Lost years

In this issue of Neurology, Yoon et al. report excellent long-term outcome among patients who were seizure-free for the first year after resective epilepsy surgery, in spite of conservative outcome measures. For example, patients were counted as surgical failures if they had a single seizure after medication withdrawal, even if they achieved complete seizure control upon restarting antiseizure drugs (ASD); these patients who “failed” epilepsy surgery could have driven to their last follow-up visit and enjoyed the same quality of life as those patients who were seizure-free after surgery. Yoon et al. not only documented excellent seizure-free rates, they also documented years of surgically treatable epilepsy during childhood, adolescence, and young adulthood before referral for surgical evaluation.1

Duration of preoperative epilepsy ≥20 years and age at surgery ≥30 years were associated with an increased risk of recurrence.1 Unfortunately, so few patients had surgery within the first 10 years of their epilepsy that we do not know if earlier intervention would have offered these patients improved odds for seizure freedom.

Traditionally, physicians, including many neurologists, have considered epilepsy surgery the last treatment option for patients with partial epilepsy. The average duration of surgically treatable epilepsy among young and middle-aged adults referred for epilepsy surgery at major adult epilepsy centers is about 20 years.2 Based upon the review of records from referring neurologists for patients evaluated for epilepsy surgery, Berg et al. recently reported that the time to fail two ASD averaged 9 years. However, the time to failure in this study may have been prolonged by the referring physicians’ slow response to continued seizures. Yet these physicians’ complacency may have been fostered by observing the relapsing and remitting course of intractable epilepsy, in which 26% of patients had a period of seizure freedom of 1 year or longer prior to being considered “intractable.”3

Concerns regarding early referral for epilepsy surgery seemed justified 20 years ago; epilepsy surgery was performed at only a handful of specialized centers, and published reports were little more than series of anecdotes. Now, standardized techniques for reporting surgical outcomes have been used in many published surgical series,4 and the poor long-term prognosis of intractable epilepsy with the increased overall mortality and risk of sudden unexplained death in epilepsy (SUDEP) has been documented.5 Wiebe et al. have demonstrated the superiority of epilepsy surgery compared to medical therapy in a randomized controlled clinical trial of temporal lobe epilepsy surgery, using rigorous methodology and intent-to-treat analysis6; predicted patient deaths in the medical treatment arm, based on estimated mortality rates of 0.5 to 1.4%/year in uncontrolled patients,5 is also noteworthy.

In spite of the optimism generated by the marketing of new ASD for partial epilepsy, there is ample evidence that these drugs render very few patients with intractable partial epilepsy seizure-free.7 Kwan and Brodie demonstrated that patients with partial epilepsy who fail two ASD have about a 10% odds of seizure freedom with additional ASD trials, and that the newer ASD fared no better than older ASD.8 It is now clear that those with partial epilepsy fall into two distinct prognostic populations: about 60% will respond to the first ASD used in monotherapy, and about 40% will fail to respond easily to the first drug and will continue to have difficult to control seizures.

Early surgical intervention has practical and theoretical advantages. Early intervention reduces the deleterious effects of seizures on the developing brain among children with intractable epilepsy. Early intervention among young children may take advantage of the brain’s enhanced plasticity during childhood. Furthermore, reducing the adverse educational and social impact of intractable epilepsy among children and teenagers should enhance the quality of life among children with epilepsy.

Given the relapsing and remitting nature of partial epilepsy, the subjective requirement of intractability prior to referral for a presurgical evaluation is a prescription for delayed treatment. Although better understanding of the natural history of partial epilepsy is a worthy goal, we suggest that the question “Is this patient intractable?” be changed to “Does this patient potentially have a surgically treatable epilepsy?” There is ample evidence to conclude that mesial temporal lobe epilepsy is surgically treatable, and that among those who fail two ASD, surgery is superior to further medical management. Additional clinical trials of temporal lobe epilepsy, such as the Early Randomized Surgical Epilepsy Trial,9 should help better define the role of surgery. There is an even greater need for clinical trials of early surgical intervention among children who have many different severe extratemporal epilepsy syndromes.

It will be many years before clinical trials of early surgical intervention for the many different types of epilepsy are designed, funded, and completed. For now, physicians will do well to refer all patients with partial epilepsy who fail two ASD for consideration of surgery. Funding agencies and those of us who work in epilepsy surgery centers should consider early intervention surgical trials a priority, and be willing to modify our clinical practice based upon the results.