ARTICLE IN BRIEF
In a post-hoc analysis of data from a multicenter prospective trial, investigators reported that 44 percent of patients who had had an intracerebral hemorrhage (ICH) had an increase in brain volume not related to the hematoma or the area next to the hematoma — and they assumed the reason for that increase in brain volume was edema.
Does intracerebral hemorrhage (ICH) only affect the local injury site, or does it actually alter the entire brain? In what some experts in the field are calling a “paradigm shift,” investigators have found that the injury is not just localized to the hemorrhage site but also to areas of the brain distant from it, as well. A research team presented new findings at the AAN annual meeting in San Diego in March, suggesting that even subjects with mild ICH showed global changes in brain volume on CT scans.
Adnan I. Qureshi, MD, professor and executive director of the Zeenat Qureshi Stroke Research Center at the University of Minnesota, and principal investigator of the ATACH (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trial, said: “Our goal was to study whether injury occurs in areas of the brain distant from the hematoma,” and we found that it does.
“We are optimistic that this shows a new mechanism by which intracerebral hemorrhage causes injury to the brain,” said Dr. Qureshi, who presented the findings. “In this study, we did not have enough patients to study the full clinical consequences; our goal was really to demonstrate the presence of global cerebral edema, which has not been described before.”
STUDY PROTOCOLS, FINDINGS
In a prospective, multicenter analysis of data from patients recruited for the ATACH study, Dr. Qureshi and colleagues studied those patients with ICH who presented within six hours of symptom onset. Each patient had a CT scan at baseline, another CT scan at 24 hours, and “infrequently a scan at 48 to 72 hours. All of these scans were sent to the clinical coordinating center for image analysis,” Dr. Qureshi told Neurology Today.
The investigators did a post-hoc analysis where they measured the volume of brain, excluding the hemorrhage and the area next to the hemorrhage, at baseline and again at 24 hours. “We found that about forty percent of the patients have an increase in brain volume not related to the hematoma or the area next to the hematoma — and presumably the reason for that increase in brain volume is edema,” Dr. Qureshi said.
Eighteen (44 percent) of the 41 patients had global cerebral edema (GCE), with a median increase in brain volume of 35 cc (ranging from 12 cc to 296 cc). Hematoma volume was similar in patients with GCE (11.5 +- 10.3) and those without GCE (13.9 ± 17). Researchers also identified higher initial serum glucose in subjects with GCE (150.5 ± 74.3 mg/dl versus 119.7 ± 34.6 mg/dl).
In the 18 patients with GCE who underwent a CT scan at 48 hours, five had either new or worsening GCE, three experienced neurological deterioration, and one died during hospitalization. There were no significant differences based on age or hours from symptom onset to arrival in the emergency department, Dr. Qureshi reported.
There were some limitations to this work, he noted, such as the small sample size, and all patients were good-grade subjects with small ICH. “It is not known whether the frequency of this event is higher and its impact on disability and mortality more pronounced in subjects with large ICHs,” he pointed out.
As well, he said, “we used an increase in brain volume, which most likely is edema, but since this is not a pathological analysis, we don't really know what kind of edema are we talking about — is this just an increase in water content around the cells, or are the cells swelling? The more in-depth measure of this increase in brain volume is not known. Whether or not this swelling is just something that happens early on and then stabilizes is not something we can answer with this study.”
Importantly, we have “opened a new door in terms of mechanism of brain injury and intracerebral hemorrhage, and I think that whole path still needs to be further explored,” Dr. Qureshi told Neurology Today.
Now that we know this occurs, Dr. Qureshi said, “and that it occurs in almost half of the patients with ICH, we need to figure out what kind of clinical consequences this edema has, and what kind of modalities can actually treat this edema and presumably make an impact on the patients with ICH.”
The ATACH II is an ongoing, multi-national study, he added, and “our goal is to study a much larger number of patients for this analysis, so we would be able to not only find out the exact problems of GCE, but also conclusively test whether GCE impacts the outcome of patients and maybe even identify certain novel protective factors that actually determine whether GCE will occur or not,” Dr. Qureshi said.
Commenting on the findings, Dar Dowlatshahi MD, PhD, associate scientist (neuroscience) at Ottawa Hospital Research Institute, assistant professor of medicine, epidemiology, and community medicine at the University of Ottawa, and director of the Ottawa Stroke Research Group, said this concept of global brain edema is new and exciting. “And it comes at a time when people have been noticing analogous finding on MRIs. In the past three years, MRIs in patients with acute ICH have identified lesions away from the hematoma that were new and never before seen.”
The other interesting finding here, Dr. Dowlatshahi said, is that elevated glucose was associated with GCE. “Elevated glucose at presentation is thought to be reflective of an underlying inflammatory process, and this fits with the notion that there's something else going on in ICH.”
This is an observational study, “so there could be unknown factors in these patients that led to that increased edema, and there's no evidence for causality here,” said Dr. Dowlatshahi, but “it's a hypothesis-generating and elegant study.”
Patrick D. Lyden, MD, chair of the department of neurology and director of the stroke program at Cedars-Sinai Medical Center in Los Angeles, said that this study documents a phenomenon “that we are well aware of clinically.” The researchers are “confirming my bedside opinion that this [global edema] is harmful to patients,” he added, “and that the patients that have this after the hematoma do poorly. I think it very powerfully points us towards further research in this area, but it does not yet guide us in any treatment.”
There is a considerable amount of experimental data, which suggest “the thrombin that is present in the hematoma leaks into the brain and sets off this edema process,” Dr. Lyden told Neurology Today. “In my lab [at Cedars-Sinai], we are studying thrombin inhibitors to try to limit edema after ischemic stroke (not hemorrhagic). So, I think we need some very complicated experiments to try to sort out in people whether it's thrombin that's leading to this, or what other causes might be leading to this edema.”
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