Conference Coverage

Does Migraine Transiently Open the Blood–Brain Barrier?

Researchers debate whether a phenomenon observed in animal studies occurs in humans and whether it is clinically meaningful.


STOWE, VT—Experimental evidence suggests that migraine, particularly migraine with aura, is associated with cortical spreading depression (CSD) that transiently disrupts the blood–brain barrier (BBB). For some, the question is not whether this disruption occurs, but whether it is clinically relevant. For others, even the basic premise of a CSD-mediated disruption of the BBB is suspect. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, a debate between two researchers from opposing sides of this controversy indicated that there was little common ground.

“Experiments in mice suggest that CSD might open the BBB and activate pain-sensitive fibers. However, you have heard nothing about data from humans, and in fact, many migraine patients report aura symptoms without head pain,” said Messoud Ashina, MD, PhD, Director of the Human Migraine Research Unit at the Danish Headache Center in Glostrup.

Messoud Ashina, MD, PhD

On the contrary, the evidence that CSD opens the BBB is “incontrovertible,” according to Cenk Ayata, MD, PhD, Director of the Neurovascular Research Unit at Massachusetts General Hospital in Charlestown. “It is not a matter of whether the BBB opens, it is a matter of magnitude. The critical question is whether it is clinically relevant.”

Cenk Ayata, MD, PhD

This controversy is of particular current interest. Although CSD has long been suspected to mediate migraine pain, a transient opening of the BBB may greatly affect the efficacy of monoclonal antibodies in development for migraine prophylaxis and treatment. Monoclonal antibodies that target the calcitonin gene-related peptide (CGRP) have shown promise in ongoing trials, but an opportunity to target the CNS directly could improve their efficacy. Monoclonal antibodies are too large to cross the BBB without increasing the latter’s permeability.

What Is CSD?

CSD is a wave of intense neurologic depolarization that is considered the electrophysiologic substrate of migraine aura, according to Dr. Ayata. The “massive transmembrane ion and water shifts hit the cerebral vasculature during CSD like a tsunami,” he said. Citing more than two decades’ worth of research, Dr. Ayata explained that CSD is accompanied by upregulation of multiple neurotransmitters and neuromodulators that trigger large blood flow responses and disrupt cerebrovascular reflexes, such as neurovascular coupling.

Initial studies of the role of CSD and its potential for disrupting the BBB were primarily related to stroke and head trauma. Numerous studies have supported the hypothesis that CSD is the underlying mechanism of migraine aura and a putative trigger for migraine headache. The specific sequence of events leading to CSD in migraine remains unclear, but Dr. Ayata and colleagues have conducted experiments that suggest that “CSD alone, without attendant tissue injury, can produce a transient opening of the BBB.”

In murine models of migraine, Evans blue leaked into the CNS after noninvasive induction of CSD. No leakage was observed in control animals that underwent a sham induction. Other controlled experiments that included objective measures of brain edema after CSD corroborated the association between CSD and BBB disruption.

“The opening of the BBB starts sometime between three and six hours [after induction of CSD], reaches a peak at six to 12 hours, and then gradually declines over the next 24 hours or so,” said Dr. Ayata. The BBB is completely restored at 48 hours, he added.

The Potential Role of Transcytosis

The BBB consists of astrocytes, pericytes, and endothelial cells with tight junctions that prevent most blood-borne substances from crossing into the CNS. Various processes can breach the BBB, and Dr. Ayata’s group is focusing on transcytosis. They hypothesize that ion pumps and other transporters cannot explain their observations that molecules as large as 70 kDa can pass through the BBB.

Transcytosis permits macromolecules from the luminal side of the endothelial cell to be brought into the cell by pinocytotic vesicles and to be released on the other side. It is a plausible mechanism for passage through the BBB, according to Dr. Ayata. Electron microscopy studies of BBB tissue from murine models strongly support this hypothesis.

“We found a significant increase in pinocytotic vesicles starting between three and six hours, but then a gradual decline to normal levels over the next 48 hours. This time course is exactly what we found in terms of leakage,” said Dr. Ayata. There was no evident change in endothelial tight junctions or in any other structure likely to provide an alternative mechanism for the observed BBB disruption, he added.

Although BBB disruption in an animal model of migraine is not proof of the same phenomenon in humans, Dr. Ayata suggested that the results are consistent with clinical observations. For example, a series of papers from 1985 to the present, including studies undertaken with gadolinium enhancement, found an association between severe migraine and documented edema. A twin study and studies of familial hemiplegic migraine also showed that CSD contributes to migraine pathogenesis and causes disruption of the BBB, he said.

Human Data Are Lacking

Although early studies provide a basis for the hypothesis that CSD is associated with migraine and might disrupt the BBB, clinical studies have consistently failed to link CSD with evidence of BBB disruption, said Dr. Ashina. In 1981, Olesen and colleagues reported cerebral hypoperfusion, a potential sign of CSD, followed by transient increases in cerebral perfusion (ie, hyperemia) during experimentally induced migraine aura.

“In some patients, headache disappeared when the hyperemia was observed, so there was no correlation,” said Dr. Ashina. Moreover, no changes in blood flow were observed when the same studies were conducted in patients with migraine without aura, and none of the studies reported changes in the permeability of the BBB in migraineurs with and without aura, according to Dr. Ashina. He and his colleagues at the Danish Headache Center remain active in this research.

He cited a 2017 study by Hougaard et al of 19 migraineurs with aura and 19 migraineurs without aura. Tissue perfusion in various parts of the brain was measured to assess change in BBB permeability. Patients underwent 3-T MRI during and in the absence of migraine attacks. “In aura patients, we found hyperperfusion in the brainstem during the headache phase of migraine with aura, while the BBB remained intact during attacks of migraine with aura,” said Dr. Ashina. Using sensitivity analyses, they looked for changes as small as 15%, but found nothing.

Other studies have looked more indirectly at the likelihood that the BBB is disrupted during migraine, but these, such as one that evaluated extracranial arterial dilatation during migraine attacks, have also been negative, according to Dr. Ashina. Studies of putative mechanisms for BBB disruption, such as one that evaluated the upregulation of matrix metalloproteinases, have also failed to support BBB disruption. “Nothing out there provides any evidence whatsoever that relates directly to BBB opening during migraine attacks with or without aura,” said Dr. Ashina.

If the BBB undergoes a transient disruption during migraine, it remains unclear whether this disruption is clinically meaningful or provides new opportunities to time treatment. The introduction of monoclonal antibodies for migraine may inspire the research needed to resolve this question.

Dr. Ashina has financial relationships with Alder BioPharmaceuticals, Allergan, Amgen, Eli Lilly, Novartis, and Teva. Dr. Ayata has no financial relationships relevant to this topic.

—Ted Bosworth

Suggested Reading

Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12(5):454-461.

Amin FM, Hougaard A, Cramer SP, et al. Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. Eur J Neurol. 2017;24(9):1116-1124.

Ashina M, Tvedskov JF, Lipka K, et al. Matrix metalloproteinases during and outside of migraine attacks without aura. Cephalalgia. 2010;30(3):303-310.

Ayata C, Lauritzen M. Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev. 2015;95(3):953-993.

Hougaard A, Amin FM, Christensen CE, et al. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura. Brain. 2017;140(6):1633-1642.

Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344-352.

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