Drug-resistant epilepsy is defined as the failure of at least 2 established, adequately dosed antiseizure medications to render an individual seizure free. Despite the introduction of more than 15 third-generation antiseizure drugs, these medications are still failing to control seizures in up to one-third of patients, so we are continually seeking to improve patient care and advance our understanding of drug-resistant epilepsy.

The patient registries and ad hoc analyses reported at AES2020 reflect the variety of research tools that can add to the knowledge base in drug-resistant epilepsy. The findings of such studies nicely complement the findings of randomized controlled trials (RCTs). For instance, the results of a long-term follow-up study of 49 patients treated with cenobamate for drug-resistant focal onset seizures were reported in abstract 989. This type of analysis can shed light on a patient population that might not be reflected in an RCT. This study was conducted in the real-world clinical practice environment, over longer periods of time than might be possible within an RCT. In addition, this type of study can reflect a more diverse patient population than might be seen in a clinical trial, with a wide range of ages. Researchers reported that, after 3 to 8 years of treatment, 45% of patients demonstrated greater than 75% seizure reduction, 29% demonstrated greater than 90% seizure reduction, and 16% demonstrated complete seizure freedom. Tonic-clonic seizures ceased in 8 out of 9 patients. Symptomatic etiologies, such as whether seizures had a genetic origin or were acquired later in life, did not reduce treatment responses. Cenobamate dosages across the range of 150 to 400 mg per day were significantly associated with higher responder rates, and concomitant antiepileptic drug dosages were reduced when cenobamate was titrated. 

Patient registries are another important tool for understanding drug-resistant epilepsy. Vagus nerve stimulation (VNS) therapy has been around for more than 25 years, and, in that time, VNS dosing strategies and device features have evolved. Abstract 517 included a description of the Comprehensive Outcomes Registry in Subjects With Epilepsy Treated With VNS Therapy (CORE-VNS) prospective outcomes registry in patients with drug-resistant epilepsy. The intent with this registry, which is the largest prospective VNS study in drug-resistant epilepsy to date, is to document the clinical and psychosocial impact of contemporary VNS therapy. Patient recruitment began in 2018, and 511 out of 558 participants have been implanted with a VNS therapy system. The patients represent a broad range of genders, age, seizure types, treatments, and number of prior failed treatments.

Also presented at AES2020 in abstract 713 was a session on the development of the international online New-Onset Refractory Status Epilepticus (NORSE) Family Registry to help advance the understanding of NORSE and febrile infection-related epilepsy syndrome (FIRES). NORSE and FIRES are rare clinical presentations of epilepsy affecting previously healthy children and adults with variable mortality and morbidity. There are many challenges associated with studying rare entities, and one of the advantages of this approach is that data can be pooled from around the globe; in fact, this registry aims to collect demographic, geographic, and outcome information from patients and families affected by the disease worldwide. The goal is to provide researchers with a wide range of clinical and epidemiological data to help guide further prospective studies and treatment of NORSE/FIRES. The registry is innovative in that it allows families, surrogate decision makers, survivors, and patients themselves to upload their own data and participate directly, unlike other registries that permit input only from physicians.

Finally, abstract 764 was noteworthy, as it illustrates that we are still trying to understand the different mechanisms of epilepsy and the causes of drug resistance at the individual level. Immune inflammation is increasingly of interest in this regard, and adjunctive natalizumab was explored in this phase 2 study in a mixed population with drug-resistant epilepsy. Although natalizumab did not reach the predetermined target of 31% relative reduction in seizure frequency over the placebo group, it did show a sizable treatment effect. The study demonstrates our growing understanding of the mechanisms that may mediate the development of epilepsy, including neuroinflammation.