Quality-of-life and behavioral outcome measures in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards

PURPOSE: To review the methodology and use of quality-of-life and behavioral measures used in randomized controlled trials (RCTs) of antiepileptic drugs in patients with epilepsy. METHODS: Trial reports were found by searching a previously developed comprehensive database of epilepsy RCTs and searching through journals by hand. Inclusion and exclusion criteria were applied, and methodological and quality-of-life and behavioral measure data were extracted. RESULTS: There were 52 different measures used in 46 trials, with the Profile of Mood States, the Minnesota Multiphasic Personality Inventory, and the Washington Psychosocial Seizure Inventory being applied the most frequently. Overall, evidence of the reliability, validity, and sensitivity of measures used in populations of people with epilepsy was sparse. There was also little information on the clinical interpretation of the results. CONCLUSION: Our results highlight a consistent failure to apply quality-of-life and behavioral measures in RCTs in a systematic way. We found repeated evidence of researchers' failure to review the use of previous measures and selection of measures without evidence of their appropriateness for use in a population with epilepsy. We recommend the use of quality-of-life and behavioral measures in RCTs with proven psychometric properties in a population with epilepsy.     

Normative Data on Neuropsychological Tests for Very Old Adults Living in Retirement Villages and Hostels

Normative data on neuropsychological tests for very old adults living in retirement villages and hostels are under-represented in the literature. This study reports normative data on the Mini-Mental State Examination, Digit Span Forwards, Digit Span Backwards, the Digit Symbol Substitution Test, the Controlled Oral Word Association Test, the Stroop Neuropsychological Screening Test and the National Adult Reading Test. Age and education showed moderate correlations with neuropsychological test performance. For all tests except the Stroop, differences between residents of retirement villages and hostels were explained by age and education. Men performed better on the NART than women, but this difference was eliminated when education was controlled for statistically.     

Epilepsy surgery,antiepileptic drug trials,and the role of evidence

Objective: We assessed whether recent randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) are informed by evidence about surgical effectiveness. We explored whether RCTs of AEDs consider the patients’ candidacy for surgery in their eligibility criteria, and whether the necessary investigations are requested in participating patients to determine their potential eligibility for surgery. Methods: We systematically analyzed RCTs published in the last 2 years investigating the efficacy of new AEDs in localization‐related epilepsy. Results from a surgical RCT and recommendations from an epilepsy surgery practice parameter were used to assess the degree to which surgical evidence informed the drug study design. Results: Eleven RCTs were analyzed. All were conducted in countries with access to epilepsy surgery. None of the studies required magnetic resonance imaging (MRI) with an epilepsy protocol or explicit statement of the epilepsy syndrome, which could lead to the identification of surgical candidates. Having temporal lobe epilepsy or being a potential surgical candidate were not exclusion criteria in any of the trials. The primary efficacy end point was the reduction in seizure frequency or responder rate. Seizure freedom was never the primary outcome, and it was reported in only seven studies. The pooled data analysis of these trials revealed that 1.9% of patients became seizure‐free on placebo and 4.4% on the study drug (p < 0.01). Conclusions: Important aspects of patient selection for new AED trials are not informed by the evidence about surgical effectiveness. Investigations that could lead to identification of patients for presurgical evaluation were not required in any of the studies.     

Normative data on neuropsychological tests for very old adults living in retirement villages and hostels

Normative data on neuropsychological tests for very old adults living in retirement villages and hostels are under-represented in the literature. This study reports normative data on the Mini-Mental State Examination, Digit Span Forwards, Digit Span Backwards, the Digit Symbol Substitution Test, the Controlled Oral Word Association Test, the Stroop Neuropsychological Screening Test and the National Adult Reading Test. Age and education showed moderate correlations with neuropsychological test performance. For all tests except the Stroop, differences between residents of retirement villages and hostels were explained by age and education. Men performed better on the NART than women, but this difference was eliminated when education was controlled for statistically.     

Following international trends while subject to past traditions: neuropsychological test use in the Nordic countries

Abstract

Objective: Historically, the neuropsychological test traditions of the four Nordic countries have spanned from the flexible and qualitative tradition of Luria-Christensen to the quantitative large battery approach of Halstead and Kløve–Matthews. This study reports current test use and discusses whether these traditions still influence attitudes toward test use and choice of tests. Method: The study is based on survey data from 702 Nordic neuropsychologists. Results: The average participant used 9 tests in a standard assessment, and 25 tests overall in their practice. Test use was moderated by nationality, competence level, practice profile, and by attitude toward test selection. Participants who chose their tests flexibly used fewer tests than those adhering to the flexible battery approach, but had fewer tests from which to choose. Testing patients with psychiatric disorders was associated with using more tests. IQ, memory, attention, and executive function were the domains with the largest utilization rate, while tests of motor, visual/spatial, and language were used by few. There is a lack of academic achievement tests. Screening tests played a minor role in specialized assessments, and symptom validity tests were seldom applied on a standard basis. Most tests were of Anglo-American origin. Conclusions: New test methods are implemented rapidly in the Nordic countries, but test selection is also characterized by the dominating position of established and much researched tests. The Halstead–Reitan and Luria traditions are currently weak, but national differences in size of test batteries seem to be influenced by these longstanding traditions.     

The use of neuropsychological tests across Europe: the need for a consensus in the use of assessment tools for dementia

Background and purpose: The centres dedicated to dementia throughout Europe use different neuropsychological tests in clinical practice. The European Federation of Neurological Societies task force on neuropsychological tests produced this survey on neuropsychological tests currently being used in different European countries to gather knowledge on the practice of dementia centres and to promote the harmonization of such instruments and future multicentre collaborations. Methods: National representatives of 34 countries received a questionnaire and 25 (73.5%) sent it back. Results: A few instruments, Mini‐Mental State Examination (MMSE), Trail Making Test (TMT), Verbal Fluency and Clock Drawing Test, were available in all countries. Wechsler Adult Intelligence Scales and MMSE were reported to be valid, respectively, in 20 (80%) and 19 (76%) countries, whereas Verbal Fluency and Stroop Test are valid in 18 (72%) of them. Of the 25 countries, 17 have validation norms for Clock Drawing Test and TMT (68%), and Neuropsychiatric Inventory, Alzheimer’s Disease Assessment Scale – Cognitive Subscale, Rey Complex Figure Test, Digit Symbol and Beck Depression Inventory were standardized in 16 countries (64%). The remaining tests were validated, at most, in about half of them. Not all countries certificate neuropsychology. Conclusions: Despite the substantial differences in the tools used by the EFNS countries for most domains surveyed by the questionnaire, there is at least one neuropsychological instrument used by about 80% of the countries. There is clearly the need for a broader consensus in the use of neuropsychological tests for dementia diagnosis.     

Role of Vigabatrin and Lamotrigine in Treatment of Childhood Epileptic Syndromes

Summary: Purpose: Vigabatrin (VGB) and lamotrigine (LTG) are two new antiepileptic drugs (AEDs) with different mechanisms of action for treatment of refractory epilepsies. Previous reports have indicated efficacy of both drugs in a number of epileptic syndromes.
Methods: We compared these new AEDs drugs to determine their respective efficacy against different types of epileptic syndrome and to develop a rational approach to their use. We reviewed the charts of 105 children, with partial and generalized epilepsies.
Results: VGB was to be significantly more effective in children with partial epilepsies, and LTG was more effective in those with generalized epilepsies.
Conclusions: VGB and LTG have different therapeutic profiles. Combination treatment with the two drugs may represent rational polytherapy for patients with epilepsy resistant to treatment with either drug alone or as add-on to other AED treatment.     

Factors determining response to antiepileptic drugs in randomized controlled trials. A systematic review and meta-analysis

Purpose: Because of the lack of head‐to‐head adjunctive‐therapy trials of antiepileptic drugs (AEDs) in refractory partial epilepsy, meta‐analyses of placebo‐controlled randomized controlled trials (RCTs) represent a potentially important source of evidence to guide treatment decisions. However, such indirect comparisons raise various methodologic issues that may hamper their relevance. Methods: All RCTs in adult refractory partial epilepsy were analyzed to assess whether efficacy outcomes are influenced by: characteristics of patients and trials ; use of last observation carried forward (LOCF) analysis; evaluation period (entire period versus maintenance period); and year of publication. A meta‐analysis of these AEDs was then performed taking these factors into consideration. Key Findings: Sixty‐three RCTs evaluating 20 AEDs were included. The following variables influenced efficacy estimates: (1) responder rates correlated positively with duration of the entire treatment period (p = 0.038); (2) response to placebo was significantly greater in the maintenance period than in the entire treatment period (p = 0.005); (3) responder rates increased over the years both for AEDs (p < 0.001) and for placebo (p = 0.001); (4) LOCF analysis overestimated responder rates for AEDs (p < 0.001) and for placebo (p = 0.001) compared with completer‐based analysis, and the overestimation correlated positively with withdrawal rates (p < 0.001). A meta‐analysis of available data showed large differences in efficacy ranking in relation to dose selection and type of analysis, but these were mostly nonsignificant due to statistical power limitations. Significance: Several methodologic issues hamper the relevance of indirect comparisons of AEDs in the adjunctive‐therapy of refractory partial epilepsy. Some of these issues could be overcome by improved standardization in the reporting of efficacy outcomes.     

Cognitive and behavioural assessments in clinical trials: what type of measure?

This paper provides an overview of the types of neuropsychological and behavioural measures used in randomised controlled trials (RCTS) of antiepileptic drugs (AEDs) in patients with epilepsy. The results of previous systematic reviews are reported in respect of the methods used in clinical trials to assess cognitive and behavioural effects of AED treatment. There were 46 trials incorporating behavioural measures and 40 trials incorporating neuropsychological measures. The evidence supporting the choice of test, and their reliability, validity, and sensitivity to change was minimal. It is concluded that poor reporting of methods and a plethora of both neuropsychological and behavioural measures make it difficult to provide any meaningful comments about the effects of AED treatment. A much more standardised approach to assessing these effects is necessary.     

Relationships between eight measures of suspect effort

Previous studies have recommended that multiple measures be employed concurrently to provide converging evidence regarding the presence of suspect effort during neuropsychological assessment. However, if the tests are highly correlated they do not represent independent sources of information. To date, no study has examined correspondence between effort tests. The present study assessed the relationships between eight measures which can be used to assess effort (Rey 15-item, Rey Dot Counting Test, Rey Word Recognition Test, RAVLT recognition trial, Rey-Osterrieth Complex Figure Test effort equation, Digit Span, Warrington Recognition Memory Test-Words, and "b" Test) in a sample of 105 patients in litigation or attempting to obtain/maintain disability compensation and who displayed noncredible symptoms based on psychometric performance and behavioral criteria. Modest to moderate correlations were observed between test summary scores with only two measures sharing more than 50% score variance (Digit Span and Dot Counting). Moderate correlations were also observed between individual test scores reflecting indices of response time, free recall, recognition, and false positive errors, providing possible evidence that patients may use specific strategies when producing noncredible performances. Overall the results suggest that the use of these various tests generally provides nonredundant data regarding patient credibility in neuropsychological evaluations.