14 Recognizing Intractability to Antiepileptic Medication

Bassel W. Abou-Khalil

Epilepsy Center, Vanderbilt University School of Medicine, Nashville, TN, USA

Introduction

The treatment of epilepsy usually starts with antiepileptic drug (AED) therapy. However, a proportion of patients will prove drug resistant. This chapter addresses when to recognize intractability to medical therapy so that alternative treatments can be considered.

Natural history of epilepsy and expected response to antiepileptic drug (AED) therapy

The recognition of intractability to AEDs is facilitated by understanding the natural history of epilepsy, best characterized with prospective studies of childhood-onset epilepsy. The longest study, which followed patients for several decades, found that two-thirds were in remission for at least 5 years, with about half achieving remission not interrupted by relapse. A remitting–relapsing pattern with terminal remission occurred in about a fifth of patients. Drug resistance was present from the outset in another one-fifth of patients, with emergence of drug resistance after remission in about one-seventh.

Drug resistance can be predicted with certain epileptic syndromes. Some idiopathic epileptic syndromes, such as benign epilepsy of childhood with centrotemporal spikes and childhood absence epilepsy, are expected to remit after puberty. Drug resistance is least common in idiopathic focal and generalized epilepsy and most common in symptomatic generalized epilepsy and symptomatic focal epilepsy, particularly temporal lobe epilepsy. In children, a high initial seizure frequency and seizure clustering during treatment predict drug resistance. Age at onset is also a predictor of seizure freedom. In children, age at onset between 5 and 9 years is the most favorable. In adults, the odds of remission are best in seniors.

While children also have decreased likelihood of seizure control after failure of two AEDs, remissions are common in those who failed two AEDs, although these remissions are followed by relapse in the majority. However, one study with several decades of followup showed that half of the children who failed two AEDs eventually achieved sustained remission. Failure to enter remission and symptomatic etiology predicted long-term drug-resistant epilepsy. On the other hand, in adults, one study showed that after failing initial AED trials, additional trials achieved remission in 14% of patients, but this remission was not stable, and relapses eventually occurred in most

EVIDENCE AT A GLANCE

An adult study quantified response to AEDs based on past treatment failures. The odds of seizure freedom were 62% with the first AED, 42% after failing one AED, 17% after failure of two to five AEDs, and 0% after failure of six or seven AEDs. For every 1.5 AEDs that proved ineffective, the seizure-free rates decreased by 50%. Despite the 0% odds of seizure freedom after failure of six to seven past AEDs, there could still be benefit from additional AED trials, as greater than 50% reduction in seizure frequency occurred in almost a third of these patients.

Definition of drug resistance in epilepsy

Based largely on the above evidence, the International League Against Epilepsy (ILAE) proposed a consensus definition of drug resistance in epilepsy as “failure of adequate trials of two tolerated and appropriately chosen AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.” The definition may appear simple but does require elaboration. It excludes trials in which the AED was not tolerated. In addition, an appropriately chosen AED must have been proven effective for the specific seizure type. For example, the choice of carbamazepine would be appropriate for a patient with focal onset seizures, but its choice for a patient with myoclonic or absence seizures would not be appropriate, and its failure in that setting could not be counted towards the definition of drug resistance. Other examples in which drug failure cannot be considered are use of a low dose, failure to titrate an AED to maximum tolerated dose, or failure to appropriately prescribe the AED in the correctly divided daily dosing regimen. It should also be noted that success of an AED requires freedom from all seizures for at least 1 year or three times the longest interval between pretreatment seizures, whichever is longer.

Historically there has been considerable controversy regarding the definition of refractory epilepsy, and it has been recognized that the definition must vary depending on its intended purpose. The definition proposed by the ILAE was intended to identify a time point for reevaluation of the diagnosis and management of epilepsy, preferably in the setting of an epilepsy center. The reevaluation of the diagnosis after identification of drug resistance usually involves video–EEG monitoring. This testing can also help determine whether the patient has a surgically remediable focal epilepsy syndrome. The therapeutic implications are highly dependent on the specific epilepsy syndrome, etiology, and localization.