|Management of treatment-resistant epilepsy. Volume 1: evidence report and appendices. Volume 2: evidence tables. Non-drug treatment strategies
|Chapell R, Reston J, Snyder D, Treadwell J, Tregear S, Turkelson C
This review evaluated non-drug treatments for patients with treatment-resistant epilepsy, and concluded that effective treatments are available, but all have disadvantages. Given the exclusion of several interventions, the paucity of good-quality data for those included, and the limitations of the review, the conclusions should be viewed with caution.
To determine which methods of non-drug treatment for epilepsy, after initial treatment failure, lead to improved outcomes for patients with treatment-resistant epilepsy. Diagnosis and drug treatments are addressed in separate abstracts (see DARE abstract numbers 12005008217 and 12005008218, respectively).
The authors searched the following: MEDLINE (1975 to 2002), EMBASE (1975 to January 2002), PsycINFO (1975 to January 2002), CIRRIE (November 2001), CINAHL (1988 to January 2002), the Cochrane Database of Systematic Reviews (Issue 4, 2001), the Cochrane CENTRAL Register (Issue 4, 2001), the Cochrane Review Methodology Database (Issue 4, 2001), DARE (Issue 4, 2001), NHS EED (to January 2002), ECRI Health Devices Alerts (1977 to January 2002), ECRI Health Devices International Sourcebase (1977 to January 2002), ECRI Healthcare Standards (1975 to January 2002), ECRI International Health Technology Assessment (1990 to January 2002), ECRI Library Catalogue (to January 2002), ECRI TARGET (to January 2002), ERIC (January 2002), Health and Psychosocial Instruments (to April 2001), LocatorPlus (to January 2002), NDA Pipeline (November 2001), REHABDATA (April 2001), U.S. Centers for Medicare and Medicaid Services (to January 2002) and the National Guideline Clearinghouse (to January 2002); the search strategies were reported. In addition, the reference lists of included studies were checked. Current Contents (Clinical Medicine) was also searched on a weekly basis. Only full length, English language articles, published in 1985 or later, were included.
Study designs of evaluations included in the review
There were no specific criteria relating to the study designs eligible for inclusion. If there were fewer than 5 studies for a given intervention, and none of these were a randomised controlled trial (RCT) with 50 or more patients in the treatment group, none of the studies were included for that intervention. If one of the studies was an RCT with 50 or more patients in the treatment group, the RCT was included even if there were fewer than 5 studies. When there were 5 or more controlled studies for a given intervention, the uncontrolled studies were excluded for that intervention. When there were 5 prospective studies for a given intervention, the retrospective studies were excluded for that intervention (except for surgical interventions).
Specific interventions included in the review
Studies eligible for inclusion were those of:
surgery (anterior temporal, frontal, parietal, occipital, lobe resections, cerebral hemispherectomy, corpus callosotomy and multiple subpial transection) published 1985 and later;
non-drug/nonsurgical interventions (vagal nerve stimulation (VNS), ketogenic diet, magnetic therapy, vitamin B6 therapy, herbal medicines, acupuncture, electrical brain stimulation, chiropracty, cranial realignment and hyperbaric oxygen therapy); and
non-medical treatments (social, psychological or psychiatric interventions).
The surgical procedures evaluated in the review were temporal and frontal lobe surgery, cerebral hemispherectomy and corpus callosotomy. The only non-drug/nonsurgical intervention evaluated was VNS. No non-medical interventions were evaluated.
Participants included in the review
Studies of people with drug-resistant epilepsy, or where results of those with drug-resistant epilepsy were reported separately, were eligible for inclusion. The studies had to have a minimum of 10 people to be eligible for inclusion.
Outcomes assessed in the review
Studies had to report quantitative outcome measures. Studies reporting the following were eligible for inclusion: absolute seizure frequency; percentage change in seizure frequency from baseline; proportion of patients seizure-free; proportion of patients with more than a 50% reduction in seizure frequency from baseline; Engel classification; rundown time to seizure-free; seizure-free period; proportion of patients with any reduction in seizures; proportion of patients with any increase in seizures; proportion of patients exiting a trials because of an increase in harmful seizures; quality of life; mood; functional status/ability; cognitive function; ability to stay in or return to work or school; ability to hold a driver's license; adverse events; mortality.
How were decisions on the relevance of primary studies made?
The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.
Assessment of study quality
The authors examined studies for sampling bias, sample specification bias, selection bias, regression bias, patient bias, investigator bias, measurement bias, attrition bias, maturation bias and extraneous event bias. Those reporting mortality were evaluated for cause validation bias, mortality ratio bias, sampling bias and sample specification bias. Studies considered to have design flaws that would bias these results were excluded from the review. Statistical power was also considered. The authors did not state how many reviewers performed the validity assessment.
The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Data relating to seizure frequency, quality of life, employment and education outcomes, mood, cognitive function, complications and mortality were extracted.
Methods of synthesis
How were the studies combined?
All of the studies were combined in a narrative. Some studies were combined in a meta-analysis using intention-to-treat, and Cohen's h or Hedge's d calculated, along with 95% confidence intervals (CIs).
How were differences between studies investigated?
Heterogeneity was assessed using the Q statistic. Sensitivity analyses were conducted to evaluate the effect of patient characteristics on the results. Study characteristics were tabulated and differences between the studies were discussed in the text. Forest plots were provided for pooled analyses, to enable a visual inspection of heterogeneity.
Results of the review
One hundred and seventy-nine studies met the inclusion criteria: 165 evaluated surgical procedures and 14 evaluated VNS.
Studies evaluating surgical techniques were either primarily retrospective (temporal lobe) or lacked suitable controls (corpus callosotomy, frontal lobe, hemispherectomy, multiple subpial transaction), therefore they were subject to potential biases. Studies of VNS were all affected by selection, reporting and measurement bias.
Seizure frequency and adverse events were referred to in the abstract as the primary outcomes. The results of several sensitivity analyses were reported for seizure frequency. Other outcomes such as quality of life were also reported. There was insufficient evidence to determine changes in quality of life, memory, mood, cognitive function, functional status/ability, or ability to work or hold a driver's licence for most of the surgical procedures.
Temporal lobe studies with seizure-free outcome measures (73 studies; n=3,978).
There were 5 prospective and 30 retrospective nested case-controlled studies, and 5 prospective and 33 retrospective case series.
Approximately 55% (95% CI: 50, 60) of patients were seizure-free with no auras (20 studies; n=734) and 68% (95% CI: 65, 72) seizure-free with auras (26 studies; 1,396). All studies reporting Engel class I (33 studies; n=1,549) or patients being seizure-free undefined (16 studies; n=977) reported a significant increase after temporal lobe surgery; however, heterogeneity precluded the calculation of a pooled estimate. Approximately 2% of patients suffered a permanent postsurgical complication, generally some form of paralysis; 0.24% died as a result of the surgery (40 studies; n=2,091).
Between 24% and 100% (6 studies) of patients were seizure-free (undefined) after frontal lobe surgery. Zero to 23% of patients had serious adverse events, while 0 to 60% had mild or transient complications (8 studies; n=369).
Hemispherectomy (3 studies).
Between 40% and 71.4% of patients were seizure-free after hemispherectomy. A variety of definitions of seizure-free were used.
Corpus callosotomy (12 studies).
All studies were case series. Between 9.1% and 36.4% of patients achieved a 90% or greater reduction in seizure frequency with corpus callosotomy (5 studies), between 0% and 13.6% were seizure-free (4 studies), and between 3.6% and 40% received no benefit (7 studies). Zero to 35% of patients had serious adverse events, while 0 to 60% had mild or transient complications.
Multiple subpial transection (9 studies).
Between 0% and 78.6% of patients were seizure-free undefined (4 studies), between 25% and 89.5% had a 90% reduction in seizures (4 studies), and between 20% and 57.1% were Engel class I (4 studies) after multiple subpial transaction. Zero to 18% of patients had serious adverse events, while 0 to 57% had mild or transient complications.
VNS (14 studies).
Two multicentre RCTs and 12 case series evaluated VNS. Between 13.3% and 62.5% of patients had a greater than 50% reduction in seizure frequency with VNS. Between 0% and 6.3% of patients died, of which one death was directly attributable to VNS (14 studies), and between 5.6% and 17.9% suffered parethesia (3 studies). Several more minor adverse events were reported individually for this intervention.
Effective treatments are available, but all have disadvantages. Temporal lobe surgery eliminates seizures in many patients, whereas hemispherectomy and frontal lobe surgery and VNS eliminate seizures in an indeterminate number of patients; corpus callosotomy reduces seizure frequency but generally does not eliminate seizures.
The research question was clear, with well-defined inclusion criteria. An extensive search was undertaken, thus reducing the potential for publication bias. Only English language studies were included in the review, therefore there is a potential for language bias. It was unclear whether the study selection, quality assessment and data extraction processes were conducted in duplicate, therefore these may be subject to error and bias. Given the lack of literature for some interventions, the exclusion of several interventions on the basis that fewer than 5 were available, even though some that were available passed the quality criteria, resulted in some important interventions not being discussed. In addition, this requirement of 5 or more studies meant that some outcomes were also not discussed for an included intervention. The review was therefore not the comprehensive overview of non-drug interventions expected. Given the paucity of good-quality data and the limitations of the review, the conclusions drawn about the interventions discussed should be viewed with caution.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors suggested prospective studies of surgical interventions, with better reporting of patient characteristics and reporting of standardised quality-of-life measures. High-quality controlled trials are also needed for non-medical treatments such as education and training. Large cohort studies evaluating mortality, particularly in patients with treatment- resistant epilepsy, are also required.
Agency for Healthcare Research and Quality, contract number 290-97-0020.
Chapell R, Reston J, Snyder D, Treadwell J, Tregear S, Turkelson C. Management of treatment-resistant epilepsy. Volume 1: evidence report and appendices. Volume 2: evidence tables. Non-drug treatment strategies Rockville, MD, USA: Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment; 77. 2003
Subject indexing assigned by CRD
Epilepsy, Temporal Lobe /therapy
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.