Introduction and first validation of EpiTrack Junior, a screening tool for the assessment of cognitive side effects of antiepileptic medication on attention and executive functions in children and adolescents with epilepsy
Introduction
Epilepsy is the most common chronic neurological disease of childhood. Although most children with epilepsy can develop normal intelligence, many suffer from transient or permanent cognitive impairment possibly resulting in school failure, unemployment, and social isolation [1], [2], [3]. The etiology of cognitive impairment in patients with epilepsy is multifactorial, including static and irreversible damage to the central nervous system, but also dynamic and potentially reversible factors characteristic of epilepsy. Examples of the latter are dysfunctions resulting from epileptic activity and seizures, anticonvulsant medication, and the interdependence between the two [4]. Those dynamic factors are in the hands of the physicians. Control of seizures and epileptic dysfunction and preservation and improvement of cognitive abilities are major targets of the treatment of epilepsy. Adverse cognitive side effects determine the tolerance and long-term retention of the antiepileptic treatment. In poorly controlled epilepsy, they can affect quality of life more than seizures, and systematic screening can help to improve the patient's satisfaction and quality of life [5], [6], [7], [8]. The situation in children is different from that in adults with respect to such dynamic factors as epilepsy and antiepileptic drug treatment; although their impact on cognition may be reversible, these factors can cause irreversible impairment when they negatively interfere with important steps in brain development. Impressive evidence of how antiepileptic drug treatment can hinder children's later cognitive development has recently been demonstrated with the effects of intrauterine exposure to higher doses of valproic acid [9]. Thus, early identification of cognitive impairment in children with epilepsy is mandatory, as such deficits adversely impact future cognitive development, schooling, employment, daily functioning, and social interactions. Cognitive and behavioral problems are often already present at epilepsy onset in children [10], [11], and optimal conditions for cognitive and behavioral development include successful seizure control and minimization of the negative and maximization of the positive effects of drug treatment on cognitive abilities [12], [13].
Particularly when an unsatisfactory degree of seizure control calls for polytherapy or high drug doses, or, independent of seizure control, patients or parents complain about cognitive or behavioral side effects, the clinician may wish to rely on objective outcomes of his or her actions. Subjective complaints or self-rating scales can be biased by mood, intellectual ability, and memory, and are often not sufficient to solve the situation [14]. Explicit trials on the cognitive effects of antiepileptic drugs (AEDs) in children are not the rule, but a gross summary of recent reviews on the neuropsychological effects of AED treatment in children and adults indicates that even when specific dysfunctions (memory/language) are indicated, nonspecific speed and executive functions are also affected (see Table 1) [12], [13], [15], [16], [17], [18], [19], [20], [21], [22], [41]. In search of measures that co-vary with number of AEDs, seizure frequency, and use/nonuse of individual drugs, we evaluated in 2004 a large database of presurgical patients who all underwent extensive (~ 3 hours) routine neuropsychological evaluation. Measures of attention, working memory, and executive functions turned out to be most sensitive with respect to the external criteria, and we condensed the test battery to a 12- to 15-minute screening tool that comprised six subtests resulting in one general score. The collected subtests were newly standardized in 220 healthy subjects aged 16 to 60 (a second edition will provide norms for > 400 subjects up to 80 years old). Retesting after an interval of ~ 5 months provided reliability of change indices, and the final test was called EpiTrack [23]. Details on the construction and validity of this tool were published in 2005 [24]. The validity of EpiTrack and its subtests has been proven in recent AED trials [25], [26], [27], [28], [29], [30], [31]. This gave rise to the idea of a similar tool for the evaluation of younger patients aged 6 to 18. The basic principle underlying the test remained the same, but the materials had to be adapted for younger children.
According to the review in Table 1, tests of attention, psychomotor speed, language, and memory functions are suitable for the assessment of cognitive side effects of AED treatment in children with epilepsy. However, different from the diagnostic approaches commonly used in drug trials, that is, choosing a set of tests for repeated application and drawing conclusions from contrasting experimental groups at different test times, individual longitudinal monitoring of the cognitive effects of AEDs requires application of statistical rules for rating performance not only as impaired or unimpaired, but also as significantly changed or unchanged. In particular, this requires knowledge of the retest reliability of the tests in use, that is, the stability of test performance over time, knowledge of the standard deviations of the test scores (the range within which the true value can be suggested), and consideration of practice effects resulting from repeated administration of the same test or a parallel test version. Review of a test compendium for neuropsychological evaluation in children reveals that retest reliabilities of tests are often not communicated; neither are the practice effects with repeated administration or the retest intervals for which test stability has been assessed [32]. In children, the retest interval is of particular importance because with long retest intervals, mental development must be considered. Better standardized test instruments usually provide retest reliability and fine-graded age norms. For assessment of the cognitive effects of AED treatment, reliability and practice effects for short-term follow-up testing would be highly appreciated. Thus, one can easily comprehend the difficulties practitioners face in the repeated administration and interpretation of different tests when monitoring individual treatment outcomes in individual patients. EpiTrack Junior, like its adult counterpart, was explicitly designed to overcome such problems in clinical practice. Tests and test constructs that had been proven to be sensitive with respect to AEDs were merged into a single age-corrected score for which the variance, stability, and practice effect within a 3-month retest interval were evaluated.
Section snippets
Test description
EpiTrack Junior comprises six tasks addressing attention, executive functions, and working memory. The six tasks are derived from the adult version and assess the same cognitive constructs, but material and task difficulty are adapted to the requirements for testing children and adolescents. The original tests from which the test concepts of EpiTrack Junior were borrowed are the German Kurztest für cerebrale Insuffizienz [33] (subtest 1); the Trail Making Test [34] (subtests 2 and 3); the
Scaling
Performance of the control sample is summarized in Table 2. The raw scores for each test were standardized into a seven-step scale so that the mean was between 4 and 5, one step representing 1 SD. With this procedure the test has greater differentiation in the lower than in the upper range; that is, it is more deficit than performance oriented.
To obtain a total score the converted EpiTrack subtest scores were summarized into an uncorrected total EpiTrack score, which can range between 10 and 42
Discussion
Cognitive impairment represents a major comorbidity in patients with epilepsy [4], and antiepileptic drug treatment can positively or negatively affect cognition directly through action on brain function or indirectly through control of epilepsy. Systematic screening of cognitive side effects has been demonstrated to positively influence drug tolerance and maintenance, as well as patient satisfaction and quality of life [5], [6]. In children, monitoring cognitive effects of antiepileptic drug
Conflict of interest statement
C. Helmstaedter receives a license fee for EpiTrack from UCB GmbH.
Acknowledgment
The normalization of this test was supported by UCB-GmbH Germany.
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