Research Roundup: New Developments in the Understanding of Epilepsy and the Application of Antiepileptic Therapies

Researchers at the American Epilepsy Society meeting reported important strides in the understanding of epilepsy, including identification of new therapeutic targets in the brain, as discussed by Esther Krook-Magnuson, PhD, as well as improved understanding of the factors involved in sudden death of patients with epilepsy, and a greater recognition of the benefits of neurosurgery in patients with epilepsy.

At the 68th annual meeting of the American Epilepsy Society (AES), researchers discussed new methods of identifying brain regions involved in epilepsy, cardiac mechanisms underlying sudden unexpected death in epilepsy (SUDEP), and predictive methods for determining the likely outcome of brain surgery for high-risk patient with epilepsy.

Shedding Light on New Intervention Targets in Epilepsy

Esther Krook-Magnuson, PhD, researcher at the University of California, Irvine, discussed some of the uses of optogenetics in identifying new targets for intervention in epilepsy. Optogenetics is a technique in which researchers use light in genetically modified mice to stimulate or inhibit neuronal activity. This allows researchers to control seizures in mice and identify where seizures originate. Regarding the technique, Krook-Magnuson noted, “It is a powerful tool to study the networks involved with seizures.”

In a press conference, Krook-Magnuson stated that she and her collaborators are interested in temporal lobe epilepsy in particular, because it is the most common form of epilepsy in adults. Previously, temporal lobe epilepsy was thought to originate primarily in the hippocampal formation, a banana-shaped structure deep in the brain. This brain structure serves an important role in regulating memory, spatial navigation, and learning.

Using a mouse model, Krook-Magnuson and colleagues analyzed the networks involved in temporal lobe epilepsy in a way that was not possible previously. Using the optogenetic technique, researchers identified a previously unknown initiating role in seizures associated with a brain region that was not traditionally associated with epilepsy—the cerebellum.

By sending inhibitory signals to neurons in specific regions of the lateral cerebellum or the midline cerebellum (the vermis), researchers achieved prolonged inhibition of seizure activity. Targeting the vermis had a unique effect on seizure control. According to Krook-Magnuson, with inhibition of activity in the vermis, seizures that did occur were not only shorter in duration, but the time between seizures was significantly prolonged. The inhibitory effect outlasted the duration of light application, indicating a long-lasting effect with minimal stimulation.

This unique finding has potential clinical applications. Therapeutic interventions targeting the cerebellum could induce the same prolonged inhibition of seizure activity observed in mice models.

Previous work in elucidating the role of the cerebellum was conducted in the 1970s, using electrical stimulation. However, because electrical stimulation is a less specific intervention and is much harder to control, the results were lackluster, and interest in the cerebellum as a seizure locus was lost. Krook-Magnuson stated, “We should no longer ignore the cerebellum ... it is a good target for inhibition of seizures.”

Cardiac Mechanisms Underlying Sudden Unexpected Death in Epilepsy

Patients with epilepsy have a more than 20-fold greater risk of dying unexpectedly than people without epilepsy. This phenomenon, known as SUDEP, is thought to be mediated by defects in cardiac and respiratory function, but little research activity has been produced in the area of SUDEP.

Researchers at the University of Michigan Medical School examined how cardiac excitability may be related to SUDEP in children with a particularly severe and intractable form of epilepsy known as Dravet syndrome (DS).

In a press release, lead author Chad Frasier, PhD, of the Isom Laboratory at the University of Michigan Medical School, stated, “Given how unpredictable SUDEP is in patients, this study will hopefully shed light on the potential mechanisms that alter cardiac excitability and make DS patients susceptible.”

Researchers compared cardiac parameters including heart rate, beat period, field potential, and sodium current density in 1 control individual and 2 patients with DS. Results of this investigation led to identification of abnormal sodium current density changes that may trigger SUDEP.

Other researchers at the University of Florida College of Medicine investigated cardiac effects immediately following seizures in 2 males, aged 12 and 17 years. In these patients, researchers Edgard Andrade, MD, MS, FAAP, and colleagues noted dangerous slowing of the heart’s ability to reach a resting state.

Learning more about the effect of epilepsy on the heart, and the potential mechanisms behind SUDEP, may lead to risk reduction strategies and therapeutic development for at-risk patients. In the future, implantable devices may be used to ultimately predict when SUDEP is likely to occur and potentially stimulate the heart to prevent acute cases of SUDEP.

Predicting Surgical Outcomes in Patients with High-Risk Epilepsy

Although medications may help improve quality of life and reduce the frequency of seizure events in patients with epilepsy, few patients achieve complete seizure control. One of the most effective treatment modalities in epilepsy is surgical removal of triggering areas of the brain. Unfortunately, surgery carries substantial risks.

To make more informed decisions about which patients are good candidates for surgery, researchers at Boston Children’s Hospital developed a model based on literature data to determine the likelihood that patients will achieve improvements in life expectancy with surgical epilepsy therapy. Compared with medical treatment alone, in a group of patients 10 years of age with temporal lobe epilepsy, investigators determined that epilepsy surgery would yield an additional 4.9 years of life, on average. In extratemporal epilepsy, a similar 5.6-year advantage in life expectancy would be expected.

Other researchers at the AES conference, associated with the Cleveland Clinic, discussed the benefits of surgery in patients with Lennox-Gastaut syndrome (LGS), a condition for which surgery has not been considered a main-line treatment.

In 36 patients with refractory LGS, patients underwent multilobar resection or hemispherectomy. Follow-up visits in the 6 months to 6.6 years after surgery indicated that 19 of the 36 patients were free of seizure events, and an additional 5 patients attained substantial reduction in seizure frequency. According to Ahsan Moosa Naduvil, MD, “Our study confirms that selected children with early brain lesions may be rendered seizure-free with epilepsy surgery.”

As researchers learn more about novel brain targets for long-lasting control of seizures, such as the cerebellum, and recognize the mechanisms behind SUDEP and the benefits of surgery, science continues to advance to help more patients with epilepsy achieve optimal outcomes. As novel research presented at the AES conference shows, innovative research continues to advance the field of epilepsy treatment.