Developing precision treatments for epilepsy using patient and animal models

ABSTRACT

Introduction: Phenytoin was the first antiepileptic drug (AED) discovered in an animal model of seizures whose clinical efficacy was subsequently confirmed. This clearly indicated that a search for other AEDs had to consider animal studies.

Areas covered: Main seizure tests used for the evaluation of possible anticonvulsive activity of potential anticonvulsants and their predictive values have been reviewed. Procedures used for the estimation of antiepileptogenic effects have been also included.

Expert opinion: First-line seizure models comprise maximal electroshock (MES)-, pentylenetetrazol (PTZ)- and kindling-induced convulsions in rodents. The MES test may be considered as a convenient and easy model of generalized tonic-clonic seizures, PTZ test – as a model of generalized myoclonic seizures and to a certain degree – absence seizures. Kindled seizures (for example, from amygdala) may be regarded as a model of focal seizures. Some tests have been suggested for the search of AEDs effective in drug-resistant seizures – for instance, 6 Hz (44 mA) test or intrahippocampal kainate model of mesial temporal lobe epilepsy. There are also recommendations from experimental epileptology on synergistic AED combinations for patients with drug-resistant seizures. The clinical evidence on this issue is scarce and favors a combined treatment with valproate + lamotrigine.

KEYWORDS:

• Antiepileptic drugs
• seizure models
• models of epileptogenesis
• drug-resistant epilepsy
• combinations of antiepileptics

Article highlights

• The prevalence of epilepsy is within 5-10 cases per 1000 population and the total number of patients with epilepsy reaches 65 million. Circa 30% of epilepsy patients suffer from drug-resistant seizures.

• The first antiepileptic drug discovered by animal testing was phenytoin in 1938.

• At present, the first-line experimental tests for the search of antiepileptic drugs are maximal-electroshock-, pentylenetetrazol- and kindling-induced seizures in rodents.

• Maximal electroshock test identifies antiepileptic drugs effective against generalized tonic-clonic seizures, pentyenetetrazol test – antiepileptic drugs for the control of generalized myoclonic seizures and to a certain degree – absences, and kindling is regarded as a procedure for the search of antiepileptics inhibiting focal (partial) seizures.

• A number of tests (for instance, 6 Hz test at 44 mA or intrahippocampal kainate model of mesial temporal lobe epilepsy) may be used for the identification of antiepileptic drugs particularly effective against drug-resistant seizures; however, none of them has been ‘clinically validated’ so far.

• Post status epilepticus model has been suggested as a procedure for the assessment of antiepileptogenic compounds. An inhibition of spontaneous seizure activity in rodents by drugs administered in the silent period after status epilepticus may be assumed as an antiepileptogenic activity.

• Possibly antiepileptogenic compounds may prove more effective than antiepileptic drugs in reducing the number of epilepsy patients with drug-resistant seizures.

• Experimental data recommend numerous positive combinations of antiepileptic drugs exerting anticonvulsant synergy and neurotoxic antagonism (or additivity). Clinical data on the effectiveness of antiepileptic drug combinations are limited. The best documented combination seems valproate + lamotrigine.

Declaration of interest

SJ Czuczwar has been a speaker for GlaxoSmithKline, UCB, Sanofi-Aventis and Janssen. He is also a recipient of an unrestrictive grant from GlaxoSmithKline. 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

The paper was not funded.