-7 would be easily understood for most Chinese people in mainland China. Although there already were Malaysia Chinese, Taiwanese Chinese and Hong Kong Chinese versions of GAD-7(He et al., 2010), those versions have not been tested in PWE. For PWE from such places, results from this version may not be applied and should be interpreted with caution. In conclusion, we proved the GAD-7 to be a reliable and valid screening tool for use in PWE. We recommend >6 as the optimal cut-off score when applying the GAD-7 in Chinese PWE. Wider usage of this scale could bring earlier detection of comorbid anxiety in PWE, promote appropriate intervention and ultimately achieve better outcome. 5. Disclosure 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 Akanuma, N., Hara, E., Adachi, N., Hara, K., Koutroumanidis, M., 2008. Psychiatric comorbidity in adult patients with idiopathic generalized epilepsy. Epilepsy Behav.: E&B 13, 248–251. Baker, G.A., Brooks, J., Buck, D., Jacoby, A., 2000. The stigma of epilepsy: a European perspective. Epilepsia 41, 98–104. Beyenburg, S., Mitchell, A.J., Schmidt, D., Elger, C.E., Reuber, M., 2005. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav.: E&B 7, 161–171. Blumenfeld, H., 2012. Impaired consciousness in epilepsy. Lancet Neurol. 11, 814–826. Brandt, C., Schoendienst, M., Trentowska, M., May, T.W., Pohlmann-Eden, B., Tuschen-Caffier, B., Schrecke, M., Fueratsch, N., Witte-Boelt, K., Ebner, A., 2010. Prevalence of anxiety disorders in patients with refractory focal epilepsy—a prospective clinic based survey. Epilepsy Behav.: E&B 17, 259–263. Cutting, S., Lauchheimer, A., Barr, W., Devinsky, O., 2001. Adult-onset idiopathic generalized epilepsy: clinical and behavioral features. Epilepsia 42, 1395–1398. de Oliveira, G.N., Kummer, A., Salgado, J.V., Portela, E.J., Sousa-Pereira, S.R., David, A.S., Teixeira, A.L., 2010. Psychiatric disorders in temporal lobe epilepsy: an overview from a tertiary service in Brazil. Seizure 19, 479–484. Delgadillo, J., Payne, S., Gilbody, S., Godfrey, C., Gore, S., Jessop, D., Dale, V., 2012. Brief case finding tools for anxiety disorders: validation of GAD-7 and GAD-2 in addictions treatment. Drug Alcohol Depend. 125, 37–42.
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