The Spectrum of Vessel Wall Imaging (VWI) Findings in COVID-19-Associated Neurological Syndromes: A Review

Since the start of the pandemic, there have been extensive studies from all over the world reporting on coronavirus disease 2019 (COVID-19)-associated neurological syndromes. Although initially thought of as primarily a respiratory pathogen, it became increasingly clear that the virus does have other systemic manifestations, including on the neurological system. Since then, the discovery of the many neuroimaging features of COVID-19-associated neurological syndromes have puzzled researchers and physicians in terms of interpretation, and how best to manage these findings to benefit patients. We sought to review the neuroimaging findings of COVID-19-associated neurological syndromes, particularly the vessel wall imaging (VWI) features, in the hope of finding a common feature that would better guide physicians in terms of further management of this group of patients. We will also look into the potential pitfalls of interpreting the VWI findings in these patients.


Introduction And Background
Coronavirus disease 2019 (COVID-19)-associated neurological syndromes have been extensively reported worldwide [1][2][3]. Among the many hypotheses as to why these patients manifest neurological signs and symptoms is attributable to an underlying inflammatory or immune mechanism. Neuropathologic studies have demonstrated the presence of vascular inflammation affecting the endothelium in these patients [4,5]. It is with this in mind that advanced imaging to better interrogate the vessel wall becomes a necessityhence the need for vessel wall imaging (VWI). However, up to this day, there are limited studies describing the VWI findings in these patients. We sought to look at the VWI findings reported by these studies, with the intention to look at the most common features that would hopefully assist in terms of planning the imaging sequence, anticipating the imaging findings, and further management of affected patients.

Review Material and methods
In order to identify relevant studies, we searched the PubMed, Google Scholar, Web of Science, and Scopus databases using search terms including "COVID-19", "coronavirus disease 2019", "neurology", "COVID-19 neurology", "MRI", "Magnetic resonance imaging", "Vessel wall imaging", "VWI" and combinations of these terms. We looked at full-text papers in the English language published from January 2020 until July 2022. Articles that described the magnetic resonance imaging (MRI) findings but did not mention the VWI findings were excluded, as these were beyond the scope of this paper. We also examined the reference lists of key papers to identify further articles that are potentially relevant for inclusion in this review.
percentage of patients with positive findings ranged from 16% (lowest) to 100% (highest); it is important to keep in mind that the smaller the cohort, the higher the chances of the percentage being higher. These extracted data are discussed briefly below, and summarized in Table 1 and Table 2

Demographics
Of the six studies where the individual patient data are available to be extracted, a total of 18 patients were included, where the majority were males (n=15) as opposed to females. The age of the patients ranged from 13 years old (the youngest and only pediatric patient in the cohort) to 79 years old, with a mean age of 62.7. The summarized demographics from the studies by Keller et al. [8] and Lovblad et al. [7] can be referred to the original publications.

Neurological History and Manifestations
In the majority of patients with positive VWI findings, the two main neurological histories and manifestations were stroke-related; these ranged from transient ischemic attacks to unilateral weakness/hemiparesis, as well as encephalopathy. However, as a considerable portion of these patients also presented with severe COVID-19 pneumonia requiring ventilation, they were also found to have pathological wakefulness after sedation, which prompted neuroimaging for further assessment. Other neurological symptoms included altered mentation/Glasgow Coma Score (GCS), confusion, agitation, abnormal movements, aphasia, gait instability, and bilateral pyramidal syndrome.

Vessel Wall Imaging (VWI) Findings
Of the 45 patients across the eight studies who had VWI done, 44 patients (98%) had circumferential, concentric vessel wall enhancement of the involved vessels, either with or without narrowing. These were, for the most part, long segmented. Only one patient from the study by Mazzacane et al. [9] had multifocal enhancement. The pattern of vessel wall enhancement mimics those seen in patients with cerebral vasculitis.

Other MRI/Neuroimaging Findings
The majority of patients had ischemic lesions involving the territories supplied by the pathologically enhanced vessels. However, a portion of these patients also demonstrated cerebral microhemorrhages, subarachnoid hemorrhages (presumably non-aneurysmal, as these were not mentioned), as well as white matter hyperintensities.

Cerebrospinal Fluid (CSF) Findings
The data regarding the CSF findings from the included studies are heterogenous, with some studies having no available data for the CSF findings. However, it would be interesting to note that in the studies that do, the SARS-CoV-2 in the CSF were all negative. The summary of the CSF findings for available individual patients can be referred to in Table 2. The summarized findings from the studies by Keller et al. [8] and Lovblad et al. [7] can be referred to in the original publications. The detailed analysis and discussion of the CSF findings is beyond the scope of this paper.

Discussion
The main aim of this review was to look at the spectrum and possible common pattern of intracranial VWI findings in patients with COVID-19-associated neurological syndromes, across all published papers thus far. Based on our review, we have found that in most patients, the pattern of vessel wall imaging is akin to those seen in patients with cerebral vasculitis. Based on the expert consensus recommendations of the American Society of Neuroradiology (ASNR), a vasculitis is suspected when the vessel wall imaging pattern is homogenous and concentric, with associated wall thickening [14]. When vessel wall enhancements are nonconcentric, the possibility of an atherosclerotic plaque needs to be considered. This is especially important to consider, because presence of atherosclerotic plaques may be associated with the development of vasa vasorum [15], a condition that may mimic vasculitis.
A possible explanation for this pattern of vessel wall thickening and enhancement is the pathophysiological mechanism by which COVID-19 attacks the blood vessels. The main receptor for SARS-CoV-2 is angiotensin converting enzyme 2 (ACE-2), which facilitates the entry of the virus and can be found among other human cell surfaces within the endothelium, leading to endotheliitis. This theory is further supported by neuropathologic studies, which have demonstrated the presence of vascular inflammation affecting the endothelium in these patients [4,5].
Apart from concentric, diffuse, vessel wall thickening and enhancement, other neuroimaging findings noted were ischemic lesions within the involved vascular territories, subarachnoid hemorrhages, cerebral hemorrhages, and white matter hyperintense lesions -which could all well be associated complications from cerebral vasculitis. Additionally, some of these patients also demonstrated cerebral microbleeds, which in some atypically involved the corpus callosum. This atypical involvement has been described in critically ill COVID-19 patients [16,17]. However, the pathophysiological mechanism bringing about this finding remains unknown. The theories that have been proposed include those related to hypoxemia as well as vasculitis. Cerebral microbleeds have also been noted in COVID-19 patients presenting with neuroimaging findings of leukoencephalopathy; in severe cases this is termed acute hemorrhagic leukoencephalopathy (AHLE). Other possible theories include the consumption coagulopathy seen in these patients, which leads to thrombosis of the small medullary veins, consequently leading to microhemorrhages [5,18].
Due to the growing need for neuroimaging in patients with COVID-19-associated neurological syndromes, the Subspecialty Committee on Diagnostic Neuroradiology of the European Society of Neuroradiology (ESNR) recently came up with an expert consensus [19] that aims to standardize the imaging protocol in this group of patients. A basic MRI protocol of T2-weighted, fluid attenuated inversion recovery (FLAIR) (preferably 3D), and diffusion weighted images, as well as hemorrhage-sensitive sequences (preferably susceptibility weighted imaging [SWI]) is recommended. Post gadolinium 3D FLAIR images are also recommended, for the detection of leptomeningeal contrast enhancement. However, the recommendation for VWI is somewhat unclear, and is recommended to be performed only in select patients where there is a strong clinical or radiological suspicion that lesions could be secondary to a vasculitic rather than a thrombotic/embolic process. The committee however also acknowledges that vasculitis in this group of patients may be much more common than initially thought. We hope that with this review, the threshold for VWI in patients with COVID-19-associated neurological syndromes becomes lower -to the benefit of patients, as well as to facilitate physicians in better managing these patients.
With regards to the neurological history and manifestations, it is worthy to note that most patients with COVID-19-associated neurological syndromes with positive VWI findings had stroke syndromes to a certain degree, as well as encephalopathy as the primary clinical manifestation. Apart from these, other neurological manifestations include altered mentation/GCS, confusion, agitation, abnormal movements, aphasia, gait instability, and bilateral pyramidal syndrome. For those with severe COVID-19 pneumonia requiring ventilation, poor GCS recovery when on sedation hold seems to be a primary feature in those with positive VWI findings. It is safe to say that although some neurological manifestations are predominant, affected patients may manifest a wide variety of neurological signs and symptoms -hence imaging with VWI needs to be considered on a case-to-case basis, within the policy of each center.

Potential pitfalls
When subjecting these patients to VWI, it is important to note that the interpretation of the VWI findings is also reliant to the patient's clinical presentation, location of the brain lesion, the therapeutic agents that the patient is currently being administered (patients on steroid therapy may not manifest vessel wall enhancement due to the effect of the therapy), as well as non-pathologic conditions that may mimic pathologies. For example, enhancement of the vasa vasorum or vascular plexus, which are present in extracranial arteries mainly but may also involve the intracranial segments of the vertebral arteries (proximal portion of the V4 segment) [20] is considered non-pathological. It is worthy to note that in children or healthy young adults, vasa vasorum is not typically present [15].
Another common misinterpretation of vascular enhancement as vasculitis or atherosclerotic plaque is the area surrounding a partially collapsed petrous carotid artery segment when there is ipsilateral hemodynamic impairment. This area, when enhanced, reflects a compensatory expansion of the venous plexus within the petrous canal, and not due to arterial wall thickening and enhancement, which is the very imaging definition of vasculitis [21].

Conclusions
COVID-19 neurological syndromes may manifest in a multitude of presentations. In those with positive VWI findings, the most common presentations based on our review are stroke syndromes and encephalopathy, with vessel wall imaging features akin to those with cerebral vasculitis. The prevalence of cerebral vasculitic changes may be much more common than initially anticipated, hence there is a need for a much more widespread use of VWI, to better assess and manage these patients. The current available guidelines may be able to help standardize imaging in this group of patients, to better understand the pathophysiological processes and better help clinicians in patient care and management.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.