Abstract
Background:
Few studies to date have captured perfusion and vascular permeability changes during a migraineur’s aura. This may be important information to the clinician in the context of the differential diagnosis of migraine with aura versus acute stroke.
Summary:
We report a case in which magnetic resonance perfusion during a migraine aura showed unilateral hypoperfusion differentially affecting gray and white matter and was associated with a hemispheric increase in permeability.
Conclusions:
Imaging in this case suggests that migraine aura is associated with oligemia below the threshold for infarction. Increased vascular permeability may be a critical mechanism contributing to perfusion changes observed in migraine with aura.
Introduction
Neuroimaging of patients during an acute attack may help clarify our understanding of the pathophysiology of migraines with aura. Depending on the point at which the attack is captured there may be a regional decrease or increase in cerebral blood flow (1). The reason for, and extent of, cerebral blood flow changes has yet to be clearly established. Changes in permeability have previously been inferred from structural imaging by the appearance of edema or contrast leakage (2,3). To our knowledge, gray–white matter perfusion differences and permeability changes have not previously been directly quantified during an acute attack. Here we report a case of migraine with aura in which imaging showed a widespread unilateral increase in vascular permeability, along with ipsilateral hypoperfusion more extensively affecting gray than white matter. This finding may provide important information to the clinician considering the differential diagnosis of a suspected acute stroke.
Case report
An 18-year-old left-handed man came to hospital complaining of headache, confusion, and word-finding difficulties. Two hours prior to presentation the patient had been in school when his classmates had noted confusion and speech disturbance. They described onset of these symptoms over 10–20 minutes. The patient had complained of headache several minutes after his confusion and speech disturbance had begun. The headache built up over several minutes with severe, throbbing pain in the left parietal region. The patient experienced nausea and at least one bout of vomiting.
In the emergency room, the patient was intermittently disoriented to time and place. He denied visual, sensory, and motor symptoms. There was a childhood history of migraine without aura from age 6–13 years. His migraines had been bifrontal and associated with nausea, vomiting, and photophobia. Past medical history was otherwise negative. The young man was not taking any medications. He denied tobacco, alcohol, and drug use.
On physical examination, vital signs were stable. The patient was drowsy, but rousable. Examination of speech suggested a global aphasia with mild impairment in fluency, repetition, comprehension, and naming, with paraphasic errors. The remainder of the neurological examination was normal. Non-contrast head computed tomography (CT) and a structural magnetic resonance image (MRI) were unremarkable. On diffusion weighted imaging (DWI), there was no restriction to suggest ischemia. A CT angiogram showed no sign of left middle cerebral artery (MCA) occlusion or vasospasm (Figure 1). Cerebrospinal fluid (CSF) studies were within normal limits.
Axonal magnetic resonance (MR) perfusion image performed at 3 hours from the headache onset when the patient continued to demonstrate aphasia. There is decreased blood flow evident throughout the left hemisphere.
Hemispheric perfusion changes during the migraine aura.
CBF: cerebral blood flow, CBV: cerebral blood volume, KPS: endothelial transfer constant.
Endothelial transfer constant (KPS) values were derived using a previously described gradient T1 sequence quantifying leakage from intravascular to extravascular spaces by tracking contrast accumulation over time using the Patlak model (5). The KPS is the endothelial transfer constant that represents the permeability change. A unidirectional two-compartment kinetic model was used to model the relationship between the tissue concentration of gadolinium-gadopentate dimeglumine (Gd-DTPA) and the blood concentration time curve of Gd-DTPA using linear regression. For each voxel, the KPS value was calculated as the slope of the best fit, assuming negligible Gd-DTPA reflux into the intravascular space. This technique is novel in that it allows for direct quantification of vascular permeability as opposed to relying on a surrogate marker such as extravascular presence of contrast. The KPS value showed a 24% mean hemispheric increase with a 34% and 24% increase in cortical gray and white matter, respectively, compared with the contralateral hemisphere.
The patient’s headache and aphasia began to significantly improve approximately 8 hours after onset. The patient was completely back to baseline by the next morning. A final diagnosis of migraine with prolonged aura was made.
The patient was seen in follow-up at 3 months and 1.5 years, and provided signed informed consent to report his case. There was no recurrence in headache or other neurological symptoms. Repeat neurological examination was normal on both occasions. A follow-up structural MRI was unremarkable. Repeat imaging demonstrated mild persistent perfusion and permeability hemispheric differences.
Discussion
In this case a young man with a history of migraine without aura presented with headache and focal neurological symptoms. He received full neuroimaging to rule out the possibility of vasospasm or infarction. There was no diffusion restriction to suggest infarction, nor did his CT angiogram reveal any evidence of vascular occlusion. His MR perfusion demonstrated holohemispheric hypoperfusion as opposed to the hypoperfusion in the distribution of a single vascular territory as would be expected with a transient ischemic attack. Classically, migraine with aura has also been associated with regional changes in perfusion, but more widespread holohemispheric perfusion abnormalities have also been observed (6,7).
Our patient’s clinical presentation met many of the International Headache Society (IHS) criteria for migraine with aura (8). He experienced a fully reversible speech disturbance, which developed gradually over more than 5 minutes and continued for longer than 5 minutes. His headache was unilateral, throbbing, and severe, and it was associated with nausea and vomiting. He did not meet the criterion for the persistence of his aura, as his aura persisted for more than 60 minutes, or the criterion for the history of at least two attacks, given that this was his first such episode. Previously the IHS has acknowledged an entity known as migraine with prolonged aura, and it is well known in the clinical world that migraine auras can occasionally persist for 24 hours or longer (2,3). Moreover, although a second attack would allow for more confidence in the diagnosis, at some point early in their course all migraineurs with aura will have experienced only one attack. A final but essential aspect of diagnosing migraine is to exclude other medical causes, which the combination of the neuroimaging findings and the patient’s clinical resolution allowed us to do. Despite some divergence from strict application of the IHS criteria, overall this case was judged to be consistent with a diagnosis of migraine with aura, and far more compatible with this diagnosis than any of the other possibilities.
Notably our patient’s aura symptoms did not include a right-sided hemiparesis, despite hypoperfusion of the full left middle cerebral artery (L MCA) territory. We hypothesize that this is, because hemiparesis may only manifest below a critical threshold of cerebral blood flow (oligemia versus ischemia). Relative whole brain cerebral blood flow (CBF) thresholds defining penumbral tissue that can recover are reported, with a relative reduction of 25–38% (relative ratios of 0.62–0.75) compared with the normal hemisphere (9). In comparison, smaller relative cerebral blood volume (CBV) ratios define penumbral recovery (>0.78–0.94) with infarction seen below a ratio of 0.69–0.84 (9). In this case the comparable whole hemisphere CBF and CBV reductions remained in the penumbral recovery ranges. This is the first study to report the differential involvement of gray and white matter involvement. Interestingly, gray matter oligemia was associated with modest underlying white matter hyperperfusion similar to that described at the boundaries of cerebral infarcts.
Global hemispheric blood flow changes may be seen in migraine, where they are often associated with complicated aura phenomena, such as aphasia and hemiplegia (2,10,11). One of the leading theories of migraine pathogenesis is that neuronal depolarization spreads forward from the posterior cortex inducing secondary cerebral vasculature changes (7). This theory may explain why multiple vascular territories or even a whole hemisphere may be affected by migraine. In this case we were able to directly establish a widespread unilateral cortical increase in vascular permeability—a potential mechanism for concomitant holohemispheric hypoperfusion. Two other groups have previously inferred vascular permeability changes associated with aura symptoms persisting over several days. One report described a 35-year-old woman with sporadic hemiplegic migraine presenting with a headache, global aphasia, right visual field cut, and right arm weakness (2). On day 4, delayed enhanced fluid attenuated inversion recovery (FLAIR) sequences showed enhancement of the left posterior cortical sulci, suggesting vasogenic leakage. These changes had resolved by the time imaging was repeated on day 11. A similar case described a 66-year-old woman with a long history of migraine presenting with a visual scotoma followed by headache and persistent global aphasia (3). Magnetic resonance imaging with gadolinium enhancement at 48 hours after onset revealed leakage of contrast on the T1 images over the temporal lobe region.
This case provides quantitative evidence to help substantiate the theory that vascular permeability changes may be involved in the manifestation of aura symptoms. Changes in vascular permeability were associated with hypoperfusion preferentially affecting the grey matter. The observed region of hypoperfusion was not confined to a single vascular territory and was within the threshold for oligema, but not ischemia. These findings may be of particular interest to clinicians considering migraine as a differential diagnosis when a young person presents with acute onset of focal neurological deficits.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
No conflicts of interest have been declared.