BETHESDA, MD—Since 2007, the field has made tremendous inroads in epilepsy research, according to advances highlighted at an all-day meeting sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), comprising leading researchers and patient advocacy groups on the NIH campus in April.
Progress on meeting benchmarks for epilepsy research set in 2007 was reflected in the title of this year's conference, “Curing the Epilepsies: Pathways Forward,” NINDS Director Story C. Landis, PhD, said in her introduction to the meeting. The title of the meeting recognizes the diversity of syndromes and diseases associated with spontaneous recurrent seizures and their comorbidities, she said, adding: “Elucidating the mechanisms responsible for the epilepsies, and developing interventions to alter or prevent them, is likely to require an equally diverse set of approaches and perspectives.”
“Progress in the last six years provides cause for optimism,” said James O. McNamara, MD, Duke University School of Medicine professor of neurosciences in the department of neurobiology and founder of the Duke Center for the Advanced Study of Epilepsy. “I look at this glass today as half full and not half empty,” added Dr. McNamara, who chaired a session at the NINDS conference on new paths to cures.
The 2007 NINDS epilepsy benchmarks covered potential causes, prevention and treatment strategies, and ways of reducing or curing the diseases associated with epilepsy. The updated document provides an overview in advances from finding candidate mechanisms for epileptogenesis to treatment advances and new understanding of the possible causes of sudden unexplained death in epilepsy. Following are highlights from this year's meeting and the new report.
Among candidate mechanisms for epileptogenesis cited in the NINDS report is hyperactivation of the mTOR (mammalian target of rapamycin) signal transduction pathway, described as a “master regulator” involved in several genetic and acquired forms of epilepsy. The mTOR inhibitor rapamycin is being studied for the prevention of seizures related to tuberous sclerosis complex (TSC), the report noted, and the drug everolimus, an mTOR inhibitor, has been approved by the US Food and Drug Administration (FDA) for preventing the growth of non-malignant tumors in TSC patients.
Other candidates for epileptogenesis include inflammatory responses involving activation of the cytokine protein interleukin-1beta (IL-1beta), opening the way to testing IL-1beta synthesis inhibitors in patients with drug-resistant epilepsy. “Anti-epileptic drugs have varying efficacy, suggesting that not all seizures are sensitive to the same mechanism,” noted Steven Petrou, PhD — deputy director and head of the Division of Epilepsy at the Florey Institute of Neuroscience and Mental Health at the University of Melbourne, Australia.
Additional candidate mechanisms cited in the NINDS report are: a disruption in the channels allowing sodium, calcium, and potassium molecules to move across cell membranes to generate electrical impulses; a breakdown of the blood-brain barrier, allowing crossing blood proteins to trigger a reaction leading to neuronal hyperactivity in the area of the breakdown; impaired astrocytes, leading to excessive levels of glutamate in the spaces between brain cells; and autoimmune or antibody-mediated impairment of the function of receptors in the brain, leading to abnormal neuronal activity.
Since the NINDS established its epilepsy benchmarks, published studies have added to the growing body of knowledge on genetic mutations implicated in epileptogenesis. The ambitious NINDS collaborative project Epi4K aims to determine the genetic basis of human epilepsies; currently, Epi4K investigators are analyzing the genomes of at least 4,000 patients with well-characterized epilepsy. The collaborative team is first focusing on the genetics of epileptic encephalopathies, including infantile spasms and Lennox-Gastaut syndrome, a severe form of epilepsy, which usually begins before 4 years of age and involves some degree of impaired intellectual functioning or information processing, along with developmental delays, and behavioral disturbances.
Mutations in single genes have now been identified in families with certain epilepsy syndromes, including Dravet syndrome, a severe form of epilepsy that appears during the first year of life with frequent febrile seizures and other types of seizures that typically arise subsequently, including myoclonus (involuntary muscle spasms), and status epilepticus. Children with Dravet syndrome typically experience poor development of language and motor skills, hyperactivity, and difficulty relating to others.
Some infants with Dravet syndrome, for example, have a mutation in the SCN1A gene that causes seizures by affecting the brain's sodium channels.
The new NINDS draft report — and speakers at the research conference — stressed that high-throughput methods of genetic sequencing have revolutionized the search for the genetic mutations that cause the epilepsies.
“The Epi4K consortium was established to bring next-generation sequencing approaches to some of the most valuable cohorts of epilepsy patients currently available,” said David B. Goldstein, PhD, director of the Center for Human Genome Variation and professor of molecular genetics, microbiology, and biology at Duke University. He is studying the correlation of genetic variation to seizure control.
BIOMARKERS, NEW TREATMENTS
The NINDS draft report identifies the need for epilepsy biomarkers as one of the “more critical areas in need of research advances,” in part because reliable biomarkers could potentially lead to seizure prevention in at-risk patients; identify and monitor seizure-onset zones; or predict seizure occurrence. “Abnormal high-frequency oscillations [HFOs] have been linked to seizure onset zones and may serve as a biomarker of epileptogenesis,” notes the NINDS draft report. It states that using microelectrodes, researchers are now better able to characterize HFOs in a frequency range of 30-600 Hz.
In addition to everolimus for TSC, the NINDS draft report cites ezogabine (retigabine), approved by the FDA for the prevention of focal seizures; rufinamide (Banzel) for Lennox-Gastaut syndrome; stiripentol (Diacomit) for Dravet syndrome; and adrenocorticotropic hormone or corticotropin for infantile spasms as major therapeutic advances.
In development are a number of potential anti-seizure therapies: brivaracetam; perampanel; YKP3089; and VX-765. The report notes that specific progress has been made in treating childhood absence epilepsy (CAE). In research comparing ethosuximide, lamotrigine, and valproic acid; ethosuximide was found to be the best single-agent therapy because of its efficacy and relatively few side effects.
Therapeutic advances raise new hope for preventive compounds. “There is good reason to hope that in the next five, seven, or 10 years, we can take advantage of preclinical and clinical research to come up with an anti-epileptogenic compound,” said Raymond Dingledine, PhD, chair of pharmacology and executive associate dean for research at Emory University School of Medicine.
A national NINDS-funded study, the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), is considered a major treatment advance because it showed that when first-responder paramedics delivered anticonvulsant therapy intramuscularly to patients in status epilepticus using an autoinjector, seizures stopped significantly earlier than when the drugs were given intravenously. Not only was it easier and faster to use an autoinjector in a patient having a prolonged seizure, but use of the autoinjector also reduced hospitalizations, RAMPART data showed. [For more about the RAMPART data, see Neurology Today's story, “En Route to the ER, an Autoinjector with Antiseizure Medications Found More Effective for Status Epilepticus”: http://bit.ly/Sk5GjF.]
The NINDS draft report cites surgery as “an effective option for treatment-resistant epilepsies,” noting that surgical techniques are being refined to make them less invasive. “There is a trend toward minimally invasive surgery,” said Edward Chang, MD — associate professor of neurological surgery and chief of epilepsy surgery at the University of California, San Francisco. But, he told Neurology Today, surgery remains an underused treatment because “the perception is that brain surgery is too dangerous.” In fact, he said, “overall, it is very safe.” Advances in neuroimaging for surgical mapping are helping to make surgery safer, according to the NINDS draft report, citing functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), and the measurement of HFOs.
About one case of Sudden Unexpected Death in Epilepsy (SUDEP) occurs for every 1,000 patients with the epilepsies, estimates the NINDS. Patients are at higher risk for SUDEP if they have tonic-clonic seizures, uncontrolled seizures, or epilepsy combined with other neurological disorders, states the draft report. Men younger than age 60 with at least a 15-year history of epilepsy from unexplained causes, who have frequent generalized tonic-clonic seizures and who take multiple anticonvulsants are at highest risk of SUDEP. Drug therapies that address respiratory arrest and implantation of cardiac devices may reduce the risk of SUDEP in some patients, according to the NINDS report.
“It is well known that seizures alter breathing and cardiac activity ….The field must move past the question of whether death is cardiac or respiratory — it is probably both,” said George B. Richerson, MD, PhD — chair of the department of neurology at the University of Iowa. “We now must define the specific pathophysiological mechanisms involved, in the CNS or heart, that lead from a seizure to SUDEP.”
For more on the research highlights, see the NINDS report, “Epilepsy Research Benchmarks Progress Report 2007-2012”: http://1.usa.gov/12edyJ6.