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Of the 217 patients, 17.5% had depressive symptoms, and 31.3% had anxiety symptoms at baseline. DRE was diagnosed in 26.7% of patients (n=58).
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Risk factor for the development of DRE included history of brain trauma, >5 seizures pretreatment, multiple seizure type, brain MRI lesion, depressive and anxiety symptoms.
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The HRs of developing DRE was 5.219 times higher in patients with both depressive and anxiety symptoms than that in patients without depressive or anxiety symptoms.
Abstract
Purpose
Literature on the complex interrelationships between psychiatric symptoms and drug resistance in newly treated patients with epilepsy (PWE) is lacking. We aimed to determine whether psychiatric symptoms are predictive of the development of drug-resistant epilepsy (DRE) in newly treated patients.
Methods
Newly treated PWE were psychiatrically evaluated at enrolment and were followed for 24 months to determine the occurrence of DRE. The impacts of depressive and anxiety symptoms on the development of DRE were investigated using the Cox proportional hazard model.
Results
A total of 217 patients were included in the final analysis. DRE was diagnosed in 26.7% of patients (n=58). In univariate analysis, depressive and anxiety symptoms were identified as risk factors for the development of DRE. In multivariate analyses, depressive symptoms were a significant independent predictor of DRE (HR: 3.253, 95% CI: 1.643-6.441; p = 0.001). Additionally, the probability of developing DRE was 5.219 times higher in patients with both depressive and anxiety symptoms than in patients without depressive or anxiety symptoms (HR: 5.219, 95% CI: 2.716-10.029; p<0.001).
Conclusion
In conclusion, psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. Our findings support the need for prospective studies to investigate whether psychiatric treatment reduces the risk of developing DRE in these patients.
]. Approximately 30% to 40% of patients with epilepsy (PWE) develop drug-resistant epilepsy (DRE) despite receiving appropriate anti-seizure medication (ASM)[
]. It is well documented that drug-resistant epilepsy is associated with an increased risk of mortality, injuries, psychosocial dysfunction, and poor quality of life [
]. Thus, identifying clinically useful predictors of the occurrence of DRE in newly treated patients would have significant clinical benefits. Predictors of DRE vary widely across prior literature, ranging from early age at onset, abnormal neuroimaging, symptomatic epilepsy, and seizure type [
Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of "new" antiepileptic drugs.
]. In a population-based case‒control study, a history of major depression was found to increase the risk for unprovoked seizure and the development of epilepsy [
Until now, however, evidence on the association between psychiatric symptoms at baseline and the development of DRE in newly treated patients has been limited. This study aimed to test our hypothesis that psychiatric symptoms are predictive of the occurrence of DRE in patients newly treated with ASMs.
2. Methods
2.1 Study design and participants
The prospective cohort study was performed at the Epilepsy Center, Neurology Department of Jilin University, First Hospital between June 2016 and May 2021. Newly treated PWE aged 18 years or older were invited to participate in our study [
Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
]. Psychiatric symptoms of each participant were evaluated before they received ASM therapy. Patients were prospectively followed up for 24 months to evaluate the occurrence of DRE. The exclusion criteria consisted of 1) previously treated with ASM therapy; 2) a history of psychiatric disorders (lifelong anxiety and depression); and 3) a history of nonepileptic seizures and severe brain diseases other than epilepsy (e.g., dementia and Parkinson's disease). These medical histories were identified by reviewing the medical records and patient self-reports. We also excluded subjects who did not have the physical, mental, and language ability to complete the self-report questionnaires and interview. Written informed consent was obtained from all participants. This study was reviewed and approved by the ethics committee of our hospital.
2.2 Psychiatric evaluation
Psychiatric evaluation was performed before starting ASM treatment. The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E, Chinese version) [
Participants were interviewed via clinical visit and/or telephone at 1, 3, and 6 months after enrolment and every 6 months thereafter. Additionally, patients were requested to contact their treating physician within days of experiencing a breakthrough seizure. At each follow-up, information on seizure recurrence, medication compliance and changes, and potential adverse effects was collected. The outcome variable was a binary variable of the occurrence of DRE during a 24-month follow-up period. The definition of DRE according to the ILEA is failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules (including monotherapies or combination therapies) to achieve sustained seizure freedom [
]. Participants were classified as “DRE cases” or “ASMs - responsive controls” according to whether they developed DRE.
2.4 Potential predictors
Eighteen variables were considered potential predictors of DRE based on the literature and clinical reasoning, and information on these variable was gathered at enrolment. Of these 18 potential predictors, 16 were binary variables: sex, employed, per capita monthly family income, age at onset (divided into binary: > 45 and ≤ 45 years), family history of epilepsy in a first-degree relative, febrile seizures, history of encephalitis, history of brain trauma, history of stroke, >50% nocturnal seizures, > 5 seizures pretreatment, symptomatic epilepsy, multiple seizure types, status epilepticus (SE), and brain MRI lesions. Here, >50% nocturnal seizures was defined as >50% of seizures occurring during sleep, including daytime naps. SE was defined if the diagnostic time exceeded 5 minutes of ongoing seizure activity for convulsive SE or 10 minutes for absence status or focal status with or without impaired consciousness [
]. Brain MRI scans were performed to confirm the presence of a structural lesion. Seizure type was divided into 3 categories: focal, generalized, and unknown.
2.5 Statistical analysis
Categorical variables are summarized as frequencies and percentages. Variables were compared using chi-squared tests, and Fisher's exact tests were employed if X2 assumptions were not met. A Cox proportional hazard model was used to identify the effect of each parameter on the occurrence of DRE and to calculate the hazard ratio (HR). Variables with p < 0.05 in the univariate analysis were subsequently included in the multivariate analysis to identify the independent predictors of DRE. The follow-up times for the occurrence of DRE were calculated using the Kaplan‒Meier method. Then, we examined the associations of psychiatric symptoms at baseline with the development of DRE using a Cox proportional hazard model that controlled for potential confounders. We measured model performance using Nagelkerke's R2 statistics. All data analyses were performed using SPSS for Windows, version 26.0 (SPSS Inc., Chicago, IL, USA). The level of statistical significance was set at 0.05 (two-sided).
3. Results
Of the 283 potentially eligible patients identified, 66 were ineligible based on the following reasons: not interested in participating in the study (n = 7), treated with ASM previously (n = 5), withdrew from the study (n = 13), never started or ceased ASM treatment (n = 19), and lost to follow-up (n = 22). A total of 217 patients were included in the final analysis. Table 1 presents the demographic, clinical and psychiatric data of the patient cohort. Of the 217 patients, 17.5% had depressive symptoms, and 31.3% had anxiety symptoms at baseline. DRE was diagnosed in 26.7% of patients (n=58) during the follow-up.
Table 1Baseline characteristics of DRE cases and controls.
Predictor variables
DRE cases (n=58)
Controls (n=159)
p-value
Total cases (n=217)
Gender
Male
30 (51.7)
99 (62.3)
0.162
129 (59.4)
Female
28 (31.8)
60 (68.2)
Employed
41 (70.7)
120 (75.5)
0.476
161 (74.2)
Per capita monthly family income (Yuan)
< 1000
3 (5.2)
19 (11.9)
0.324
22 (10.1)
1000-5000
44 (75.9)
109 (68.6)
153 (70.5)
> 5000
11 (19.0)
31 (19.5)
42 (19.4)
Age at onset, years
≤45
47 (81.0)
107 (67.3)
0.048
154 (71.0)
>45
11 (19.0)
52 (32.7)
63 (29.0)
Family history of epilepsy
8 (13.8)
12 (7.5)
0.159
20 (9.2)
Febrile seizures
5 (8.6)
14 (8.8)
0.966
19 (8.8)
History of encephalitis
4 (6.9)
8 (5.0)
0.844
12 (5.5)
History of brain trauma
14 (24.1)
17 (10.7)
0.012
31 (14.3)
History of stroke
4 (6.9)
9 (5.7)
0.995
13 (6.0)
>50% nocturnal seizures
34 (58.6)
90 (56.6)
0.79
124 (57.1)
Seizure type
Generalized
10 (17.2)
27 (17.0)
0.842
37 (17.1)
Focal
44 (75.9)
117 (73.6)
161 (74.2)
Unknown
4 (6.9)
15 (9.4)
19 (8.8)
> 5 seizures pretreatment
39 (67.2)
63 (39.6)
< 0.001
102 (47.0)
Symptomatic epilepsy
21 (36.2)
36 (22.6)
0.044
57 (26.3)
Multiple seizure types
32 (55.2)
43 (27.0)
< 0.001
75 (34.6)
Status epilepticus
8 (13.8)
13 (8.2)
0.216
21 (9.7)
Brain MRI lesion
33 (56.9)
42 (26.4)
< 0.001
75 (34.6)
Anxiety symptoms
34 (58.6)
34 (21.4)
< 0.001
68 (31.3)
Depressive symptoms
26 (44.8)
12 (7.5)
< 0.001
38 (17.5)
DRE, drug-resistant epilepsy; MRI, magnetic resonance imaging.
The baseline characteristics of DRE cases and controls are compared in Table 1. Significant differences in history of brain trauma, age at onset, > 5 seizures pretreatment, and brain MRI lesions were noted between DRE cases and controls. The proportions of symptomatic epilepsy and multiple seizure types were higher among DRE cases than controls. Depressive and anxiety symptoms at baseline were both more common in DRE cases (p<0.001). No significant differences in other variables were observed between the DRE cases and controls (p>0.05).
In univariate analysis, risk factors for the development of DRE included history of brain trauma, >5 seizures pretreatment, multiple seizure type, and brain MRI lesion (Table 2). The HRs were also high for age at onset and for symptomatic epilepsy, but they were not statistically significant. Depressive symptoms (HR: 6.046, 95% CI: 3.583-10.2; p<0.001, Fig. 1 A) and anxiety symptoms (HR: 4.083, 95% CI: 2.416-6.899; p<0.001, Fig. 1 B) were associated with increased HRs of drug resistance. No other factor was associated with the HRs for DRE.
Table 2Univariate analysis showing the predictors of DRE.
A univariate analysis was performed for preliminary identification of factors related to drug resistance. A history of brain trauma, >5 seizures pretreatment, multiple seizure type, brain MRI lesion, depressive and anxiety symptoms were identified at a significance level of p < 0.05 (Table 2) and were retained for the multivariate analysis. Multivariate analysis suggested that the HRs of patients with depressive symptoms developing DRE were 3.253 times greater than those of patients without these symptoms (HR: 3.253, 95% CI: 1.643-6.6441; p = 0.001) (Table 3). In addition, >5 seizures pretreatment and brain MRI lesions were also significant independent predictors of DRE. The model explained 38.9% (Nagelkerke's R2) of the variance.
Table 3Multivariate analysis showing the independent predictors of DRE.
Table 4 and Fig. 2 show the incidence rate of DRE and the HRs for occurrence of DRE according to psychiatric symptoms. The lowest incidence rate of DRE (15.2%) was observed in patients without depressive or anxiety symptoms. The highest incidence rate of DRE (69.2%) was noted in patients with both depressive and anxiety symptoms. Multivariate analysis suggested that the HRs of developing DRE were 5.219 times higher in patients with both depressive and anxiety symptoms than in patients without depressive or anxiety symptoms (HR: 5.219, 95% CI: 2.716-10.029; p<0.001).
Table 4Associations of psychiatric symptoms with the risk of DRE.
This is the first study to follow a representative cohort of adults with newly diagnosed epilepsy to determine whether psychiatric symptoms at baseline are predictive of a high likelihood of developing DRE. We found that psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. To some extent, our findings are consistent with prior literature showing that a history of psychiatric conditions is an important predictor of ASM resistance in PWE [
]. The wide variation in the definition of DRE among the studies may lead to significant heterogeneity in the prevalence. Most prior studies on the topic of DRE were performed before the publication of the ILAE definition of DRE in 2010 [
]. A total of 26.7% of adults with epilepsy developed DRE in our cohort, which was slightly lower than the pooled prevalence of 30% reported by Kalilani et al. [
]. One explanation may be the relatively short follow-up period, which may lead to an underestimation of the incidence rate of DRE. Another possible explanation could be that some patients at high risk of developing DRE were not included in our study based on the exclusion criteria.
Our results suggested that psychiatric symptoms at baseline were predictive of the development of DRE in patients newly treated with ASMs. The predictive value of depressive and anxiety symptoms with respect to DRE is significant. In this study, the NDDI-E and GAD-7 are rapid and user-friendly clinical questionnaires used to evaluate the severity of depressive and anxiety symptoms, respectively, which have been validated in Chinese PWE [
]. Prior literature suggested that the first occurrences of depression and anxiety were significantly increased both before and after epilepsy diagnosis [
]. It is well known that the burden of an epilepsy diagnosis and the long-term use of ASMs may lead to psychiatric disorders. Depression and anxiety trajectories were predicted by the patient's sense of loss of seizure control early after epilepsy diagnosis, and the use of ASMs was related to increased levels of distress [
]. The impacts of psychiatric conditions on epilepsy have also been widely investigated. A history of depression is associated with an increased risk of developing epilepsy [
]. Furthermore, treated depression is related to worse seizure outcomes in PWE, indicating that the severity of depression is associated with the severity of epilepsy [
]. Supportive evidence for the negative effect of depression on seizure control is also found in a recent randomized trial for the treatment of depression in epilepsy, in which significantly fewer seizures occurred in patients who achieved remission for depression [
The biological explanation for the relationship we have confirmed between the emerging psychiatric symptoms and the occurrence of DRE in newly treated patients remains unclear. Common pathogenic mechanisms potentially exist in psychiatric conditions and epilepsy [
]. Abnormalities in serotonergic and noradrenergic transmission are vital pathogenic mechanisms of psychiatric disorders that could also facilitate the kindling process of seizure foci, exacerbate seizure severity, and intensify seizure predisposition [
]. Structural and functional abnormalities of the same neuroanatomic regions may be involved in the pathogenic mechanisms of psychiatric disorders and epileptic disorders [
]. Additionally, cognitive function in major depression disorders may be related to aberrant functional connectivity in cognitive networks, and patterns of alternate brain networks could influence cognitive processes [
Several limitations should be noted in the present study. First, depressive and anxiety symptoms were diagnosed according to the scores of the C-NDDI-E and GAD-7 scales in this study, which have been widely used in Mainland China [
]. However, clinical diagnosis is clearly the gold standard. These scales were not substitutes for clinical interviews or the Diagnostic and Statistical Manual (4th ed.) diagnosis. Second, data on counselling or psychological treatments were not available. Thus, this variable could not be included as a possible confounder. The impacts of psychological treatments on the development of DRE require more investigation. Third, it was not possible to collect all potential risk factors for DRE, and the possibility of residual confounding remains. Finally, we cannot provide an independent sample, and our model lacks confirmation in an independent sample. We also did not report sensitivity, specificity or predictive values.
In conclusion, psychiatric symptoms provide prognostic information regarding the occurrence of DRE in patients newly treated with ASMs. Well-designed and statistically powered studies are required to confirm our findings. Furthermore, our findings might inform prospective studies investigating whether psychiatric treatment reduces the risk of developing DRE in patients newly treated with ASMs.
Author contributions statement
WL and RZ conceived of and designed the study. RZ, XZ, and NL were involved in data acquisition. QC and RJ analysed the data and wrote the manuscript. All authors contributed to the article and approved the submitted version.
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declaration of Competing Interest
The authors of this work have nothing to disclose.
Acknowledgements
The authors would like to thank all of the participants for their valuable information, cooperation, and participation.
Funding
This work was supported by funds from the Clinical Research Development Fund of The First Hospital of Jilin University (grant number: lcpyjj2017006).
Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of "new" antiepileptic drugs.
Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
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