Margaret P. Jacobs

Felbamate for partial seizures Results of a controlled clinical trial

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Models for Epilepsy and Epileptogenesis: Report from the NIH Workshop, Bethesda, Maryland

Summary:  Purpose: The workshop explored the current problems, needs, and potential usefulness of existing methods of discovery of new therapies to treat epilepsy patients. Resistance to medical therapy (pharmacoresistance) and the development of epilepsy (epileptogenesis) are recognized as two of the major problems in epilepsy treatment today. At the same time, there is growing awareness that the development of new therapies has slowed, a trend that has economic and scientific roots. To move toward new and more effective therapies, novel approaches to therapy discovery are needed.

Future directions for epilepsy research.

The authors propose that epilepsy research embark on a revitalized effort to move from targeting control of symptoms to strategies for prevention and cure. The recent advances that make this a realistic goal include identification of genes mutated in inherited epilepsy syndromes, molecular characterization of brain networks, better imaging of sites of seizure origin, and developments in seizure prediction by quantitative EEG analysis. Research directions include determination of mechanisms of epilepsy development, identification of genes for common epilepsy syndromes through linkage analysis and gene chip technology, and validation of new models of epilepsy and epileptogenesis. Directions for therapeutics include identification of new molecular targets, focal methods of drug delivery tied to EEG activity, gene and cell therapy, and surgical and nonablative therapies. Integrated approaches, such as coupling imaging with electrophysiology, are central to progress in localizing regions of epilepsy development in people at risk and better seizure prediction and treatment for people with epilepsy.

Curing epilepsy: progress and future directions.

During the past decade, substantial progress has been made in delineating clinical features of the epilepsies and the basic mechanisms responsible for these disorders. Eleven human epilepsy genes have been identified and many more are now known from animal models. Candidate targets for cures are now based upon newly identified cellular and molecular mechanisms that underlie epileptogenesis. However, epilepsy is increasingly recognized as a group of heterogeneous syndromes characterized by other conditions that co-exist with seizures. Cognitive, emotional and behavioral co-morbidities are common and offer fruitful areas for study. These advances in understanding mechanisms are being matched by the rapid development of new diagnostic methods and therapeutic approaches. This article reviews these areas of progress and suggests specific goals that once accomplished promise to lead to cures for epilepsy.

Common data elements in epilepsy research: Development and implementation of the NINDS epilepsy CDE project

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience‐related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start‐up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS‐funded clinical research, and where appropriate, facilitate the development of evidenced‐based guidelines and recommendations. Epilepsy‐specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy‐specific CDE initiative can be viewed as part of the larger international movement toward “harmonization” of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Nonepileptic Events in Childhood

Summary: The medical records of 27 children admitted to the MINCEP Epilepsy Program for evaluation of intractable epilepsy but later shown to have nonepileptic events by EEG with simultaneous video monitoring were reviewed. Four groups were identified: pure psychogenic events (5 patients), psychogenic events plus epileptic seizures (3 patients), pure nonepileptic physiologic events (5 patients), and nonepileptic physiologic events plus seizures (14 patients). Historical data, physical examinations, and neurodiagnostic evaluations (including previous EEGs, neuroradiologic evaluations, and neuropsychologic testing) were reviewed. Children in all groups, except for those with pure psychogenic seizures, had a history of multiple seizure types identified by parents or caretakers. A history of status epilepticus was obtained in 64% (of 22 patients), including 11 of 14 patients with physiologic events plus seizures. Abnormal findings on neurologic examination were common, especially in children with nonepileptic physiologic events. AH but two patients had a history of interictal epileptiform abnormalities on previous routine EEGs. Based on identification of nonepileptic events, antiepileptic drugs (AEDs) were discontinued completely in eight patients (30%) and the total number of AEDs was reduced in nine others (33%). A diagnosis of nonepileptic events should be considered in all children with refractory seizures or multiple seizure types. Abnormal findings on routine (interictal) EEG may actually confound the diagnosis. Intensive neurodiagnostic EEG‐video recording is the preferred method for distinguishing nonepileptic from epileptic seizures.

Progressive myoclonus epilepsy treated with zonisamide

Two patients with progressive myoclonus epilepsy of the Unverricht-Lundborg type and with intractable seizures in spite of standard anticonvulsant regimens were treated with zonisamide. After zonisamide therapy was initiated, both had a marked decrease in seizure frequency and significant improvement of functioning. Serum zonisamide concentrations were 43 and 27 μg/ml, respectively, with doses of 8.8 and 10.5 mg/kg/d. Both patients also continue to receive valproic acid and a benzodiazepine.

The NINDS Epilepsy Research Benchmarks

The field of epilepsy research has undergone a dramatic transformation in the past decade. However, substantial gaps exist in our understanding of epilepsy, from its causes and prevention to its clinical impact and treatment. In March 2000, prominent epilepsy research scientists, health care providers, and leaders of epilepsy organizations came together for a seminal conference to discuss what it would take to reach a cure for epilepsy, defined as the prevention of epilepsy in people at risk, and by effective and safe therapy (‘‘no seizures, no side effects’’) for those with the disorder. Cosponsored by the National Institute of Neurological Disorders and Stroke (NINDS), the American Epilepsy Society, Citizens United for Research in Epilepsy, the Epilepsy Foundation, and the National Association of Epilepsy Centers, this White House–initiated conference highlighted advances in neuroscience, imaging, genetics, and clinical research related to mechanisms of epileptogenesis, and emphasized the vital need for further research that would lead to new treatments and cures. Participants were eager to identify a way to evaluate progress resulting from this historic event, and a session was added to the conference to ‘‘benchmark’’ the outcomes. The NINDS subsequently worked with more than a dozen Epilepsy Research Stewards—established leaders in the field of epilepsy research—to define a series of goals for the field that could serve as a research agenda. The NINDS and the Stewards developed a series of Epilepsy Research Benchmarks based on the three major topic areas of the 2000 Conference: (1) interrupting and monitoring epileptogenesis; (2) genetic strategies; and (3) developing new therapies. The first of these Benchmarks entailed goals that would hasten progress toward understanding the fundamental causes of epilepsy at the anatomic, physiologic, and genetic ⁄ molecular levels; and defining markers of epileptogenicity. This Benchmark also encouraged the validation and use of improved animal models for therapeutics testing. The second Benchmark focused on prevention through the use of epileptogenicity markers to identify tissue targets for preventive therapies, and the completion of large clinical trials of neuroprotective or antiepileptogenic compounds in high-risk individuals. The third Benchmark highlighted the development of improved therapies. Markers of epileptogenicity were again emphasized, in this case for the efficacy testing of therapeutics. Other factors were recognized as important for improved personalization of therapies, including an individual’s developmental stage, hormonal status, and genetic profile. Multiple treatment strategies were encouraged, including the continued refinement of biosensors and seizure suppression systems, new approaches for epilepsy surgery, and novel therapies such as cell transplants or vaccines. This Benchmark also called for the achievement of a complete cure for a form of genetic epilepsy through appropriate translation through preclinical research studies. A complete list of the original Epilepsy Research Benchmarks is available at: http://www.ninds.nih.gov/funding/research/epilepsyweb/epilepsybenchmarks.htm. Over the subsequent 5 years, the research community made substantial progress on these Benchmarks, including but not limited to advances such as: • Improvements in neurotransmitter imaging through the development of magnetized nanoparticles. • The development of a collaborative project to understand changes in gene expression associated with epileptogenesis in different animal models. • The establishment of a database that enables researchers to search nonproprietary structural and biologic data on anticonvulsant drugs. • The initiation of clinical trials designed to prevent the development of epilepsy after brain injury. • An improved understanding of both age and hormonal influences on the underlying cellular mechanisms of epilepsy. • New discoveries related to epilepsy pharmacogenetics ⁄ pharmacogenomics. • Progress in seizure detection and brain stimulation to control epilepsy, as well as other surgical approaches to treatment. • The development of the Epilepsy Phenome ⁄ Genome Project to facilitate the discovery of genes responsible for more common forms of epilepsy. These and other advances associated with the original Benchmarks—as well as roadblocks to progress in some Benchmark areas—are detailed in a series of reports available at: http://www.ninds.nih.gov/funding/research/ epilepsyweb/epilepsybenchmarks.htm. As these reports illustrate, research goals are never static, and the evolving needs of the research community, along with the increasing recognition that the comorbidities of epilepsy present a significant challenge to the goal of ‘‘no seizures, no side effects,’’ strongly indicated that a reassessment of the Benchmarks was warranted. In March 2007, this reassessment took place, with more than 400 researchers, physicians, patients, family members, and epilepsy organization leaders convening on the National Institutes of Health campus to participate in the ‘‘Curing Epilepsy 2007: Translating Discoveries into Therapies’’ Conference. Organized by the NINDS in collaboration with epilepsy research and voluntary GRAY MATTERS

Models of Pediatric Epilepsies: Strategies and Opportunities

Pediatric epilepsies are among the most devastating of neurologic disorders. The developing brain is particularly susceptible to seizures, and seizure activity early in brain development can cause profound neurologic impairment, enhance subsequent seizure propensity during maturation and in adulthood, and lead to abnormalities in cognitive function (1). In infancy and childhood, two broad categories of epilepsy are of particular concern because of their intractability to treatment and association with cognitive decline: (a) The so-called “catastrophic” childhood epilepsies (including infantile spasms, Lennox–Gastaut syndrome, and the progressive myoclonic epilepsies) are characterized by numerous etiologies, by age-specific developmental windows of seizure onset, by refractoriness to medical treatment, and by progressive cognitive deterioration (epileptic encephalopathy). Seizures associated with catastrophic epilepsy syndromes tend to have bilateral/generalized manifestations: (b) Refractory partial epilepsies are often associated with dysplastic brain lesions (i.e., tuberous sclerosis complex, TSC), or severe perinatally induced injuries (i.e., perinatal stroke or hypoxia); seizures of this type may be also seen with mesial temporal lobe epilepsy, but this latter condition is more prevalent in late childhood and adolescence. Often an overlap exists between these two broad categories of medically intractable epilepsies; for example, TSC is commonly associated with generalized infantile spasms as well as with multifocal partial seizures. This overlap suggests that common features may exist in the pathogenesis of different epilepsy types during early brain development. Regardless of the epilepsy type, etiology, or syndrome, the mechanisms of epilepsies in infancy and early childhood likely differ significantly from those of epilepsies in older children and adults. These mechanistic differences have important implications for therapeutic strategy and therapeutic efficacy (2,3). The lack of appropriate animal models is a major impediment to a more complete understanding of pediatric epilepsy and to more effective treatments. Animal models serve numerous functions. They provide opportunities to investigate and elucidate basic mechanisms, to test and/or develop new antiepileptic medications (AEDs) and other therapeutic modalities, to devise new diagnostic approaches, and to study the neurologic consequences of seizures at various stages of brain development (4–7). Given the many (and often significant) differences between human and animal (i.e., rodent) brain structure and developmental profiles, no animal model is likely to reproduce faithfully every aspect of a human epilepsy syndrome. However, the insightful use of such models can play a pivotal role in generating hypotheses about the mechanisms, pathogenesis, and consequences of seizures in the developing brain, and for testing potential therapies. This report summarizes discussions held during a workshop on Models of Pediatric Epilepsies, held in Bethesda, MD, on May 13–14, 2004. The Workshop was sponsored by NINDS/NIH and supported by grants from the American Epilepsy Society and the International League Against Epilepsy. Whereas previous NIH workshops have examined general priorities for epilepsy research (8,9), the current Workshop focused explicitly on epilepsies in the developing brain. Invited participants included clinical pediatric epileptologists, basic epilepsy researchers, and developmental neurobiologists (Appendix A).

Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it.