Delay of switch from hypo- to hyperperfusion in migraine aura evidenced by arterial spin labeling (ASL): case series and pooled-data analysis

doi:10.21203/rs.3.rs-1321448/v1

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Delay of switch from hypo- to hyperperfusion in migraine aura evidenced by arterial spin labeling (ASL): case series and pooled-data analysis

https://doi.org/10.21203/rs.3.rs-1321448/v1

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Introduction: Arterial Spin Labeling (ASL) is an MRI technique used to non-invasively assess cerebral blood flow in clinical practice. In migraine aura, previous studies have shown both cortical hypoperfusion and hyperperfusion patterns. Sequential perfusion changes with alternation of hypoperfusion and hyperperfusion has been scarcely reported, only in children. Our goal was to determine the delay of conversion between hypoperfusion and hyperperfusion at acute phase, using ASL technique, in adult patients presenting migrainous aura.

Materials and methods: Six local patients with migrainous aura presenting as stroke mimics were explored with ASL sequence. Two had repeated ASL exploration. Literature search allowed to include 9 additional patients. Mann-Whitney-U test, logistic regression and ROC curve analysis were conducted on pooled data with a total of 15 patients.

Results: Median age was 30 years (range 17-87). Hypoperfusion was present on 7 ASL acquisitions and hyperperfusion on 10. Median onset-to-MRI delay was higher in hyperperfused pattern group than in hypoperfused pattern group (17.6 vs 3.5 hours, p<0.001). Best cut-off for separating hypoperfused and hyperperfused patterns was 4.5 hrs (95% confidence interval: 3.75-8.5-hrs).

Conclusion: Cerebral blood perfusion pattern in ASL switches from hypoperfusion to hyperperfusion 4.5 hours after symptom onset time in adult population. Repeated ASL exploration is an asset for the differential diagnosis between stroke and migraine.

migraine

aura

arterial spin labeling

hypoperfusion

Although a complex association between migrainous aura and vascular disease unarguably exists[1], the precise causes of migrainous aura have yet to be determined[2]. Cortical spreading depression (CSD), a slowly progressing wave of neuronal depolarization[3], is the main electrophysiological mechanism proposed for explaining migrainous aura. Experiments evaluating cerebral blood perfusion seem to be consistent with this hypothesis, with initial focal hyperoxygenation of brain cortex during the initial minutes at the beginning of aura[4], followed by spreading oligaemia in surrounding cortex[5, 6]. The subsequent tardive cortical hyperperfusion, described in literature[7, 8], has been proposed to be related to headache and vasodilation[9].

Arterial spin labeling (ASL) is a non-invasive MRI sequence used to assess cerebral blood flow. Its use has been proposed for identifying migraine aura as a stroke mimic in patients eligible for thrombolysis[10], thus preventing unnecessary stroke treatment. However, as ASL can show non-systematized hypoperfusion at the acute phase, it can be misleading when suspecting an acute ischemic stroke that also manifests as systematized hypoperfusion. As this technique is non-invasive, non-irradiating, and does not require contrast enhancement, it can be easily repeated over time and used to confirm a suspicion of migrainous aura. Moreover, easy access to perfusion imaging may allow better understanding of the relation between migrainous aura, headache and brain perfusion changes.

A previous study conducted on ten children aged 8–16 years[8] has shown that brain hypoperfusion pattern was present before 14 hours and hyperperfusion pattern after 14 hours following onset of aura symptoms. These figures are not consistent with our clinical practice in adult imaging, where we often see earlier hyperperfusion patterns. The delay of switch from hypoperfusion and hyperperfusion seems important to understand migrainous aura pathophysiology, and to better diagnose stroke mimics. The goal of our study was thus to evaluate the time of conversion between hypoperfusion and hyperperfusion patterns, using ASL technique, in adult patients presenting migrainous aura. We present here the data of six patients, two of which have had sequential ASL exploration, and pooled these results with literature cases for analysis.

Local patients

We retrospectively reviewed six retrospective cases of migrainous aura presenting as stroke mimics among a cohort of patients presenting with sudden neurological deficits between September 2016 and March 2017, two of which had repeated exploration with ASL. All methods were carried out in accordance with relevant guidelines and regulations.

Informed consent

was obtained from all subjects. The study was approved by the Pitié-Salpêtrière University Hospital Ethics Committee.

Technical parameters

The MRI was performed on a 3T MR GE (HDxT, GE Healthcare, Milwaukee, USA) whole- body scanner, using an eight-channel head coil. The imaging protocol included at least axial diffusion-weighted imaging (DWI), axial T2 gradient echo WI, susceptibility WI, and 3D Time- of-Flight (TOF) images. ASL images were acquired using the pc-ASL technique with a large number of short pulses simulating continuous labeling. The labeling was performed 2 cm below the image acquisition plane. The imaging parameters were: TR/TE 4733/9.8 ms, NEX 3, post label delay 2025 ms, FOV 24 cm3, spiral acquisition with 8 arms and 512 points per arm resulting in in-plan resolution of voxel resolution 3.49*3.49*4, scan time 4’41 min. The cerebral blood flow (CBF) maps were calculated using GE AW workstation, GE Healthcare, Milwaukee, USA).

Pooled literature analysis

We searched PubMed with the following search query: “((ASL) OR arterial spin labeling) AND migraine”. Among 31 scientific papers, we manually excluded 21 papers whose abstract did not relate to usage of ASL sequence in migrainous aura. We excluded 3 articles exploring migraine on patients ≤ 16 years[8, 11, 12] and one article exploring interictal perfusion[13]. Among the 6 remaining papers, we looked for delay between aura onset and imaging, as well as pattern ASL perfusion (hypoperfused of hyperperfused). We excluded one study where the hypo/hyperperfused criteria was unequivocal[14]. We analyzed 5 papers[7, 15–18] with 9 patients, and pooled these patients with our 6 patients. The total number of ASL perfusion sequences studied was 17 (two of our patients had sequential ASL exploration).

Statistical analysis

Results are expressed as median and Interquartile Range (IQR). Mann-Whitney-U test was used to compare hypoperfused or hyperperfused pattern according to onset-to-MRI delay. Logistic regression model was used to fit time-curve response to hypoperfused or hyperperfused pattern according to onset-to-MRI delay. Confidence intervals (CI) were computed with bootstrapping technique with B = 10000 repetitions. Optimal cut-off delay between hypoperfused and hyperperfused pattern was chosen using ROC curve analysis. Statistical analysis was made with “R” software version 3.3.1 with “rms” and “pROC” packages.

Local patients

The six included patients had a median age of 32 years (IQR: range 22–58). Two patients were scanned sequentially (Fig. 1 and Fig. 2). Median onset-to-MRI delay was 4 hours (range 1–40). Among the 8 scans, hypoperfusion was visible in 5 patients (delay 1 to 5 hours) and hyperperfusion in 3 patients (delay 4 to 40 hours). Details are shown in Table 1.

Table 1

Local patients presenting migrainous aura and explored with ASL
Patient	Age (years)	Symptoms	Perfusion pattern	Location	Onset-to-MRI delay (hours)
Patient 1	21	Right hemianopsia	Hypoperfusion	Left temporo occipital	1
	-	-	Hyperperfusion	Left temporo occipital	4
Patient 2	35	Aphasia and right hemiparesia	Hypoperfusion	Left temporo occipital	3
	-	-	Hyperperfusion	Left temporo occipital	24
Patient 3	30	Aphasia	Hypoperfusion	Right occipital lobe	4
Patient 4	54	Vertigo and nystagmus	Hyperperfusion	Left parietooccipital	40
Patient 5	30	Right brachiofacial paresis	Hypoperfusion	Left hemisphere	3
Patient 6	58	Right hemianopsis	Hypoperfusion	Left occipital	3.5

Pooled literature analysis

Details of included articles and hypo/hyperperfusion status is given in Table 2. After pooling our results with literature’s results, median age was 30 years (range 17–87). Hypoperfusion was present on 7 ASL acquisitions and hyperperfusion on 10 acquisitions. Median onset-to-MRI delay was 5 hours (IQR 3.75–23.3) and was higher in hyperperfused pattern group (17.6 hours, IQR 5–24 vs. 3.5 hours, IQR 2-3.8, p < 0.001). Hyperperfusion rate according to time is shown in Fig. 3. Best cut-off for separating hypoperfused and hyperperfused patterns was 4.5-hrs (95%CI: 3.75–8.5 hrs), with 86% specificity (95%CI: 71–100%) and 90% sensitivity (95%CI: 60–100%) for predicting hyperperfused pattern.

Table 2

Literature review of adult patients presenting migrainous aura explored with ASL
Author	Publication year	Number of patients	Age (years)	Perfusion pattern	Onset-to-MRI delay (hours)
Grangeon et al.	2016	1	30	Hypoperfusion	1
Law-ye et al.	2017	1	17	Hypoperfusion	3.75
Moreton et al.	2015	1	27	Hyperperfusion	24
Pollock et al.	2008	3	55	Hyperperfusion	6
	-	-	52	Hyperperfusion	24
	-	-	87	Hyperperfusion	12
Yger et al.	2015	3	27	Hyperperfusion	5
	-	-	41	Hyperperfusion	23.3
	-	-	30	Hyperperfusion	4

Our results indicate that the cerebral blood perfusion pattern in ASL switches from hypoperfusion to hyperperfusion about 4.5 hours after symptom onset time in adults.

These data have important clinical implications as acute migrainous aura may mimic stroke and hypoperfusion at the early phase may also be mistaken for medium vessel occlusion. In case of clinical doubt, such as aura without migraine, an imaging control at 6 hours may be proposed for comforting the differential diagnosis.

This also give insights into understanding the pathophysiology of migraine, comforting vascular theory of migraine onset[19]. One main interest of ASL is that it can be performed several times without the need of injection and without radiation unlike CT or contrast-enhance MR. The time frame given by our study will allow to plan future prospective studies evaluating cerebral blood perfusion in migraine aura. Indeed, repeating ASL 6 hours after initial imaging in future studies may provide new perspectives on migraine aura physiopathology.

We underlined the potential difference between children and adult populations, as a previous study reported the cut-off of 14-hours in children[8]. However, this may be due to selection bias, as acute stroke management is more developed in adults, with higher access to MRI within short delays.

Our study has several limitations. First, it is retrospective and the sample is limited. However, as demonstrated in our paper, migraine exploration with ASL is still sparse in literature. Second, we used a mixed approach with local cases and literature review, with various ASL protocols that could cause discrepancies for the interpretation of blood flow cartographies. It also favors publication bias. Third, we did not dispose of enough clinical information in literature to relate hyperperfusion with headache onset or aura offset, which could be an interesting relation to evaluate.

Finally, super-selective ASL and 4D ASL-based MR angiography was able to reveal time-resolved flow signals of the distal ICA and predict territorial perfusion and collateral vessels in Moyamoya disease [20]. This approach would be interesting to apply in migrainous aura as well in order to study perfusion more precisely in various territories, since the main perfusion anomalies are usually located posteriorly.

In conclusion, the ASL sequence allows to explore migrainous aura, and repeated ASL exploration may be an asset for the differential diagnosis between stroke and migraine. Further studies are needed to appreciate the physiopathological explanation of the transition between hypoperfused and hyperperfused pattern in ASL.

ASL = arterial spin labeling, MRI = magnetic resonance imaging,

Funding: No funding was secured for this study

Financial disclosure: All the authors declare they have no conflicts of interest to disclose

Ethical Statement: Our study was approved by the Pitié-Salpêtrière University Hospital Ethics Committee

Patient Consent Statement: The patients have consented to the submission of this manuscript

Data availability: The datasets generated and analyzed during the current study are available on demand in the form of an Excel table. The datasets generated during and analyzed during the current study are not publicly available due to confidentiality reasons but are available from the corresponding author on reasonable request.

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No competing interests reported.

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You are reading this latest preprint version

Delay of switch from hypo- to hyperperfusion in migraine aura evidenced by arterial spin labeling (ASL): case series and pooled-data analysis

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Version 1

Abstract

Figures

Introduction

Materials And Methods

Local patients

Technical parameters

Pooled literature analysis

Statistical analysis

Results

Local patients

Pooled literature analysis

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1