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At the Bench-Subarachnoid Hemorrhage: Spreading Depolarizations Cause Acute, Not Just Delayed, Damage in Subarachnoid Hemorrhage

Robinson, Richard

doi: 10.1097/01.NT.0000527093.72170.64
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In an animal model, investigators were able to demonstrate that subarahnoid blood acutely induces speading depolarizations and early cortical infarction. Independent experts said the study is important because it shows that these depolarizations may be a very important part of early brain injury pathophysiology in subarachnoid hemorrhage.

Blood on the surface of the brain induces spreading depolarizations and increases the risk of infarcts in the acute period after subarachnoid hemorrhage (SAH), according to a new study published in the October 1 Brain. The study showed that blood, especially clotted blood, introduced into an otherwise healthy pig brain, led to spreading cortical depolarizations and widespread infarcts. Additionally, electrode recording in human patients showed that spreading depolarizations were strongly associated with infarcts in the acute period after SAH.



“This paper is important because it shows that blood in the subarachnoid space can by itself cause these cortical spreading depolarizations,” commented Alex Choi, MD, assistant professor of neurosurgery at the University of Texas Health Science Center at Houston, who was not involved in the study. “And it demonstrates that these depolarizations may be a very important part of early brain injury pathophysiology in subarachnoid hemorrhage.”

Spreading cortical depolarizations are as different from the normal firing and repriming of neurons as a tsunami is from a gentle wave on the shore. They are, in fact, often called “brain tsunamis”. During a spreading depolarization, there is a complete breakdown of the electrochemical potential of masses of neurons, according to lead author Jed A. Hartings, PhD, research associate professor in the department of neurosurgery at the University of Cincinnati College of Medicine in Ohio. “It's like a cardiac arrest of the tissue.”

The normal neurovascular coupling that brings a surge of blood to active neural tissue is lost, and the affected region becomes electrically silent for anywhere from a minute to indefinitely, he explained. “If it persists for more than 15 minutes or so,” said Dr. Hartings, “the tissue is irreversibly damaged.”

The spreading depolarizations in brain injury are unlike those associated with migraine aura, he noted, since in migraine, neurovascular coupling remains intact, and the tissue recovers rapidly.

Spreading cortical depolarizations following brain injury have been known from animal models for many years, and more recently have been shown to occur in patients following ischemic stroke, traumatic brain injury, intracerebral hemorrhage, and in the delayed period following SAH, but their relevance to the first few days following SAH, when the majority of brain damage occurs, has been less clear.

“That early damage has not received a lot of the attention in the research world,” Dr. Hartings said, despite that almost 90 percent of the mortality occurs in this period. Post-hemorrhage infarcts have been seen in regions where blood has accumulated, and in band-like patterns that don't match up to the regions directly supplied by the burst artery, suggesting the possibility that the blood might set off waves of depolarization that could then cause infarcts.

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To test that hypothesis, Dr. Hartings and colleagues applied one milliliter of fresh or clotted blood unilaterally just under the arachnoid membrane in pigs, whose relatively large and gyrencephalic brain provides a better model for study than those of rodents. Subdural electrode strips were placed to allow electrical recording of brain activity before and after application of the blood.

While both fresh and clotted blood caused spreading depolarizations, the most consistent results occurred with clotted blood, which caused depolarizations in five out of six animals. Depolarizations began to appear after a median of 22 minutes, lasted from one to several minutes, and in one representative animal, were spaced about 11 minutes apart over the course of six hours of recording. No depolarizations were observed on the side contralateral to the introduced blood. All animals receiving clotted blood had “substantial infarction through the full thickness of the cortex adjacent to the sulcal clot,” Dr. Hartings reported.

The effect was due to the presence of blood, not just fluid, Dr. Hartings said. Injection of one milliliter of saline caused ischemic lesion volumes of about one percent of those caused by blood, and only one of four animals experienced cortical spreading depolarizations.

“The major results were that any blood in the subarachnoid space can induce spreading depolarizations,” Dr. Hartings said. “Particularly if it clots and persists, infarcts are likely to develop.”

Which blood constituents trigger the depolarizations is not yet clear. “It could be the lysis of the red blood cells, spilling potassium and hemoglobin into the tissue,” he said, but there are other possibilities as well. “We didn't define that, and that's a very important area for future research,” which will also be possible in this pig model.

To understand the clinical relevance of these results, Dr. Hartings worked with colleagues in Germany, led by co-author Jens Dreier, MD, of Charité University Medicine in Berlin. They studied 23 SAH patients who had subdural electrodes placed at the time of surgical aneurysm repair. They examined the occurrence and timing of spreading cortical depolarizations, and correlated them with evidence of infarction from MRI performed within 48 hours of treatment.

They found that spreading depolarizations occurred in 10 out of 12 patients who showed focal lesions on magnetic resonance imaging, versus in one of 11 without focal lesions.

“The bottom line was that the occurrence of spreading depolarizations was shown to be a specific marker for developing infarcts in the brain,” Dr. Hartings said. “That had been shown for infarcts that developed in the delayed period, but had never been shown for the early period. We didn't prove the causality of the depolarizations in these patients, but it is certainly the leading hypothesis.”

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“This study is exciting because of its focus on the early phase of injury,” commented C. William Shuttleworth, PhD, Regent's Professor of Neuroscience at the University of New Mexico in Albuquerque, who was not involved in the study. “The evidence about mechanisms, including spreading depolarizations, in the delayed phase has been pretty good, but there is more injury in the early phase.”

The demonstration that spreading depolarizations are likely to contribute significantly to that injury “is a big deal, and not something we have thought about before.”

Of major importance for future work, he said, is the development of the pig model, which is likely to be valuable in pursuing tissue-level and molecular-level contributions to subarachnoid hemorrhage pathophysiology. “There is a lot of detail to figure out to know how to target these phenomena, and the pig may be useful in that regard.”

Clinically, he added, “knowing that these unusual events propagate through large areas of the brain and can cause injury, fuels the opportunity for a whole different way of treating them. Pharmaceutical intervention to block depolarizations hasn't been thought about before for the early phase of subarachnoid hemorrhage, and that's pretty exciting.”

Ketamine, which blocks N-methyl-D-aspartate receptors, appears to have some utility in this regard, “but it might not be the best drug,” Dr. Shuttleworth said. “Knowing these early events are so important might lead to some good rational design of drugs to interrupt them.”

Nimodipine, which antagonizes vasoconstriction, is also in use for SAH, Dr. Hartings pointed out. “It has some inhibitory effect on the depolarization wave itself, but more so on the spreading ischemia.” Clinical trials specifically designed to interrupt spreading depolarizations have not yet been undertaken, but Dr. Hartings is hopeful this study, and others that have highlighted the relevance of spreading depolarizations for brain injury, will help build a consensus that such trials should be undertaken.

Assuming a treatment is developed, there may be no need to implant electrodes to demonstrate the occurrence of spreading depolarizations before administering it in the individual patient, Dr. Choi of the University of Texas pointed out. “We can assume they are occurring, and deliver the treatment to prevent or interrupt them.”

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•. Hartings JA, York J, Carroll CP, et al Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction Brain 2017;140(10):2673–2690.
    •. Cooperative Study on Brain Depolarizations, an international research consortium: http://
      © 2017 American Academy of Neurology