New Data on Antiepileptic Drugs and Birth Defects

Hans-Christoph Diener, MD, PhD


September 25, 2019

This transcript has been edited for clarity.

Dear colleagues, I am Christoph Diener from the faculty of medicine at the University of Duisburg-Essen in Germany, here to discuss some highlights from the recent literature. I have five papers to share with you today: one in epilepsy, two in stroke, and two in headache.

Antiepileptic Drugs to Avoid in Pregnancy

We all know that some antiepileptic drugs have teratogenic properties. In a recent study published in Neurology,[1] researchers accessed the French healthcare database to identify women who were pregnant between 2011 and 2015. They analyzed approximately 1.8 million pregnancies, out of which 800,794 patients took an antiepileptic drug as monotherapy in the first 2 months of the pregnancy. Then the authors looked at 23 specific malformations associated with prenatal exposure to 10 different antiepileptic drugs.

As you would expect, the one drug that really stuck out was valproic acid. It had an increased risk for eight different malformations, in particular spina bifida, ventricular or septal heart defects, and cleft palate. Topiramate had an increased risk for cleft lip or cleft palate. The other antiepileptic drugs had a very low risk of being associated with malformations.

These results very clearly show that valproic acid should only be used in women where everything else has failed. It should not be used in women of childbearing age for migraine prevention or bipolar disease.

Benefits of Lowering Blood Pressure Following Intracranial Hemorrhage

The next study, published in Lancet Neurology,[2] is a meta-analysis of two trials looking at early reduction of blood pressure in patients with intracranial hemorrhage—the INTERACT2 study and the ATACH-II study. In aggregate, these two studies had 3829 patients with a mean age of 63.1 years and a median neurologic impairment of 11, as scored on the National Institutes of Health Stroke Scale.

The mean reduction in systolic blood pressure was 29 mm Hg, which resulted in a better functional outcome, as defined by the distribution of scores on the modified Rankin Scale. There were very few adverse events reported.

In contrast to ischemic stroke, obviously, early aggressive lowering of increased blood pressure has an impact on the prognosis of intracranial hemorrhage.

Intensive Glucose Control Fails to Improve Post-stroke Function

The SHINE study, which was published in JAMA,[3] investigated intensive versus standard treatment of hyperglycemia in patients with acute ischemic stroke who either had a history of diabetes or glucose ≥ 150 mg/dL. Researchers randomized 1151 patients (mean age, 66 years) to an intensive-treatment group receiving IV insulin with a target blood glucose concentration of 80-130 or to a standard-treatment group receiving subcutaneous insulin with a target of 80-179 for 72 hours.

The intensive-treatment group achieved a mean blood glucose of 118 versus 179 in the standard-treatment group, but unfortunately there was no benefit for functional outcome between the groups.

New Treatments for Migraine and Cluster Headaches

In a randomized trial published in the New England Journal of Medicine,[4] investigators reported findings with a new drug for the treatment of acute migraine attacks. Rimegepant is a calcitonin gene-related peptide receptor antagonist targeted to patients who have a contraindication for sumatriptan due to its vasoconstrictive properties.

Investigators included 1186 patients, who received either 75 mg of rimegepant or placebo. The percentage of patients who were pain-free after 2 hours was 19.6% for active drug and 12% for placebo. The number of patients in the study was very large, which was necessary because the efficacy is very low. For example, sumatriptan 100 mg orally has a pain-free rate of 45%-60%, so it is much more effective. Therefore, rimegepant most probably will be used only in patients who have clear contraindications for sumatriptan.

A number of monoclonal antibodies are now successfully used for the prevention of either episodic or chronic migraine, particularly in patients in whom everything else has failed. Now we have the first data on using a monoclonal antibody for episodic cluster headache, which was recently published in the New England Journal of Medicine.[5]

Investigators enrolled 106 patients who had, on average, 18 attacks per week at baseline. They were randomized to placebo or to 300 mg of galcanezumab, which was administered at study entry and again after 1 month. The primary endpoint was weekly reduction in the number of cluster attacks in weeks 1-3. Patients receiving galcanezumab experienced a reduction of -8.7 attacks per week compared with -5.2 attacks per week for placebo, which was a statistically significant difference (P = .04).

These results indicate that for the first time, we have a new drug that obviously is effective for prevention of cluster attacks in patients with episodic cluster headaches. We still need data on patients with chronic cluster headache. Although studies are ongoing, their results are not yet published.

Additional Studies of Interest

I also have two bonus papers I wanted to mention briefly. One is a review in Lancet Neurology[6] on medication overuse headache that is worth reading.

The other study is a meta-analysis in the Annals of Internal Medicine,[7] which you should read before you consider buying supplements or changing your diet. In reviewing publications with 992,129 participants, investigators clearly show that supplements, vitamins, and special diets have no impact on cardiovascular mortality and all-cause mortality. It is certainly something to consider before you sit down to dinner tonight.


Ladies and gentlemen, in summary, there were several important studies published last month. One study on epilepsy concludes that valproic acid should not be used if possible in women with epilepsy at childbearing age. In patients with intracerebral hemorrhage, we have a small benefit of aggressive lowering of blood pressure. Unfortunately, we have no benefit of aggressive lowering of increased blood glucose in acute ischemic stroke. We also have a new class of drugs for the acute treatment of migraine attacks in patients who cannot take a triptan, and for the first time, evidence that a monoclonal antibody is effective in episodic cluster headache.

I'm Christoph Diener. Thank you very much for watching and listening.

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