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COVID-19 Associated Central Nervous System Vasculopathy

Published online by Cambridge University Press:  02 June 2020

Ana R. Matos
Affiliation:
Internal Medicine Department, Hospital de Braga, Braga, Portugal
Miguel Quintas-Neves*
Affiliation:
Neuroradiology Department, Hospital de Braga, Braga, Portugal
Ana I. Oliveira
Affiliation:
Internal Medicine Department, Hospital de Braga, Braga, Portugal
Luís Dias
Affiliation:
Internal Medicine Department, Hospital de Braga, Braga, Portugal School of Medicine, Universidade do Minho, Braga, Portugal
Sofia Marques
Affiliation:
Neurology Department, Hospital de Braga, Braga, Portugal
Raquel Carvalho
Affiliation:
Neuroradiology Department, Hospital de Braga, Braga, Portugal
José N. Alves
Affiliation:
Neurology Department, Hospital de Braga, Braga, Portugal
*
Correspondence to: Miguel Quintas-Neves, Serviço de Radiologia, Hospital de Braga, Sete Fontes – São Victor, 4710-243Braga, Portugal. Email: mlqneves@gmail.com
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Abstract

Type
Letter to the Editor
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© The Author(s), 2020. Published by Cambridge University Press on behalf of The Canadian Journal of Neurological Sciences Inc.

A 42-year-old man presented to the emergency department with fever, asthenia, myalgias, dry cough, and hyposmia. After detection of viral nucleic acid from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a nasopharyngeal swab, the diagnosis of coronavirus disease 2019 (COVID-19) was made. As there were no severe criteria for admittance, the patient was discharged on symptomatic medication.

One week later, he was brought to the hospital due to altered mental status, slowness of movements, and apathy. Neurological examination revealed dysexecutive syndrome, perseveration, and mild dysphonia/dysphagia; there were no pyramidal/extra-pyramidal signs. Blood work-up was unremarkable, and brain computed tomography (CT) showed multiple hypodense lesions involving the white matter, basal ganglia, and thalami. Lumbar puncture revealed mild elevated proteins (0.78 mg/dL) without pleocytosis; cerebrospinal fluid (CSF) viral workup was negative, including SARS-CoV-2. Extensive serological immune and infective panels were negative. Suspecting an inflammatory response related to SARS-CoV-2 infection, intravenous immunoglobulin (30 g/day) was initiated.

Brain magnetic resonance imaging (MRI) (Figure 1A–D) confirmed multiple lesions involving the deep and subcortical white matter on both hemispheres, as well as the thalami, basal ganglia, and basal pons, that were hyperintense on fluid-attenuated inversion recovery sequence; some showed restricted diffusion on diffusion-weighted imaging, namely on both corona radiata and bilateral deep frontal white matter. Three-dimensional time of flight (Figure 1E) did not show any major vessel occlusion; however, a prominent irregularity was depicted on the P3 segment of the left posterior cerebral artery. There were no hemorrhages on susceptibility-weighted imaging. Digital subtraction angiography was performed 1 week later, only showing a mild irregularity in a lenticulostriate artery. Cardiac investigation and carotid bulb evaluation by angio-CT were unremarkable. The findings were suggestive of multiple chronologically distinct ischemic lesions on several arterial territories, with the most recent on deep watershed zones; given the current infection by SARS-CoV-2 and presuming an infection-related vasculopathy, immunoglobulin therapy was switched to high-dose intravenous methylprednisolone (1 g/day, 5 days), tapered to 1 mg/kg prednisolone, and aspirin (100 mg/day).

Figure 1: (A, B) Axial fluid-attenuated inversion recovery (FLAIR) sequence depicts multiple hyperintense lesions involving the deep and subcortical white matter on both hemispheres, as well as the thalami and basal ganglia; some of the lesions showed restricted diffusion on diffusion-weighted imaging (DWI) (C, D), namely on both corona radiata and bilateral deep frontal white matter. (E) Three-dimensional time-of-flight (3D TOF) sequence, Maximum intensity projection (MIP) reconstruction on coronal view reveals prominent irregularity (arrow) on the P3 segment of the left posterior cerebral artery.

After 13 days, the patient improved and was discharged under corticosteroids, with no new MRI lesions.

Stroke in the setting of viral vasculopathy has been described with other viruses, such as varicella zoster virus (VZV) or cytomegalovirus Reference Nagel, Mahalingam, Cohrs and Gilden1 ; more recently, it has also been associated with other coronavirus, namely, Middle East respiratory syndrome coronavirus, during the outbreak in Saudi Arabia in 2012. Reference Arabi, Harthi and Hussein2

The clinical presentation of altered mental status and dysexecutive syndrome, 1 week after being diagnosed with COVID-19, made us consider a probable causal association.

The imaging presentation of multiple lesions involving deep and subcortical white matter, as well as deep gray nuclei, with marked restricted diffusion of some, has been described in the setting of VZV vasculopathy. Reference Gilden, Cohrs, Mahalingam and Nagel3 In SARS-CoV-2 infection, vascular injury can occur through direct and/or indirect mechanisms: the first as result of viral affinity to angiotensin-converting enzyme-2 expressed by endothelial cells, Reference Varga, Flammer and Steiger4,Reference Varga, Flammer and Steiger5 and the second by misdirected host immune response that induces coagulopathy and vasoconstriction Reference Zhou, Yu and Du6 (possibly without CSF viral isolation). Moreover, the association between SARS-CoV-2 and large vessel occlusion has been recently described. Reference Oxley, Mocco and Majidi7

In our case, vascular imaging did not depict large vessel stenosis/occlusion, only detecting minor irregularities on medium-/small-sized vessels; this could be due to preferential involvement of such arteries or a falsely negative result in the setting of concomitant immunosuppressive therapy. It is also important to note the absence of detectable SARS-CoV-2 ribonucleic acid in CSF could be due to a predominant indirect pathophysiological mechanism of vasculopathy and/or lack of sensitivity of the analytical technique used. Primary angiitis of the central nervous system was also considered, but the absence of obvious large vessel irregularities, normal CSF cellular count, and concomitant SARS-CoV-2 infection led us consider a COVID-19-related vasculopathy as the most probable diagnosis, potentially induced by misdirected immune mediated-vasoconstriction of medium-/small-sized arteries; we believe this represents a new imaging presentation of a SARS-CoV-2-related complication. The patient was managed empirically with steroids and antiplatelets, showing no new lesions on subsequent imaging evaluations.

Conflict of interest

None.

Statement of authorship

ARM: acquisition of data, clinical data review, literature review, and final manuscript writing; MQ-N: acquisition of data, imaging data review, literature review, and final manuscript writing; AIO: clinical data review, acquisition of data, and literature review; LD: clinical data review, and literature review; SM: clinical data review, acquisition of data, and literature review; RC: acquisition of data and imaging data review; JNA: clinical data review, literature review and final manuscript writing.

Ethics information

This study complies with the Declaration of Helsinki and was conducted in accordance to the local ethics committee requirements. No figures or videos contain information which allows patient identification, and therefore, written patient consent for the publication was not obtained.

Footnotes

*

These authors contributed equally to the manuscript.

References

Nagel, MA, Mahalingam, R, Cohrs, RJ, Gilden, D. Virus vasculopathy and stroke: an under-recognized cause and treatment target. Infect Disord Drug Targets. 2010;10:105–11.CrossRefGoogle ScholarPubMed
Arabi, YM, Harthi, A, Hussein, J, et al. Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-Cov). Infection. 2015;43:495501.CrossRefGoogle Scholar
Gilden, D, Cohrs, RJ, Mahalingam, R, Nagel, MA. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol. 2009;8(8):731–40.CrossRefGoogle ScholarPubMed
Varga, Z, Flammer, AJ, Steiger, P, et al. Endothelial cell infection and endotheliitis in COVID-19. JAMA. 2020;395(10234):14171418.Google ScholarPubMed
Varga, Z, Flammer, AJ, Steiger, P, et al. Electron microscopy of SARS-CoV-2: a challenging task – authors’ reply. Lancet. 2020;395(10238):e100.CrossRefGoogle ScholarPubMed
Zhou, F, Yu, T, Du, R, et al. Clinical course of risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–62.CrossRefGoogle ScholarPubMed
Oxley, TJ, Mocco, J, Majidi, S, et al. Large-vessel stroke as a presenting feature of covid-19 in the young. N Engl J Med. 2020;382(20):e60.CrossRefGoogle Scholar
Figure 0

Figure 1: (A, B) Axial fluid-attenuated inversion recovery (FLAIR) sequence depicts multiple hyperintense lesions involving the deep and subcortical white matter on both hemispheres, as well as the thalami and basal ganglia; some of the lesions showed restricted diffusion on diffusion-weighted imaging (DWI) (C, D), namely on both corona radiata and bilateral deep frontal white matter. (E) Three-dimensional time-of-flight (3D TOF) sequence, Maximum intensity projection (MIP) reconstruction on coronal view reveals prominent irregularity (arrow) on the P3 segment of the left posterior cerebral artery.

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