For release: Thursday, October 7, 2004
By using sophisticated magnetic resonance imaging (MRI) technology, researchers have been able to study early changes in the blood-brain barrier (BBB), a semi-permeable membrane that surrounds and protects the brain, to predict a stroke patient's outcome. This study showed that the patients who had disruption in the BBB were more likely to experience bleeding in the brain and have a poor clinical outcome. The researchers say this technique could help identify patients who are most likely to do the best with thrombolytic therapy, and to help clinicians offer additional therapies to those who might suffer complications.
The only Food and Drug Administration approved treatment for acute stroke is a "clot-busting" drug called t-PA, which helps to restore blood flow in the brain. This "reperfusion" of the brain can sometimes result in too much blood flow and cause hemorrhagic bleeds. t-PA is given to patients with the most common type of stroke, "ischemic," which is caused by a clot in the brain, and must be given to the patient within 3 hours of the onset of symptoms.
The standard imaging tool for stroke assessment is a computed tomography (CT) scan. MRI scans, which are also used in the study of stroke, provide more information than CT about brain blood flow, water movement, and chemical abnormalities. For this study, Steven Warach, M.D., Ph.D, and his team at the National Institute of Neurological Disorders and Stroke (NINDS), looked at MRI scans of the brains of 144 patients who had suffered an ischemic stroke and had the MRI within 24 hours after their stroke. The majority of patients received their MRI within 6 hours of the onset of the stroke. The patients were seen between June 2000 and March 2002 at the National Institutes of Health Stroke Center at Suburban Hospital in Bethesda, Maryland, home to the NIH Stroke Team. The study appears in the October issue of the Annals of Neurology 1 .
The research team tested a hypothesis, based on animal studies, that there was a connection between disruption of the BBB and subsequent bleeding in the brain. Patients received injections of a paramagnetic contrast agent which allowed the researchers to visualize a leak in the BBB as a bright enhancement in the MRI scans. The contrast agent does not cross an intact BBB, so when the researchers observed image enhancement on the scan, they knew that a part of the BBB was no longer intact.
The study authors found BBB disruption in 47, or 33 percent of the 144 patients in the study. They also found hemorrhages in 22 patients, or 72 percent, of those who had early BBB disruption. Thrombolytic therapy had been given to 38 of the 144 patients. Fifteen of the t-PA-treated patients showed evidence of early BBB disruption on the MRI. Eight of the nine t-PA treated patients who bled had BBB disruption. However, the results showed a link between BBB disruption and poor clinical outcome, independent of whether patients had treatment with t-PA, successful reperfusion, or bleeding. In addition to leaking in the BBB, another strong indicator of poor outcome was the patient's score on the NIH Stroke Scale, a clinical tool that allows doctors to evaluate the severity of a stroke. If the stroke was severe, and the BBB was disrupted early, the doctors found that the patient was more likely to suffer subsequent hemorrhage.
"Using this simple tool may help us broaden the arsenal of weapons we have to fight stroke, as well as the time we have to do so," said Dr. Warach. "Watching for these significant changes in the brain may help us target which patients may need additional therapies to fight the complications of the thrombolytic therapies and ultimately improve outcomes for all stroke patients."
The researchers do not know precisely at what time the BBB disruption occurred, because they could not see the contrast agent until a second, follow-up MRI was done. Therefore, the researchers could only estimate that on average the opening of the BBB occurred at 3.8 hours after the onset of the stroke, which is beyond the targeted 3-hour window of opportunity for t-PA treatment. But the researchers are now exploring ways to have the contrast agent administered earlier, and to look for markers on the MRI that could help them identify which patients are at the highest risk of bleeding. Since this study was done, they have learned that they can detect BBB disruption as early as 15 minutes after the contrast agent is injected. They also say this finding may identify which patients would benefit from so-called adjunctive therapies that are given in combination with t-PA, to prevent reduce the risk of bleeding. Preliminary studies are now looking at these possibilities.
The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.
1 Early blood-brain barrier disruption in human focal brain ischemia," Latour L, Kang D-W, Ezzeddine M, Chalela J, Warach S. Annals of Neurology, Vol. 56, pp. 468-477.
-By Margo Warren
Last Modified March 5, 2015