key: cord-0887323-ir4nijva
authors: Weinstein, Joseph D.; Hamam, Omar; Urrutia, Victor C.; Lu, Hanzhang; Luna, Licia P.; Tekes-Brady, Aylin; Bahouth, Mona; Yedavalli, Vivek
title: Added Value of Arterial Spin Labeling in Detecting Posterior Reversible Encephalopathy Syndrome as a Stroke Mimic on Baseline Neuroimaging: A Single Center Experience
date: 2022-03-03
journal: Front Neurol
DOI: 10.3389/fneur.2022.831218
sha: 643a0d4ef2e76a7a001063ec96773b8b5c4694ee
doc_id: 887323
cord_uid: ir4nijva

Differentiating stroke from stroke mimics is a diagnostic challenge in every day practice. Posterior Reversible Encephalopathy Syndrome (PRES) is an important stroke mimic with nonspecific symptomatology, making prompt and accurate diagnosis challenging. Baseline neuroimaging plays a pivotal role in detection and differentiation of stroke from many common mimics and is thus critical in guiding appropriate management. In particular, MR perfusion (MRP) imaging modalities provide added value through detection and quantification of multiple physiological parameters. Arterial Spin Labeling (ASL) is a non-contrast, noninvasive MRP technique increasingly used in clinical practice; however, there is limited description of ASL in PRES in the existing literature. In this single center retrospective pilot study, we investigate the added value of ASL in detecting PRES in the largest series to date. We hope this study can serve as the basis for larger scale investigations exploring the utility of ASL in detecting stroke mimics such as PRES for accurate and efficient management of such patients.

Posterior reversible encephalopathy syndrome (PRES) is a common stroke mimic thought to be related to cerebrovascular dysregulation, resulting in blood-brain barrier disruption and vasogenic edema (1) . This dysregulation can result in structural and perfusion abnormalities on neuroimaging that can assist in differentiating PRES-an otherwise often-challenging diagnosisfrom ischemic stroke and other stroke mimics. This differentiation is critical in determining appropriate patient care. MR perfusion techniques have significant utility in characterizing ischemic stroke and stroke mimics. Arterial Spin Labeling (ASL) is one such technique that has seen recent increased utilization and application in everyday practice (2) . ASL has multiple advantages compared to the more commonly used dynamic susceptibility contrast MR perfusion (DSC-MRP) or CT perfusion (CTP) techniques in that it offers a repeatable, non-contrast, noninvasive imaging alternative without ionizing radiation. To date, few studies have explored or demonstrated the clinical utility of ASL in PRES.

The goal of our study was to characterize the patterns and frequency of abnormal ASL signal in clinically suspected or confirmed cases of PRES in order to identify the potential utility of ASL perfusion imaging in supporting the gold-standard clinical diagnosis.

In this retrospective single-center experience, we reviewed 490 consecutive MRI brain examinations performed between July 2016 to March 2021 that all included standard structural imaging of the brain, time-of-flight MR angiography of the head (TOF MRA), and ASL perfusion. We subsequently excluded cases without a clinically suspected or confirmed diagnosis of PRES during the same hospital encounter based on chart review with particular attention to neurology documentation. We also excluded one case of suspected PRES because of significant motion degradation on ASL and multiple additional MR pulse sequences. In total, we identified six patients who qualified per our inclusion and exclusion criteria. Of note, gadoliniumenhanced dynamic susceptibility contrast (DSC) MR perfusion was not ordered as a part of the performed exams in any of the six patients who qualified for this study.

Comprehensive data points on each patient were collected, including age, race/ethnicity, presence of seizure activity at or immediately prior to presentation, clinically suspected triggering etiology, systolic and diastolic blood pressure at initial presentation, and presence of corresponding MR signal abnormalities on ASL, FLAIR, and DWI sequences. Images were independently reviewed by a neuroradiology fellow (JW) and a fellowship-trained attending neuroradiologist with 3 years of experience (VY). Any conflicting interpretations were resolved by consensus review.

The diagnosis of PRES was established clinically by the treating neurologist through evaluation of electronic health records. All patients underwent structural MR imaging of the head supplemented by MRA of the head and ASL perfusion imaging prior to the clinically confirmed diagnosis. ASL parameters at our institution were performed with 2D PASL (n = 5) or 3D PCASL (n = 1) labeling schemes on 3T 

Of the six cases, 66.7% (4/6) were male with an average age of 52 years (ranging from 21 to 68 years of age including two with uncontrolled systolic blood pressure >200 on presentation, 33.3% (2/6) with history of organ transplantation on Tacrolimus, 16.7% (1/6) with COVID-19 infection, 16.7% (1/6) with sickle cell anemia, and 16.7% (1/6) with controlled HIV on HAART.

Of our cohort of clinically suspected or confirmed cases of PRES with both structural and functional ASL perfusion imaging of the brain, we found that all patients (6/6) demonstrated both FLAIR and ASL signal abnormalities, suggesting that ASL offers additional perfusion imaging support to both structural imaging and the gold-standard clinical diagnosis. This is the largest series to date exploring the role of ASL in detecting PRES where most of the current literature is limited to case reports only. This concordance between ASL and FLAIR in our study lays the groundwork for future larger scale studies to further explore the robustness of this association. Cerebral autoregulation is capable of maintaining constant blood flow to brain tissues despite fluctuations in systemic blood pressure and cardiac output. As previously described in the literature, PRES can demonstrate MR perfusion signal abnormality that can (1) be more extensive and (2) even precede signal abnormalities on FLAIR imaging (3). The concept of perfusion signal abnormality preceding FLAIR signal abnormality is rather intuitive given the consensus that alterations in cerebral autoregulation eventually result in cerebral vasogenic edema seen on FLAIR imaging. This notion is exemplified and reinforced by our findings in Case #6 in which the most conspicuous abnormality is identified on ASL perfusion imaging.

Hyperperfusion and hypoperfusion imaging patterns in PRES have been described in both CT perfusion and DSC MR perfusion, and multiple competing hypotheses exist to explain the variability seen in such advanced imaging techniques (4). The most often described explanation for hyperperfusion in PRES is felt to result from breakdown of cerebral autoregulation, often in the setting of severe hypertension, resulting in excessive blood flow, elevated capillary hydrostatic pressure, and subsequent vasogenic edema (3). This is exemplified in a case report by Hedna et al., which describes a patient with PRES presenting as a stroke mimic with uncontrolled hypertension and abnormal CT perfusion demonstrating increased cerebral blood volume (CBV), increased cerebral blood flow (CBF), and decreased time to peak (TTP) in the classic posterior cerebrovascular distribution (5) . An alternative hypothesis for hypoperfusion in PRES suggests that compensatory vasoconstriction results in decreased blood flow/capillary perfusion pressure, eventual brain ischemia, and subsequent edema, possibly secondary to increased vascular permeability (3). Brubaker et al. examined MR DSC perfusion imaging in 8 patients with PRES and noted decreases in both CBV and CBF in the areas of characteristic FLAIR signal abnormality, supporting the hypoperfusion hypothesis; however, they also noted a lack of abnormal vascular permeability on K2 perfusion maps and very low rates of infarction/cytotoxic edema in most (7/8) patients (6) . As a result, the authors hypothesized the possibility of both arterial and disproportionate venous vasoconstriction as a plausible explanation for elevated capillary hydrostatic pressure and vasogenic edema despite counterintuitively low perfusion parameters. In our case study, we identified 83.3% (5/6) with hyperperfusion on ASL imaging and 16.7% (1/6) with mixed ASL signal, primarily indicating support for the hyperperfusion theory although with notable lack of hypertensive history in 50% (3/6) of cases, raising the question of how the other variable risk factors may contribute to the underlying mechanism.

Prior literature has described sequential hypoperfusion and hyperperfusion phenomena in the same patient with PRES citing that the progression of imaging findings mechanistically suggested a loss of autoregulatory control, resulting in initial hypoperfusion, followed by arteriolar vasoconstriction to maintain perfusion pressures, followed by resultant rebound hyperperfusion and vasogenic edema (7) . This variability in perfusion characteristics is much akin to perfusion imaging of hemodynamic changes observed in peri-ictal and post-ictal states of patients with recent seizure activity, which is a common presentation in patients with PRES (2) . Despite the absence of clinically detectable seizure activity in 33% (2/6) of cases, both of those cases (#5 and #6) still demonstrated hyperperfusion pattern on ASL imaging, suggesting that the perfusion anomalies were more likely secondary to the underlying pathogenic mechanism rather than a consequence of the resultant seizure activity. While the mechanism is still incompletely understood, ASL remains a valuable tool in evaluating dynamic changes in cerebral perfusion secondary to its repeatable and quantifiable nature for evaluating trends within the same patient over time.

Additionally, while predominantly symmetric physiologic regional hyperperfusion has been described in the bilateral occipital lobes corresponding to visual cortex activation (8), our cases are notably distinct from this entity due to the asymmetrical signal abnormality and the strong correlation with signal abnormalities on structural imaging.

Our study has some limitations due to its retrospective nature and small case number due to the variable use of ASL perfusion imaging in routine practice outside of our designated MRI stroke protocol. Another potential difficulty with this study is the reference standard for the diagnosis of PRES. While PRES may be suspected based on patient history and risk factors, symptoms are often nonspecific and imaging is often heavily relied upon to suggest or "rule in" the diagnosis (3, 9) . This reliance on imaging and the well-documented patterns on FLAIR imaging may tend to introduce a bias in favor of FLAIR positive cases. On the other hand, the lack of standardized ASL imaging protocols and unknown inter-reader agreement of ASL perfusion imaging in PRES both potentially limit the external validity of this technique in generalized practice. Nevertheless, in this single center experience, both FLAIR and ASL were positive in all six cases suggesting a correlation. ASL can potentially add value in cases where the FLAIR abnormality may be subtle (such as Case #6 in our series described above). Although our case series is the largest in the literature to date, larger-scale retrospective and prospective studies are necessary to further assess the strength of the correlation between ASL and structural imaging as well as the potential added value of ASL not only detection but also management of PRES.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

JW: data collection, primary manuscript creation, and editing. LL, VU, HL, MB, and AT-B: editing. OH: editing and data collection. VY: idea generation, data collection, secondary manuscript creation, and editing. All authors contributed to the article and approved the submitted version.

Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features

Arterial spin labeling perfusion of the brain: Emerging clinical applications

Neuroimaging features in posterior reversible encephalopathy syndrome: A pictorial review

Advanced imaging techniques in diagnosis of posterior reversible encephalopathy syndrome (PRES)

Posterior reversible encephalopathy syndrome (PRES) and CT perfusion changes

Hemodynamic and permeability changes in posterior reversible encephalopathy syndrome measured by dynamic susceptibility perfusion-weighted MR imaging

Arterial spin-labeling in routine clinical practice, part 3: hyperperfusion patterns

Arterial spin-labeling in routine clinical practice, part 1: technique and artifacts

Posterior reversible encephalopathy syndrome: Utility of fluidattenuated inversion recovery MR imaging in the detection of cortical and subcortical lesions

The authors acknowledge the support from the Johns Hopkins Department of Radiology Physician Scientist Incubator Program.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.Copyright © 2022 Weinstein, Hamam, Urrutia, Lu, Luna, Tekes-Brady, Bahouth and Yedavalli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.