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Brain MRI findings in COVID-19 patients with PRES: A systematic review

      Highlights

      • PRES is a potential neurological complication of COVID-19 disease.
      • Compared to non-COVID-19 PRES patients, COVID-19 patients with PRES may exhibit similar to mildly greater rates of superimposed hemorrhage.
      • Compared to non-COVID-19 PRES patients, COVID-19 patients with PRES exhibit comparable rates of restricted diffusion.

      Abstract

      Background

      Numerous case reports and case series have described brain Magnetic Resonance Imaging (MRI) findings in Coronavirus disease 2019 (COVID-19) patients with concurrent posterior reversible encephalopathy syndrome (PRES).

      Purpose

      We aim to compile and analyze brain MRI findings in patients with COVID-19 disease and PRES.

      Methods

      PubMed and Embase were searched on April 5th, 2021 using the terms “COVID-19”, “PRES”, “SARS-CoV-2” for peer-reviewed publications describing brain MRI findings in patients 21 years of age or older with evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and PRES.

      Results

      Twenty manuscripts were included in the analysis, which included descriptions of 30 patients. The average age was 57 years old. Twenty-four patients (80%) required mechanical ventilation. On brain MRI examinations, 15 (50%) and 7 (23%) of patients exhibited superimposed foci of hemorrhage and restricted diffusion respectively.

      Conclusions

      PRES is a potential neurological complication of COVID-19 related disease. COVID-19 patients with PRES may exhibit similar to mildly greater rates of superimposed hemorrhage compared to non-COVID-19 PRES patients.

      Abbreviations:

      COVID-19 (Coronavirus disease 2019), SARS-CoV-2 (severe acute respiratory syndrome coronavirus), PRES (posterior reversible encephalopathy syndrome), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), MRI (magnetic resonance imaging), SWI (susceptibility-weighted imaging)

      Keywords

      1. Introduction

      The novel Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) can affect multiple organ systems in addition to its primary effect on the respiratory system.
      • Abobaker A.
      • Raba A.A.
      • Alzwi A.
      Extrapulmonary and atypical clinical presentations of COVID-19.
      Several central nervous system (CNS) complications have been described, including intracranial hemorrhage, acute infarction, cerebral vein thrombosis, and CNS inflammatory disorders.
      • Hughes C.
      • Nichols T.
      • Pike M.
      • Subbe C.
      • Elghenzai S.
      Cerebral venous sinus thrombosis as a presentation of COVID-19.
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      • Radmanesh A.
      • Derman A.
      • Lui Y.W.
      • et al.
      COVID-19 -associated diffuse leukoencephalopathy and microhemorrhages.
      Recently, posterior reversible encephalopathy syndrome (PRES) has also been described in association with COVID-19 infections, with more cases emerging as the pandemic progresses. The clinical presentation of PRES varies from headache, altered mental status, seizures, and visual loss, while MRI demonstrates white matter edema predominating in the posterior parietal and occipital cerebrum.
      • Sudulagunta S.R.
      • Sodalagunta M.B.
      • Kumbhat M.
      • Settikere Nataraju A.
      Posterior reversible encephalopathy syndrome(PRES).
      Currently, the brain MRI findings of PRES in the setting of COVID-19 infection is limited to case reports and case series. Utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines,
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Group P
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      we performed a systematic review in order to collect and evaluate the brain MRI findings in COVID-19 associated PRES.

      2. Methods

      2.1 Data sources and searches

      A systematic search of the PubMed and Embase databases was performed to identify published manuscripts that described brain MRI findings in patients with COVID-19 disease and PRES. Search terms included: “COVID”, “PRES”, and “SARS-CoV-2”. Literature searches were performed on April 5th, 2021.

      2.2 Study selection and data extraction

      We included articles published in peer-reviewed journals if they described brain MRI findings in patients older than 21 years of age with SARS-CoV-2 infection and a provided diagnosis of PRES. Duplicate manuscripts from literature search results were removed prior to the screening process. Three reviewers (E.G., J.S., R.Y.) examined titles and abstracts from the literature searches to identify potential manuscripts for inclusion. Articles included after initial screening were reviewed for final inclusion by two neuroradiologists (E.G., J.S.).

      2.3 Data synthesis and analysis

      Data extraction from each manuscript was performed by two board-certified radiologists, one with a certificate of added qualification in neuroradiology (E.G.) and the other with specialty training in neuroradiology (J.S.). Data extracted from each article included: authors, title, country of origin, number of patients with brain MRI imaging findings described, age and gender of the patients, clinical presentation, clinical parameters, and specific findings on brain MRI exams. One patient (Table 3, patient #2) was described in two different manuscripts.
      • Princiotta Cariddi L.
      • Tabaee Damavandi P.
      • Carimati F.
      • et al.
      Reversible encephalopathy syndrome (PRES) in a COVID-19 patient.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      Table 3Manuscripts describing Brain MRI findings in COVID-19 patients with PRES.
      Patient no./sex/age(y)First authorClinical presentationClinical interventionMRI brain findingsClinical Outcome
      Blood pressureVisual changesAltered mental statusSeizuresHighest level O2 therapyImmunotherapy statusFindingsHemorrhageDiffusion restriction
      P1/M/64Doo FX et al.
      • Doo F.X.
      • Kassim G.
      • Lefton D.R.
      • Patterson S.
      • Pham H.
      • Belani P.
      Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.
      NRNRPresentPresentMechanical ventilationTocilizumabParietooccipital edema with small foci of hemorrhage.PresentNRNR
      P2/F/64Princiotta et al., and Colombo et al.
      • Princiotta Cariddi L.
      • Tabaee Damavandi P.
      • Carimati F.
      • et al.
      Reversible encephalopathy syndrome (PRES) in a COVID-19 patient.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      HypertensivePresentPresentAbsentMechanical ventilationNRMRI brain consistent with PRESPresentNRDischarged
      P3/M/58Kishfy L et al.
      • Kishfy L.
      • Casasola M.
      • Banankhah P.
      • et al.
      Posterior reversible encephalopathy syndrome (PRES) as a neurological association in severe Covid-19.
      HypertensiveAbsentPresentNRMechanical ventilationTocilizumabT2 FLAIR hyperintensity involving subcortical occipital and temporal white matter. Convexity subarachnoid hemorrhage. No abnormal contrast enhancement.PresentAbsentDischarged
      P4/F/67Kishfy L et al.
      • Kishfy L.
      • Casasola M.
      • Banankhah P.
      • et al.
      Posterior reversible encephalopathy syndrome (PRES) as a neurological association in severe Covid-19.
      HypertensiveAbsentPresentNRMechanical ventilationNRT2 FLAIR hyperintense foci in right occipital subcortical white matter and left cerebellum. SWI with petechial hemorrhage. No abnormal contrast enhancement.PresentAbsentDischarged
      P5/F/63Conte G et al.
      • Conte G.
      • Avignone S.
      • Carbonara M.
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      HypertensivePresentNRPresentMechanical ventilationAnakinraPartially confluent, tumefactive white matter lesions, with posterior predominance. Left precentral subarachnoid blood products. Perivascular contrast enhancement within white matter.PresentPresentDischarged
      P6/M/59Rogg J et al.
      • Rogg J.
      • Baker A.
      • Tung G.
      Posterior reversible encephalopathy syndrome (PRES): another imaging manifestation of COVID-19.
      HypertensiveNRPresentNRMechanical ventilationNRExtensive FLAIR hyperintensity within subcortical greater than deep white matter, internal and external capsules, and cerebellar white matter. No contrast enhancement.NRAbsentDeath
      P7/NR/NRDias DA et al.
      • Dias D.A.
      • de Brito L.A.
      • Neves L.O.
      • RGS Paiva
      • Barbosa Júnior O.A.
      • JWL Tavares-Júnior
      Hemorrhagic PRES: an unusual neurologic manifestation in two COVID-19 patients.
      NRNRPresentNRMechanical ventilationNRBilateral parieto-occipital vasogenic edema with superimposed blood products. Foci of restricted diffusion attributed to blood products.PresentAbsentNR
      P8/M/64Parauda SC et al.
      • Parauda S.C.
      • Gao V.
      • Gewirtz A.N.
      • et al.
      Posterior reversible encephalopathy syndrome in patients with COVID-19.
      HypertensivePresentPresentPresentMechanical ventilationNRT2 FLAIR hyperintensities occipital white matter, and within left thalamus and internal capsule.AbsentAbsentDischarged
      P9/M/73Parauda SC et al.
      • Parauda S.C.
      • Gao V.
      • Gewirtz A.N.
      • et al.
      Posterior reversible encephalopathy syndrome in patients with COVID-19.
      HypertensiveNRPresentPresentMechanical ventilationNRConfluent T2 hyperintensity bilateral parietooccipital white matter.AbsentAbsentDischarged
      P10/F/65Parauda SC et al.
      • Parauda S.C.
      • Gao V.
      • Gewirtz A.N.
      • et al.
      Posterior reversible encephalopathy syndrome in patients with COVID-19.
      HypertensiveNRPresentAbsentMechanical ventilationNRNon enhancing bilateral occipital subcortical white matter T2 hyperintensities.NRAbsentDischarged
      P11/F/74Parauda SC et al.
      • Parauda S.C.
      • Gao V.
      • Gewirtz A.N.
      • et al.
      Posterior reversible encephalopathy syndrome in patients with COVID-19.
      HypertensiveNRPresentAbsentMechanical ventilationTocilizumabT2 hyperintensities in bilateral parietooccipital lobes with restricted diffusion and SWI hypointense foci.PresentPresentDischarged
      P12/F/27Agarwal A et al.
      • Agarwal A.
      • Pinho M.
      • Raj K.
      • et al.
      Neurological emergencies associated with COVID-19: stroke and beyond.
      NRNRPresentNRMechanical ventilationNRSubcortical vasogenic edema in occipital subcortical white matter.NRAbsentDeath
      P13/F/24*López Pérez V et al.
      • López Pérez V.
      • Cora Vicente J.
      • Echevarría Granados C.
      • Salcedo Vázquez M.L.
      • Estol F.
      • Tebar Cuesta M.Y.
      Postpartum consciousness disturbance: can covid-19 cause posterior reversible encephalopathy syndrome?.
      HypertensiveNRPresentPresentMechanical ventilationTocilizumabFLAIR hyperintensity in bilateral parietal and parasagittal fronal regions.NRNRDischarged
      P14/F/64D'Amore F et al.
      • D'Amore F.
      • Vinacci G.
      • Agosti E.
      • et al.
      Pressing issues in COVID-19: probable cause to seize SARS-CoV-2 for its preferential involvement of posterior circulation manifesting as severe posterior reversible encephalopathy syndrome and posterior strokes.
      NRPresentPresentNRNRNRVasogenic edema and occipital hemorrhages.PresentNRNR
      P15/F/33Ghosh R et al.
      • Ghosh R.
      • Lahiri D.
      • Dubey S.
      • Ray B.K.
      • Benito-León J.
      Hallucinatory palinopsia in COVID-19-induced posterior reversible encephalopathy syndrome.
      NormotensivePresentAbsentNRNRNRFLAIR hyperintensity bilateral occipital subcortical white matter.AbsentAbsentDischarged
      P16/F/25*Sripadma PV et al.
      • Sripadma P.V.
      • Rai A.
      • Wadhwa C.
      Postpartum Atypical posterior reversible encephalopathy syndrome in a COVID-19 patient - an obstetric emergency.
      HypertensiveNRNRPresentMechanical ventilationNRBilateral parietal-occipital T2 hyperintensities with bilateral small hemorrhages.PresentAbsentDischarged
      P17/F/61Anand P et al.
      • Anand P.
      • Lau K.H.V.
      • Chung D.Y.
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      HypertensiveNRPresentPresentMechanical ventilationAnakinraT2 hyperintensities in bilateral parietooccipital lobes. Susceptibility in right fontal lobe.PresentAbsentDischarged
      P18/F/52Anand P et al.
      • Anand P.
      • Lau K.H.V.
      • Chung D.Y.
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      HypertensiveAbsentPresentPresentMechanical ventilationNRT2 hyperintensities within bilateral parietal, occipital, frontal, temporal white matter. Punctate hemorrhages in temporal and occipital lobes.PresentAbsentDischarged
      P19/M/48Franceschi AM et al.
      • Franceschi A.M.
      • Ahmed O.
      • Giliberto L.
      • Castillo M.
      Hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of COVID-19 infection.
      HypertensiveNRPresentNRMechanical ventilationNRVasogenic edema in the posterior parieto-occipital regions with subacute blood products. SWI with petechial hemorrhages diffusely throughout the corpus callosum.PresentPresentNR
      P20/F/67Franceschi AM et al.
      • Franceschi A.M.
      • Ahmed O.
      • Giliberto L.
      • Castillo M.
      Hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of COVID-19 infection.
      HypertensiveNRPresentNRNRNRMultiple areas of restricted diffusion and edema, greatest within the parietooccipital regions, and within the right frontal lobe, basal ganglia, and cerebellar hemispheres. Extensive superimposed hemorrhages in the parietooccipital region with abnormal contrast enhancement.PresentPresentDischarged
      P21/M/46Ordoñez-Boschetti L et al.
      • Ordoñez-Boschetti L.
      • Torres-Romero C.M.
      • Ortiz de Leo M.J.
      Associated posterior reversible encephalopathy syndrome (PRES) to SARS-CoV-2. Case report.
      NormotensiveAbsentPresentNRMechanical ventilationNRT2 FLAIR hyperintensities in frontal and occipital white matter.NRAbsentDischarged
      P22/M/74Gómez-Enjuto S et al.
      • Gómez-Enjuto S.
      • Hernando-Requejo V.
      • Lapeña-Motilva J.
      • et al.
      Verapamil as treatment for refractory status epilepticus secondary to PRES syndrome on a SARS-Cov-2 infected patient.
      HypertensivePresentPresentPresentNRCarfilzomibT2 FLAIR hyperintensities frontalparietal and occipital subcortical areas.NRNRDischarged
      P23/M/54Colombo A et al.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      HypertensivePresentAbsentPresentMechanical ventilationNRMRI brain consistent with PRESNRNRDischarged
      P24/F/63Colombo A et al.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      HypertensivePresentPresentPresentMechanical ventilationIL-1 antagonistMRI brain consistent with PRESNRNRDischarged
      P25/M/64Colombo A et al.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      NormotensivePresentPresentPresentMechanical ventilationNRSymmetric white matter alterations, mainly occipital lobes. No enhancement.PresentNRDischarged
      P26/M/68Colombo A et al.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      HypertensivePresentPresentAbsentMechanical ventilationNRMRI brain consistent with PRESNRNRDischarged
      P27/F/57Colombo A et al.
      • Colombo A.
      • Martinelli Boneschi F.
      • Beretta S.
      • et al.
      Posterior reversible encephalopathy syndrome and COVID-19: a series of 6 cases from Lombardy, Italy.
      HypertensivePresentAbsentPresentNon-invasive ventilationNRMRI brain consistent with PRESNRNRDischarged
      P28/F/43Santos de Lima F et al.
      • Santos de Lima F.
      • Klein S.
      • El Ammar F.
      • et al.
      Rapid development of seizures and PRES in a COVID-19 patient.
      NormotensiveAbsentPresentPresentMechanical ventilationNR1st MRI-Area of hyperintensity in the splenium. 2nd MRI- extensive T2/FLAIR hyperintensity in bilateral cererbal hemispheres with mild sulcal enhancement, and gyroform restricted diffusion in right temporooccipito-parietal region. Lesion in the splenium resolved. 3rd MRI-progression of white signal abnormality.NRPresentDischarged
      P29/M/55Wijeratne T et al.
      • Wijeratne T.
      • Wijeratne C.
      • Karimi L.
      • Sales C.
      • Crewther S.G.
      Case report: posterior reversible leukoencephalopathy syndrome (PRES) as a Biologically predictable neurological association in severe COVID-19. First reported case from australia and review of internationally published cases.
      HypertensiveAbsentPresentAbsentNRNRBilateral parietal-occipital T2 FLAIR hyperintensities. Diffuse petechial hemorrhages in basal ganglia and deep white matter. Small foci of restricted diffusion in deep white matter.PresentPresentDischarged
      P30/M/70Talluri K et al.
      • Talluri K.
      • Lall N.
      • Moreno M.A.
      • Nichols L.
      • Bande D.
      Posterior reversible encephalopathy syndrome in a patient with SARS-CoV-2 infection treated with tocilizumab.
      HypertensiveAbsentPresentAbsentMechanical ventilationTocilizumabCortical and subcortical FLAIR signal in bilateral occipital lobes and paramedian frontal and parietal lobes. Restricted diffusion bilateral occipital lobes, posterior thalami and left temporal lobe.NRPresentDeath
      NR = Not recorded. Patient #2 was described in two separate manuscripts. * = Patients were pregnant.

      3. Results

      3.1 Manuscript searches

      We identified 166 articles (Fig. 1). After removal of duplicates, 79 articles remained for screening. After screening, 25 articles were fully assessed for eligibility. Of the 25 articles evaluated for eligibility, 5 articles were excluded secondary to: 4 articles not describing brain MRI findings, and 1 with discordant description of brain MRI findings and the provided figure. This resulted in the inclusion of 20 manuscripts (Table 1). These included: 11 case reports, 8 case series, and a letter to an editor. The manuscripts originated from 7 different countries (United States: 9, Italy: 4, India: 2, Spain: 2, Australia: 1, Brazil: 1, and Mexico: 1).
      Table 1Manuscripts describing Brain MRI findings in COVID-19 patients with PRES.
      Manuscripts describing MRI findings in Covid-19 patients with PRES
      Articles20
      Journals16
      Countries7
       USA9
       Italy4
       India2
       Spain2
       Australia1
       Brazil1
       Mexico1
      Patients with MR imaging of the brain described30
      Case report11
      Case series8
      Letter to editor1

      3.2 Patients

      Thirty patients with COVID-19 and PRES with described brain MRI findings were included in the analysis (Table 2). The mean age was 57 years (range 24–74), and 16 were female. Of the clinical presentations associated with PRES, there were 22 patients with hypertensive episodes, 14 with visual changes, 25 with altered mental status and 14 with seizure. Twenty-four (80%) of the patients required mechanical ventilation, and 9 patients (30%) received immunotherapy. In most cases, patients exhibited symptoms of COVID-19 related illness prior to hospitalization and development of PRES as an inpatient. Eight manuscripts provided descriptions of CSF results, most of which were within normal limits. Only two manuscripts mentioned if CSF was tested for the SARS-CoV-2 virus. Only 2 manuscripts mentioned that patients were given pressors (patients 17 and 18), and three were administrated steroid therapy (patients 15, 22, 29).
      Table 2Patient characteristics and brain MRI findings in COVID-19 patients with PRES.
      COVID-19 patients with PRES (n = 30)
      DemographicsAge
       Range24–74
       Mean57
       Median63
      n%
      Male1343%
      Female1653%
      Gender not reported13%
      Clinical presentation>1 hypertensive episode2273%
      Visual changes1445%
      Altered mental status2583%
      Seizure1442%
      Clinical interventionMechanical ventilation2480%
      Immunotherapy930%
      Imaging findingsHemorrhage1550%
      Diffusion restriction723%
      Clinical outcomeDeath310%
      Discharged2377%

      3.3 Imaging findings

      MRI brain findings varied from briefs statements such as, “MRI brain consistent with PRES”, to more comprehensive explanations detailing findings on different pulse sequences. Most manuscripts did not provide MRI protocols utilized, nor field strength of the MRI magnet used. Most manuscripts did not specify whether gradient echo or susceptibility-weighted imaging sequences were used for detecting blood products, and was only provided in ten cases. Eight cases (patients 3, 4, 5, 7, 17, 19, 20, 29) utilized SWI, and two cases (patients 2, 14) utilized gradient echo sequences. On brain MRI, 15 patients (50%) had foci of hemorrhage superimposed on described findings of PRES, and 7 patients (23%) had superimposed foci of restricted diffusion. The described brain MRI findings within the manuscripts precluded adequate tabulation of the distribution of FLAIR signal abnormalities typical of PRES. Additionally, few articles mentioned whether or not there was abnormal intracranial contrast enhancement.

      4. Discussion

      This first systematic review of brain MRI findings in COVID-19 patients with PRES utilizing PRISMA guidelines shows that PRES patients who have COVID-19 may have similar to mildly increased rates of hemorrhage compared to PRES patients who do not have COVID-19.
      Numerous neurological and neuroimaging manifestations of COVID-19 infection have been described including intracranial hemorrhage, acute strokes, leukoencephalopathy, and CNS inflammatory disorders. As the pandemic continues, more and more case reports and case series are describing an association of COVID-19 disease with clinical and imaging findings typical of PRES. While the complex pathogenesis and possible neurotropism of the SARS-CoV-2 virus is still being elucidated, there is growing evidence that the intracranial complications of COVID-19 disease may at least in part be due to the cytokine release syndrome (a.k.a. ‘cytokine storm’).
      • Ye Q.
      • Wang B.
      • Mao J.
      The pathogenesis and treatment of the `cytokine storm' in COVID-19.
      • Mehta P.
      • DF McAuley
      • Brown M.
      • et al.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      Typical laboratory findings of cytokine release syndrome include decreased T-cells and natural killer cells, and an increase in interleukin 6,
      • Franceschi A.M.
      • Ahmed O.
      • Giliberto L.
      • Castillo M.
      Hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of COVID-19 infection.
      among elevation of other inflammatory markers.
      • Ye Q.
      • Wang B.
      • Mao J.
      The pathogenesis and treatment of the `cytokine storm' in COVID-19.
      PRES is commonly linked to alterations in the blood-brain barrier secondary to loss of autoregulation or endothelial dysfunction.
      • Franceschi A.M.
      • Ahmed O.
      • Giliberto L.
      • Castillo M.
      Hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of COVID-19 infection.
      The massive release of cytokines and inflammatory markers that can occur in COVID-19 patients, may result in breakdown of the blood-brain barrier and endothelial injury that leads to PRES.
      • Franceschi A.M.
      • Ahmed O.
      • Giliberto L.
      • Castillo M.
      Hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of COVID-19 infection.
      • Rogg J.
      • Baker A.
      • Tung G.
      Posterior reversible encephalopathy syndrome (PRES): another imaging manifestation of COVID-19.
      In the absence of established diagnostic criteria, PRES is often diagnosed in the context of clinical and imaging findings after other possibilities have been excluded.
      • Fischer M.
      • Schmutzhard E.
      Posterior reversible encephalopathy syndrome.
      Typical clinical presentations include either seizure, headache, visual disturbance, or altered mental status and often occurs in the setting of elevated blood pressures.
      • Osborn A.G.
      Osborn's brain: imaging, pathology, and anatomy..
      Numerous additional causes have been associated with PRES including: eclampsia, immunosuppressive drugs, as well as an array of additional drugs and diseases.
      • Osborn A.G.
      Osborn's brain: imaging, pathology, and anatomy..
      On imaging, typical PRES is characterized by vasogenic edema preferentially involving the parietooccipital regions, whereas atypical PRES can involve the frontal lobes, basal ganglia, brainstem, and cerebellum (Fig. 2) .
      • Osborn A.G.
      Osborn's brain: imaging, pathology, and anatomy..
      Three hemispheric pattern variants can be observed (holohemispheric, superior frontal sulcal, and primary parietal-occipital), which resemble brain watershed zones.
      • Bartynski W.S.
      Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features.
      Predominate involvement of the basal ganglia, brain stem, and deep white matter with less hemispheric involvement can lead to a challenging diagnosis of PRES.
      • Bartynski W.S.
      Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features.
      Catheter cerebral angiogram or MRA time-of-flight imaging reveals vasculopathy with diffuse vasoconstriction, focal vasoconstriction/vasodilatation, and usually resolves on repeat imaging.
      • Bartynski W.S.
      Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features.
      Reports of perfusion patterns in PRES have varied including descriptions of hyperperfusion and hypoperfusion.
      • Bartynski W.S.
      Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features.
      Fig. 2
      Fig. 2PRES in a patient with COVID-19.
      Brain MRI images in a 61-year-old female with COVID-19 and respiratory failure requiring mechanical ventilations. Axial T2/FLAIR images (A and B) demonstrate T2/FLAIR hyperintensities predominately with the bilateral parietooccipital regions. Foci of T2/FLAIR hyperintensities were also present with the bilateral cerebellum. Imaging findings were consistent with PRES. A follow-up Brain MRI exam (C and D) approximately 3 weeks later demonstrated resolution of the parenchymal abnormalities. There was no evidence of restricted diffusion or hemorrhagic foci on the first Brain MRI exam.
      The key difference between PRES associated with COVID-19 and PRES in other settings appears to be the similar to mildly higher rate of hemorrhage, while the rate of restricted diffusion is approximately the same. Prior reports described hemorrhage in PRES patients occurring in approximately 15–17% of patients,
      • Bartynski W.S.
      Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features.
      • Hefzy H.M.
      • Bartynski W.S.
      • Boardman J.F.
      • Lacomis D.
      Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features.
      and a more recent report demonstrated 36% of hemorrhage in PRES patients.
      • Schweitzer A.D.
      • Parikh N.S.
      • Askin G.
      • et al.
      Imaging characteristics associated with clinical outcomes in posterior reversible encephalopathy syndrome.
      T2-star weighted imaged was utilized in two of these manuscripts.
      • Hefzy H.M.
      • Bartynski W.S.
      • Boardman J.F.
      • Lacomis D.
      Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features.
      • Schweitzer A.D.
      • Parikh N.S.
      • Askin G.
      • et al.
      Imaging characteristics associated with clinical outcomes in posterior reversible encephalopathy syndrome.
      In a more recent report that utilized SWI, hemorrhage was present in 64.5% of patients with PRES.
      • McKinney A.M.
      • Sarikaya B.
      • Gustafson C.
      • Truwit C.L.
      Detection of microhemorrhage in posterior reversible encephalopathy syndrome using susceptibility-weighted imaging.
      In our analysis, MRI techniques for detecting hemorrhage was described in only ten patients (SWI was used in eight patients) resulting in a limitation to our study. Foci of restricted diffusion can in occur 16–17% of cases
      • McKinney A.M.
      • Short J.
      • Truwit C.L.
      • et al.
      Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings.
      , and we observed 23%. In our analysis, too few manuscripts commented on the absence or presence of intracranial contrast enhancement, precluding adequate comparison with non-COVID-19 PRES patients.
      PRES is typically associated with a favorable outcome with proper medical management.
      • Osborn A.G.
      Osborn's brain: imaging, pathology, and anatomy..
      However, the presence of hemorrhage or restricted diffusion is associated with worse clinical outcomes.
      • Schweitzer A.D.
      • Parikh N.S.
      • Askin G.
      • et al.
      Imaging characteristics associated with clinical outcomes in posterior reversible encephalopathy syndrome.
      Of the cases we reviewed, 3 patients (10%) expired. Our study is limited in evaluating outcomes in COVID-19 patients with PRES due to a small sample size, and a formal meta-analysis with a larger patient sample would be needed to compare mortality rates between PRES patients with and without COVID-19.
      The majority of patients in our study required mechanical ventilation, indicative of severe disease, and 9 of the patients received immunotherapy. Guidelines from the national institutes of health recommend use of baricitinib and tocilizumab in certain hospitalized patients: 1) hospitalized patients requiring oxygen through a high-flow device or noninvasive ventilation, and with increasing oxygen need and systemic inflammation after a recent hospitalization, and 2) hospitalized patients requiring mechanical ventilation or ECMO, and are within 24 h of ICU admission. Larger studies are needed to investigate whether immunomodulators cause PRES in COVID-19 patients.

      Therapeutic Management of Hospitalized Adults With COVID-19. Updated July 8, 2021. Accessed July 19, 2021.

      Our study is limited by reliance on descriptions rather than direct interpretation of brain MRI findings, and the presumed diagnosis of PRES. This precludes adequate review of the distribution of parenchymal abnormalities which can be variable in PRES. Insofar as there may be overlap in the imaging findings of PRES and COVID-19 related neuroimaging findings, such as COVID-19 related leukoencephalopathy or acute hemorrhagic leukoencephalities, this may be a significant source of bias. Recent reports
      • Radmanesh A.
      • Derman A.
      • Lui Y.W.
      • et al.
      COVID-19 -associated diffuse leukoencephalopathy and microhemorrhages.
      • Sachs J.R.
      • Gibbs K.W.
      • Swor D.E.
      • et al.
      COVID-19-associated Leukoencephalopathy.
      • Lang M.
      • Buch K.
      • Li M.D.
      • et al.
      Leukoencephalopathy associated with severe COVID-19 infection: sequela of hypoxemia?.
      • Freeman C.W.
      • Masur J.
      • Hassankhani A.
      • Wolf R.L.
      • Levine J.M.
      • Mohan S.
      Coronavirus disease (COVID-19)-related disseminated leukoencephalopathy: a retrospective study of findings on brain MRI.
      have described confluent white matter T2 hyperintensities in patients with severe COVID-19 disease and prolonged mechanical ventilation, in some cases with superimposed foci of restricted diffusion and microhemorrhages, possibly due to hypoxemia.
      • Radmanesh A.
      • Derman A.
      • Lui Y.W.
      • et al.
      COVID-19 -associated diffuse leukoencephalopathy and microhemorrhages.
      In two studies the leukoencephalopathy was reported to have a posterior predominance.
      • Sachs J.R.
      • Gibbs K.W.
      • Swor D.E.
      • et al.
      COVID-19-associated Leukoencephalopathy.
      • Radmanesh A.
      • Raz E.
      • Zan E.
      • Derman A.
      • Kaminetzky M.
      Brain imaging use and findings in COVID-19: a single academic center experience in the epicenter of disease in the United States.
      Microhemorrhages have also been described as a common finding in patients with COVID-19.
      • Gulko E.
      • Oleksk M.L.
      • Gomes W.
      • et al.
      MRI brain findings in 126 patients with COVID-19: initial observations from a descriptive literature review.
      Recent reports of acute hemorrhagic leukoencephalitis in COVID-19 patients, have described multifocal white matter lesions with hemorrhages and foci of restricted diffusion.
      • Yong M.H.
      • YFZ Chan
      • Liu J.
      • et al.
      A rare case of acute hemorrhagic leukoencephalitis in a COVID-19 patient.
      • Varadan B.
      • Shankar A.
      • Rajakumar A.
      • et al.
      Acute hemorrhagic leukoencephalitis in a COVID-19 patient-a case report with literature review.
      Distinction between PRES, COVID-19 related leukoencephalopathy, and acute hemorrhagic leukoencephalitis may be relevant clinically as it may alter clinical management. Further studies may be helpful in confidently distinguishing between these entities on brain MRI.
      The medical community's understanding of COVID-19 is rapidly changing as the pandemic evolves. While our study aimed to incorporate all cases of COVID-19 and PRES, there may be some cases that were missed or will subsequently be published. Additional and larger studies will be needed to further understand the interplay between COVID-19 and PRES.

      5. Conclusion

      PRES is a potential neurological complication of COVID-19 related disease. COVID-19 patients with PRES may exhibit similar to mildly greater rates of hemorrhage compared to non-COVID-19 PRES patients.

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