CHICAGO—Large hemispheric strokes represent less than 10% of the approximately 800,000 cerebrovascular accidents that occur in the United States annually. But the fatality rate associated with the malignant edema that commonly results can exceed 50% even with the most advanced critical care, according to an update presented at the 140th Annual Meeting of the American Neurological Association.
Malignant brain edema from large hemispheric stroke adds, on average, about 75 cm3 of volume, said W. Taylor Kimberly, MD, PhD, Associate Director of the Neuro ICU at Massachusetts General Hospital in Boston and Assistant Professor of Neurology at Harvard Medical School in Cambridge, Massachusetts. “This [edema] corresponds to about 15% of the volume in the hemisphere. It’s like trying to add two ping-pong balls into the fixed space of the cranium,” he said.
W. Taylor Kimberly, MD, PhD
Although decompressive surgery can sometimes prevent a secondary neurologic injury superimposed on a severe initial ischemic insult, emergent medical and surgical treatment of malignant edema is reactive, Dr. Kimberly emphasized. Investigators, however, are conducting trials aimed at preventing the massive accumulation of fluid in the brain.
Sedating Drugs Interfere With Neurologic Exam
Progressive decline in level of arousal, often occurring within the first 24 to 48 hours, is the hallmark of malignant edema, Dr. Kimberly said. “The challenge is to try to differentiate that declining level of arousal from other causes that are also quite common in this severe stroke patient population,” such as infection and hemorrhagic transformation. Perhaps the most common cause is the sedating effect of drugs used to manage these patients, which can interfere with the neurologic exam, he added.
General medical care of malignant edema includes airway management, with intubation as needed; glucose management; and nasogastric nutritional support. Avoiding a decrease in sodium levels is also crucial, Dr. Kimberly noted, although questions about the role of prophylactic bolus osmotherapy remain. Anticoagulation is typically avoided because of the anticipated need for decompression surgery.
Craniectomy Is Not a Panacea
Trials have shown that a large craniectomy and dural expansion with a synthetic flap to relieve the pressure helps many patients, but it is not problem-free. It requires two surgeries—the acute removal of a portion of the skull, followed two to four months later by either the return of the original bone or implantation of a customized prosthesis. Furthermore, some patients with malignant edema are not eligible for craniectomy, and others receive only limited benefit, Dr. Kimberly said.
Glyburide Holds Promise as Preventive Strategy
Preclinical experiments have identified several channels—the candidates are either ion channels or water channels—that may play a role in post-stroke edema, Dr. Kimberly said. The identification of these channels raises the prospect of preventing edema. Dr. Kimberly highlighted sulfonylurea receptor-1 transient receptor potential melastatin 4 (SUR-1 TRPM4).
Glyburide, an FDA-approved sulfonylurea, binds to SUR-1 and inhibits the activity of associated ion channels, Dr. Kimberly said. “In the setting of the brain, it gets upregulated after stroke and becomes dysregulated, and allows the passage of ions into the brain, with water following passively.”
In studies of rats with a high mortality rate from large hemispheric stroke, researchers in the laboratory of J. Marc Simard, MD, PhD, Professor of Neurosurgery at University of Maryland Medical Center in Baltimore, found that if glyburide was started within 10 hours after the onset of stroke, the death rate declined. Furthermore, a significant improvement in neurologic function, compared with placebo, was found.
IV Formulation Is Essential
This finding led to an academic–industry partnership to develop an IV formulation of glyburide, now under development by Remedy Pharmaceuticals under the trade name Cirara. A continuous infusion was needed, Dr. Kimberly explained, because of the pharmacokinetics. Administering an oral drug like glyburide results in a peak and a subsequent decline, and therefore the drug only blocks the channel half of the time. “That’s not an effective strategy if you’re trying to prevent the accumulation of edema.”
A phase I study evaluated multiple doses of IV glyburide in healthy volunteers. A dose of 3 mg/day, the researchers found, was sufficient to achieve a plasma level similar to or higher than that seen in the rodents.
Dr. Kimberly was invited to join an open-label safety and feasibility trial by Kevin Sheth, MD, Associate Professor of Neurology and of Neurosurgery at Yale University in New Haven, Connecticut. Their teams enrolled 10 patients and treated them with 3 mg/day of IV glyburide for three days, starting within the first 10 hours of stroke onset. The driving principle behind the trial design was to select as homogeneous a patient population as possible, Dr. Kimberly said. “So, the main selection criterion ended up being diffusion-weighted imaging lesion volume on acute MRI between 82 and 210 cm3,” a validated measure with high sensitivity and specificity.