Edited by: Mario Farin Dulay, Methodist Hospital Neurological Institute, USA
Reviewed by: Patricia Braga, Instituto de Neurología, Uruguay; Mario A. Vanegas, Instituto Nacional de Neurologia y Neurocirugia, Mexico
†Present address: Maya J. Ramirez, Psychology Services, Tampa General Hospital, Tampa, FL, USA; Ava B. Dorfman, Department of Psychiatry, Maria Fareri Children’s Hospital at Westchester Medical Center, Westchester, NY, USA
This article was submitted to Epilepsy, a section of the journal Frontiers in Neurology.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Children with epilepsy have a high rate of mood and behavior problems; yet few studies consider the emotional and behavioral impact of surgery. No study to date has been sufficiently powered to investigate effects of both side (left/right) and site (temporal/frontal) of surgery. One hundred patients (aged 6–16) and their families completed measures of depression, anxiety, and behavioral function as part of neuropsychological evaluations before and after surgery for pharmacoresistant epilepsy. Among children who had left-sided surgeries (frontal = 16; temporal = 38), there were significant interactions between time (pre to post-operative neuropsychological assessment) and resection site (frontal/temporal) on anhedonia, social anxiety, and withdrawn/depressed scales. Patients with frontal lobe epilepsy (FLE) endorsed greater pre-surgical anhedonia and social anxiety than patients with temporal lobe epilepsy (TLE) with scores normalizing following surgery. While scores on the withdrawn/depressed scale were similar between groups before surgery, the FLE group showed greater symptom improvement after surgery. In children who underwent right-sided surgeries (FLE = 20; TLE = 26), main effects of time (patients in both groups improved) and resection site (caregivers of FLE patients endorsed greater symptoms than those with TLE) were observed primarily on behavior scales. Individual data revealed that a greater proportion of children with left FLE demonstrated clinically significant improvements in anhedonia, social anxiety, and aggressive behavior than children with TLE. This is the first study to demonstrate differential effects of both side and site of surgery in children with epilepsy at group and individual levels. Results suggest that children with FLE have greater emotional and behavioral dysfunction before surgery, but show marked improvement after surgery. Overall, most children had good emotional and behavioral outcomes, with most scores remaining stable or improving.
Children with epilepsy are at higher risk of developing behavioral and emotional disturbances than children in the general population or those with other chronic illnesses (i.e., asthma, diabetes mellitus) (
Surgical intervention for intractable epilepsy during childhood has become a standard and increasingly effective treatment option. Rates of seizure-freedom following surgery for intractable pediatric epilepsy have been estimated between 59 and 80% (
To date, we are aware of only four published studies that have used standardized measures to assess emotional and behavioral change following epilepsy surgery in children (
The goal of the present study was to extend the existing literature by evaluating behavioral and emotional outcome in a substantially larger sample of children following surgery for intractable childhood epilepsy. Specifically, our aim was to examine differences in outcome as a function of side and site of surgery at the group level as well as in individual patients.
This study involved an Institutional Review Board-approved, retrospective review of previously collected and archived data from children with medically intractable epilepsy, who were evaluated through the Neuropsychology Section at Cleveland Clinic as part of routine pre- and post-operative surgical investigations. Patients were included in the study, if they: (1) were between the ages of 6 and 16; (2) underwent a temporal lobe or frontal lobe resection for the treatment of intractable epilepsy between 1992 and 2012; (3) completed pre-surgical and post-surgical neuropsychological evaluations that included the measures of interest in this study; and (4) had no history of previous neurosurgery. From the available sample of 408 patients, a total of 100 children and adolescents met all inclusion/exclusion criteria. Patients were sequentially excluded from this study for the following reasons: age less than 6 years old (69 patients), did not undergo surgery (134 patients), resection site not frontal or temporal (5 parietal, 6 occipital, 45 multilobar), and did not complete post-surgical neuropsychological assessment (49 patients).
Patients included 51 males and 49 females with a mean age of 10.96 (SD = 2.84) and mean WISC-III or WISC-IV FSIQ of 84.12 (SD = 18.76). Mean duration of epilepsy was 5.27 years (SD = 3.61), and mean age at seizure onset was 5.81 (SD = 3.93). Patients were taking an average of 2.10 (SD = 0.83) antiepileptic medications at the time of their pre-operative neuropsychological assessment and an average of 1.68 (SD = 0.89) antiepileptic medications at the time of their post-operative assessment. Ninety-one percent of patients were Caucasian, and 89% were right-handed. Temporal lobe resections were conducted on 64 patients (38 left and 26 right) and frontal lobe resections were conducted on 36 patients (16 left and 20 right). A summary of demographic and seizure variables for study patients is provided in Table
Left-sided |
Right-sided |
|||||||
---|---|---|---|---|---|---|---|---|
Temporal |
Frontal |
Temporal |
Frontal |
|||||
Number (%) | Number (%) | |||||||
Gender | 0.01 | 0.57 | 2.97 | 0.09 | ||||
Male | 16 (42) | 7 (44) | 13 (50) | 15 (75) | ||||
Female | 22 (58) | 9 (56) | 13 (50) | 5 (25) | ||||
Race | 4.54 | 0.34 | 2.85 | 0.24 | ||||
Caucasian | 33 (87) | 15 (94) | 24 (92) | 19 (95) | ||||
African American | 3 (8) | 0 (0) | 0 (0) | 1 (5) | ||||
Hispanic/Latino | 1 (3) | 0 (0) | 0 (0) | 0 (0) | ||||
Asian | 0 (0) | 1 (6) | 2 (8) | 0 (0) | ||||
Other | 1 (3) | 0 (0) | 0 (0) | 0 (0) | ||||
Handedness | 0.74 | 0.84 | 0.13 | 1.00 | ||||
Right | 34 (89) | 13 (81) | 24 (92) | 19 (95) | ||||
Left | 3 (8) | 2 (13) | 2 (8) | 1 (5) | ||||
Ambidextrous | 1 (3) | 1 (6) | 0 (0) | 0 (0) | ||||
Seizure outcome at neuropsych follow-up | 8.70 | 0.03 | 2.72 | 0.62 | ||||
Engel I | 35 (92) | 10 (59) | 23 (88) | 16 (80) | ||||
Engel II | 2 (5) | 2 (17) | 1 (4) | 0 (0) | ||||
Engel III | 1 (3) | 2 (12) | 0 (0) | 1 (5) | ||||
Engel IV | 0 (0) | 2 (12) | 2 (8) | 3 (15) | ||||
Seizure outcome at last medical follow-up |
3.93 | 0.19 | 0.81 | 0.76 | ||||
Engel I | 20 (57) | 7 (44) | 17 (68) | 11 (55) | ||||
Engel II | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||||
Engel III | 14 (40) | 6 (37) | 7 (28) | 8 (40) | ||||
Engel IV | 1 (3) | 3 (19) | 1 (4) | 1 (5) | ||||
Primary pathologies |
||||||||
Cortical dysplasia | 11 (29) | 12 (75) | 7 (27) | 12 (60) | ||||
MTS | 18 (47) | 0 (0) | 11 (42) | 0 (0) | ||||
Neuronal heterotopia | 4 (11) | 3 (19) | 0 (0) | 1 (5) | ||||
Infarct | 6 (16) | 0 (0) | 1 (4) | 5 (25) | ||||
Contusion | 4 (11) | 2 (13) | 0 (0) | 2 (10) | ||||
Tumor | 0 (0) | 1 (6) | 8 (31) | 4 (20) | ||||
Tuberous sclerosis | 0 (0) | 0 (0) | 2 (8) | 0 (0) | ||||
Age | 11.3 (3.1) | 9.1 (2.4) | 4.95 | 0.01 | 11.3 (2.7) | 11.2 (2.5) | 0.04 | 0.84 |
Age at seizure onset | 5.6 (3.9) | 4.3 (3.5) | 1.41 | 0.24 | 7.1 (4.0) | 5.5 (3.9) | 1.8 | 0.18 |
Duration of epilepsy | 5.7 (3.5) | 4.9 (3.8) | 0.58 | 0.45 | 4.3 (3.4) | 6.2 (3.9) | 3.31 | 0.08 |
Number of pre-surgical AEDs | 2.1 (0.8) | 2.3 (1.0) | 0.50 | 0.49 | 1.8 (0.7) | 2.3 (0.8) | 3.72 | 0.06 |
Number of post-surgical AEDs |
1.6 (0.8) | 1.8 (1.1) | 1.07 | 0.31 | 1.6 (0.9) | 1.9 (0.9) | 1.12 | 0.30 |
As part of routine comprehensive pre-operative and post-operative neuropsychological evaluations, children in this study and/or their parents completed the following questionnaires to assess behavior, mood, and anxiety difficulties: Achenbach Child Behavior Checklist – First or Second Edition (CBCL) (
Temporal |
Frontal |
|||
---|---|---|---|---|
Pre-surgery | Post-surgery | Pre-surgery | Post-surgery | |
Anxious/depressed | 58.03 (7.83) | 57.97 (8.32) | 52.50 (3.48) | 52.50 (3.67) |
Withdrawn/depressed | 57.59 (7.70) | 58.68 (9.48) | 59.43 (8.72) | 54.86 (6.13) |
Somatic complaints | 58.88 (7.84) | 55.56 (6.87) | 56.57 (4.89) | 55.86 (5.80) |
Social problems | 58.79 (8.37) | 57.32 (8.86) | 60.57 (4.89) | 59.64 (10.98) |
Thought problems | 58.03 (8.89) | 56.91 (7.98) | 59.64 (7.61) | 56.43 (7.67) |
Attention problems | 60.00 (9.52) | 58.15 (9.75) | 63.50 (9.26) | 65.50 (13.01) |
Rule-breaking behavior | 54.29 (5.35) | 53.82 (5.62) | 55.07 (5.97) | 55.07 (6.13) |
Aggressive behavior | 55.15 (6.37) | 55.38 (8.55) | 56.64 (6.97) | 52.93 (4.34) |
Total depression | 48.28 (7.98) | 46.40 (7.90) | 55.75 (10.47) | 47.88 (9.96) |
Negative mood | 48.00 (9.86) | 44.68 (6.01) | 51.25 (10.40) | 41.87 (5.41) |
Interpersonal problems | 49.00 (8.44) | 48.60 (8.99) | 52.75 (11.81) | 52.75 (12.07) |
Ineffectiveness | 48.56 (10.15) | 46.88 (8.18) | 56.25 (10.44) | 52.50 (14.23) |
Anhedonia | 50.36 (8.71) | 50.25 (8.50) | 59.25 (9.41) | 50.25 (8.50) |
Negative self-esteem | 46.88 (7.98) | 45.72 (6.20) | 50.25 (6.16) | 45.88 (10.15) |
Total anxiety | 50.00 (14.21) | 46.15 (10.21) | 54.43 (7.55) | 42.43 (10.63) |
Physiological anxiety | 47.27 (11.90) | 44.42 (10.36) | 49.57 (6.73) | 45.71 (11.66) |
Worry/oversensitivity | 48.69 (13.07) | 45.27 (9.46) | 52.71 (9.96) | 41.71 (8.42) |
Social concerns | 49.08 (12.15) | 47.85 (7.72) | 59.43 (7.66) | 41.71 (8.04) |
Temporal |
Frontal |
|||
---|---|---|---|---|
Pre-surgery | Post-surgery | Pre-surgery | Post-surgery | |
Anxious/depressed | 54.42 (7.43) | 52.81 (4.64) | 58.67 (9.08) | 57.28 (8.48) |
Withdrawn/depressed | 56.19 (8.29) | 53.81 (5.85) | 62.78 (8.78) | 60.83 (10.65) |
Somatic complaints | 55.54 (8.48) | 55.69 (7.31) | 61.28 (9.00) | 57.11 (7.28) |
Social problems | 58.58 (9.74) | 56.08 (7.58) | 69.44 (12.40) | 63.72 (9.81) |
Thought problems | 58.42 (10.72) | 54.69 (6.23) | 63.72 (7.28) | 59.22 (8.00) |
Attention problems | 59.58 (11.19) | 57.65 (9.83) | 69.00 (10.53) | 64.39 (9.97) |
Rule-breaking behavior | 52.81 (4.39) | 52.88 (4.34) | 57.22 (7.79) | 56.78 (8.54) |
Aggressive behavior | 54.81 (6.17) | 53.81 (6.88) | 60.28 (9.35) | 58.50 (7.59) |
Total depression | 48.00 (9.78) | 46.18 (9.11) | 54.54 (12.72) | 51.08 (8.32) |
Negative mood | 50.68 (12.69) | 47.27 (6.92) | 53.54 (12.79) | 52.69 (11.84) |
Interpersonal problems | 49.55 (12.46) | 47.64 (12.22) | 49.00 (6.25) | 49.08 (10.56) |
Ineffectiveness | 47.45 (9.51) | 46.73 (8.81) | 53.23 (12.96) | 50.92 (10.79) |
Anhedonia | 51.36 (12.63) | 48.14 (10.34) | 55.54 (9.72) | 52.23 (8.11) |
Negative self-esteem | 42.59 (4.82) | 45.50 (7.40) | 52.23 (14.23) | 48.77 (7.72) |
Total anxiety | 48.64 (11.22) | 46.77 (14.99) | 56.20 (14.38) | 50.73 (11.02) |
Physiological anxiety | 47.64 (10.33) | 46.77 (12.54) | 54.87 (14.08) | 48.73 (13.39) |
Worry/oversensitivity | 47.14 (11.60) | 48.00 (13.28) | 53.60 (10.63) | 46.80 (11.14) |
Social concerns | 48.24 (12.66) | 47.33 (11.37) | 55.29 (12.26) | 51.43 (11.61) |
Post-surgical neuropsychological evaluations were conducted on average 8.5 months (SD = 12.7) following surgical resection for treatment of intractable seizures and 10.6 months (SD = 6.2) following the pre-operative neuropsychological evaluation. At the time of post-surgical neuropsychological assessment, seizure outcomes were as follows: Engel class I (84 patients), Engel class II (5 patients), Engel class III (4 patients), and Engel class IV (7 patients). Longer term seizure outcome data (mean = 62 months after pre-operative neuropsychological evaluation; range = 12–223 months) were available on a large subset of patients (
First, patients were categorized into groups based on resection site (frontal, temporal). Then, one-way ANOVAs and chi-square tests were conducted to examine potential group differences on relevant demographic and seizure variables separately by side of surgery (left, right). Next, a series of repeated measures ANCOVAs (left-sided surgeries controlled for age) or ANOVAs (right-sided surgeries) were performed using bootstrapping to adjust for influential cases and small sample size. One thousand replications were performed, and bootstrap-adjusted
Finally, to examine post-operative changes in mood and behavior at the individual patient level, change scores were calculated for each patient on each scale by subtracting their post-surgical scores from their pre-surgical scores. A series of chi-square analyses with exact test were then conducted to examine potential differences in clinically meaningful change (decline, no change, improvement) as a function of site of surgery (frontal, temporal) separately in patients who underwent left versus right-sided resections. Change scores were considered to be clinically meaningful if they were greater than or equal to one standard deviation (i.e., ±10 points).
One-way ANOVAs and chi-square tests (Table
Repeated measures ANCOVAs revealed a group × time interaction on the anhedonia subscale,
An interaction was seen on the social concerns subscale,
A group × time interaction was also observed on the withdrawn/depressed subscale,
There were no significant group differences on demographic or seizure variables among patients who underwent right-sided surgery (Table
No significant interactions were seen; however, there was a main effect of group on the negative self-esteem subscale such that children in the FLE group had higher scores than the TLE group on this subscale collapsed across time,
No significant interactions or main effects were seen on any of the subscales from the RCMAS in children who underwent right-sided resections.
No significant interactions were found on the CBCL. Main effects of time were observed on the following scales: withdrawn/ depressed,
In children who underwent left-sided surgery, there was a significant difference in the proportion of patients demonstrating clinically meaningful post-operative change as a function of surgical site on the CDI anhedonia scale, χ2(2) = 11.24,
No significant differences were found in children who underwent right-sided surgery, although a trend was noted on the CDI negative self-esteem subscale, χ2(2) = 5.75,
The current investigation demonstrates differences in post-surgical emotional and behavioral outcome as a function of surgical side and site in a large sample of pediatric patients with epilepsy. Children with left FLE had higher pre-surgical scores on the CDI scale of anhedonia and the RCMAS scale of social anxiety than children with left TLE. However, mean scores among FLE patients improved following surgery to the degree that post-operative symptom endorsements were similar to those of the TLE group. An additional interaction was noted on the CBCL withdrawn/depressed scale: While group scores were similar prior to surgery, the left FLE group demonstrated greater improvement in symptoms following surgery than the left TLE group. We are aware of only four prior studies (
Interestingly, the interaction effects observed between surgical site and time in the current study were only observed in children who underwent left-sided surgeries. This finding is consistent with existing literature. Numerous studies over the years have demonstrated differential effects of lesion laterality on mood in adult clinical populations such that mood difficulties are most frequently associated with anterior lesions in the dominant hemisphere (
While no significant interaction effects between site of surgery and time were observed in children who underwent right-sided resections, several potentially important main effects were observed. First, parents of children with right FLE reported more mood symptoms and greater behavioral dysfunction on a number of CBCL syndrome scales than parents of children with TLE. Thus, these findings support the notion that anterior lesions have more profound effects on mood/behavior (
Studies in the adult epilepsy literature have demonstrated that mood improvement is related to surgical outcome (
One of the limitations of prior research on this topic is that most data analyses are limited to examining differences in group means with little attention paid to potential differences in mood or behavior change at the individual level. The current study found that when change is examined in individuals, patients with left FLE were more likely than their TLE counterparts to show clinically significant improvement on several mood and behavior scales following surgery. The differences in the proportion of individual improvements were most apparent on the RCMAS social concerns scale and CDI anhedonia scale, where interactions were seen in the group data. In fact, all of the patients with left FLE reported clinically significant post-surgical improvement on the social concerns scale (range 12–32
While group mean scores on the measures used in this study were generally in the normal range (Tables
Although the left-sided FLE group showed the most benefit on both the group level and at the individual level, examination of the data shows that most children showed clinically significant improvement or had stable scores across measures regardless of surgical resection site, and rates of seizure-freedom did not differ in children whose scores improved, remained stable, or declined. However, the small percentage of children who demonstrated clinically significant post-operative declines on several scales must not be overlooked. Future studies will be required to better characterize the factors that place this small subset of children at risk for worsening mood and/or behavior issues following epilepsy surgery. Interestingly, review of post-operative neuropsychological reports for children who showed mood declines after surgery revealed that for about half of these patients this decline appeared to be in response to difficulty with a recent transition (i.e., transition to a more difficult stage in school, transition away from the sick role) rather than surgery
Several limitations to the current study deserve mention. Given that there was not a non-surgical control group included in this study, we cannot definitively conclude that the interaction and time effects observed in this study are the result of the surgery itself and not simply the passage of time. However, if passage of time were the primary factor related to change, one would not expect differences in mood/behavior outcome as a function of side and site of resection. Nevertheless, future studies that include control patients will be necessary to confirm that our findings are indeed related to surgery. Information regarding the relationship between extent of resection and post-operative mood/behavior outcome was not examined. The location and extent of surgical resection likely plays an important role in outcome in this regard, particularly among patients who undergo frontal lobectomies. Future studies will be required to investigate the potential impact of resection extent and effects of different resection sites within the frontal lobe on various aspects of mood and anxiety. Additionally, it is known that antiepileptic medications can negatively affect mood and behavior in children (
In sum, these results suggest generally favorable psychological outcomes in pediatric patients following epilepsy surgery. Neuropsychologists and other providers at epilepsy centers are often asked by parents of children being evaluated for epilepsy surgery whether there will be significant changes in their child’s mood, behavior or personality after surgery. To date, there has been little research to support our clinical sense that most children do well following surgery. The current study provides reassurance that mood and behavior outcomes in most children are quite favorable based on both group and individual data.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This publication was made possible, in part, by the Epilepsy Foundation through the Partnership for Pediatric Epilepsy Research and the Targeted Research Initiative for Youth. Additional support for this research was provided by the Cleveland Clinic Epilepsy Center and the Clinical and Translational Science Collaborative of Cleveland, KL2TR000440 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.