PHILADELPHIA—For patients whose epilepsy is refractory to monotherapy, rational polypharmacy may become a consideration. But which factors should physicians deem most important when contemplating which treatments to add to the regimen? Josiane LaJoie, MD, Associate Professor of Neurology and Pediatrics at the New York University Langone Medical Center in New York City, suggested that combining medications with different mechanisms of action is more likely to produce seizure freedom, and that combining drugs with similar side effect profiles produces poorer outcomes.
“When you have been following patients for many years, and they begin to develop more seizures, or if a patient comes to you for a third or fourth opinion, you may not be quite sure about which direction to take,” she said at the 69th Annual Meeting of the American Epilepsy Society. “Before embarking on a new therapy, go back to basics, starting from diagnosis, especially if the patient is experiencing a new seizure type. What may seem to be a new seizure could possibly be medication side effects that are exacerbated by adding on more medications.” She also noted that polytherapy can include nondrug treatments, such as dietary therapies (eg, the ketogenic diet, the Atkins diet, low glycemic index) and vagus nerve stimulation.
How Many Medications?
Refractory epilepsy is a significant problem that occurs in about one-third of patients, said Dr. LaJoie. Uncontrolled seizures not only increase the possibility for physical injury, but also are associated with sudden death. “In practice, we typically think that after two failed monotherapy trials, perhaps combination therapy can be more effective.”
But how many drugs are enough? In Stephen and Brodie’s study of 2,881 treated patients with epilepsy, 21% were seizure-free for at least the previous year while taking more than one antiepileptic drug. Of these patients, 86% were controlled on two drugs, about 13% were controlled on three drugs, and only a few were controlled on four drugs, said Dr. LaJoie.
“Another study showed that using sodium channel blockers in combination with a drug that was more GABAergic may be more advantageous,” she said. “It also showed that using two sodium channel agents together was less promising.”
Research on Treatment Combinations
In a seminal study by Brodie and Yuen, 347 patients with epilepsy who were not fully controlled on sodium valproate, carbamazepine, phenytoin, or phenobarbital monotherapy were given lamotrigine as add-on therapy. The responder rate was significantly higher with the addition of lamotrigine to valproate, compared with the addition of lamotrigine to any of the other study drugs, Dr. LaJoie noted. Rash was a common side effect among patients on valproate. Slower lamotrigine dose escalation, however, resulted in fewer withdrawals due to rash in that group.
Another study yielded similar positive results with valproate and lamotrigine. In addition, among the 17.5% of patients who were seizure-free on three medications, valproate and lamotrigine along with either topiramate or levetiracetam were found to be the best combinations.
“In patients with severe myoclonic epilepsy in infancy, a syndrome known to be refractory to treatment, stiripentol has been shown to be effective,” said Dr. LaJoie, citing a randomized trial of patients on valproate and clobazam who were given add-on stiripentol or placebo. Moderate side-effects (eg, drowsiness and loss of appetite) in the stiripentol group disappeared when the dose of comedication was decreased. Stiripentol does not have FDA approval.
“In Lennox-Gastaut, another type of epilepsy known to be refractory to treatment, valproate is usually first-line therapy. Felbamate is also effective,” said Dr. LaJoie. “Researchers have found an increased efficacy when these drugs are used together.” Data also have shown clonazepam and valproate to be an effective combination in this patient group, she added.
One of the newer antiepileptic drugs, lacosamide, is a sodium channel blocker, and research indicates it to be effective in combination with other, traditional sodium channel blockers. “This may be the case because of different rates of activation among the drugs,” said Dr. LaJoie.
To illustrate another option for polytherapy, she cited a small study of children with medically intractable epilepsy who had been treated with a dietary regimen (ie, ketogenic or modified Atkins diet) or vagus nerve stimulation. Over a six-year period, subjects received a combination of both treatment modalities. After three months, 70% of patients had a greater-than-50% reduction in seizures, compared with the previous single treatment. No side effects were noted.
Alternative Treatments and Future Directions
“To date, studies have been inconsistent in pointing out pharmacokinetic interactions among drugs,” said Dr. LaJoie. “They don’t look at toxicity, drug tolerance, or the impact on quality of life.” Treatment alternatives such as immunomodulatory agents and cannabidiol deserve further investigation, she added.
