Impact of epilepsy surgery on quality of life and burden of caregivers in children and adolescents

Epilepsy & Behavior 106 (2020) 106961

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Impact of epilepsy surgery on quality of life and burden of caregivers in children and adolescents Suenia Timotheo Figueiredo Leal a, Marcelo Volpon Santos b,c, Ursula Thomé b, Helio Rubens Machado b,c, Sara Escorsi-Rosset b,d, Antônio Carlos dos Santos b,d, Lauro Wichert-Ana b,e, João Pereira Leite a, Regina Maria França Fernandes a, Ameriko Ceiki Sakamoto a,b, Ana Paula Andrada Hamad a,b,⁎ a

Department of Neurosciences and Behavioural Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil Center for Epilepsy Surgery (CIREP), Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil c Division of Pediatric Neurosurgery, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil d Radiology Division-Internal Medicine Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil e Section of Nuclear Medicine, Internal Medicine Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil b

a r t i c l e

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Article history: Received 7 October 2019 Revised 31 January 2020 Accepted 1 February 2020 Available online xxxx Keywords: Burden of caregivers Children Epilepsy Epilepsy surgery Quality of life

a b s t r a c t Objective: The objective of this study was to analyze the impact of pediatric epilepsy surgery on the quality of life (QOL), determining whether patients improve, worsen, or maintain their preoperative patterns, as it relates to the burden of caregivers, as well as evaluating potential related factors, from both the children and caregivers perspectives. Material and methods: This is a retrospective study of children and adolescents who underwent epilepsy surgery and were evaluated through clinical data, videoelectroencephalogram (V-EEG), neuroimaging findings, neuropsychological testing, and aspects of QOL. These assessments were performed prior to surgery and after six months and two years of follow-up. Quality of life was assessed with epilepsy-specialized questionnaires, namely Questionnaire health-related quality of life for children with epilepsy (QVCE-50), Autoquestionnaire Qualité de Vie Enfant Image Scale (AUQUEI), Quality of life in epilepsy inventory for adolescents (QOLEI-AD-48); and burden of caregivers with Burden Interview — ZARIT scale. Postoperative changes in QVCE-50 were quantified using measures of the analysis of variance (ANOVA MR) for comparison of the difference between the three times of the scale and domains. Results: Fifty patients were enrolled. Of these, 27 (54%) were male, with a mean age at surgery of 8.2 years (range: 1–18 years). Thirty-five patients (70%) were Engel I and one was Engel II (2%) at six months of follow-up, whereas 28 (56%) were Engel I and 32 (64%) were Engel I or II at two years of follow-up. Preoperatively, 21 (42%) presented with moderate or severe intellectual disability. Postoperative cognitive evaluations at the two-year follow-up showed 18 (36%) maintained similar deficits. The QVCE-50 showed postoperative improvement in the two-year follow-up period, but not at six months after surgery. Postoperative improvements were associated mainly with better seizure outcome. Autoperception evaluations were limited because of the clinical and cognitive severity of patients. The burden of caregivers was quoted as mild to moderate and remained unchanged postoperatively. Conclusions: Children and adolescents with surgically treated epilepsy reach a good seizure outcome, stabilize in intellectual and adaptive functions, and have an increase in QOL, from the caregiver's perspective. Nevertheless, their burden remains unchanged. Seizure outcome is the main factor for improvement in the QOL. The upgrading of structured questionnaires and QOL instruments specific to pediatric epilepsy can be helpful to assess patientand caregiver-reported surgical outcomes, allowing for better planning of therapeutic approaches. © 2020 Elsevier Inc. All rights reserved.

1. Introduction

⁎ Corresponding author at: CIREP – Centro de Cirurgia de Epilepsia – HCFMRP-USP, Avenida Bandeirantes 3900 Monte Alegre, CEP 14049-900 Ribeirão Preto, SP, Brazil. E-mail address: [email protected] (A.P. Hamad).

https://doi.org/10.1016/j.yebeh.2020.106961 1525-5050/© 2020 Elsevier Inc. All rights reserved.

Epilepsy is one of the most common chronic disorders in childhood and adolescence. About 30% of patients with epilepsy have seizures that do not respond to antiepileptic medications (AEMs) [1,2]. Surgical treatment becomes an option for these subjects with pharmacoresistant epilepsy, and this approach may provide significant control of seizures,

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S.T.F. Leal et al. / Epilepsy & Behavior 106 (2020) 106961

2. Material and methods

(IQ): 70–79), or extremely low (Intelligence Quotient (IQ): below 69). According to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD), the lower extreme was divided into mild (Intelligence Quotient (IQ): 50–69), moderate (IQ: 35–49), or severe (IQ: b 35) intellectual disabilities [22]. Certain measures had been discontinued or not used because of lack of patient's cooperation. For those patients who could not complete these neuropsychological tests, the Vineland Adaptive Behavior Scales (VABS) were used [23]. In this, raw scores are converted to IQ-type standard scores (mean: 100 Standard Deviation (SD): 15) for each domain and for the composite adaptive behavior score. Score ranges are as follows: 70–80: borderline adaptive functioning; 55–70: mildly deficient adaptive functioning; 40–55: moderately deficient adaptive behavior; 20– 40: severely deficient adaptive behavior. A comparative analysis was then performed between the preoperative evaluation and the postoperative periods, to define whether there was improvement, worsening, or stabilization of intellectual or adaptive behavior abilities. Comparative data on preoperative versus postoperative six-month and two-year follow-up QOL scores were assessed using the following instruments: Questionnaire health-related quality of life for children with epilepsy (QVCE-50), Autoquestionnaire Qualité de Vie Enfant Image Scale (AUQUEI), Quality of life in epilepsy inventory for adolescents (QOLIE-AD-48), and Burden Interview — ZARIT scale (ZARIT) [24–29]. This study was approved by the Hospital das Clínicas - Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo Research Ethics Committee (approval no. 3.117.969).

2.1. Participants

2.2. Measurements

The present study is a retrospective analysis of the medical records and database of children and adolescents (under 19 years of age at the time of surgery) who underwent surgery for treatment of refractory epilepsy at the Epilepsy Surgery Center of our institution, from October 2013 to October 2016, including resective and disconnective surgeries. Patients treated with vagus nerve stimulation (VNS) were excluded. Clinical data, videoelectroencephalogram (V-EEG) recordings, neuroimaging findings, as well as neuropsychological testing, were analyzed. Clinical data included etiology, seizure semiology, seizure onset, seizure frequency, age at surgery, type of surgery, number of AEM, use of psychiatric medication, presence of behavioral disturbances, and postoperative motor deficits. They were also assessed from an economic and social standpoint, with systematic questioning by a social worker specialized in pediatric epilepsy, to provide insights on their QOL. These evaluations included whether the family pattern was constituted by one or two parents (so that the caregiver could be the mother only, father only, or mother and father). Parental education (graduation from high school or greater versus did not graduate from high school) was also noted. Concerning the caregiver's employment, they were categorized as employed versus unemployed or homemaker. Family income was classified as higher or lower than two Brazilian minimum wages (circa R$ 2.040,00 or $243.83 USD). According to the economic indexes of the Brazilian Institute of Geography and Statistics (IBGE), two Brazilian minimum wages are indicative of poverty. https://www. ibge.gov.br School attendance of the child and leisure activities were also evaluated. Quality of life assessment was performed before surgery and after six months and two years of follow-up, regardless of the time of disease progression or seizure type. Along with QOL assessment, a clinical evaluation, especially with regard to seizure outcome, and neuropsychological testing were also performed six months and two years after surgery. Seizure outcome was classified according to Engel classification. Presurgical neuropsychological abilities were also available. The Brazilian version of the Wechsler Scales of Intelligence (WISC IV) was applied to measure cognitive ability [21]. Neuropsychological assessment was categorized as follows: typical (Intelligence Quotient (IQ): 80–109), borderline (Intelligence Quotient

The QVCE-50 scale is a 50-item parent-rated epilepsy-specialized instrument, systematically developed with items derived from previous scales, literature review, and clinical experience of the authors. This instrument was built for Brazilian children with epilepsy. Its questions are organized through the following main domains: physical (9 items), psychological (18 items), social-family (8 items), and cognitive-educational (16 items); each item is scored on a scale from zero to four points. These domains were equally weighted using percentage scores. This instrument has good psychometric properties. The QVCE-50 has good validity and reliability. It is a useful tool for analyzing children with epilepsy [24,25]. The Zarit Burden Interview has 22 items and assesses the impact on caregivers' lives of patients diagnosed with chronic diseases. It is a selfreport measure that is divided into five domains: health, personal and social life, financial status, emotional well-being, and interpersonal relationships. Each item on the scale should be scored from 0 to 4, where 0 = never, 1 = rarely, 2 = sometimes, 3 = quite often, and 4 = almost always. Final scores are obtained by summing up all items, and possible outcomes are as follows: 0–20 little or no burden, 21–40 mild to moderate, 41–60 moderate to severe, and 61–88 severe burden. The use of Zarit Burden Interview inventory (Zarit Burden Interview) is reliable to be used as a measure of the impact on the caregiver's physical and emotional well-being, their social and family life, and financial aspects [26]. The AUQUEI and QOLIE-AD-48 are epilepsy-specialized instruments applicable to children and adolescents, respectively, designed to evaluate QOL from a patient's perspective [27–29]. They both have been proven to show good validity and reliability.

reduction of medications, and improvement in development, behavior, and cognition [1]. Therefore, the clinical and therapeutic impact of epilepsy extends to the physical, social, behavioral, and cognitive spheres, which constitute the domains of the quality of life (QOL) [3,4]. The assessment of QOL is essential to improve and understand the reality of patients and their caregivers, because it reflects the functional impact of the illness and its consequent treatment on them, encompassing physical, psychological, and social factors [5]. Since its recognition as a critical measurement for evaluating treatment efficacy by the International League Against Epilepsy (ILAE) Epidemiology Commission, Health-related quality of life (HRQL) has been increasingly included as an essential patient-reported outcome in studies examining the impact of epilepsy surgery [6]. There are some epilepsy-specialized questionnaires available to measure QOL in childhood currently and medical literature exploring the effect of the surgical treatment of epilepsy in the domains of QOL in this population [7–20]. The establishment of QOL domains of patients with epilepsy should be further explored to improve assessments, implications, prognosis, as well as to perform presurgical counseling and to identify targets for perioperative interventions [12,18]. The objective of this study was to evaluate the impact of pediatric epilepsy surgery on QOL, determining whether patients improve, worsen, or maintain their preoperative patterns, and analyze the burden of care for caregivers, as well as potential correlates, from both the children and caregivers' perspectives.

2.3. Statistical analyses For the QOL scales, data were analyzed using the repeated measures analysis of variance (ANOVA MR) method for comparison between all three times of the scale. If there was any significant difference between times, we applied Bonferroni's post hoc test. The ANOVA MR Mixed Model method was used to verify the influence of independent

S.T.F. Leal et al. / Epilepsy & Behavior 106 (2020) 106961

variables on the evolution of scores, confirming whether interaction between scales and independent variables was significant. Finally, we compared the QVCE-50 values between independent variable categories using ANOVA when possible and the nonparametric Kruskal–Wallis test and Mann–Whitney test, as an alternative. 3. Results 3.1. Clinical data and seizure outcome Data from 114 operated children and adolescents were reviewed. Twenty-four patients were excluded because they were lost to followup, 32 due to lack of clinical data, and eight were excluded for having Table 1 Demographic, clinical and social-economic characteristics of patients. Data Sex Female Male Age at surgery 0 to 12 years 13 to 19 years School attendance before surgery Attending school Not attending school Caregivers Mother only Father only Mother and father Caregiver's employment Not employed or homemaker Employed (various occupations) Family income Higher than two Brazilian minimum wages Lower than two Brazilian minimum wages Caregiver's education Graduation from high school or greater No graduation Etiology of epilepsy Malformation of cortical development Acquired injuries Progressive injuries Seizure semiology Generalized motor seizures Focal motor seizures Nonmotor seizures Frequency of preoperative seizures Status or epilepsia partialis continua Daily seizures Weekly seizures Monthly seizures Type of surgery Hemispherotomy Lobectomy or multilobar resection/disconnection Lesionectomy Corpus callosotomy Behavioral disorders Presence of behavioral disorder before surgery Presence of behavioral disorder after surgery Psychiatric medication In use of psychiatric medication before surgery In use of psychiatric medication after surgery Postoperative impairments Behavioral disorder Motor deficits No severe impairment Number of AEM in use (mean) Preoperative Postoperative Engel classification: 2-year follow-up Engel I Engel II Engel III Engel IV

n

%

23 27

46 54

39 11

78 22

36 14

72 28

42 6 2

84 12 4

19 39

38 62

26 24

52 48

9 41

18 82

26 14 10

52 28 20

15 34 10

30 68 20

42 43 6 1

84 86 12 2

12 21 11 7

24 42 22 14

14 25

28 50

10 23

20 46

10 20 20

20 40 40

3

a follow-up shorter than two years. There were 50 patients left for analysis. Of these, 27 (54%) were male, and 23 (46%) were female, with a mean age at surgery of 8.2 years (range: 1–18 years), mean age at seizure onset of 2.4 years (range: 0.3–13 years), and mean epilepsy duration of 5.1 years (range: 0–17 years). The clinical characteristics of the 50 participants are presented in Table 1, which also highlights the great number of patients with behavioral disorders after surgery and the increased use of psychiatric medication, postoperatively. Thirty-five patients (70%) were Engel I and one was Engel II (2%) at six months of follow-up, whereas 28 (56%) were Engel I and 32 (64%) were Engel I or II at two years of follow-up. In both follow-up periods, 11 patients (22%) were Engel IV. Preoperatively, the patients used a mean of 3.5 AEM (range: 2–8). Postoperatively, all patients were still on medication, with a mean of 2.7 AEM after two years of follow-up (range: 1–5). 3.2. Social–economic data The monthly family income was R$ 2.771,70 on average ($ 661.03 USD), ranging from R$ 901,49 (215.00 USD) to R$ 12.8029,02 (3053.99 USD). Income was categorized as higher or lower than two Brazilian minimum wages (circa R$ 2.040,00 or 243.83 USD); 24 families (48%) had an income higher than this value, and in 26 (52%), income was lower. Regarding family patterns and caregivers, in 42 families (84%), they were represented by mothers only, in six (12%), by mothers and fathers, and in two (4%), by fathers only. Concerning the caregiver's employment, 19 (38%) were unemployed or homemaker and the remaining 62% had very diverse jobs. All remaining relevant data are listed on Table 1. 3.3. Neuropsychological and adaptive behavior assessment

3.5 2.7 28 4 7 11

– – 56 8 14 22

For 30 patients (60%), we collected data on intellectual ability. For the remaining 20 (40%), only VABS scores were obtained. Preoperatively, 7 patients (14%) presented with normal intellectual ability, whereas 21 (42%) presented with moderate or severe intellectual disability. Postoperative cognitive evaluations at the two-year follow-up showed that 5 patients (10%) presented with normal intellectual ability, whereas 18 (36%) presented with moderate or severe intellectual disability, according to WISC and VABS. The comparison between pre- and postoperative intellectual or adaptive behavior evaluations is shown in Table 2. 3.4. Quality of life and burden of caregivers assessments 3.4.1. QVCE-50 All caregivers fulfilled this questionnaire. For this, higher scores indicate better HRQL, and there is not a clear cutoff of the level of impact in QOL. The maximum score possible is 200. Preoperatively, our patients reached a mean of 122.3 points (range: 92.4–152.3), whereas at the six-month follow-up, the mean was 127.1, and at the two-year followup it was 132.3. Comparative data of the applied scores of QVCE-50 are shown in Table 3. In the comparison of the global score of QVCE50, between the preoperative and postoperative follow-up, a statistically significant difference was observed regarding the QOL assessment Table 2 Neuropsychological evolution. Neuropsychological (comparative data)

Baseline to 6-month follow-up

%

6-Month to 2-year follow-up

Improvement Worsening Stabilization Total

5 4 41 50

10 2 8 2 82 46 100 50

%

Baseline to 2-year follow-up

4 5 4 7 92 38 100 50

%

10 14 76 100

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Table 3 QVCE-50: total and domain scores. QVCE-50

Baseline

6-Month follow-up

2-Year follow-up

Total scores Minimum Maximum Average values Physical domain Psychological domain Social-familial domain Cognitive-educational domain

92.36 152.3 122.3 52.05 76.15 72.71 44.06

94.83 161.35 127.12 58.58 77.86 73.17 44.78

97.7 175.46 132.26 70.36 75.80 72.53 46.82

among those intervals: preoperative and two-year follow-up (p = 0.001) and between six months and two years of follow-up (p = 0.04). No statistically significant change was found between the preoperative and the six months of follow-up period (Table 4). The influences of the independent variables on the QVCE-50 global score were verified and reported in Table 4. The lower level of parental education was the variable that was associated with QOL presurgically. At 2 years of follow-up, not only parental education, but also their employment were statistically significant, as well as school attendance before surgery, age at seizure onset, seizure frequency, longer duration of epilepsy, number of AEM, use of psychiatric medications, and postoperative presence of behavior disturbances were negatively related to the QOL. On the other hand, seizure freedom (p = 0.001) and parents with higher educational levels were statistically significant variables that were positively related with QOL. Domains in which improvement was particularly statistically significant in QVCE-50 were the physical and the cognitive-education ones when compared pre- and postoperatively. 3.4.2. AUQUEI and QOLIE-AD-48 The AUQUEI was effectively answered by only 8 children of those 39 older than 12 years (21%); the remainder could not fulfill this evaluation

Table 4 Independent variables and QVCE-50: univariate analysis, comparing the preoperative and the 2-year postoperative follow-up. Factors correlated with QVCE-50 scores

Family and social data Caregivers occupation (employed × unemployed or homemaker) Parental education (graduation from high school or greater × did not graduate from high school) Family income (higher × lower than two Brazilian minimum wages) School attendance before surgery (attending school × not attending school) Epilepsy data Age at seizure onset (younger × older than one year old) Age at surgery (younger × older than 12 years old) Duration of epilepsy (shorter × longer duration of epilepsy) Preoperative seizure frequency Status or EPC Daily Weekly or monthly Engel class (Engel class I × Engel class II, III, or IV) Use of psychiatric medication (in use × not in use) Postoperative behavioral disorder (yes × no) EPC: epilepsia partialis continua.

p-Value (6 month–2 years)

p-Value (baseline–2 years) 0.3

0.001*

0.004*

0.39

0.56

0.01*

0.008*

0.02*

0.11

0.48

0.59

0.04*

0.05*

0.86 0.12 0.009* 0.001*

0.6 0.03* 0.06* 0,001*

0.01*

0,001*

0.02*

0.001*

because of cognitive impairment, clinical issues, or epilepsy severity. Preoperatively, the mean score was 47.1 (range: 39–58). At six months and two years of follow-up, scores were 53.7 (range: 42–63) and 49.6 (range: 34–71), respectively. The cutoff value is 48. It was not possible to calculate QOLIE-AD-48 scores for any of those patients because none of them could fulfill the questionnaire adequately, either for reasons of low collaboration, cognitive impairment, or seizure frequency. 3.4.3. Zarit Burden Interview All caregivers fulfilled this questionnaire. Preoperatively, mean score was 34.7 (range: 10–61). At six months and two years of follow-up, scores were 31.7 (range: 5–56) and 34 (range: 1–55), respectively. All these scores were quoted as mild to moderate burden. Among preand postoperative comparison, no statistically significant difference was observed (p = 0.32). Young age at surgery, age at seizure onset, and epilepsy duration were not associated with better QOL (p = 0.57, p = 0.54, p = 0.12) or Burden scores (p = 0.74, p = 0.91, p = 0.33). 4. Discussion In the assessment of QOL and epilepsy, some studies show that QOL is significantly better in surgically treated patients compared with the clinically treated patients, and further show that QOL was better postoperatively than preoperatively in each patient. Nevertheless, these reports are mostly related to adults, and only a few studies are available focusing in QOL of children who underwent surgical treatment for epilepsy [7–20]. Traditionally, the effectiveness of epilepsy surgery has been measured predominantly by seizure reduction. Surgical treatment for epilepsy is a therapeutic method with very good seizure remission rates, showing its efficacy for severe epilepsies [30]. In this study, which included different epilepsy etiologies and surgery types, seizure outcome was good with 72% of improvement in 6 months and 64% 2 years after the surgical procedure. Considering that preoperatively, 86% of patients had daily seizures, these results confirm how positive is the impact of surgical treatment in seizure control. Most of those predictors that may be associated with better Engel scores according to the medical literature, like etiology, age at seizure onset, age at surgery, epilepsy duration, and type of surgery are also significant for improvement in QOL [31–34]. Quality of life has increasingly been included as an important outcome assessment in examining the impact of the surgery, particularly in children [6,15,16]. A meta-analysis that reviewed studies about QOL and epilepsy surgery in children showed that patients who obtained complete seizure freedom after surgery had a considerable improvement in QOL, whereas patients with residual seizures did not substantially improve postoperatively, validating that Engel I is the most desirable outcome of epilepsy surgery [15]. The same results were observed in our series in which Engel I was statistically significant and considered the most relevant positive factor for a better QOL. In addition, besides seizure control, cognition and behavior are also relevant factors that must be considered when analyzing outcomes regarding pediatric epilepsy. It is well known that patients with pharmacoresistant epilepsies are at risk of some level of intellectual disability, mostly moderate or severe, as we observed in our series. There are numerous risk factors for the cognitive decline seen in children with epilepsy as per reported in the medical literature: the occurrence of the seizure itself, seizure-related variables such as frequency and/or severity, duration of epilepsy, underlying pathology, and AEMs [35– 45]. In general, the cognitive and adaptive outcomes of our cases have demonstrated neither cognitive decline nor improvement, but the intellectual or adaptive abilities remained mostly unchanged. This is in accordance with other larger cohorts, which agree that stability of

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cognitive and adaptive abilities should be considered a good result when it comes to encephalopathies [31,33,35–37,39,42]. Statistically, no differences in change in HRQL related to intellectual level or to the postoperative neuropsychological outcome were found. These results showed that children with more severe cognitive or adaptive disabilities achieved similar improvements in HRQL after epilepsy surgery of those with normal or borderline intelligence. Conway, Widjaja, and Smith, 2018, presented similar data in one study evaluating QOL in epilepsy-operated children comparing those with and without low intellectual ability [8]. Nevertheless, this intellectual impairment could play a role in the caregiver's burden. This might be one of the explanations for the unchanged pre- and postoperative results in the burden interview, despite seizure control. Overall, this study showed an improvement in the QOL at the two years of follow-up assessments, according to QVCE-50. It is noteworthy that no changes were observed in the first six months after surgery. We could infer that six months could be a short-time follow-up to measure many items, especially those who are complex and interconnected. Other series evaluated patients operated on at one year or two years of follow-up and found improvement for these periods [8,11,12,19]. The QVCE-50 was designed to be answered by parents who, from their inferences, will evaluate their children's QOL. As it is a specific instrument, it has a higher sensitivity to measure the impacts of epilepsy [24,25]. Quality of life global scores depend on social, cognitive, and behavioral factors. In our study, the best postoperative results, represented by the most significant improvement, were achieved on physical and cognitive-education domains. Increases in physical domain scores are more easily understandable since there is a seizure reduction in up to 78% of patients. This reduction probably decreases the severity of symptoms, as well as side effects of AEM, and improves general health and well-being after surgery. The physical domain addresses factors related to the epilepsy itself, such as seizure frequency and clinical treatment of the disease. For instance, question number 6 is: “How many seizures did your child have in the last year?” Thus, with the successful postoperative outcome, this domain shows an effective improvement in the QVCE-50 scores. Moreover, another topic questioned in the physical domain is the deleterious effects of AEMs, which tend to be reduced in a good seizure outcome scenario. On the other hand, the number of AEMs in our series were not frankly reduced because most of the patients come from distant regions of Brazil, with poorly specialized medical assistance there, and they only visit our center for long-term outpatient appointments. In addition, we have adopted a more conservative policy for medication dropout in the first two postoperative years, as discussed in the literature [46–48]. Furthermore, the possibility of postoperative behavior disturbances secondary to the use of psychiatric medications, as well as the motor sequelae (as expected in hemispherectomy) may also somehow decrease the final score of this domain. Nevertheless, seizure control is the most important factor particularly for this domain, in which we find major differences in QOL improvement. Most patients were stable from a cognitive and adaptive behavior standpoint postoperatively, which can be considered a good result, as previously discussed [31,33,35–37,39,42]. Prior to surgery, these children have been already exposed to their own epileptic encephalopathies, with delay or regression in intellectual abilities due to clinical and epileptic EEG patterns. When the main factor related to the cognitive outcome (seizures) becomes under control, the children tend to improve in terms of high cortical performance and adaptive functions. Even though 72% of these children used to attend school before surgery, their higher incidence of seizures and status epilepticus, hospitalization, outpatient clinical attendance, and AEM side effects accounted for missing school days and/or not improving in learning abilities. Control of these adverse factors makes for better school attendance, with cognitive-educational gains, and justifies a tendency for improvement seen in the cognitive-educational domain of QOL, which evaluates school attendance, school behavior, autonomy, organization, memory, and

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activities. Thus, QOL may be considered an additional method to estimate those gains besides formal psychometric tests. They may represent a more qualitative improvement factor. This has been discussed in the literature as an additional and complementary outcome in operated patients according to psychosocial factors [7,12,18,49]. The QVCE-50 also encompasses psychological and social–familial domains, with no specific significant changes in our study. In the psychological domain, in which aggression, joy, sadness, anxiety, and fear, as well as autonomy, and social interaction were evaluated, there was no evidence of improvement. The presence of psychiatric disorders and the use of psychiatric medications two years after surgery were significant factors negatively associated with QOL. These postoperative impairments have been described, and they were attributed to problems that used to be masked by seizures, becoming more evident and disturbing after seizure control [31,33,50]. Regarding the social–familial domain, including physical limitation of epilepsy, stigmatization, prejudice, and family relationship, this was also unchanged. Even though epilepsy has psychological, biological, cognitive, social, and economic implications, the treatment of the disease did not change the social and financial conditions of these underprivileged families. The population analyzed herein received a meager income (mean mensal family income, circa 661.03 USD); the caregiver has to stay at home caring for the child with a chronic disease and multiple related impairments (38% were not employed); mostly, families were constituted by a sole caregiver (the mother in 84%); the parental's level of education is primarily low. All these make it even more challenging to deal with such a severe disease and its comorbidities, and these factors were above and beyond what might be expected from epilepsy alone and thus associated negatively or prevented changes in QOL after surgery [9]. All these together, particularly the psychological and social–familial domains, negatively impact in the burden of caregivers, who remain overcharged or unchanged despite epilepsy amelioration. These patients still require specific care either for motor or cognitive sequelae, often maintaining the need for use of AEMs and extensive rehabilitation care; thus, overload tends to remain unchanged, and in our study, no significant difference regarding the BURDEN scale was seen [9,51,52]. It should be noted that, in our series, negative factors such as family income and the presence of a sole caregiver were not relevant statistically probably because most families presented with a similar, quite homogeneous, condition, decreasing statistical power. Overall, we agree with studies published previously, which suggested that researchers and health professionals should use scales as a viable option to reduce the burden of caregivers in the HRQL of children with epilepsy [10,49,52]. It is also believed that assessment of QOL should be obtained from the perspective of both caregivers and children as an outcome measure, turning it into an active area for clinical care and research in pediatric epilepsy [6,10,17,19]. One of the objectives of this paper was to evaluate the QOL of children with epilepsy from the child's perspective. Nevertheless, in a population with such severe epilepsy, with clinical and cognitive impairments, patients may be incapable of providing reliable answers, and the caregivers' reports become even more important [8,10,15,16]. However, we have not overlooked the answers of children and adolescents in the scales AUQUEI and QOLIE-48-AD, even if they could only be obtained in a few children. In the eight patients who were able to fulfill the AUQUEI, an impact in QOL was observed, but which did not change significantly among pre- and postoperative evaluations. The small number of respondents did not allow for any comparison concerning QVCE-50. Unfortunately, no answers from the QOLIE-48-AD scale were obtained. This was a limitation of this study since the evaluation of adults is based mostly on inferences about the real state of satisfaction of their children, and in some cases, this might be more prone to inaccurate conclusions in comparison with the assessment of children directly.

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5. Conclusion Health-related quality of life (HRQL) improves after pediatric epilepsy surgery and should be included as an outcome to evaluate the impact of epilepsy surgery in children and adolescents. Seizure control is the most powerful factor for QOL outcome. Recognition of associated factors and variables is important for the establishment of an effective and comprehensive rehabilitation program that improves the QOL of these patients. Children with low intellectual ability are also expected to achieve improvements in QOL, even though psychometric tests showed no changes in cognitive functions. On the other hand, a QOL-based approach has a much broader meaning than just its relationship to health because it encompasses several factors such as cultural, religious, social, collective, economic, political, dynamic, and individual aspects. In an isolated way, treatment of seizures may not improve QOL in epilepsy because these other aspects are independent factors, which evoke the need for interdisciplinary assessments and approaches and their relationship with health issues. This may also explain the unchanged burden of caregivers found herein. This report of QOL for a stigmatized disease as epilepsy in a complex social–economic context may contribute to improve health policies in our country and in other places that face similar challenges. Finally, upgrading structured questionnaires and pediatric epilepsyspecialized QOL instruments can help refine patient and caregiver outcome reports after epilepsy surgery, and outline, which factors most significantly influence these subjects, allowing for better planning of therapeutic approaches. Declaration of competing interest 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. Acknowledgments The study was possible because of the tireless work of the Epilepsy Surgery Center (CIREP) team of the Ribeirão Preto Medical School — University of São Paulo. We are particularly grateful to Vanderci Bianchi Silva and Sandra Souza Funayama for their efforts and assistance with the database, as well as the application of the abovementioned QOL scales. We also would like to thank Geraldo Cassio dos Reis for the statistical analysis and interpretation. Funding support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) – Brazil (#2016/17882-4). References [1] Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334:168–75. [2] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342:314–9. [3] Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46: 470–2. [4] WHOQOL Group. The World Health Organization quality of life assessment. Development and general psychometric properties. Soc Sci Med 1998;46:1569–85. [5] Schipper H, Clinch J, Clweny C. Quality of life studies: Definitional and conceptual issues. In: Spilker B, editor. Quality of life and pharmacoeconomics in clinical trials. 2nd e. New York: Lippincott-Raven; 1996. [6] Thurma DJ, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia 2011;52:2–26. [7] Bajaj J, Tripathi M, Dwivedi R, Sapra S, Gulati S, Garg A, et al. Does surgery help in reducing stigma associated with drug refractory epilepsy in children? Epilepsy Behav 2018;80:197–201. [8] Conway L, Widjaja E, Smith ML. Impact of resective epilepsy surgery on health-related quality of life in children with and without low intellectual ability. Epilepsy Behav 2018;83:131–6.

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