LAS VEGAS—Several newer antiepileptic drugs (AEDs) are, along with new surgical options and nontraditional interventions such as medical marijuana, among a growing number of epilepsy treatments offering the potential for increased efficacy and improved patient care. However, subpopulations such as pregnant women pose special challenges for treatment selection, and the large number of patients who remain refractory to any epilepsy therapy represents perhaps the greatest challenge of all. Of the estimated three million people in the United States who have epilepsy, approximately one-third have uncontrolled seizures because no available treatment works for them, said Tracey A. Milligan, MD, at the American Academy of Neurology’s Fall 2016 Conference. Dr. Milligan is Vice Chair for Education in the Department of Neurology at Brigham and Women’s Hospital and Assistant Professor of Neurology at Harvard Medical School in Boston.
Tracey A. Milligan, MD
Illustrating the challenges of trying to achieve more widespread seizure control, Dr. Milligan cited a study of new-onset epilepsy by Brodie and colleagues, who found that 37% of patients had their seizures initially controlled, 22% had them eventually controlled, 16% had fluctuating control, and 25% had seizures that were refractory to treatment. This breakdown resonated with Dr. Milligan in terms of what she sees in her own practice—starting with the patients whose seizures are initially controlled. “They start a medication, they do well, they go on to live very full, active lives,” she said. “For the other 22%, we need to spend a little more time adjusting medications. Maybe they are adjusting lifestyle factors, but they do get to full control as well.”
Patients in the refractory group should be referred to epilepsy treatment centers, where surgical options can be considered. It is patients with fluctuating seizure control whom Dr. Milligan finds particularly interesting. “This is our sort of ‘relapsing-remitting’ epilepsy,” she said. “You start an agent, you think you have the seizures under control, and the drug works for a little while. Then the patient starts having seizures again…. These patients also need to be referred to an epilepsy treatment center to … be worked up and think about surgery if it is drug-resistant epilepsy.”
Questions for AED Selection
Clinical decisions such as the choice of an AED should be informed by the latest guidelines. Citing a 2015 report on unprovoked first seizures in adults, Dr. Milligan said that after one unprovoked seizure, there is a 21% to 45% risk of another seizure in two years. In her view, this new guideline raises more questions than it provides answers—like the new International League Against Epilepsy definition of epilepsy, in which one unprovoked seizure (rather than the previously required two) can be enough to support a diagnosis of epilepsy.
“How do we know which [patients] to diagnose with epilepsy after a single seizure?” she asked. “How do we know which patients are at highest risk of having a second seizure and we’re going to start with an AED?.... At this point we do not have an agreed-upon and reliable formula where we can plug in the demographics and the factors of the seizure and calculate the risk.”
In lieu of such information, clinicians need to ask several questions when selecting an AED, including which epilepsy syndrome the patient has, which medicines work best with it, and which patient factors apply. Dr. Milligan discussed four newer AEDS that are clinically available—clobazam, perampanel, eslicarbazepine, and brivaracetam. “These, for the most part, have been in trials involving patients with refractory seizures and all have a similar efficacy as add-on therapy.”
Onfi (Clobazam)
A benzodiazepine that offers fewer tolerance/sedation issues than others in its class, clobazam has been used since the 1970s as an anxiolytic/anticonvulsant. In 2011, Onfi (clobazam) was approved by the FDA for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients age 2 and older. Adverse effects include dizziness, somnolence, restlessness, and aggression. “It is a nice option when you are thinking about a benzodiazepine, because it does not have the same sort of tolerance/dependence [issues] as the other benzodiazepines do with epilepsy,” said Dr. Milligan.
Fycompa (Perampanel)
Fycompa (perampanel) is a noncompetitive AMPA-receptor inhibitor with a long half-life (70 to 100 hours). It is indicated for adjunctive treatment of focal epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Side effects include dizziness, somnolence, and rash. The drug’s labeling includes a black-box warning for an occurrence Dr. Milligan described as unusual but important to be aware of: “Very interesting conversations you have with your patients when you prescribe this—where you have to say, ‘You may develop homicidal ideation on this medication. If you start to feel like killing somebody, please let me know right away.’”
Aptiom (Eslicarbazepine)
Approved by the FDA in 2013 for partial epilepsy (monotherapy or adjunctive treatment), Aptiom (eslicarbazepine) is a sodium-channel blocker whose longer half-life (20 hours) may help with peak effects and reduce hyponatremia and rash. It has few drug interactions and can be used with carbamazepine, though not with oxcarbazepine. Although the list of its most common side effects is long—dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor—it “probably has fewer adverse effects associated with it [overall] than other AEDs do.”
Briviact (Brivaracetam)
The newest agent, Briviact (brivaracetam), was approved in February 2016 as add-on therapy for refractory partial seizures in patients age 16 and older. Clinical trial results showed adverse effects such as somnolence, headache, dizziness, and fatigue to be mild and similar to what control patients experienced on placebo, but with a higher incidence of psychiatric/cognitive problems versus placebo. It is 20 times more potent at the SV2A receptor than levetiracetam, a related agent. “Unlike levetiracetam, it does [affect] oral contraceptives at a higher dose,” said Dr. Milligan, adding that she is inclined to use it after she has “tried tried agents that have been around longer”—at least until more data are in.
Marijuana, Pregnancy, and Depression
Dr. Milligan devoted the rest of her lecture to pregnancy, depression, and “the thing that everybody asks us about”—marijuana. She cited an open-label interventional trial by Devinsky and colleagues that found that cannabidiol might reduce seizure frequency and have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. “We do not have many randomized placebo-controlled trials at this point,” she said. “[Cannabidiol] probably works well for some syndromes but it does have adverse effects.”
Regarding pregnancy, a study by MacDonald and colleagues that examined complications in women giving birth showed a 10-times higher risk of death in women with epilepsy, along with a greater rate of every complication the investigators assessed. Other risks are associated with AED therapy. “We know that there are risks of seizures during pregnancy, and these are important to control,” said Dr. Milligan. “There are also risks that come along with taking certain AEDs—neural tube defects, small for gestational age, cleft lip and palate, and autism.”
One drug associated with cleft lip/palate and small size for gestational age is topiramate (FDA pregnancy category D). “Being a baby with small for gestational age carries an increased risk of obesity, cardiovascular disease, diabetes, and cognition [problems]—so it is important for us to be aware of [this fact] when we use topiramate,” said Dr. Milligan, who also cited findings from the North American Pregnancy Registry showing lamotrigine and levetiracetam to be the safest among AEDs assessed.
Depression is present in more than 33% of patients with epilepsy and entails a three- to four-times greater risk of suicide. Sudden death is 27 times more likely in patients with epilepsy than in the general population. “Seizures kill—this is something people are not aware of,” Dr. Milligan emphasized. “Depression is very prevalent, but there is also this high risk of death that goes along with epilepsy that is not just sudden unexplained death in epilepsy [SUDEP] but accidental death, assault….
“Mortality risk and years of potential life lost from epilepsy are second only to stroke. We need to think about education. For example, most patients who are found dead after a presumed seizure or from SUDEP are in a prone position. Maybe we should have for those refractory patients [something] like the sudden infant death syndrome campaign for babies to sleep on their backs, and not prone. It’s something to think about.”
—Fred Balzac
Suggested Reading
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Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.
Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: a call for action. Neurology. 2016;86(8):779-786.
Hernandez-Diaz S. Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts. Pharmacoepidemiol Drug Saf. 2014;23(10):1026-1028.
Krumholz A, Shinnar S, French J, et al. Evidence-based guideline: management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2015;85(17):1526-1527.
Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077.
MacDonald SC, Bateman BT, McElrath TF, et al. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol. 2015;72(9):981-988.
Martin RC, Faught E, Richman J, et al. Psychiatric and neurologic risk factors for incident cases of new-onset epilepsy in older adults: data from U.S. Medicare beneficiaries. Epilepsia. 2014;55(7):1120-1127.
Pennell PB. Use of antiepileptic drugs during pregnancy: evolving concepts. Neurotherapeutics. 2016;13(4):811-820.
Vajda FJ, O’Brien TJ, Lander CM, et al. The teratogenicity of the newer antiepileptic drugs - an update. Acta Neurol Scand. 2014;130(4):234-238.
