DENVER—The topic is controversial, the science is soft, and efficacy data are largely anecdotal. Nonetheless, use of herbal remedies is skyrocketing in the United States, and some patients are turning to herbal remedies for the treatment of epilepsy.

In preparing to lecture on what they called “a new approach to an innovative topic” on the use and misuse of alternative and complementary medicine in epilepsy at the 54th Annual Meeting of the American Academy of Neurology, Phillip L. Pearl, MD, said he and his co-presenter Joan A. Conry, MD, both pediatric neurologists at Children’s National Medical Center in Washington, DC, found “an incredible paucity of rigorous clinical trials of both safety and efficacy of these agents.”

According to Dr. Pearl, the Epilepsy Foundation categorizes alternative treatments into four classes: (1) those with excellent efficacy and tolerability, such as pyridoxine (vitamin B6), used to treat rare cases of pyridoxine-dependent neonatal seizures and, in some cases, infantile spasms; (2) those with excellent efficacy but poor tolerability, such as adrenocorticotropic hormone, used for infantile spasms and Lennox-Gastaut syndrome; (3) those that are promising but without proof of efficacy, such as intravenous immunoglobulin; and (4) those with unproven efficacy but also little evidence of side effects: herbal remedies, vitamin supplements, and other treatments, such as acupuncture.

THE DANGERS OF ANECDOTAL EFFICACY

In the United States, dietary supplements are not regulated by the Food and Drug Administration (FDA), which means that in addition to there being no standard doses or formulations, “there is no systematic, long-term prospective collection of safety data of adverse interactions and of drug interactions,” Dr. Conry said. As a result, “there are very real risks from direct toxicities and from herb/drug interactions,” Dr. Pearl added. An estimated 18% of those taking prescription drugs in the United States also take herbs or megavitamin therapy. Given that this use is “ubiquitous,” he said, “we have to know more about these than some of our traditional FDA-approved drugs.”

Anecdotal reports support the efficacy of many herbs for the treatment of seizures; however, objective data of a response are scant. “If you look very hard, much of it is folklore,” Dr. Conry said. “Assuming some herbal treatments do decrease seizures—and I do believe that some of them do—these are still medications with the potential for significant interactions with other medications. Herbs or supplements may increase or decrease the metabolism or transport of antiepileptic drugs into the central nervous system,” she said. In addition, they “may change, increase, or decrease the effect of medication a patient is taking for another medical condition.”

THE ELITE EIGHT?

The top eight herbs described as effective or possibly effective for the treatment of seizures—“and these are alphabetized because there is really no way to prioritize them”—are American hellebore, betony, blue cohosh, kava, mistletoe, mugwort, pipsissewa, and scullcap, Dr. Pearl said.

In discussing these herbs, Dr. Pearl concentrated primarily on risks and adverse effects of each herb, which are actually “more available in the literature than good evidence of efficacy,” while Dr. Conry reviewed pharmacokinetics, direct effect on seizures, and pharmacodynamic interactions. She reported that she could find no mechanism of action or laboratory or clinical evidence of effect on seizures for American hellebore, betony, blue cohosh, mugwort, pipsissewa, or scullcap.

AMERICAN HELLEBORE

BETONY

BLUE COHOSH

KAVA

Kava, the herb for which the mechanism of action has been best established, is used as an anxiolytic. It is a strong L-type calcium channel inhibitor and weak sodium channel blocker, although “some references say it’s actually a stronger sodium channel blocker,” Dr. Conry observed. Kava increases early potassium outward current with hyperpolarization and may increase gamma-aminobutyric acid (GABA) transmission.

“This is similar to several traditional antiepileptic medications,” Dr. Conry said, including lamotrigine, phenytoin, and carbamazepine. “This is important because if you’re trying to use a rational approach to antiepileptic therapy, by and large many people try to choose agents that have different mechanisms of action.” A patient not responding to lamotrigine, therefore, most likely will not be helped by adding kava, she said, whereas if a parent says, “Kava helped my child’s seizures tremendously,” it suggests the patient is amenable to traditional antiepileptic drugs.

Dr. Conry noted that there have been several reports in Europe and the United States of serious hepatotoxicity with the use of kava, leading to consideration by the FDA and Commission E, the leading German regulatory group with oversight responsibility for therapeutic use of herbs prescribed and sold for medicinal use, “of whether this should be made a regulated substance.”

MISTLETOE

Adverse effects of mistletoe include bradycardia, cardiac arrest, coma, hepatitis, psychosis, seizures, and uterine stimulation. However, these known toxicities notwithstanding, mistletoe is a widely sought-after remedy for various ailments, particularly in Germany, one of the top international consumers of medicinal herbs and alternative medicines, remarked Dr. Conry.

In mice studies, mistletoe protected against lead zirconate-titanate- and bicuculline-induced seizures but appeared to have no effect on N-methyl-D-aspartate (NMDA)-induced tonic seizures, Dr. Conry said. She added that it appeared to modulate NMDA receptors by decreasing glutamate and glycine binding in rat hippocampus synaptic membranes and may or may not be a calcium channel inhibitor.

MUGWORT

PIPSISSEWA

SCULLCAP

A NON-HERBAL POSSIBILITY?

Safety concerns include drowsiness, disrupted sleep, nightmares, autonomic changes, hypertension, gynecomastia and low sperm counts in men, and abdominal pain.

“There are potential problems such as desensitization, where you get a tachyphylactic effect [that] simply wears off after a while,” he said. Sexual dysfunction, drug interactions, vasoconstriction, and movement disorders have also been reported, and “chronic use in animal models has been associated with inhibition of sexual maturation, so there’s some real concern about using it in children and adolescents, because of neuroendocrinologic effects,”added Dr. Pearl.

Melatonin has been found to increase the outward potassium current, hyperpolarizing cells. It also augments the GABA(A) current and reduces low magnesium bursting, Dr. Conry observed. However, animal and human data regarding its use in epilepsy are “fairly soft,” she admitted. In animals, when anti-melatonin antibody is administered, the number of seizures increases. Pinealectomy in rats led to an increased seizure rate, and audiogenic seizures have been found to induce pineal damage in rats. “In children, low melatonin has been reported in patients with photosensitive epilepsy,” she said. “However, to my knowledge, there are no data that correction of the low melatonin has any effect on photosensitive epilepsy.”

Dr. Conry emphasized that additional support for the role of melatonin in epilepsy “is controversial, with both an increase in seizures and a reduction in seizures associated with increased sleep induced by melatonin.”

ON THE ALERT FOR INTERACTIONS

“This is important enough that the National Institutes of Health National Center for Complementary and Alternative Medicine is now sponsoring an ongoing study to screen for drug interactions,” she said. The five-year, multicenter trial in healthy volunteers ages 18 to 40 is examining the effect of the 10 most popular herbs to determine whether they induce or inhibit cytochrome P-450 enzymes. Anecdotal evidence suggests St. John’s wort, garlic, echinacea, pycnogenol, milk thistle, mugwort, and pipsissewa all inhibit the cytochrome P-450 system; the effects of American hellebore on cytochrome P-450 are not known.

Dr. Conry also discussed the effect of herbs on P-glycoprotein, an ATP-dependent pump that moves substrates out of cells. “It is controlled by the human multidrug resistance 1 (MDR1) gene; this gene was actually discovered by oncologists when they were looking for an explanation for drug resistance in cancer chemotherapy,” she said. P-glycoprotein transport protein is found in the endothelium, vessels in the blood-brain barrier, the choroid plexus, and intestinal mucosa epithelium. “It limits entry of drugs to the brain and also limits absorption of drugs through the gut, and it is said to be affected by many naturally occurring compounds,” Dr. Conry said.

Four herbs affect the P-glycoprotein-mediated transport system, Dr. Conry said: St. John’s wort, garlic, pycnogenol, and American hellebore. Not including their effects on cytochrome P-450 enzymes and P-glycoprotein transport systems, ginkgo, evening primrose, and mistletoe are all pro-convulsants, she noted, with ginkgo and mistletoe clearly having induced seizures in children, she added.

In summary, Dr. Conry suggested that if patients have classic signs of conventional antiepileptic drug toxicity and report the use of herbal medications, physicians should consider ordering a drug level. In some Asian countries, herbal preparations, when analyzed, were found to contain powdered formulations of phenytoin and phenobarbital.

NR

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