Researchers have discovered a new mechanism that contributes to cell death after a subarachnoid hemorrhage (SAH), providing a new target for therapeutic intervention.
The mechanism — known as spreading depolarization, in which neurons undergo self-propagating waves of electrical depolarization — has previously been identified in experimental models of cerebral ischemia, hemorrhage, and trauma. It has now also been shown to contribute to the pathogenesis of early brain injury after SAH.
The study, by an international group of researchers, was published online in Neurology on December 28.
In an accompanying editorial, Stephan Mayer, MD, Henry Ford Health System, Detroit, Michigan, and Raimund Helbok, MD, Medical University of Innsbruck, Austria, describe spreading depolarization as a "brain tsunami."
Mayer explained to Medscape Medical News that when brain tissue is deprived of oxygen and glucose after an injury, neurons around the injured area become distressed. "A complex chain reaction of different cellular processes occurs, resulting eventually in tissue infarction and cell death," Mayer said.
"It is well known that neurons undergo depolarization to connect to each other in a normal healthy way, but this happens very briefly — just in a fraction of a second," he said. "But when a neuron is in trouble — in a distressed state after a brain insult such as a stroke or hemorrhage — this electrical depolarization is much more intense and lasts much longer, up to 15 or 20 minutes.
"This is like a tidal wave or tsunami of depolarization and is an extremely pathological reaction of brain tissue," he added. "We believe this spreading depolarization sucks up the remaining energy in the cell and is the mechanism that tips the cells over the edge from being distressed to dead."
He noted that a normal compensatory response to cell depression would be vasodilation of small blood vessels in the area, as occurs, for example, in migraine, but in spreading depolarization, pathogenic vasoconstriction also occurs, causing even greater harm.
The discovery of this spreading depolarization as the mechanism of brain cell death after a brain injury has provided a new potential target for treatment.
"We're just at the point of having identified this mechanism and correlating it with poor outcome," Mayer says. "We think it is an important part of the puzzle. It hasn't been recognized until recently, and its importance has been underemphasized. This latest study confirms the process of spreading depolarization occurs and correlates with infarct size and poor outcome in patients with subarachnoid hemorrhage. The next step will be try to block it somehow."
He suggests possible candidates that could be investigated for this purpose include the analgesic/sedative ketamine and the calcium blocker nimodipine.
"Suppression of these depolarizations might one day become an important tactic for minimizing acute brain injury as it evolves in the emergency setting," Mayer and Helbok conclude. "We do not have sufficient data yet on what might work, or whether spreading depolarizations can be suppressed at all. It seems clear, however, that we will be hearing a lot more about this phenomenon in the near future."
In the Neurology article, the researchers, led by Nina Eriksen, PhD, University of Copenhagen, Denmark, explain that spreading depolarization is the principal mechanism that initiates cytotoxic edema in various gray matter structures, including the neocortex. Accordingly, spreading depolarization occurs in patients with aneurysmal SAH, traumatic brain injury, spontaneous intracerebral hemorrhage, and malignant hemispheric stroke. In addition, it occurs within minutes after circulatory arrest, they report.
Eriksen and colleagues investigated whether spreading depolarization–related variables at two different time windows (days 1–4 and 5–8) after aneurysmal SAH correlated with the stereologically determined volume of early focal brain injury on the preinterventional CT scan in 54 patients.
Patients were electrocorticographically monitored using subdural electrodes during the first 8 days after the hemorrhage.
Results showed that in 33 of 37 patients (89%) with early focal brain injury (intracerebral hemorrhage and/or hypodensity), spreading depolarization occurred during days 1–4, compared with 7 of 17 patients (41%) who had not experienced early focal brain injury, giving a positive predictive value of 83% and a negative predictive value of 71%.
The number and magnitude of spreading depolarizations also correlated with the volume of focal pathology during this early period.
"Our findings suggest that early focal brain injury after aneurysmal subarachnoid hemorrhage is associated with early spreading depolarizations and further support the notion that spreading depolarizations are a biomarker of focal brain lesions," the researchers conclude. "Overall, our findings add another piece of evidence that spreading depolarization is a biomarker for excitotoxic injury," they add.
Other results showed that all four spreading depolarization–related variables measured during days 1–4 significantly correlated with the volume of early focal brain injury. A multiple ordinal regression analysis identified the peak total spreading depolarization–induced depression duration of a recording day as the most important predictor.
The researchers point out that this peak spreading depolarization–induced depression duration could occur any time throughout the 8-day course.
"This reflects the clinical experience that a particular day may determine the further fate of a patient with aneurysmal subarachnoid hemorrhage. Although early rather than delayed brain injury after aneurysmal subarachnoid hemorrhage is statistically more important for death and disability, this fateful day can also occur late in the course of the disease," they add.
The study authors' sources of financial support are listed in the original article. Dr Mayer has received consulting fees from Idorsia Pharmaceuticals and Edge Therapeutics, both of which are developing antivasospasm therapies for SAH. Dr Helbok has disclosed no relevant financial relationships.
Medscape Medical News © 2019
Cite this: 'Brain Tsunami': Spreading Depolarization After SAH - Medscape - Jan 04, 2019.