How can we overcome neuropsychological adverse effects of antiepileptic drugs?

Figures & data

Table 1. Hierarchy of AEDs according to their known effects on cognition (assessed via objective tests) and behavior.

	Attention and executive functions	Memory	Language	Behavior and mood^a
Lamotrigine	0/↑	0	0	(↓)/↑
Lacosamide	0			0
Levetiracetam	0/↑	0/(↑)		↓/(↑)
Oxcarbazepine	(↓)/(↑)	0		(↑)
Rufinamide	0
Eslicarbazepine acetate	(↓)	0
Vigabatrin	0	0	0	↓
Perampanel	0	0		↓
Stiripentol				↓
Pregabalin	0	(↓)	0	↓/↑
Valproic acid	↓	0/(↓)	0	↑
Tiagabine	0	0/(↓)	0	↓
Ethosuximide	(↓)			↓
Felbamate	(↓)			↓
Gabapentin	0/(↓)	0/(↓)	0	(↓)/↑
Clobazam	↓	0		(↓)/↑
Carbamazepine	↓	↓	(↓)	↑
Zonisamide	(↓)	(↓)	(↓)	↓
Phenobarbital/primidone	↓	(↓)		↓
Phenytoin	↓	↓		↓/(↑)
Topiramate	↓	↓	↓	↓/(↑)

↓: negative effect; ↑: positive effect; (): possible effect; 0: no effect; blank: no sufficient evidence; AED: antiepileptic drug.

^aFor details see [1].

No sufficient information on neuropsychological side effects was available for brivaracetam, retigabine, and sultiame.

Table 2. Strategies to address and overcome adverse neuropsychological side effects of antiepileptic drugs (AEDs).

Strategy	Expert opinion
Treatment decisions
Selecting AEDs with superior neuropsychological side effect profiles ○ Also considering positive effects on mood and behavior	The neuropsychological side effect profiles can vary among the different antiepileptic agents. Choosing AEDs according to their cognitive and behavioral risk (and benefit) profile is one major factor to overcome neuropsychological side effects.
Restricting polytherapy to few compatible AEDs ○ Avoiding adverse interactions	Keeping the total drug load low is another decisive factor. With each additional drug in polytherapy, objective cognitive performance may decrease, especially with regard to attention and executive functions.
Striving for low efficacious target doses and blood serum levels	Again, keeping the drug load low is an important factor. However, not all AEDs exert a dose-dependent impact on cognition and behavior. Individual susceptibilities may lead to side effects even with low doses.
Employing careful titration rates when clinically feasible	Subjective complaints may become less likely, because this approach may lead to a poorer recognition of actual side effects. There is no evidence that slower uptitration will prevent any objective neuropsychological side effect.
Considering pharmacokinetics	Controlled-release variants of an antiepileptic agent may prevent high serum peak levels and associated cognitive side effects.
Individual balancing of the degree of seizure control and AED-related side effects	Especially necessary if complete seizure control cannot be achieved with acceptable side effects. The aim of this balancing is a constellation that provides the highest possible quality of life for the individual patient.
Prescribing cognition-enhancing pharmacological agents (nootropics) to counteract side effects	An option of last resort in case of an efficacious antiepileptic treatment with unacceptable side effects, not compatible with keeping the total drug load low.
Non-pharmacological strategies
Informing the patient and his/her relatives about potential side effects of a newly prescribed AED	A higher awareness of cognitive side effects may increase the acceptance of actually occurring side effects and may lead to earlier follow-up visits that give the opportunity for countermeasures.
Detection and monitoring of neuropsychological AED effects ○ Employing valid objective and subjective measures	A systematic screening before and after relevant treatment changes is highly recommended for the reliable detection of neuropsychological side effects. This information can guide treatment decisions to achieve a reduction of adverse AED effects.
Cognitive training to address specific cognitive side effects	An option of last resort in case of an efficacious antiepileptic treatment with unacceptable side effects. No evidence available.

Perucca P, Mula M. Antiepileptic drug effects on mood and behavior: molecular targets. Epilepsy Behav. 2013;26(3):440–449. ​ ​

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