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. 2023 Jul 5;13(7):e064263. doi: 10.1136/bmjopen-2022-064263

Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE): the change in quality of life after resective epilepsy surgery–protocol for a multicentre, prospective cohort study

Julia T F Kellenaers 1,, Kim Rijkers 1, Ghislaine A P G van Mastrigt 2, Olaf E M G Schijns 1,3, Govert Hoogland 1,3, Jim Dings 1, Sander van Kuijk 4, Marielle C G Vlooswijk 5, Louis G L Wagner 6, Sander Idema 7, Ilse E C W van Straaten 8, Sandra M A van der Salm 9, Marian H J M Majoie 6
PMCID: PMC10335478  PMID: 37407053

Abstract

Introduction

Resective epilepsy surgery is often seen as a last resort when treating drug-resistant epilepsy. Positive results on quality of life (QoL) and economic benefits after surgery argue for a less restrictive attitude towards epilepsy surgery for drug-resistant epilepsy. QoL and economic benefits are country-dependent. The objective of the Resective Epilepsy Surgery, QUality of life and Economic evaluation (RESQUE) trial is to evaluate the change in QoL before and after epilepsy surgery in Dutch people with drug-resistant epilepsy. The results will form part of an economic evaluation of epilepsy surgery in people with epilepsy (PWE) in The Netherlands.

Methods and analysis

A longitudinal prospective multicentre cohort study involving 100 PWE undergoing epilepsy surgery between 2019 and 2025 is being performed in three Dutch academic hospitals. Excluded are PWE who have a lower level of intelligence (TIQ<70) or who do not master the Dutch language. Before surgery and 3, 6, 12 and 24 months after surgery, PWE receive validated online questionnaires (QOLIE-31, EQ-5D, iMCQ and iPCQ) on QoL, cost of care, expectations and satisfaction. Primary outcome is the change in QoL. Secondary outcomes are change in generic QoL, seizure reduction (International League Against Epilepsy Outcome Classification), medical consumption, productivity, the correlation between QoL and seizure reduction and expectation of and satisfaction with the surgery.

Ethics and dissemination

The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019–1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. There is no veto on publication by the involved parties.

Trial registration

NL8278; Pre-results.

Keywords: epilepsy, surgery, neurosurgery


STRENGTHS AND LIMITATIONS OF THIS STUDY.

  • Prospective longitudinal paired-samples study with validated questionnaires.

  • Nation-wide, multicentre study.

  • Data collection of disease-specific quality of life (QoL), generic QoL and costs of healthcare use for calculation of quality-adjusted life years and execution of an economic evaluation at a later phase.

  • No randomised controlled trial because of ethical considerations.

  • Children and caregivers are not included, which might lead to underestimation of the increase in QoL and economic benefits.

Introduction

Epilepsy is one of the most common neurological conditions1 and is defined by any of the following:

  1. At least two unprovoked (or reflex) seizures occurring >24 hours apart.

  2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.

  3. Diagnosis of an ‘epilepsy syndrome’.2

The global incidence varies from 45 (developed countries) to 82 (developing countries) per 100 000 people per year;3 4 in a recent Dutch study, it was 55 per 100 000.5 This amounts to 5000–10 000 new patients per year in the Netherlands.

Epilepsy, therapy resistance and quality of life

Epilepsy is associated with diminished quality of life (QoL).6 7 Treatment objectives are seizure reduction and improvement of QoL. Antiepileptic drugs (AED) are considered to be the standard treatment, with satisfactory results in 60% of people with epilepsy (PWE). However, 40% of PWE suffer from drug-resistant epilepsy, defined as failure of adequate trials of two tolerated, appropriately chosen AEDs (as monotherapy or in combination) to achieve sustained seizure freedom.2 8 Part of this group is eligible for resective epilepsy surgery, further referred to as epilepsy surgery.

Clinical effectiveness of epilepsy surgery

Epilepsy surgery involves the surgical removal of the part of the brain in which the excessive paroxysmal discharges originate (focus or origin), often located within the temporal lobe. Randomised controlled trials (RCTs) have established that epilepsy surgery is an effective treatment option for drug-resistant epilepsy. One year postsurgery, 58%–80% of PWE are seizure-free9–11 and the risk of complications is low (0%–3%).11–13

Previous studies

Since 2000, approximately 200 studies have been published on QoL following epilepsy surgery.14 These studies illustrate that epilepsy surgery leads to seizure freedom or seizure reduction and that this in turn leads to an increase in QoL. To assess QoL, both generic and disease-specific questionnaires are used:15 Short-Form 36, EQ-5D and the Health Utility Index (generic), QOLIE-89, QOLIE-31 and 31-P and QOLIE-16 (disease-specific). Domain-specific questionnaires, like the Beck Depression Inventory or the Beck Anxiety Inventory, are also applied.

Both RCT9–11 and cohort studies with AED control groups, either retrospective15 or prospective,16–18 which compared preoperative to postoperative QoL after resective epilepsy surgery, show that QoL increases after surgery and that this increase is related to seizure reduction. Some studies match positive outcomes to the Minimal Clinically Important Change (MCIC); this is the minimum change in points that is considered clinically relevant,10 19 mostly set at 11.8 points increase on the QOLIE-31 questionnaire.19

In their RCT, Wiebe et al (2001) demonstrated the effectiveness and safety of temporal lobe resection in 80 drug-resistant temporal lobe epilepsy patients, of whom 40 were treated surgically and 40 with AEDs. One year after surgery, seizure freedom was achieved in 58% of the surgery group versus 8% of the AED group. The surgery group reported a significant improvement in QoL on the QOLIE-89.9 Engel et al (2012) performed a multicentre RCT on 76 drug-resistant epilepsy patients who were randomised for either surgery or AED treatment. The trial ended prematurely because of slow accrual. One year after surgery, 11 of 15 surgery patients were seizure-free, versus 0 of 23 people on AED. Although results looked promising, the authors were not able to demonstrate a statistically significant increase in QoL on the QOLIE-89 because of lack of power.20 In another RCT studying QoL after epilepsy surgery or AED-treatment in 80 PWE, Fiest et al (2014) demonstrated that at 6 and 12 months after surgery, 62% of the surgery group versus 17% of the AED group reached the MCIC in QoL on the QOLIE-31.8

Several prospective cohort studies established a positive correlation between seizure reduction and QoL, with both postsurgery seizure-free PWE and PWE with significant seizure reduction reporting an increase in QoL.17 18 Also, the greater the seizure reduction, the greater the increase in QoL.21 Other studies showed that seizure reduction is positively associated with important determinants of QoL, such as work situation, relationship, driving skills and mood.15 18 A Swedish study compared Health-Related Quality of Life (HRQoL)-scores on the QOLIE-89 of a surgical and a non-surgical control group to the HRQoL-scores of a Swedish normative population. After 14 years of follow-up, the surgical group reported HRQoL-scores that were equal or better than the HRQoL-scores of the normative population.16 In another study, the non-surgical control group reported significantly greater deterioration in several domains of HRQoL than the surgical group during 8 years of follow-up (p=0.045 with cognitive stress scores and a trend towards a decline in the overall, mental health and epilepsy target scores on the QOLIE-89).16 In two studies, 50% and 80.5% of postsurgery seizure-free patients or patients with a significant seizure reduction reported an increase in QoL of at least the MCIC.11 19

Problem statement

Despite its well-established effectiveness, based on two RCTs, many cohort studies and a Cochrane review, epilepsy surgery is generally considered to be a treatment of last resort.10 15 International epilepsy literature reveals that QoL before and after epilepsy surgery differs considerably between developing and developed countries, and depends on various factors including the quality of medical care and living conditions.16 Data on QoL and cost-effectiveness are lacking for PWE undergoing epilepsy surgery in the Netherlands. We believe that the societal impact of the clinical effectiveness of epilepsy surgery for Dutch PWE, and for Dutch society in general, may be underestimated. The Dutch Neurological Association (Vereniging voor Neurologie) states that people with drug-resistant epilepsy should be referred for neurosurgical consultation,2 but also in the Netherlands, there is relatively little surgical uptake among people with drug-resistant epilepsy.

Objective

This study has the following objectives: (1) to evaluate the change in QoL before and after resective epilepsy surgery; (2) to correlate seizure reduction and QoL in PWE due to surgery, corrected for confounders; (3) to assess dynamics between the change in QoL and medical consumption and productivity. In addition to this QoL-study, an economic evaluation will be carried out at a later stage using the same data. The outcomes of this study will broaden knowledge on QoL after epilepsy surgery, providing information which can be used in future to set up an implementation strategy aimed at improving referral patterns for epilepsy surgery.

Methods and analysis

Study design

A prospective longitudinal cohort study was designed to evaluate QoL before surgery and 3, 6, 12 and 24 months after surgery. An RCT design was not considered as this requires a control group of drug-resistant PWE who are being treated with AEDs. However, two RCTs (REFS) and one Cochrane systematic review have shown that resective surgery is the recommended treatment for this group of AED-resistant PWE. This also accounts for the Dutch National Guideline for diagnosis and treatment of epilepsy.2

Study population

Eligible for inclusion will be adult drug-resistant PWE referred to Maastricht UMC+, Amsterdam UMC (VUmc) and UMC Utrecht for resective surgery. PWE with a lower level of intelligence (IQ IQ<70) or those do not master the Dutch language will be excluded, because they are limited in their ability to fill in the questionnaires. In the case of disharmonic intelligence profiles, that is, profiles with discrepancies between the verbal and non-verbal components of cognitive development, the verbal IQ (<70) will be leading.

The study inclusion started in 2019 and will be completed in 2025.

Power calculation

The primary outcome is the difference in points on the QOLIE-31 questionnaire before and after surgery. The SD at baseline is estimated at 20 points on the QOLIE-31. Wiebe et al showed that the MCIC (ie, the change in QoL that people find clinically relevant) for people after epilepsy surgery is an 11.8 point change on the QOLIE-31.19 To measure this MCIC of 11.8 with a power of 80%, at least 25 patients must be included. In order to account for a 25% drop-out, 32 patients must be included. For an economic evaluation, the size of the study group is not based on power analysis. Health Technology Assessment scientists advise an inclusion of 100 participants for a reliable economic evaluation. Also, Hollingworth et al (2012) showed that for economic evaluations to reach the same power as regular studies, a greater number of inclusions is required, compared with regular studies. Quality-adjusted life year (QALYs) are less sensitive to change.22 In the future, a trial-based economic evaluation with a follow-up of 24 months will be performed, using the data of the QoL study. In this economic evaluation, the cost per averted seizure and cost per QALY will be calculated.

Every year, about 120 PWE undergo resective epilepsy surgery in the Maastricht UMC+, Amsterdam UCM (VUmc) and UMC Utrecht (fewer during the years of COVID-19 restrictions).

Questionnaires

According to Dutch ‘Guidelines for economic evaluations in healthcare’, an economic evaluation requires data on direct and indirect costs to be collected, as well as QoL data for the calculation of QALYs, determined by the EQ-5D.23

Data will be collected by means of online non-invasive validated questionnaires. These evaluate a patient’s perception of QoL over the past months and include questions about health service use (medication, number of Emergency Department visits, hospital admissions and neurology consultations) and productivity (work situation, social functioning).

Measuring QoL and demonstrating differences between patient groups by means of questionnaires has often been proven to be a valid and reliable method. This study will use generic and disease-specific questionnaires. The disease-specific questionnaires will also (1) provide additional information about small, but clinically relevant, aspects of disease or treatment that are not always detected by a clinician; (2) provide an insight into the burden and consequences of disease and (3) describe the relationship between treatment and change in QoL related to this disease.24 25

The present study will use QOLIE-31, EQ-5D, iMCQ and iPCQ questionnaires.

The QOLIE-89, as well as its shorter versions QOLIE-31 and QOLIE-16, are disease-specific, validated and frequently used.26 Research has demonstrated that the QOLIE-31, consisting of 31 questions about the main domains of QoL, that is, overall QoL, seizure worry, emotional well-being, energy, social functioning and medication,26 is the most sensitive version.9

EQ-5D is a validated questionnaire for measuring generic health in five domains: mobility, self-care, daily activities, pain/discomfort anxiety/depression.27

The iMCQ is a validated instrument for measuring costs of health service use.28

The iPCQ is a validated instrument for measuring productivity losses.29 Finally, a few questions will be included about expectation of and satisfaction with the procedure.

Study procedure

For this study, candidates will be selected from those referred for epilepsy surgery to the Department of Neurosurgery of the Maastricht UMC+, Amsterdam UMC (VUmc) or UMC Utrecht. Before consultation, patients will receive an information leaflet by mail about the Resective Epilepsy Surgery, QUality of life and Economic (RESQUE) study, with a request to return a completed informed consent form. Following neurosurgical consultation, the patient will be given the opportunity to ask questions and return the signed informed consent form. The patient is free to withdraw from the study at all times without explanation or treatment consequences.

Once informed consent has been given, the patient will be sent a survey package with the above-mentioned questionnaires, by email or by post/mail, before surgery and 3, 6, 12 and 24 months after surgery. This will require the patient on each occasion to spend about 40 minutes in completing the questionnaires.

In addition, data from patient charts, including epilepsy diagnosis, seizure frequency, medication and side-effects will be collected by means of Castor, a secure tailor-made database for electronic data collection that adheres to all guidelines of good clinical practice. A secure SPSS-document with patient numbers, but without personal data, such as name or date of birth, will be stored on a hospital secure computer and a hard drive in a hospital safe. Only designated researchers have access to this data and will act according to Dutch privacy laws and regulations.

Outcomes and statistics

Researchers involved in analysis and interpretation of the data will be blinded to patient personal details.

It is hypothesised that drug-resistant epilepsy patients will report a significant and clinically meaningful improvement in QoL after epilepsy surgery.

Baseline characteristics of patients are described as means and SD for continuous variables, and absolute numbers and percentages for categorical variables.

The primary outcome is the difference in disease-specific QoL between the preoperative evaluation and the postoperative evaluations on the QOLIE-31, expressed in points changed on the QOLIE-31 questionnaire. Differences in preoperative and postoperative scores will be tested with a paired t-test.

Secondary outcomes are the differences between presurgery and 3-6-12-24 months postsurgery with regard to (1) generic QoL (EQ-5D), (2) seizure frequency in International League Against Epilepsy (ILAE) outcome scale (table 1),30 (3) medical care (iMCQ) and (4) productivity (iPCQ).25–28 Correlations between QoL change and seizure reduction will be analysed. Seizure frequency, based on the ILAE Outcome Classification, will be described as absolute numbers and percentages and will be dichotomised in 1–2 versus 3–5. The McNemar test will be used to test for differences in proportions presurgery and postsurgery. The association between the change in QoL and seizure reduction will be tested with an unpaired two-sample t-test by calculating the difference in scores and comparing the average change in scores of ILAE 1–2 patients and ILAE 3–5 patients.

Table 1.

ILAE outcome classification of postoperative seizure outcome

ILAE classification Definition
1 Completely seizure-free, no auras
2 Only auras, no other seizures
3 1–3 seizure days per year; ±auras
4 4–12 seizure days per year; ±auras
5 Daily seizures; ±auras
6 More than 100% increase in baseline seizure days; ±auras

ILAE, International League Against Epilepsy.

Patients and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

Ethics and dissemination

The study design has been approved by the Medical Ethics Review Committee (METC) of Maastricht UMC+ (2019–1134) and the Amsterdam UMC (vu). At the time of writing, UMC Utrecht is in the process of considering approval. The study will be conducted according to the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals. Any adverse outcomes will be reported if applicable. There is no veto on publication by the involved parties. The study is not sponsored. The study protocol has been published in the Dutch trial registration: NL8278.31

Supplementary Material

Reviewer comments
Author's manuscript

Footnotes

Twitter: @gvanmastrigt

Contributors: JTFK (author and principal investigator, MD), KR (protocol development, author, investigator and neurosurgeon), GAPGvM (protocol development, HTA-specialist and epidemiologist), OEMGS (protocol development, neurosurgeon), GH (protocol development, neurophysiologist), JD (review, neurosurgeon), SvK (protocol development, epidemiologist), MCGV (review, neurologist), LGLW (review, neurologist), SI (SMJ (protocol development, neurosurgeon), IECWvS (SMJ (protocol development, neurologist), SMAvdS (review, neurologist), MHJMM (protocol development, author and neurologist).

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

Provenance and peer review: Not commissioned; externally peer reviewed.

Ethics statements

Patient consent for publication

Not required.

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