Monitoring the cognitive effects of antiepileptic pharmacotherapy — approaching the individual patient

doi:10.1016/j.yebeh.2012.09.015

Epilepsy & Behavior

Volume 26, Issue 3, March 2013, Pages 450-456

https://doi.org/10.1016/j.yebeh.2012.09.015 Get rights and content

Abstract

Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, compliance, and long-term retention of the treatment. Furthermore, adverse cognitive effects of pharmacotherapy significantly affect everyday functioning and quality of life. Consequently, preservation of cognitive functions is an important aspect of epilepsy therapy. Knowledge of the patient’s neuropsychological status before and after pharmacological interventions can help to decide on the appropriate treatment and, thus, can potentially improve individual medical care. Here, we suggest that cognitive monitoring of antiepileptic pharmacotherapy – like the assessment of seizure frequency, blood serum levels, electroencephalography or structural imaging – should be carried out as a matter of routine. In contrast to subjective measures, there are only very few neuropsychological instruments explicitly validated for the assessment of cognition along with antiepileptic pharmacotherapy. This review (1.) outlines indications and requirements for individual cognitive monitoring, (2.) discusses available diagnostic tools, and (3.) discloses relevant pitfalls. Neuropsychology, as demonstrated, provides evidence-based methods for monitoring cognitive effects of individual pharmacological treatments and, therefore, serves as a valuable tool for the quality and outcome control of antiepileptic therapies.

This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.

Highlights

► Cognition is a major aspect of treatment outcome. ► Cognitive deficits in epilepsy reflect synergistic effects of epilepsy and treatment. ► Antiepileptic drugs primarily affect attention and executive functions. ► Objective and subjective instruments allow for tracking cognitive side effects. ► Routine diagnostics may improve individual medical care and treatment outcomes.

Introduction

The pharmacological treatment of epileptic seizures strives for maximum seizure control along with preservation of cognitive functions and improvement of quality of life (QOL). However, cognitive and behavioral side effects of antiepileptic drugs (AEDs) commonly affect daily functioning and QOL. Beyond efficacy, tolerance of the pharmacological treatment is relevant for adherence and long-term retention [1].

Consequently, routine cognitive monitoring of an individual antiepileptic therapy would be highly valuable in order to optimize outcomes and improve adherence to the prescribed medication. In this context, neuropsychology serves as an essential tool for outcome control and quality management in the individual medical care of patients with epilepsy.

Section snippets

Cognitive side effects of antiepileptic drugs

Antiepileptic drugs alter excitation levels of the central nervous system by different mechanisms of action [2]. By this means, AEDs may also induce or exacerbate cognitive deficits [3]. The risk of adverse cognitive side effects increases with (1.) rapid titration, (2.) higher target doses and blood serum levels, and (3.) a higher number of concurrent AEDs. Fortunately, all these factors are under direct control of the treating physician, and countermeasures to minimize the risk of cognitive

Indications for monitoring cognition along with AED treatment

In clinical practice, a brief screening for adverse cognitive side effects can provide an individualized quality and outcome control of pharmacological interventions. Furthermore, screening for eventual cognitive AED side effects guarantees valid results when more extended neuropsychological evaluations of patients with epilepsy are planned (e.g., for counseling or before invasive treatments like surgery, deep brain stimulation, radio- or stereotactic surgery) [18]. In the case of negative drug

Synergistic effects of epilepsy, drug load, and specific AEDs

Antiepileptic drugs represent only one of many possible factors which may affect cognition in epilepsy [19], [20], [21]. Even if there are good reasons to suggest a negative drug effect, it is hardly possible to attribute observed deficits solely to the pharmacological treatment.

In this regard, it is important to know that there is a high prevalence of cognitive deficits already at the onset of the epilepsy or at the time of its diagnosis [22], [23]. In an analysis of 247 untreated patients

Subjective awareness of AED side effects

Whereas severe cognitive side effects due to the initiation or change of an antiepileptic treatment are likely to generate spontaneous complaints by the patient, less severe side effects might only be reported if the patient is directly asked, and only then if the patient is aware of the actual side effects. But as it stands, subjective complaints and objective neuropsychological test performance are often uncorrelated [25]. Therefore, it is not sufficient to solely rely on subjective report

Subjective measures for monitoring pharmacological side effects

Subjective rating scales that have explicitly been developed and validated for the assessment of AED-induced side effects are the Aldenkamp and Baker Neuropsychological Assessment Scale (ABNAS) [32], [33], the Adverse Event Profile (AEP) [34], the Portland Neurotoxicity Scale (PNS) [35] and the Side Effect and Life Satisfaction Scale (SEALS) [36], [37]. Another subjective measure, the Multiple Abilities Self-Report Questionnaire (MASQ) [38], was not developed for epilepsy, but it has been

Criteria for selecting neuropsychological tests

Choosing and combining neuropsychological instruments to monitor cognitive effects of an individual antiepileptic treatment is challenging due to the competing demands for sensitivity versus brevity. Because of (1.) lack of resources, (2.) time constraints, and (3.) burden to the patient, application of a comprehensive neuropsychological test battery is not feasible for daily practice. An alternative approach could be the individual selection and combination of tests according to subjective

Suitability of available tools for approaching the individual patient

In order to screen for negative cognitive side effects of AEDs which may corrupt comprehensive presurgical neuropsychological assessments, Helmstaedter and Lutz developed a screening tool in 2005 which was called the EpiTrack® [56]. The EpiTrack is a 12–15-minute test for the tracking of cognitive side effects. Its six subtests (fluency, response inhibition, working memory, anticipation, speed, and flexibility) focus on attention and executive functions. The test selection was based on a

Defining meaningful cognitive change

As stated above, the reliable detection of adverse cognitive side effects requires a longitudinal approach applying, at least, a baseline evaluation and a reassessment. This directly leads to the question of statistical significance versus clinical significance of the assessed changes. Statistically significant change can be determined by applying confidence intervals (CIs) of regression-based test–retest norms or RCIs.

Regression-based test–retest norms provide expected retest scores which

Pitfalls in the evaluation of cognitive AED effects

Even with optimal assessment tools at hand, there are still some pitfalls that may be encountered by the neuropsychologist:

(1.)
Successful seizure control due to AED treatment can also have positive effects on cognition and behavior. Consequently, negative cognitive side effects may be masked or underestimated. Disentangling the respective cognitive effects of AEDs and seizure control is hardly possible, at least in the individual patient.
(2.)
Since AEDs also have indications for psychiatric diseases [89]

The way forward

As pointed out in the preceding sections, the establishment of routine cognitive monitoring of pharmacological antiepileptic therapies seems to be a feasible and promising approach to improve the medical care of patients with epilepsy. Having been established as an essential tool for the monitoring of invasive treatments of epilepsy, it is about time that neuropsychological methods find their way into routine care of pharmacologically treated patients with epilepsy. In this regard, future

Conflict of interest

CH received royalties from UCB Pharma for the EpiTrack® and royalties from Eisai GmbH for the Neurocog FX®. JAW has no conflicts of interest.

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ReviewMonitoring the cognitive effects of antiepileptic pharmacotherapy — approaching the individual patient

Abstract

Highlights

Introduction

Section snippets

Cognitive side effects of antiepileptic drugs

Indications for monitoring cognition along with AED treatment

Synergistic effects of epilepsy, drug load, and specific AEDs

Subjective awareness of AED side effects

Subjective measures for monitoring pharmacological side effects

Criteria for selecting neuropsychological tests

Suitability of available tools for approaching the individual patient

Defining meaningful cognitive change

Pitfalls in the evaluation of cognitive AED effects

The way forward

Conflict of interest

Seizure

Pharmacol Ther

Epilepsy Behav

Lancet

Epilepsy Behav

Epilepsy Behav

Lancet Neurol

Epilepsy Behav

Clin Psychol Rev

Epilepsy Res

Epilepsy Behav

Seizure

Epilepsy Behav

Seizure

Epilepsy Res

Epilepsy Res

Seizure

Epilepsy Behav

Epilepsy Res

Epilepsy Res

Epilepsy Behav

Epilepsy Behav

Epilepsy Behav

Epilepsy Behav

Epilepsy Res

Epilepsy Behav

Clin Neurophysiol

Alzheimers Dement

Lancet Neurol

Epilepsy Res

Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects

J Child Neurol

Neuropsychological and behavioral effects of antiepilepsy drugs

Neuropsychol Rev

Cognitive side effects of antiepileptic drugs

Can J Neurol Sci

Cognitive side effects of antiepileptic drugs

Epilepsy Behav

Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS subcommittees of the American Academy of Neurology and the American Epilepsy Society

Epilepsia

Newer antiepileptic drugs and cognitive issues

Epilepsia

Effects of antiepileptic drugs on cognition

Epilepsia

Cognitive effects of antiepileptic drugs

J Clin Neurol

Evaluating risks for vigabatrin treatment

Epilepsy Curr

Management issues for women with epilepsy—focus on pregnancy (an evidence-based review): II. teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society

Epilepsia

Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs

N Engl J Med

Neuropsychology in epilepsy part I: cognitive impairments in focal epilepsies

Fortschr Neurol Psychiatr

Patients with epilepsy: cognitively compromised before the start of antiepileptic drug treatment?

Epilepsia

Should cognition be screened in new-onset epilepsies? A study in 247 untreated patients

J Neurol

Impaired verbal fluency under topiramate — evidence for synergistic negative effects of epilepsy, topiramate, and polytherapy

Eur J Neurol

Review
Monitoring the cognitive effects of antiepileptic pharmacotherapy — approaching the individual patient