Longitudinal trajectory of quality of life and psychological outcomes following epilepsy surgery

Abstract

Objective:

This study investigated self-reported longitudinal quality of life (QOL) and symptoms of depression and anxiety in patients who had resective surgery. The study characterized the extent, sustainability, and longitudinal trajectory of psychosocial postsurgical outcomes.

Methods:

This retrospective study included adults who underwent resective epilepsy surgery in Cleveland Clinic Epilepsy Center between 2008 and 2013. Clinic visits were between October 2007 and December 2014. Data studied were from visits prior to surgery, early postsurgery follow-up (mean: 0.9 years; range: 0.5 to 3.4), and most recent follow-up (mean: 3.2 years; range: 0.8 to 6.9). Patient demographics, clinical features, and surgical factors were collected. Analysis focused on self-reported quality of life (QOLIE-10), depression (PHQ-9), and anxiety (GAD-7).

Results:

The study included 229 adults, of whom 178 had complete follow-up with data from all three time points. Following surgery, scores on Quality of life in epilepsy inventory (QOLIE-10), Patient health questionnaire (PHQ-9), and General anxiety disorder (GAD-7) improved significantly with time. After adjusting for gender, age, marital status, and type of surgery using linear modeling, the mean QOLIE-10 score decreased by 1.157 points/year, mean PHQ-9 score by 0.331 points/year, and mean GAD-7 score by 0.299 points/year. Improvement in QOL continued to be observed throughout the follow-up duration, whereas both depression and anxiety improved the most within the first postoperative year and then stabilized. Seizure freedom was strongly correlated with improved QOL (p = 0.001), while depressive symptoms showed a nonstatistically significant correlation with worse QOL (p = 0.07). Patients who underwent frontal resection had significantly superior QOL and depression symptom improvement compared with temporal resections during full data analysis (QOLIE-10, p = 0.024; PHQ-9, p = 0.027), but only significant depression symptom improvement on secondary analysis of complete follow-up patients only (PHQ, p = 0.040; QOL, p = 0.104).

Significance:

This study provides a longitudinal perspective of QOL and psychological symptoms in patients with postresective epilepsy with a cohort with 38% extratemporal cases. Results illustrate positive trajectory of psychosocial outcomes postsurgery with early QOL and mood improvement, and years of further QOL gains. Frontal lobe surgery patients may have superior improvement in some psychosocial measures compared with temporal lobe surgery patients.

1. Introduction

The dynamic correlation between epilepsy, psychiatric illness, and quality of life (QOL) is a well-established, though complicated, relationship. Prior work has demonstrated a consistent correlation between postoperative improvement in QOL and seizure control [1]. Conversely, an independent contribution of depression and anxiety to QOL was proposed but has not been fully investigated [2,3]. A glaring limitation of the existing literature on the topic of psychological surgical outcomes and QOL remains the lack of robust analyses of the long-term evolution of postoperative psychological or QOL benefits. Additionally, many of the studies have exclusively or nearly exclusively looked at patients who had temporal lobe surgery. Studies investigating whether lobe of surgery impacts psychosocial outcomes have shown inconsistent findings due to small sample sizes, particularly among extratemporal subgroups.

In this project, we describe self-reported longitudinal QOL and depressive and anxiety symptoms in a large, well-characterized cohort of temporal, frontal, and parietal lobe epilepsy resective surgery patients to characterize the extent, sustainability, and longitudinal trajectory of psychosocial postsurgical outcomes.

2. Material and methods

2.1. Subject characteristics and data collected

This retrospective study included 229 adults (18 years or older) who underwent resective epilepsy surgery in Cleveland Clinic Epilepsy Center from 2008 to 2013. We included all available frontal and parietal lobe surgery patients to optimize representation of extratemporal patients. We then randomly selected a cohort of consecutive temporal lobe surgery patients from the same timeframe to allow comparisons of outcomes of interest (detailed in Data analysis and statistical methods section) between temporal and extratemporal surgery. Temporal lobe cohort size was based on estimated sample size needed. Visit data were collected between October 2007 and December 2014 by review of medical records. Demographic (gender, race, marital status), clinical (seizure status, pathology, etiology, magnetic resonance imaging (MRI), medications, Emergency Room (ER) hospitalizations, and hospital admissions), social factors (alcohol use, driving status, employment status), and surgical factors (age at surgery, side of surgery, type of surgery) were reviewed. Type of surgery referred to resection of the temporal lobe, frontal lobe, or parietal lobe. Magnetic resonance imaging studies were determined to be normal or abnormal based upon review of the formal radiology report as well as documented impressions from patient management discussions among epileptologists, neurosurgeons, and radiologist. Pathology findings were noted as documented in the pathology report. Etiology was reported as determined by pathology report findings and patient management conference impressions.

2.2. Instrument definition

Patient-reported questionnaires are provided below.

2.2.1. QOLIE-10

Questionnaire assesses self-reported QOL. Ten questions encompass aspects from the longer QOLIE-89 scale. This scale contains items from the three areas of epilepsy effects (memory, physical effects, mental effects of medication), mental health (energy, depression, overall QOL), and role functioning (seizure worry, work, driving, social limits) [4]. It asks how much of the time in the past 4 weeks the patient has faced each item. Total score ranges from 10 to 50 with better QOL correlating with a lower score. This scale has previously been validated in patients with epilepsy [4].

2.2.2. PHQ-9

This nine-item questionnaire assesses depression symptoms that align with the nine criteria from the diagnosis of Diagnostic and statistical manual of mental disorders-IV (DSM-IV) depressive disorders. The checklist asks how much the patient has been bothered by each symptom over the preceding two weeks. Scores range from 0 to 27 with a lower score correlating with less depressive symptoms. A score of ≥10 has a sensitivity of 88% and specificity of 88% for major depression, and score of ≥15 had sensitivity of 68% and specificity of 95% [5]. This scale has been validated for use in patients with epilepsy, which found a cutoff value of 10 yielded a 92% sensitivity and 74% specificity [6].

2.2.3. GAD-7

This seven-item questionnaire assesses anxiety symptoms reflective of DSM-IV criteria for generalized anxiety disorder. The checklist asks how much the patient has been bothered by each symptom over the preceding two weeks. Scores range from 0 to 21 with a lower score correlating with less anxiety symptoms. A cutoff of score of ≥10 had a 89% sensitivity and 82% specificity [7]. The GAD-7 has been validated for use in patients with epilepsy [8].

2.2.4. LSSS

The Liverpool Seizure Severity Scale (LSSS) is a twenty-item scale assessing perception of seizures and symptoms ictal and postictal. Total score ranges from 20 to 80 with higher scores indicating greater symptom severity [9]. Prior studies used a score greater than 40 to signify “severe” epilepsy [10].

2.3. Instrument collection

Patients completed the self-report questionnaires including QOLIE-10, PHQ-9, GAD-7, and LSSS as part of the Cleveland Clinic’s Knowledge Program (KP) initiative. Cleveland clinic established the KP program that collects clinical information in the electronic health record for use in research, quality projects, and patient care [11]. Patients answer these self-report questionnaires before their scheduled clinic visits. The provider then has these responses available during the clinic visit to incorporate into their clinical care. This is especially important to identify individuals with concerning high scores on depression and anxiety screening requiring urgent care. Prior studies have demonstrated that availability of PHQ-9 scores during clinic visit enables practitioners to identify more individuals with current depression [12]. Data are also stored in data repository for research purposes to better understand the epilepsy clinic population and improve care. These measures were extracted from the data repository and confirmed with patient medical records.

2.4. Time points

Three time points were selected to allow for longitudinal assessment. First time point, called “presurgery” was scores immediately prior to surgery. Immediately following surgery, patients often experience life adjustments and fluctuating mental health measures; however, the objective of our study was more long-term psychosocial outcomes. Thus, our second time point, called “early follow-up”, was the first visit that is at least six months after surgery. The third time point, called “most recent follow-up”, was the most recent values available before our data collection period began December 31, 2014.

2.5. Data analysis and statistical methods

Patient characteristics were summarized with appropriate descriptive statistics. Scores from all three time points were first analyzed using the linear mixed-effects models, which included a random intercept at the patient level. The unadjusted analyses only included time, while the adjusted analyses included patient characteristics as covariates. Analysis of trajectories of QOLIE-10, PHQ-9, and GAD-7 values was completed first examining all patients together then with subgroup analyses by surgery type (temporal, frontal, and parietal). The PHQ-9 and GAD-7 scores were then dichotomized and analyzed using the mixed-effects logistic models. Change in QOL and psychological symptoms that a patient experiences over time was thought to change with most dramatic changes seen earlier following surgery. Thus, we further explored the score trajectories as nonlinear functions over time using restricted cubic spline. All analyses were performed with R-studio (Boston, MA), and statistical significance was established with two-sided p-values less than 0.05.

3. Results

3.1. Patient characteristics

A total of 229 adult patients fulfilling study criteria were analyzed. Of these, 140 patients had temporal surgery, 68 frontal, and 21 parietal. Mean age at time of surgery was 38.4 years (range: 18 to 71 years of age). Demographic and clinical characteristics are summarized in Table 1. Patients were 51.5% women, 50% single, 50.7% underwent left-sided surgery, and 85% had abnormal brain MRI (Table 1). Baseline average LSSS was 45.9, indicating “severe” epilepsy. Average number of antiseizure medications (ASMs) used at presurgery visit was 2.35 (ASMs: one, n = 26; two, n = 111; three, n = 75; four or more, n = 14).

Table 1.

Summary of patient characteristics (229 patients).

Variable		N or mean	% or SD
Age at surgery (years)		38.367	12.769
Race	White	205	0.895
	Black	17	0.074
	Hispanic	2	0.009
	Other (Mediterranean, Asian, Unknown)	5	0.022
Sex	Female	118	0.515
	Male	111	0.485
Marital status	Divorced	13	0.057
	Married	91	0.397
	Single	115	0.502
	Widowed	7	0.031
	Legally separated	3	0.013
Alcohol usage	No	130	0.734
	Yes	47	0.266
Type of surgery	Frontal lobectomy	68	0.297
	Parietal lobectomy	21	0.092
	Temporal lobectomy	140	0.611
Side of surgery	Left	116	0.507
	Right	113	0.493
Pathology	Encephalomalacia	11	0.048
	Malformation cortical development (MCD)	69	0.301
	Mesial temporal sclerosis (MTS)	45	0.197
	MTS + MCD	18	0.079
	Nonspecific	50	0.218
	Tumor	19	0.083
	Vascular	17	0.074
Etiology	Cavernous angioma	17	0.074
	Cryptogenic	46	0.201
	Malformation cortical development (MCD)	68	0.297
	Mesial temporal sclerosis (MTS)	45	0.197
	MTS + MCD	19	0.083
	Other	12	0.052
	Tumor	22	0.096
MRI	Abnormal	195	0.852
	Normal	34	0.148
Time of presurgery visit (years)		−0.183	0.169
Time of early follow-up visit (years)		0.887	0.474
Time of most recent follow-up visit (years)		3.207	1.686

3.2. Time points

At the presurgery time point, data were available for all 229 patients. The time points for presurgery, early follow-up, and most recent follow-up visits are the average time from surgery in our dataset. At early follow-up, data from 225 patients (98% of original patient group) were available with a mean time of 0.9 years after surgery (range: 0.5 to 3.4). At most recent follow-up time point, data were available for 178 patients (77% of original patient group), at a mean time of 3.2 years after surgery (range: 0.8 to 6.9). Those 178 patients with scores from all three time points are referred to as having “complete follow-up”. The time between the early and most recent visit was a mean of 2.35 years and median of 1.96 years. When assessing each individual, 90% of patients had at least 0.5 years (six months) between early and most recent follow-up visits (161 of 178 patients).

3.3. Trajectories of quality of life, depression, anxiety change with surgery

Prior to surgery, the mean QOLIE score was 24.9. Mean PHQ-9 score was 7.2, and mean GAD-7 was 5.7. Following surgery, scores on QOLIE-10, PHQ-9, and GAD-7 decreased significantly with time, reflecting an improvement in all measures and significant change between all three time points. After adjusting for gender, age, marital status, and type of surgery using linear modeling, the mean QOLIE-10 score decreased by 1.157 points/year, mean PHQ-9 score by 0.331 points/year, and mean GAD-7 score by 0.299 points/year (Table 2). Even when secondary analysis was done using only patients with complete follow-up, then QOLIE-10, PHQ-9, and GAD-7 continued to show significant decreases over time.

Table 2.

Estimated longitudinal trajectories of three outcomes.

Outcome		Analysis: 229 patients Unadjusted analysis			Analysis: 229 patients Adjusted analysis*			Secondary analysis: 178 patients with complete follow-up Adjusted analysis*
		Estimate	SE	p-Value	Estimate	SE	p-Value	Estimate	SE	p-Value
QOLIE 10	Mean score at surgery	24.937	0.545	<0.001
	Change per year	−1.175	0.173	<0.001	−1.157	0.174	<0.001	−1.1079	0.177	<0.001
PHQ 9	Mean score at surgery	7.185	0.423	<0.001
	Change per year	−0.339	0.128	0.008	−0.331	0.128	0.009	−0.345	0.131	0.008
GAD 7	Mean score at surgery	5.749	0.385	<0.001
	Change per year	−0.296	0.112	0.008	−0.299	0.112	0.008	−0.264	0.110	0.017

Adjusted for sex, marital status, race, and type of surgery.

First two sections are unadjusted and adjusted analysis using all available patient data from 229 patients. Third section is secondary analysis, an adjusted analysis only using data from the 178 patients who had complete follow-up from all three time points. Bold values indicate key values that are significant p<0.05

This longitudinal change is visually depicted with nonlinear trajectories of mean QOLIE-10, PHQ-9, and GAD-7 at each of the presurgery, early follow-up, and most recent follow-up time points in Fig. 1. This illustrates that improvement in QOL continued to be observed throughout the follow-up duration, whereas both depression and anxiety improved the most within the first postoperative year and then stabilized.

Fig. 1.

Estimated nonlinear trajectories of QOLIE-10, PHQ-9, and GAD-7 self-reported measures over time. The time points for presurgery, postsurgery, and follow-up visits are the averages in our dataset.

3.4. Factors correlated with quality of life change

Gender, race (white vs other), and marital status prior to surgery did not correlate with QOL change. Seizure freedom was identified as having a strong correlation with QOL change (p = 0.001). After accounting for seizure freedom, depressive symptoms showed a trend toward improvement in QOL (p = 0.07), and anxiety scores were not significant.

3.5. Subgroup analysis by type of surgery

This study’s substantial representation of patients with frontal and parietal lobe resections in addition to temporal lobe allowed for further analysis by type of surgery. When visits from all 229 patients was analyzed, patients who underwent frontal resection compared with temporal resection had significantly superior improvement in QOLIE-10 (p = 0.024), PHQ-9 (p = 0.027), and trend toward improved GAD-7 (p = 0.063) (Table 3). However, on secondary analysis using only complete follow-up patients, only PHQ remained significant (p = 0.040), whereas QOL was no longer (p = 0.104).

Table 3.

Comparison of outcome profiles between patient subgroups defined by patient characteristics.

Outcome	Subgroup comparison	Analysis: 229 patients			Secondary analysis: 178 patients with complete follow-up
		Estimate	Std. error	p-Value	Estimate	Std. error	p-Value
PHQ-9	Gender	0.076	0.256	0.767	0.089	0.262	0.734
	Married vs. other	0.424	0.265	0.110	0.433	0.272	0.112
	White vs. other	0.623	0.440	0.157	0.5	0.447	0.264
	Type of surgery (parietal vs. frontal)	0.620	0.557	0.265	0.475	0.567	0.402
	Type of surgery (temporal vs. frontal)	0.677	0.307	0.027	0.65	0.316	0.040
QOLIE-10	Gender	−0.186	0.347	0.591	−0.164	0.353	0.641
	Married vs. other	0.444	0.354	0.209	0.333	0.359	0.354
	White vs. other	0.525	0.613	0.392	0.442	0.616	0.473
	Type of surgery (parietal vs. frontal)	0.194	0.799	0.809	−0.185	0.815	0.820
	Type of surgery (temporal vs. frontal)	1.021	0.453	0.024	0.76	0.467	0.104
GAD-7	Gender	0.210	0.225	0.350	0.212	0.221	0.337
	Married vs. other	0.128	0.232	0.580	0.187	0.227	0.412
	White vs. other	0.702	0.389	0.071	0.598	0.378	0.114
	Type of surgery (parietal vs. frontal)	1.042	0.478	0.029	0.906	0.469	0.053
	Type of surgery (temporal vs. frontal)	0.505	0.271	0.063	0.411	0.269	0.126

First section is analysis using all available patient data from 229 patients. Second section is secondary analysis only using data from the 178 patients who had complete follow-up from all three time points. Bold values indicate key values that are significant p<0.05

Comparing frontal lobe resections with parietal lobe, GAD-7 anxiety improved significantly more in frontal resections (p = 0.029) during all data analysis, however, not on the secondary analysis (p = 0.053) (Table 3). Comparison of PHQ-9 and QOLIE-10 between frontal and parietal lobes was not significant.

Nonlinear trajectories by lobe illustrate the different trajectories of the temporal, frontal, and parietal lobe groups (Fig. 2). This depicts how improvement in QOL continued to be observed throughout the entire follow-up duration. Depression and anxiety in the temporal and frontal lobe surgery patients improved the most within the first postoperative year then stabilized, whereas parietal lobe appeared to worsen over time.

Fig. 2.

Exploratory analysis of nonlinear trajectories of QOLIE-10, PHQ-9, and GAD-7 self-reported measures over time. The time points for presurgery, postsurgery, and follow-up visits are the averages in our dataset.

3.6. Seizure freedom by lobe

Sixty percent of the overall group were seizure-free after surgery. These included 55% of the frontal resections, 40% of the parietal resections, and 66% of the temporal resections. These differences in seizure freedom had a trend toward statistical significance favoring better outcomes in the temporal lobe group (p = 0.06).

4. Discussion

This study provides a longitudinal perspective of QOL and psychological health after epilepsy surgery in a variety of patients. Previous studies on psychosocial outcomes had either small or no representation of extratemporal lobe epilepsy, which was a notable limitation. Our study was specifically designed for a larger representation of extratemporal epilepsy and thus included 38% extratemporal cases [29% (68) frontal and 7% (21) parietal cases]. This allowed for further study of an underrepresented population within surgical epilepsy. Analysis of the 229 patients demonstrated a sustained improvement of patient-reported QOL, depression, and anxiety. It also suggested superior depressive symptom improvement in frontal lobe patients compared with temporal lobe patients. This information can help clinicians care for patients both being considered for epilepsy surgery of all types as well as in long-term follow-up after epilepsy surgery.

4.1. Patient population representative of surgical epilepsy population

Our patient population was representative of medically intractable epilepsy surgery patients. Average LSSS score of our patient population was 45.9 consistent with severe epilepsy based upon prior studies noting severe epilepsy as greater than 40 [10]. Additionally, 88% of patients were taking two or more ASMs at time of surgery. These patients meet standard criteria for intractable epilepsy and are likely comparable with patients with intractable epilepsy at other centers.

4.2. Longitudinal quality of life

Studies comparing surgical with medical therapies for treatment of epilepsy have often focused on temporal lobe epilepsy and included analysis of QOL as a secondary outcome. Beginning with Wiebe et al., it was shown that following temporal lobe epilepsy surgery, patients have improved QOL at 12-month follow-up [13]. Later studies have had longer follow-up periods: Seiam et al. review ranged from 6 months to 17 years, and 90% showed significant improvement of QOL after surgery [14]. Edelvik et al. even found QOL stability at 14 years postsurgery [15]. Our study focused on further early and late outcomes with longitudinal analysis.

Our review of nonlinear longitudinal trajectories showed QOL improvement at early follow-up (mean: 0.9 years) with continued improvement until most recent follow-up (mean: 3.2 years). This illustration of QOL long-term trajectory is encouraging. By comparison, Elsharkawy et al.’s 2009 study of temporal cases noted QOL for the first 2 years of seizure freedom, then a plateau [16]. Their study also found continued cognitive function improvement over 10 years or more [16]. Thus, we may hypothesize that our population’s continued improvement is reflective of certain facets of QOL, like cognitive function, which could be better investigated with more extensive QOL measures.

Because of our study’s high representation of frontal and parietal lobe patients, we were able to investigate trajectories of each epilepsy type. Regardless of lobe of surgery, all patients had improved QOL over time. Additionally, frontal lobe patients had even more notable depressive symptom improvement, and possibly QOL improvement. This suggests inherent differences in frontal lobe patients. Differences may be related to patients’ with frontal epilepsy ability to regain social functioning, comorbid disease, or lack thereof, surgical complications, or particular facets of QOL, like cognition. This should prompt further investigation into functional lobe differences.

4.3. Longitudinal psychological symptoms

Our longitudinal analysis of self-reported depression and anxiety symptoms showed improvement at early follow-up visit, which was sustained at most recent visit. This pattern is consistent with other studies including Devinsky et al.’s, which specifically showed most improvement by three months with only smaller increases at 12 months and 24 months [17]. Given this postoperative mood improvement, mood dysfunction should not be a barrier to epilepsy surgery, and potential for mood improvements can be incorporated into presurgical counseling. However, our longitudinal data do suggest that when mood dysfunction persists be-yond one postoperative year, then it is unlikely to improve spontaneously. Focusing attention and treatment to address depression and anxiety symptoms is needed, even among those with stable epilepsy.

Previous research has not reached a clear consensus on whether lobe of surgery alters expected mood outcomes following surgery. Prior data have suggested either no difference between lobes or worse in temporal lobe [17,18]. Our surgery type subgroup analysis discovered less postresection depression in frontal patients compared with temporal patients. The trajectory of the depression and anxiety symptoms in the temporal and frontal lobe patients improved the most within the first postoperative year and then stabilized. Trajectory of parietal lobe appeared to worsen over time, though this may be secondary to limited patients at most recent follow-up. Differing trajectories of mood outcomes in the various lobes raise questions about the network of mood disorders.

4.4. Reasons for better outcomes in frontal lobe

Frontal lobe patients have better QOL and mood scores presurgery. After surgery, all data analysis showed superior QOL and depression improvement in frontal lobe compared with temporal lobe patients though secondary analysis only showed superior depression improvements. When considering why frontal patients did better, we note that it was not due to seizure freedom as it was actually the temporal lobe cohort who had higher rate of seizure freedom compared with the frontal lobe. Thus, we hypothesize that group differences may be related to seizure burden, or other aspects like cognitive decline, as a course of the disease process and surgery.

Prior studies have reported that patients with preexisting mood issues are more likely to experience postoperative mood difficulty. Thus, lower rates of preexisting mood issues in frontal patients may explain how they continue to do better following resection.

4.5. Factors correlated with quality of life

Consistent with prior studies, we discovered seizure freedom to have significant correlation with QOL improvement [1,14,16,19]. Many prior studies have found QOL to be further associated with depression and anxiety measures. In particular, Hamid et al. with a cohort of 12% extratemporal cases and up to 48-month follow-up found that depression and anxiety had a strong independent association with QOL postsurgery in patients with excellent or good seizure control [3]. In our analysis, depressive symptoms showed only a trend toward worse QOL, and anxiety was not correlated. Our study’s lack of significant correlation between mood and QOL may reflect our higher number of extratemporal cases, as the relationship between QOL and mood may differ by lobe.

4.6. Limitations

Although we analyzed our outcomes longitudinally in a relatively large sample of epilepsy surgery patients, our study is retrospectively carrying the limitations of such a design. For feasibility of use in our clinical setting, a ten-question QOLIE-10 is used; however, a more extensive scale would have allowed for a more detailed analysis of specific QOL facets, in particular cognition. The same limitation could be mentioned about the use of PHQ-9 and GAD-7. There are certainly more detailed measures of depression and anxiety that could have been used, but we chose these measures given: 1) their ease of use (facilitating their in-corporation in the routine clinical workflow as patients complete these questionnaires in the outpatient clinic) and 2) QOLIE-10, PHQ-9, and GAD-7 are the measures recommended by the National institute of neurological disorders and strokes (NINDS) Common Data Elements project to screen for QOL, depression, and anxiety symptoms. Lastly, division of epilepsies by lobe at times can oversimplify the complex nature of epilepsy and psychosocial wellbeing, which may be more interwoven networks.

4.7. Conclusion

Our study continues the work investigating QOL and mood outcomes in patients with resective epilepsy with longitudinal analysis of a large patient population with extratemporal patients highly-represented. With knowledge gained from this study, practitioners can feel confident that QOL following resection can improve not only in short-term but also long-term. Also, patients with comorbid anxiety and depression can have improvement in mood following epilepsy surgery. In particular, frontal lobe patients may have even better psychosocial outcomes despite lower seizure freedom rates than temporal cases. The different trajectories and psychosocial outcomes in temporal versus extratemporal surgeries warrant further investigation to develop a better understanding of the mechanistic and therapeutic aspects of psychosocial comorbidities in the context of epilepsy surgery.