Understanding mechanisms of drug resistance in epilepsy and strategies for overcoming it

ABSTRACT

Introduction

The present evidence indicates that approximately 70% of patients with epilepsy can be successfully treated with antiepileptic drugs (AEDs). A significant proportion of patients are not under sufficient control, and pharmacoresistant epilepsy is clearly associated with poor quality of life and increased morbidity and mortality. There is a great need for newer therapeutic options able to reduce the percentage of drug-resistant patients.

Areas covered

A number of hypotheses trying to explain the development of pharmacoresistance have been put forward. These include: target hypothesis (altered AED targets), transporter (overexpression of brain efflux transporters), pharmacokinetic (overexpression of peripheral efflux transporters in the intestine or kidneys), intrinsic severity (initial high seizure frequency), neural network (aberrant networks), and gene variant hypothesis (genetic polymorphisms).

Expert opinion

A continuous search for newer AEDs or among non-AEDs (blockers of efflux transporters, interleukin antagonists, cyclooxygenase inhibitors, mTOR inhibitors, angiotensin II receptor antagonists) may provide efficacious drugs for the management of drug-resistant epilepsy. Also, combinations of AEDs exerting synergy in preclinical and clinical studies (for instance, lamotrigine + valproate, levetiracetam + valproate, topiramate + carbamazepine) might be of importance in this respect. Preclinically antagonistic combinations must be avoided (lamotrigine + carbamazepine, lamotrigine + oxcarbazepine).

KEYWORDS:

• Antiepileptic drugs
• epilepsy
• drug combinations
• pharmacoresistance
• seizures

Article highlights

• Epilepsy, as a chronic neurological disease, affects circa 65 million people of the world’s general population.

• Up to 30% of patients with epilepsy do not properly respond to antiepileptic drugs and cannot be sufficiently controlled with pharmacological treatment. After all, pharmacoresistance is associated with enhanced morbidity and mortality, and quality of life is markedly reduced.

• Although no animal model has been so far validated as a model of drug-resistant epilepsy, some existing models can help in the search for more effective drugs (also drug combinations) or compounds in this respect. The most frequently used are: 6 Hz psychomotor seizure model, 6 Hz corneal kindled mouse, intrahippocampal kainate model of mesial temporal lobe epilepsy in mice or posttraumatic seizures in rats.

• The existing hypotheses aimed to explain pharmacoresistance consider the significance of altered targets for antiepileptic drugs, overexpression of brain, and/or peripheral efflux transporters, initial considerable seizure frequency, existence of aberrant brain networks and genetic polymorphisms. In the light of the above hypotheses, antiepileptic drugs may not fully exert their effects, and their brain concentrations may not reach the therapeutic level. Also, a suppression of endogenous defense system against seizure activity or altered AED pharmacokinetics by genetic polymorphisms may be considered.

• Increased inflammatory or mTOR signaling and production of free radicals, blood–brain barrier dysfunction, and disturbed renin–angiotensin system may contribute to pharmacoresistance as well.

• Management of drug-resistant epilepsy must consider various approaches. Probably, antiepileptic drugs with anti-epileptogenic potential (eslicarbazepine, levetiracetam, and topiramate), especially combined, might be of importance. Anti-inflammatory and antioxidative treatments, as well as mTOR inhibitors, may also be considered. The recent preclinical evidence points to losartan (an angiotensin receptor blocker) as a possible drug, especially in terms of epileptogenesis inhibition.

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Declaration of interest

SJ Czuczwar has received financial support from Bayer, GlaxoSmithKline, Janssen, Novartis, Sanofi-Aventis for lecturing, and is a recipient of an unrestricted grant from GlaxoSmith Kline in 2007. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper received no funding.