Cognitive Side Effects of Antiepileptic Drugs

Albert P. Aldenkamp

Joanne Taylor

Gus A. Baker

Introduction

Cognitive impairment is the most common comorbid disorder in epilepsy.¹³^,²⁸ Memory impairments, mental slowing, and attentional deficits are the most frequently reported cognitive disorders.¹⁴^,²⁹ Such consequences may be more debilitating for a patient than the seizures; thus, it is worthwhile to explore the factors that lead to cognitive impairment. The exact cause of cognitive impairment in epilepsy has not been explored fully, but three factors clearly are involved: Etiology, the seizures, and the “central” side effects of drug treatment.³ In this chapter we will concentrate on the unwanted effects of antiepileptic medication on cognitive function. When evaluating this factor separately, it is imperative to realize that in clinical practice most cognitive problems have a multifactorial origin and that, for the most part, the three aforementioned factors, combined, are responsible for the makeup of a cognitive problem in an individual patient. Moreover, the factors are related, which causes therapeutic dilemmas in some patients when seizure control can only be achieved with treatments that are associated with cognitive side effects.

The interest in the cognitive side effects of antiepileptic drug (AED) treatment is of recent origin. The possibility that cognitive impairment may develop as a consequence or aftermath of epilepsy was raised as early as 1885 when Gowers described “epileptic dementia” as an effect of the pathologic sequela of seizures. Nonetheless, the topic was not coupled to AED treatment until the 1970s,²⁷^,³⁸ probably stimulated by the widening range of possibilities for drug treatment during that period (i.e., the introduction of carbamazepine and valproate). Since then, a plethora of studies have been published, the majority on the commonly used AEDs: valproate (VPA), carbamazepine (CBZ), and phenytoin (PHT).

In the last decade, several new AEDs have been introduced. Although it is claimed that these drugs have different efficacy profiles and that some drugs are particularly efficacious in specific syndromes (e.g., vigabatrin [VGB]), head-to-head comparisons between the newer drugs and the commonly used drugs (such as CBZ and VPA) are rare. The types of studies used to investigate the newer AEDs are summarized in Table 1. Nonetheless, meta-analyses such as the influential Cochrane reviews³⁹^,⁵⁴ do not show significant differences in efficacy between these newer and commonly used drugs. Also, studies analyzing long-term retention do not show differences between the drugs.⁷⁸^,⁹⁰ Several studies have shown retention rate to be the best parameter of the long-term clinical usefulness of a particular drug.⁴⁷ Retention rate is considered to be a composite of drug efficacy and drug safety and expresses the willingness of patients to continue drug treatment. It is therefore the best standard for evaluating the clinical relevance of side effects. The 1-year retention rate is reported not to be higher than 55% for topiramate (TPM),⁴¹ 60% for lamotrigine (LTG), 58% for VGB, and 45% for gabapentin (GBP).⁵³ Long-term (mostly 3-year) retention is about 35% for all newer AEDs.⁵² Side effects appear to be the major factor affecting long-term retention for most drugs.⁴^,²² In clinical practice, tolerability is therefore a major issue and the choice of a certain AED is at least partially based on comparison of tolerability profiles of the drugs. Also, the tolerability profiles of the newer drugs have become a more important issue in drug development, stimulated by the interest of regulatory agencies.⁴ Cognitive side effects have been demonstrated to be one of the most important tolerability problems in chronic AED treatment.

Method

In evaluating studies of the cognitive effects of AEDs, we will follow an evidence-based approach.¹²^,⁸⁷ Randomized clinical trials with monotherapy in patients with newly diagnosed epilepsy represent the most accurate procedure for assessing the cognitive impact of AEDs.⁴ These studies are not clouded by the effect of concurrent or previous AED use and permit the accurate collection of nondrug baseline data that is required for determining whether a particular treatment affects cognitive processing (i.e., to isolate drug-induced impairments from those due to other sources such as the seizures). Data from such studies can be supplemented with information from studies using add-on or polytherapy designs. In these studies, the use of two AEDs makes identifying the components of the treatment that are responsible for the observed effects more complex. In many cases, however, patients with epilepsy require dual AED therapy before adequate seizure control is obtained; therefore, data from add-on studies does warrant consideration. Also, data from healthy volunteers should be treated with caution. In general, the power of such studies is limited by small sample sizes, and drug exposure periods are typically brief. It is possible that chronic treatment results in entirely different types of cognitive impairment that cannot be observed during short-term treatment. For example, such differences in side effect profile between acute and long-term administration have been found with PHT. Finally, the differing cerebral substrate in patients with epilepsy and healthy volunteers suggests that cognitive responses to AEDs may be different in these populations. Nonetheless, volunteer studies may provide an early insight into the cognitive effects of an AED and therefore provide a foundation for further studies in patients with epilepsy (see reference 87 for a discussion of methodologic aspects of cognitive drug trials in epilepsy).

Table 1 Type of Study to Investigate the Cognitive Side-Effects of Newer AEDs

AED	Volunteer studies	Controlled studies in patients with newly diagnosed epilepsy	Add-on clinical studies in patients with epilepsy
OXC	Curran & Java (1993)	Laaksonen et al. (1985) Sabers et al. (1995) Äikiä et al. (1992) McKee et al. (1994)
TPM	Martin et al. (1999)	Donati et al. (2006)	Meador (1997) Aldenkamp et al. (2000) Burton & Harden (1997) Bootsma et al. (2004) Thompson et al. (2000) Fritz et al. (2005)
LTG	Cohen et al. (1985) Hamilton et al. (1993) Martin et al. (1999) Meador et al. (2000) Aldenkamp et al. (2002)	Gillham et al. (2000)	Smith et al. (1993) Banks and Beran (1991) Aldenkamp et al. (1997)
LEV			Neyens et al. (1995)
TGB		Dodrill et al. (1997)	Kälviäinen et al. (1996) Sveinbjornsdottir et al. (1994)
GBP	Martin et al. (1999) Meador et al. (1999)		Leach et al. (1997)
RUF			Aldenkamp and Alpherts (2006)
AED, antiepileptic drug; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; RUF, rufinamide; TGB, tiagabine; TPM, topiramate.

Results

Phenobarbital

The main anticonvulsant mechanism of action is the increase of the duration (not the frequency) of the γ-aminobutyric acid
(GABA)-activated chloride ion channel opening,⁸⁶ hence potentiating GABA-mediated inhibitory neurotransmission. Phenobarbital (PB) can also activate the GABA_A receptor in the absence of GABA, which is sometimes considered to be a mechanism leading to its sedative properties. PB is used for the treatment of epilepsy since the discovery of its antiepileptic effect by Hauptman in 1912.

For PB one study⁴⁹ is available allowing the evaluation of the cognitive effects of PB relative to a nondrug condition. This study show relative serious memory impairment (short-term memory recall) in 19 patients with epilepsy.

Comparisons with other AEDs are available from four studies²¹^,³⁵^,⁶⁰^,⁸⁸ of patients with epilepsy. One of these shows more impairment for PB than for PHT or CBZ on visuomotor and memory tests³⁵ and two other studies show convincing and clinically highly relevant impairments of intelligence scores after long-term PB treatment in comparison with VPA.²¹^,⁸⁸ A randomized, double-blind, crossover study of healthy volunteers also found more impairment on some measures for PB compared to PHT and VPA.⁶¹ Only the study by Meador et al.⁶⁰ does not show differences between PB and PHT or CBZ.

Phenytoin

The main anticonvulsant mechanism of action is use-dependent (voltage- and frequency-dependent) sodium channel blocking.⁷⁵ It binds to the fast inactivated state of the channel, reducing high-frequency neuronal firing. PHT has a stronger effect on the sodium channel than CBZ, delaying recovery stronger than CBZ. PHT may also have mild effects on the excitatory glutamate system and on the inhibitory GABA system. PHT has been used as an antiepileptic drug since it was introduced for the treatment of epilepsy in 1938 by Merritt and Putnam. For 20 years PHT was (together with PB) the universal treatment of epilepsy. PHT has excellent anticonvulsant properties and is used as a broad-range AED.

For PHT five studies are available⁵⁸^,⁵⁹^,⁷⁷^,⁸²^,⁸³ comparing PHT with a nondrug condition. These studies all reveal PHT-induced cognitive impairment in the areas of attention, memory, and especially mental speed. The magnitude of the reported effects is moderate to large. A caveat is in order, however, as all these studies were carried out in normal volunteers, which opens the possibility that these effects represent short-term outcomes of the drug.

The results of head-to-head comparisons with other AEDs are somewhat more confusing. Using an ingenious long-term treatment and withdrawal design, Gallassi et al.³⁵ found more cognitive impairment than CBZ. On the other hand, no difference with CBZ, VPA, oxcarbazepine (OXC), and even PB are reported.²^,³³^,⁵⁸^,⁵⁹^,⁶⁰^,⁷⁴

Ethosuximide

Ethosuximide (ESX) modifies the properties of voltage-dependent calcium channels, reducing the T-type currents and thereby preventing synchronized firing. The reduction is most prominent at negative membrane potentials and less prominent at more positive membrane potentials. Most effect is assumed to take place in thalamocortical relay neurons. ESX was introduced in 1960 and is mainly used for the treatment of generalized absence seizures.

No controlled studies are available to evaluate the cognitive effects of ESX.

Carbamazepine

The main anticonvulsant mechanism of action is similar to that of PHT with a less “slowing” effect in the recovery state than obtained for PHT. The mechanism of action is also voltage and frequency dependent. CBZ was first synthesized in the early 1950s⁶⁸^,⁶⁹ and introduced as an antiepileptic drug by Bonduelle in 1964 in Europe. CBZ is used for patients with partial complex seizures, with or without secondary generalization. Approval by the Food and Drug Administration (FDA) for use in the United States followed much later (1978) because of concerns about serious hematologic toxicity (e.g., aplastic anemia).

For CBZ two studies, one in normal volunteers⁸² and one in patients with epilepsy,⁶ report “no cognitive impairment” compared to a nondrug condition. This is challenged by the group by Meador et al.⁵⁸^,⁵⁹ that reported impairments of memory, attention, and mental speed, largely the areas that may also be affected by phenytoin.

When evaluating the comparisons of CBZ with other AEDs, there are the conflicting results of the Italian study by Gallassi et al., showing a more favorable profile compared with PHT and PB³⁵ and the U.S.-based study by Meador et al.⁵⁸^,⁵⁹^,⁶⁰ that showed no differences compared with PHT and PB.

Valproate

VPA, a fatty acid, is believed to possess multiple mechanisms of action. A number of studies have demonstrated an effect on sodium channels, however, different from PHT and CBZ. An effect on T-type calcium channels has also been demonstrated. Recent studies have, however, demonstrated that a predominant effect concerns the interaction with the GABAergic neurotransmitter system. More precisely, VPA elevates brain GABA levels and potentiates GABA responses, possibly by enhancing GABA synthesis and inhibiting degradation. Furthermore, VPA may augment GABA release and block the reuptake of GABA into glia cells. VPA is one of the most effective drugs against generalized absence seizures. It was introduced in approximately the same period as CBZ.

For VPA, three studies²⁴^,⁷¹^,⁸⁴ allow the interpretation of absolute effects and show mild to moderate impairment of psychomotor and mental speed. The comparison with other drugs shows lower performance of memory and visuomotor function compared to CBZ³⁵ and a favorable profile compared to PHB on tests for intelligence.²¹^,⁸⁸ One study does not show a difference with PHT.³³

Oxcarbazepine

Oxcarbazepine (OXC) is essentially a prodrug, a keto homolog of CBZ, structurally very similar to CBZ, but with a different metabolic profile. In humans, the keto group is rapidly and quantitatively reduced to form a monohydroxy derivative that is the main active anticonvulsant agent during OXC therapy. Metabolism of OXC does not result in the formation of 10,11-epoxy carbamazepine that is sometimes considered to be the main metabolite causing side effects. The mechanism of action is similar to CBZ. However, OXC is also considered to reduce presynaptic glutamate release, possibly by reduction of high-threshold calcium currents. OXC was approved in the European Union in 1999 and is indicated for use as monotherapy or adjunctive therapy for partial seizures with or without secondarily generalized tonic–clonic seizures in patients 6 years of age or older.

The effects of OXC on cognitive function have been evaluated in one study in healthy volunteers and in four studies in patients with epilepsy. A double-blind, placebo-controlled, crossover study was conducted in 12 healthy volunteers.²⁵ The effects of two doses of OXC (300 mg/day and 600 mg/day) and placebo on cognitive function and psychomotor performance were assessed. The treatment duration for each condition was 2 weeks. Cognitive function tests were administered before treatment initiation and 4 hours after the morning doses on days 1, 8, and 15. In this study, OXC improved performance on a focused attention task, increased manual writing speed, and had no effect on long-term memory proces-ses.

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