Implication of Augmented Vasogenic Leakage in the Mechanism of Persistent Aura in Sporadic Hemiplegic Migraine

Abstract

The aim of this study is to report a possible implication of augmented vasogenic leakage in the mechanism of prolonged aura in sporadic hemiplegic migraine. A 35-year-old woman with sporadic hemiplegic migraine presented with headache followed by right arm weakness, right visual field defect, aphasia and confusion that persisted for 1 week. During the acute stage, focal hyperaemia was seen in the left cerebral hemisphere corresponding to persistent aura symptoms. Augmented vasogenic leakage was demonstrated on delayed enhanced fluid-attenuated inversion recovery image. Magnetic resonance angiography showed dilation of the left middle cerebral artery. During the convalescent stage, such abnormal findings were not seen. Based on these results, we speculate that augmented vasogenic leakage from the leptomeningeal vessels, probably associated with activation of the trigeminovascular system, may delay the recovery of hemiplegic migraine aura.

Introduction

Typical migraine aura usually disappears within an hour, but migraine aura persisting longer than 60 min had been defined as ‘prolonged aura’ by the International Headache Society criteria (1). The newly revised International Classification of Headache Disorder II (ICHD-II) released in 2004 (2) introduced a new term ‘persistent aura without infarction’ to define migraine aura persisting longer than a week without radiographic evidence of infarction, whereas the duration of each aura symptom in sporadic or hereditary hemiplegic migraine was defined to be longer than 5 min but less than 24 h (2). However, it has been well documented that migraine aura, particularly in hemiplegic migraine, may persist for longer than a couple of days or even several weeks, but the mechanism for persistent aura remains unknown.

Migraine aura is now believed to be a primary neuronal event reflecting a wave of spreading depolarization analogous to cortical spreading depression (CSD) (3). Modern neuroimaging techniques demonstrated a brief hyperaemia followed by spreading hypoperfusion in the brain regions corresponding to aura in human (4) as seen in CSD of animals (5). However, in several case reports of prolonged hemiplegic migraine (6–10), focal hyperperfusion has been demonstrated in the brain regions corresponding to persistent aura. Furthermore, a case of migraine with persistent aura showing vasogenic leakage as well as hyperperfusion was recently demonstrated (11). The mechanism of persistent aura may be different from that of typical aura. The trigeminovascular system has been implicated in the mechanism of migraine headache, but not usually considered in the pathophysiology of aura.

We report a case of sporadic hemiplegic migraine (SHM) suggesting a possible link between persistent aura and the trigeminovascular system, of which activation may also be implicated as a mechanism of persistent aura.

Case report

A 35-year-old right-handed woman with SHM was admitted to our hospital because of migraine attack accompanied by aphasia and right arm weakness. She began to have migraine without aura fulfilling the ICHD-II criteria at the age of 12 years. Since the age of 20 she had developed visual scintillation prior to the onset of headache, which was on some occasions accompanied by right hemiparesis and aphasia. A family history including headache or episodic ataxia was negative. She had no habits of smoking, drinking or the use of illicit drugs.

One day before admission, she began to have bilateral throbbing headache and vomiting, and 2 h later noticed stiffness in the right arm and difficulty in talking. On the following morning she became unable to talk or to raise the right arm. She was transferred to hospital.

On admission and day 2, she was in confusion with global aphasia, right visual field defect and mild right arm weakness. CSF was normal. EEG showed low-voltage background activity over the left cerebral hemisphere without epileptiform discharges. Diffusion-weighted MR imaging (DWI) was unremarkable. The first brain blood flow single photon emission computed tomography (SPECT) using ^99mTc-d,l-hexamethyl-propyleneamine oxime (HM-PAO) (740 MBq) as a flow tracer showed widespread hyperperfusion in the left cerebral hemisphere with crossed cerebellar diaschisis on the right side, suggesting the presence of uncoupled hyperperfusion with low function in the left cerebral hemisphere, which corresponds to the neurological deficits (Fig. 1a). On day 2 she first received i.v. furosemide 20 mg to terminate prolonged aura but with no beneficial effect, and she was then put on acetazolamide 750 mg a day. On day 3 headache and right arm weakness improved but aphasia remained unchanged. Magnetic resonance angiography showed prominence of the branches of the left middle cerebral artery (Fig. 1f). On day 4 she became very agitated, confused and walked around naked. The second SPECT showed continuous spread of hyperperfusion involving the left anterior frontal cortex (Fig. 1b), suggesting ongoing cerebrovascular changes related to neuropsychological dysfunction. Delayed enhanced fluid-attenuated inversion recovery (FLAIR) images, obtained 2 h after i.v. gadolinium-diethylenetriaminepantacetate, showed CSF enhancement in the sulci of the left posterior cortex corresponding to prolonged aura (Fig. 1d), suggesting the presence of augmented vasogenic leakage from the leptomeningeal vessels. In the evening she began to receive corticosteroid 60 mg a day. On the morning of the following day (day 5) she dramatically improved and became able to talk and follow verbal commands. She continued to improve on corticosteroid and on day 10 neurological deficits completely resolved. On day 11 the second delayed enhanced FLAIR images showed no CSF enhancement (Fig. 1e). The third SPECT showed no abnormality (Fig. 1c).

Figure 1

Serial neuroimaging studies obtained during persistent migraine aura. Shown are the results of neuroimaging studies obtained during the acute (a,b,d,f) and convalescent stages (c,e). Blood flow single photon emission computed tomography (SPECT) shows widespread hyperperfusion in the left cerebral hemisphere corresponding to persistent aura symptoms (a). Continuous spread of hyperperfusion from the left posterior cortex (a) to the anterior frontal cortex (b) reveals ongoing neurovascular changes related to neuropsychological dysfunction. Delayed enhanced fluid-attenuated inversion recovery images obtained 2 h after i.v. gadolinium-diethylenediaminepentaacetate demonstrates CSF enhancement in the sulci of the left posterior cortex with mild brain oedema, suggesting the presence of focally augmented vasogenic leakage (d, arrowheads). Dilation of the left middle cerebral artery is shown on MR angiography (f, arrows); both coronal (top) and axial views (bottom) during the acute stage. Neither hyperperfusion nor vasogenic leakage is seen during the convalescent stage (c,e). A was obtained on day 2, f on day 3, b and d on day 4, e on day 11, and c on day 23. All SPECT studies were performed using ^99mTc-d,l-hexamethyl-propyleneamine oxime as a flow tracer.

Discussion

This patient provided several important clues to the mechanism of persistent aura. First, focal hyperperfusion was seen in the brain regions corresponding to persistent aura symptoms. Second, augmented vasogenic leakage in the most affected posterior brain was demonstrated on delayed enhanced FLAIR image. Third, these focal cerebrovascular changes completely resolved when persistent aura symptoms disappeared following corticosteroid therapy.

Although hypoperfusion was recently demonstrated in a single case of persistent aura without infarction (12), focal hyperperfusion associated with persistent aura has been documented, particularly in familial or sporadic hemiplegic migraine (6–11) despite persistent neuronal suppression in the affected brain. The present observation suggested that an uncoupling hyperaemia might exist in the brain regions corresponding to persistent aura of hemiplegic migraine.

Delayed enhanced FLAIR images were studied in this patient because it was reported to be a sensitive technique to detect minor vasogenic leakage in the brain (13). CSF enhancement in the sulci can be seen in various conditions (13), including meningitis, brain tumour, status epilepticus and acute ischaemic stroke, which are unlikely in this patient.

It is important to note that augmented vasogenic leakage was seen focally in the hyperaemic brain regions corresponding to the persistent aura, suggesting that both hyperaemia and vasogenic leakage serve as an underlying mechanism for persistent aura. Activation of the trigeminovascular system in migraine is the most likely explanation for both conditions because a link between migraine aura and trigeminovascular activation has been well established (14). Bolay et al. demonstrated that CSD activates trigeminovascular afferents and evokes cortical leptomeningeal and brainstem events, leading to plasma protein extravasation within the dura mater. Although there are no in vivo data of plasma extravasation within the dura mater in human, leptomeningeal plasma leakage in our patient may be analogous to so-called ‘neurogenic inflammation’ and could be indirect evidence of plasma extravasation that can occur in migraineurs.

The mechanism of focally augmented vasogenic leakage remains elusive, but regional vascular factors, including regional cerebrovascular reactivity under the influence of trigeminovascular activation, may play a role. We have reported previously a case of secondary migraine due to Sturge–Weber syndrome (15) presenting with persistent left homonymous hemianopsia and migraine headache, in which focal hyperaemia as well as focally augmented gadolinium leakage were considered due to the overreaction of leptomeningeal angiomatosis overlying the right occipital cortex. Therefore, regional vascular factors could contribute to regional increase of vasogenic leakage.

The effect of vasogenic leakage on cortical neuronal activity remains elusive. One might argue that vasogenic leakage is an epiphenomenon of migraine attacks, not a cause of persistent aura. However, based on focally augmented vasogenic leakage restricted to the brain regions corresponding to persistent aura and dramatic improvement of aphasia following corticosteroid therapy, we speculate that focally augmented vasogenic leakage may delay the spontaneous recovery of neuronal suppression, presumably by sustained release of neurotransmitters such as glutamate (16), or inducing brain oedema though activation of matrix metalloproteinases (17), or by changing ion homeostasis in the extracellular fluid.