OJAI, CA—Blood-vessel microemboli appear to be a potential source not only of ischemia and stroke, but also of migraine with aura, according to Michael A. Moskowitz, MD.
“The idea is that at the severe end of a continuum, one may develop a stroke,” he said. “On the other end, one can experience migraine with aura. And somewhere in between, transient ischemic attacks may reside. This is not to suggest that the spectrum is always progressive—we know that most patients with migraine aura don’t develop strokes. But certainly a subpopulation is at higher risk.”
Dr. Moskowitz, Professor of Neurology at Harvard Medical School in Boston, discussed emerging research on the overlap between migraine and stroke at the Fourth Annual Meeting of the Headache Cooperative of the Pacific. He described recent data on the role of microemboli in triggering cortical spreading depression, a source of migraine with aura.
Defining Cortical Spreading Depression and Peri-infarct Depolarization
Cortical spreading depression is a propagating wave of intense neuronal and glial depolarization that spreads through the cortex, especially the visual areas, and is followed by a wave of neuronal inhibition. It is believed to underlie migraine aura and to be a critical upstream driver of the rest of the migraine attack through its effects on trigeminal nerve branches lying on the surface of the brain, near blood vessels. Although cortical spreading depression does not cause overt cell death in a normal brain, it is noxious, can injure tissues, and stresses the brain when brain blood flow is compromised.
Cortical spreading depression is “accompanied by major blood vessel changes,” Dr. Moskowitz emphasized. The event is characterized by propagating hyperperfusion during the early depolarization phase followed by hypoperfusion. It also renders the brain more resistant to subsequent injury, such as ischemic events repeated several days later, probably through genetic regulation. “If cortical spreading depression is initiated on day one and an ischemic injury occurs on day three, the size of the infarct is reduced to about 50% of what it might have been without the cortical spreading depression,” said Dr. Moskowitz.
Peri-infarct depolarization is a “close first cousin” to cortical spreading depression, he added. Instead of propagating hyperperfusion and shrinking infarcts, however, it propagates as a hypoperfusion and enlarges infarcts. Peri-infarct depolarization also differs from cortical spreading depression in that it can kill neurons.
A Hypoperfusion Syndrome
Cortical spreading depression appears to be triggered by microemboli that become stuck in blood vessels just long enough to depolarize the surrounding tissue, said Dr. Moskowitz. This event might occur in patent foramen ovale or pulmonary arteriovenous malformation, both of which are associated with a higher risk of migraine with aura.
Dr. Moskowitz noted that he and other researchers in his laboratory were able to evoke cortical spreading depression in mice by injecting small cholesterol particles into their carotid arteries. The risk of developing the event in this context was related to the magnitude and duration of the blood flow deficit. Tissue damage afterward was surprisingly infrequent when assessed pathologically and with MRI tools.
“What we propose is that a subpopulation of migraine with aura patients exhibits a transient, regional, hypoperfusion syndrome,” Dr. Moskowitz said. This hypoperfusion appears to cause, in turn, local hypoxia, the disruption of ionic gradients, and local depolarization—which then propagates.
More serious hypoperfusion, however, may produce more dangerous consequences. “Based on our work, we believe there are at least three possible scenarios,” Dr. Moskowitz said. “One is that microemboli travel to cerebral blood vessels but quickly find their merry way out on the venous side and into the lungs. Another scenario, more relevant to migraine with aura, is that these particles get stuck for ultra-short periods of time, but long enough to depolarize surrounding tissue and trigger cortical spreading depression. Unfortunately, another scenario, and this also occurs in patients harboring a patent foramen ovale, is that embolic particles may stay within the blood vessel and cause an infarct.”
The hypoperfusion that causes cortical spreading depression also may explain why delayed stroke sometimes occurs during prolonged migraine attacks, Dr. Moskowitz said.
Mutations and Cortical Spreading Depression
Research has found that genetic mutations increase susceptibility to cortical spreading depression. For example, human mutations that cause migraine with aura have been knocked into the genome of mice and cause a cortical spreading depression phenotype.
At least six mutations that cause migraine aura syndromes have been identified. Many are associated with mutations in pumps or channels that transport or transfer ions, such as sodium, potassium, or calcium, across cell membranes. These translocation processes are needed to maintain ionic gradients or control transmitter release and recycling.