Expanding Horizons in Our Knowledge of Epilepsy and
Its Management

This edition of The Neurology Report focuses on the recent renaissance in our knowledge of the pathology of epilepsy and, in particular, generalized epilepsies; the expanding number of therapeutic options available for controlling seizures in both adults and children, and the side effects of epilepsy therapy.

VIEW Report
Alison M. Pack, MD, MPH
 Alison M. Pack, MD, MPH

Recent years have proven very productive for researchers and clinicians dedicated to understanding the origins and course of different types of epilepsy and devising safer, more effective treatments to diminish or prevent seizure activity. The 68th Annual Meeting of the American Epilepsy Society (AES), held this past December in Seattle, Washington, was attended by over 5,000 physicians, scientists, nurses, and allied health professionals. Speakers participating in poster and platform presentations, symposia, workshops, educational courses, scientific exhibitions, and lectures referred to past clinical and investigative practices, spoke about current best practices, and looked forward to new directions for epilepsy research and management. The articles in this issue of The Neurology Report were contributed by five senior neurology fellows who attended illuminating sessions during this premier meeting and share with us the exciting developments they learned there.

An understanding of cerebral changes that lead to epileptic activity depends upon imaging technology. Ambica M. Tumkur, MD, from the Emory University School of Medicine in Atlanta, covered the popular "Hot Topics" session at the AES meeting. She discusses the risk of permanent brain damage from seizures and the role of novel imaging techniques in examining the effect of epilepsy on brain structure and connectivity. Speakers at this session looked closely at the impact of epilepsy on the default mode network; they also described changes in the structure of the brain's cortex and electrical impulses of white matter that occur with uncontrolled epileptic discharges. As part of the discussion, Dr. Tumkur considers the crucial role of resting-mode networks in normal neurologic functioning and the problems that can ensue when their machinations are disrupted.

In her overview of generalized epilepsies, Elizabeth A. Felton, MD, PhD, from The Johns Hopkins Hospital, discusses historic changes in how the medical community refers to and classifies seizure disorders. Along with these semantic differences came greater understanding of the genetic origins of different epilepsy subtypes and an appreciation of the differences and similarities among these seizure disorders. In particular, her article examines childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy and other epileptic pathologies. Dr. Felton also explores prognostic, social, and cognitive aspects of these epileptic syndromes. Finally, her article presents an overview of the effectiveness of medical, surgical, and dietary interventions in their treatment, cautioning that some antiepileptic drugs (AEDs) may be entirely inappropriate in some syndromes, based upon what we now know of their pathophysiology.

A number of novel AEDs have been approved by the US Food and Drug Administration (FDA) in recent years. Madhu Jasti, MD, from the University of Alabama at Birmingham School of Medicine, reviews the pharmacologic properties of eight new AEDs that received marketing approval from the FDA in the past decade for controlling various types of seizures in both adults and children—clobazam, eslicarbazepine, ezogabine, lacosamide, perampanel, rufinamide, stiripentol, and vigabatrin.

Dr. Jasti systematically describes the mechanisms of action and pharmacokinetics of these AEDs, their on- and off-label indications, dosing, side effects, tolerability, and drug interactions. Discussions on the efficacy and safety of each AED are based upon recently published studies by international research teams and provide a valuable synopsis of the current role of each of these AEDs in our therapeutic armamentarium.

The drug perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate-receptor antagonist, offers a unique mechanism of action that has proven useful in managing partial-onset seizures in patients with epilepsy, especially in patients whose seizures are refractory to treatment with other AEDs. The results of three large randomized, placebo-controlled phase 3 studies in patients who continued to have seizures despite treatment with up to three other AEDs provided due cause for the FDA's approval, and subsequent studies and ad hoc analyses related to that research continue to contribute important information about the promise of this drug.

Michelle Bell, MD, from the Columbia University Medical Center in New York, summarizes the results of trials evaluating perampanel in patients of different genders, races, ages, and epilepsy diagnoses. In particular, these data focus upon the efficacy of this drug among various patient and seizure types and adverse events related to perampanel therapy. Importantly, Dr. Bell takes a close look at possible neuropsychiatric reactions that have been linked to perampanel in a small number of patients, including aggression and suicidal ideation. She also explores the potential of perampanel in treating primary generalized epilepsy, based on clinical evidence presented for the first time at the AES meeting.

Adverse events are a huge concern related to the use of any treatment prescribed for a medical condition. Given the many different therapeutic strategies available for epilepsy, drug selection demands a thorough knowledge of the benefits and adverse events related to these treatments as well as their potential for drug interactions.

Pawan V. Rawal, MD, MHA, from the Vanderbilt University School of Medicine in Nashville, discusses the common and not-so-common side effects of current AEDs and the tools available to screen patients for adverse reactions to these drugs. His review examines the toxicities related to the use of conventional and novel AEDs, including the safety of current treatments for status epilepticus. Dr. Rawal expands the conversation to the adverse effects of neurostimulation using such devices as vagal nerve stimulators, deep brain stimulators, and responsive neurostimulators, although much more research into such treatments is needed. Another portion of his paper examines the hazards associated with evaluating patients for epilepsy and surgical resection. Finally, he discusses the benefits and risks of complementary and alternative treatments for epilepsy, including dietary modification and hormonal therapy.

On the whole, this issue of The Neurology Report provides us not only with much information about the current status of epilepsy management but also with many interesting subjects that are ripe for discussion and debate. Certainly, additional research into AEDs, neurostimulation devices, and alternative epilepsy treatments will clarify the advantages and disadvantages of each therapeutic modality. Future editions of this publication will herald these new discoveries, help make the treatment of epilepsy safer and more effective, and improve the quality of life of our patients.

Dr. Pack is Associate Professor of Neurology at Columbia University Medical Center, New York, New York.

This activity is supported by an educational grant from Eisai Inc.