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Cognitive side-effects due to antiepileptic drug combinations and interactions

Last updated on October 8, 2021

Cognitive side-effects due to antiepileptic drug combinations and interactionsThe 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 pathological sequela of seizures. Nonetheless, the topic was not coupled to antiepileptic drug treatment until the 1970s.

It has now been established that antiepileptic drug treatment may be associated with a variety of side-effects. Some effects appear immediately after the start of drug exposure, such as nystagmus, but are relatively benign because they show habituation, or are reversible when they are dose dependent. Others may be of insidious onset, emerging only after extended periods of treatment (i.e. chronic side-effects). A multitude of such chronic side-effects have been documented, but the most frequently reported effects concern central nervous system effects. This post reviews some of our knowledge about a specific subgroup of such central nervous system-related chronic side-effects of antiepileptic drug treatment, that is, cognitive side effects: the adverse effects of drug treatment on information-processing systems.

Such effects are considered to be much more moderate than for example, some of the idiosyncratic reactions to drugs and normally do not lead to discontinuation of drug treatment. Nonetheless, a number of studies have claimed that the drug-induced cognitive impairments may have a much greater impact on daily life function than had hitherto been suspected, for example through the impact on critical functions, that is, learning in children or driving capacities in adults (often requiring milliseconds precision), or on vulnerable functions such as memory function in elderly. Moreover, as the cognitive side-effects represent the long-term outcome of antiepileptic drugs, the effects may increase with prolonged therapy, which may contribute to the impact on daily life functioning in patients with refractory epilepsies.

Review of psychometric studies

Clinical effects

Subjective patient complaints


Systematic analysis of subjective patients complaints about side-effects of antiepileptic drugs show that the impact of side-effects maybe larger than hitherto suspected both in number of patients involved (our community-based sample suggests that almost 60% of the patients with antiepileptic drug have complaints) and the frequency of the complaints. Especially the behavioral (and within this class the cognitive) side-effects occur frequently and require careful monitoring and possible interventions.

Still using subjective patient complaints it is clear that a switch from monotherapy to polytherapy entails a serious risk of increasing side-effects. This has been reported from clinical groups, in patients with refractory epilepsy and within the context of many drug trials (most recently for topiramate), but is now also confirmed in a community-based sample.

Table Differences per area of complaint between the four groups: valproate, carbamazepine, combination of phenytoin and polytherapy. Results from a community-based study in 346 patients

  Overall difference: Chi Square Differences between the four groups based
Complaint based on the Kruskall-Wallis test on the Mann-Whitney (7-test
Tiredness 9.276; df3;P = 0.03 Polytherapy > carbamazepine (U = 1834; P = 0.02) Polytherapy > combination of phenytoin (U = 1041; P = 0.005)
Ataxia 11.073; df3;P = 0.01 Polytherapy > valproate (U = 2226.5; P = 0.007) Polytherapy > carbamazepine (U = 1952.5; P = 0.02) Polytherapy > combination of phenytoin (U = 1170; P = 0.03)
Nausea 8.389; df3;P = 0.04 Polytherapy > valproate (U = 2334; P = 0.03) Polytherapy > combination of phenytoin (U = 1184; P = 0.02)
Tiredness 10.047; df 3; P = 0.02 Polytherapy > valproate (U = 2089; P = 0.02) Polytherapy > carbamazepine (U = 1724.5; P = 0.003)
General slowing 9.830; df3;P = 0.02 Polytherapy > valproate (U = 1995.5; P = 0.005) Polytherapy > carbamazepine (U = 1789; P = 0.009)
Concentrationdifficulties 8.253; df3;P = 0.04 combination of phenytoin > valproate (U = 1799; P =S 0.05)
Polytherapy > valproate (U = 2084.5; P = 0.01)
Weight gain 8.040; df 3; P =S 0.05 valproate > carbamazepine (U = 3234; P = 0.05) combination of phenytoin > carbamazepine (U = 1617; P = 0.004) Polytherapy > carbamazepine (U = 2117.5; P = 0.02)

On the other hand, Bourgeois reports reduction of side effects when reducing polytherapy; this is considered proof for a partially cumulative toxic effect. When in clinical decision-making the option of polytherapy arises, the serious risk of an increase in side-effects should be taken into consideration carefully. This is especially important in the light of recent revivals of polytherapy, for example, within the context of rational polytherapy.

A similar effect is often observed when new drugs proceed from initial add-on studies to studies in monotherapy. Although the efficacy profile often remains unchanged, the tolerability profiles often have to be adjusted with much more moderate profiles in monotherapy.

Formal psychometric studies are much more difficult to interpret, especially when formal scientific standards in line with evidence-based medicine are applied.

Nonetheless, we may claim that a systematic review supports these conclusions. It may be considered conceivable that polytherapy increases the risk of behavioral and specifically cognitive impairments. We may therefore hypothesize a potentia-tion of tolerability problems leading to cognitive impairments due to interactions between antiepileptic drugs. This seems to be a general effect as it occurs in many combinations of drugs and so far no specific combination has been identified.

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