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Understanding the Role of Blood Vessels in the Neurologic Manifestations of Coronavirus Disease 2019 (COVID-19)

  • Hannah A.B. Whitmore
    Affiliations
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts

    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
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  • Leo A. Kim
    Correspondence
    Address correspondence to Leo A. Kim, M.D., Ph.D., 243 Charles St., Boston, MA 02114.
    Affiliations
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts

    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally identified as an outbreak in Wuhan, China, toward the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and Middle East respiratory syndrome (MERS), concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain barrier. Severe symptoms, termed coronavirus disease 2019 (COVID-19), often result in neurologic complications, regardless of patient age. These neurologic complications range from mild to severe across all demographics; however, the long-term repercussions of neurologic involvement on patient health are still unknown.
      Currently, there are approximately 140 million confirmed infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, and about 3,000,000 deaths associated with SARS-CoV-2 infection (Johns Hopkins University & Medicine, Coronavirus Resource Center, https://coronavirus.jhu.edu, last accessed April 17, 2021) manifesting as severe coronavirus disease 2019, or coronavirus disease 2019 (COVID-19). Approximately 15% of individuals affected by COVID-19 develop severe disease, and 6% are critically ill, resulting in respiratory failure and/or multiple organ dysfunction or failure.
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      The original outbreak of SARS-CoV-2 infection originated from Wuhan, Hubei province, China, in late 2019.
      • Leisman D.E.
      • Deutschman C.S.
      • Legrand M.
      Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Genomic characterization indicates that bats and rodents are the likely gene sources of α- and β-coronaviruses (CoVs), whereas γ- and δ-CoVs likely arise from avian sources.
      • Al-Sharif E.
      • Strianese D.
      • AlMadhi N.H.
      • D'Aponte A.
      • dell'Omo R.
      • DiBenedetto R.
      • Costagliola C.
      Ocular tropism of coronavirus (CoVs): a comparison of the interaction between the animal-to-human transmitted coronaviruses (SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, NL63, OC43, HKU1) and the eye.
      To date, seven human coronaviruses have been identified with the ability to cause respiratory, enteric, hepatic, and neurologic diseases in different animal species, including cattle and cats. These viruses are responsible for about 5% to 10% of acute respiratory infections, including the common cold.
      • Al-Sharif E.
      • Strianese D.
      • AlMadhi N.H.
      • D'Aponte A.
      • dell'Omo R.
      • DiBenedetto R.
      • Costagliola C.
      Ocular tropism of coronavirus (CoVs): a comparison of the interaction between the animal-to-human transmitted coronaviruses (SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, NL63, OC43, HKU1) and the eye.
      ,
      • Yin Y.
      • Wunderink R.G.
      MERS, SARS and other coronaviruses as causes of pneumonia.
      SARS-CoV-2 is a member of the β- coronaviruses and is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with high sequence homology.
      • Wu A.
      • Peng Y.
      • Huang B.
      • Ding X.
      • Wang X.
      • Niu P.
      • Meng J.
      • Zhu Z.
      • Zhang Z.
      • Wang J.
      • Sheng J.
      • Quan L.
      • Xia Z.
      • Tan W.
      • Cheng G.
      • Jiang T.
      Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
      These coronaviruses appear to infect the respiratory and gastrointestinal tract, with patients presenting symptoms of fever, cough, and shortness of breath, whereas less common symptoms include diarrhea, vomiting, and nausea.
      • De Wit E.
      • Van Doremalen N.
      • Falzarano D.
      • Munster V.J.
      SARS and MERS: recent insights into emerging coronaviruses.
      In addition, cytokine release syndrome was found to be the major cause of morbidity in patients infected with SARS-CoV and MERS-CoV.
      • Channappanavar R.
      • Perlman S.
      Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.
      Aside from the respiratory system, with acute respiratory distress syndrome affecting roughly one-third of COVID-19 hospitalized patients,
      • Tzotzos S.J.
      • Fischer B.
      • Fischer H.
      • Zeitlinger M.
      Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey.
      COVID-19 appears to also involve multiple organ systems with pathologic manifestations, including the heart, kidney, and brain.
      • Su H.
      • Yang M.
      • Wan C.
      • Yi L.-X.
      • Tang F.
      • Zhu H.-Y.
      • Yi F.
      • Yang H.-C.
      • Fogo A.B.
      • Nie X.
      • Zhang C.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China - Kidney International.
      • Keller E.
      • Brandi G.
      • Winklhofer S.
      • Imbach L.L.
      • Kirschenbaum D.
      • Frontzek K.
      • Steiger P.
      • Dietler S.
      • Haeberlin M.
      • Willms J.
      • Porta F.
      • Waeckerlin A.
      • Huber M.
      • Abela I.A.
      • Lutterotti A.
      • Stippich C.
      • Globas C.
      • Varga Z.
      • Jelcic I.
      Large and small cerebral vessel involvement in severe COVID-19.
      • Altable M.
      • De La Serna J.M.
      Cerebrovascular disease in COVID-19: is there a higher risk of stroke?.
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • Sapozhnikov S.
      • Dandu V.
      • Toom S.
      • Glaser A.
      • Elsayegh D.
      COVID-19 presenting as stroke.
      • Haider A.
      • Siddiqa A.
      • Ali N.
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      Because of the multiorgan involvement of COVID-19, it has been hypothesized that COVID-19 is a vascular disease that primarily affects endothelial cells.
      • Libby P.
      • Lüscher T.
      COVID-19 is, in the end, an endothelial disease.
      ,
      • Siddiqi H.K.
      • Libby P.
      • Ridker P.M.
      COVID-19 - a vascular disease.
      These organs, and their associated blood vessels, may be affected by direct viral tissue injury and localized disordered cytokine release.
      • Moore J.B.
      • June C.H.
      Cytokine release syndrome in severe COVID-19.
      This direct injury and release of inflammatory and apoptosis inducing mediators leads to localized microvascular inflammation, which triggers endothelial activation, leading to vasodilation and prothrombotic conditions, which cause increased patient mortality.
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      Viral infections of the brain are less common than those of other organs as they involve penetration of the blood-brain barrier (BBB). Several viruses, including polio and West Nile virus, are able to cause neurologic complications, but the reasons why they occur in <1 in 100 patients are not understood.
      • van den Pol A.N.
      Viral infection leading to brain dysfunction: more prevalent than appreciated?.
      The route of entry of the virus into the brain, such as in the blood supply, or by direct infection of vascular endothelial cells, plays a role in the number and type of neurologic symptoms presented by the patient.
      • van den Pol A.N.
      Viral infection leading to brain dysfunction: more prevalent than appreciated?.
      ,
      • Swanson P.A.I.
      • McGavern D.B.
      Viral diseases of the central nervous system.
      Investigations into MERS-CoV indicated that viral particles enter the bloodstream and are able to infect endothelial cells.
      • Hocke A.C.
      • Becher A.
      • Knepper J.
      • Peter A.
      • Holland G.
      • Tönnies M.
      • Bauer T.T.
      • Schneider P.
      • Neudecker J.
      • Muth D.
      • Wendtner C.M.
      • Rückert J.C.
      • Drosten C.
      • Gruber A.D.
      • Laue M.
      • Suttorp N.
      • Hippenstiel S.
      • Wolff T.
      Emerging human Middle East respiratory syndrome coronavirus causes widespread infection and alveolar damage in human lungs.
      In the case of SARS-CoV-2, viral-like particles have been seen in brain capillary endothelium and actively budding across endothelial cells.
      • Paniz-Mondolfi A.
      • Bryce C.
      • Grimes Z.
      • Gordon R.E.
      • Reidy J.
      • Lednicky J.
      • Sordillo E.M.
      • Fowkes M.
      Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
      Although the route of entry of the virus may still be unknown, recent publications have highlighted neurologic manifestations that have been observed in 42% of COVID-19 patients at disease onset, 63% during hospitalization, and 82% at some time during the course of the disease.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      ,
      • Liotta E.M.
      • Batra A.
      • Clark J.R.
      • Shlobin N.A.
      • Hoffman S.C.
      • Orban Z.S.
      • Koranic I.J.
      Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients.
      In addition, a significant link was seen between magnetic resonance imaging abnormalities and persistent neurologic deficits, which continued 3 months after disease onset in 55% of patients.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      This review explores the role of the vasculature, specifically within the context of the neurologic manifestations of COVID-19. Herein, the neurologic manifestations reported with SARS-CoV-2 infection are reviewed. The evidence that suggests blood vessels are involved in SARS-CoV-2 infection is surveyed. Finally, the multiple pathologic processes (thromboembolic, inflammatory, and secondary processes) within blood vessels that may contribute to the neurologic manifestations of COVID-19 infection are considered.

      Composition, Function, and Weaknesses of the Blood-Brain Barrier

      The structure and mode of replication of coronaviruses are related, and the relatedness of human CoVs to the neurotropic animal coronaviruses is predictive of the ability of SARS-CoV-2 to invade the central nervous system (CNS), suggesting some tropism for neural tissue.
      • Paniz-Mondolfi A.
      • Bryce C.
      • Grimes Z.
      • Gordon R.E.
      • Reidy J.
      • Lednicky J.
      • Sordillo E.M.
      • Fowkes M.
      Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
      ,
      • Reddy S.T.
      • Garg T.
      • Shah C.
      • Nascimento F.A.
      • Imran R.
      • Kan P.
      • Bowry R.
      • Gonzales N.
      • Barreto A.
      • Kumar A.
      • Volpi J.
      • Misra V.
      • Chiu D.
      • Gadhia R.
      • Savitz S.I.
      Cerebrovascular disease in patients with COVID-19: a review of the literature and case series.
      • Ghoush M.S.A.
      • ElBashari M.
      • Alzaabi A.
      • Aboelnaga M.
      COVID-19 vasculitis: a case report with complicated course.
      • Hanafi R.
      • Roger P.-A.
      • Perin B.
      • Kuchcinski G.
      • Deleval N.
      • Dallery F.
      • Michel D.
      • Hacein-Bey L.
      • Pruvo J.-P.
      • Outteryck O.
      • Constans J.-M.
      COVID-19 neurologic complication with CNS vasculitis-like pattern.
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      • Antinone S.E.
      • Smith G.A.
      Retrograde axon transport of herpes simplex virus and Pseudorabies virus: a live-cell comparative analysis.
      SARS-CoV-2 has a particularly strong affinity for the angiotensin-converting enzyme 2 (ACE2) receptor, which it attaches to via its spike protein.
      • Moore J.B.
      • June C.H.
      Cytokine release syndrome in severe COVID-19.
      ,
      • Bougakov D.
      • Podell K.
      • Goldberg E.
      Multiple neuroinvasive pathways in COVID-19.
      The ACE2 receptor is ubiquitous across several organ systems, including the lungs, heart, and kidney, but the expression of ACE2 in the brain is significantly lower than that of other organs.
      • Bougakov D.
      • Podell K.
      • Goldberg E.
      Multiple neuroinvasive pathways in COVID-19.
      ,
      • Lukiw W.J.
      • Pogue A.
      • Hill J.M.
      SARS-CoV-2 infectivity and neurological targets in the brain.
      However, in an in vitro model of the human BBB, the function of the BBB is negatively affected by the SARS-CoV-2 spike protein, and brain endothelial cells showed a distinct proinflammatory response when exposed to the spike protein.
      • Buzhdygan T.P.
      • DeOre B.J.
      • Baldwin-Leclair A.
      • Bullock T.A.
      • McGary H.A.
      • Khan J.A.
      • Razmpour R.
      • Hale J.F.
      • Galie P.A.
      • Potula R.
      • Andrews A.M.
      • Ramirez S.H.
      The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier.
      Therefore, the virus must likely overcome the BBB, which plays a critical role in CNS homeostasis, and provides a fundamental level of protection from microorganisms and viruses.
      • Alexopoulos H.
      • Magira E.
      • Bitzogli K.
      • Kafasi N.
      • Vlachoyiannopoulos P.
      • Tzioufas A.
      • Kotanidou A.
      • Dalakas M.C.
      Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: studies in 8 stuporous and comatose patients.
      • Engelhardt B.
      • Liebner S.
      Novel insights into the development and maintenance of the blood-brain barrier.
      • Liebner S.
      • Dijkhuizen R.M.
      • Reiss Y.
      • Plate K.H.
      • Agalliu D.
      • Constantin G.
      Functional morphology of the blood-brain barrier in health and disease.
      The BBB is composed of the endothelial cells that line blood vessels, as well as pericytes, astrocytes, neurons, and the extracellular matrix.
      • Liebner S.
      • Dijkhuizen R.M.
      • Reiss Y.
      • Plate K.H.
      • Agalliu D.
      • Constantin G.
      Functional morphology of the blood-brain barrier in health and disease.
      Specifically, the interaction between endothelial cells and pericytes within a common basal lamina via peg-and-socket junctions, as well as the direct encasing of retinal capillaries by astrocytic end feet and microglia, form the neurovascular unit.
      • Liebner S.
      • Dijkhuizen R.M.
      • Reiss Y.
      • Plate K.H.
      • Agalliu D.
      • Constantin G.
      Functional morphology of the blood-brain barrier in health and disease.
      Furthermore, the endothelial cells in particular, within the CNS, form a tight barrier via continuous tight junctions, lack of fenestration, and low pinocytic activity, drastically limiting the transport of molecules between the vascular system and the CNS.
      • Engelhardt B.
      • Liebner S.
      Novel insights into the development and maintenance of the blood-brain barrier.
      Despite this barrier, the CNS can be reached by some viruses that can infect neurons and glial cells.
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      Although experimental evidence regarding SARS-CoV-2 neuroinvasiveness is still lacking, there is evidence obtained through post-mortem studies that indicate that the virus has reached the brain microvasculature, cerebrospinal fluid (CSF), as well as the neurons.
      • Baig A.M.
      • Sanders E.C.
      Potential neuroinvasive pathways of SARS-CoV-2: deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19).
      This may in part be due to the fact that not all blood vessels within the CNS are composed of the cellular constituents of the neurovascular unit, and the integrity of the BBB varies throughout some portions of the CNS, such as the choroid plexus or the circumventricular organs, allowing for secretion of CSF and other neurosecretory functions.
      • Swanson P.A.I.
      • McGavern D.B.
      Viral diseases of the central nervous system.
      ,
      • Sisó S.
      • Jeffrey M.
      • González L.
      Sensory circumventricular organs in health and disease.
      Thus, there is heterogeneity within CNS regions with respect to the barrier function of the BBB.
      • Wilhelm I.
      • Nyúl-Tóth Á.
      • Suciu M.
      • Hermenean A.
      • Krizbai I.A.
      Heterogeneity of the blood-brain barrier.
      Because of the similarities between coronaviruses, it is highly likely that SARS-CoV-2 is neuroinvasive and neurotropic, just like SARS-CoV.
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      Neuronal retrograde dissemination as well as hematogenous dissemination are potential pathways for SARS-CoV-2 to enter the CNS. Neuronal retrograde dissemination uses a protein called dynein to move viruses along the axon in the retrograde direction, from synapse to soma.
      • Keyhanian K.
      • Umeton R.P.
      • Mohit B.
      • Davoudi V.
      • Hajighasemi F.
      • Ghasemi M.
      SARS-CoV-2 and nervous system: from pathogenesis to clinical manifestation.
      This is known to occur in viral infections, such as HIV, where it contributes to viral latency.
      • Antinone S.E.
      • Smith G.A.
      Retrograde axon transport of herpes simplex virus and Pseudorabies virus: a live-cell comparative analysis.
      The proposed route of retrograde viral transport originates at the nasal cavity, the site of the mild SARS-CoV-2 neurologic symptom anosmia,
      • Meinhardt J.
      • Radke J.
      • Dittmayer C.
      • Franz J.
      • Thomas C.
      • Mothes R.
      • et al.
      Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.
      and ends at the brainstem, as follows: nasal cavity > olfactory nerve > olfactory bulb > piriform cortex > brainstem.
      • Bougakov D.
      • Podell K.
      • Goldberg E.
      Multiple neuroinvasive pathways in COVID-19.
      ,
      • De Santis G.
      SARS-CoV-2: a new virus but a familiar inflammation brain pattern.
      Another proposed route of infection involves endothelial cells and leukocyte trafficking. While in a healthy state, the CNS is devoid of leukocytes,
      • Zwijnenburg P.J.
      • van der Poll T.
      • Roord J.J.
      • van Furth A.M.
      Chemotactic factors in cerebrospinal fluid during bacterial meningitis.
      in an inflammatory setting, such as a viral infection, the infection can be established in the CNS by taking advantage of leukocyte trafficking.
      • Drevets D.A.
      • Leenen P.J.
      Leukocyte-facilitated entry of intracellular pathogens into the central nervous system.
      This process may involve direct infection of cerebral vascular endothelial cells due to leukocyte tethering, which allows immediate passage across the BBB into the CNS.
      • Swanson P.A.I.
      • McGavern D.B.
      Viral diseases of the central nervous system.
      ,
      • Pober J.S.
      Endothelial activation: intracellular signaling pathways.
      In addition to leukocyte activation and the trafficking of infected leukocytes through the blood-brain, the blood-CSF barrier may also be utilized as a hematogenous dissemination route, whereby infected hematopoietic cells are used as Trojan horses to transport virus into the CNS via the blood supply.
      • Swanson P.A.I.
      • McGavern D.B.
      Viral diseases of the central nervous system.
      ,
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      ,
      • Drevets D.A.
      • Leenen P.J.
      Leukocyte-facilitated entry of intracellular pathogens into the central nervous system.
      A systemic viral infection can also lead to inflammation-induced breakdown of the BBB, allowing viruses to slip through literal cracks between endothelial cells and into the CNS.
      • Swanson P.A.I.
      • McGavern D.B.
      Viral diseases of the central nervous system.
      ,
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      ,
      • Drevets D.A.
      • Leenen P.J.
      Leukocyte-facilitated entry of intracellular pathogens into the central nervous system.
      Although the activation, inflammation, and immune response of endothelial cells may be enough to compromise the BBB alone, the actions of the matrix metalloproteinase family of proteins may play a role in BBB integrity loss. Matrix metalloproteinase proteins are specifically relevant to BBB integrity, and up-regulation of SARS-CoV-2 spike protein has been shown to significantly up-regulate many of these key proteins.
      • Buzhdygan T.P.
      • DeOre B.J.
      • Baldwin-Leclair A.
      • Bullock T.A.
      • McGary H.A.
      • Khan J.A.
      • Razmpour R.
      • Hale J.F.
      • Galie P.A.
      • Potula R.
      • Andrews A.M.
      • Ramirez S.H.
      The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier.
      This highly specific, localized proinflammatory response may offer a route for SARS-CoV-2 to breach the BBB.
      • Buzhdygan T.P.
      • DeOre B.J.
      • Baldwin-Leclair A.
      • Bullock T.A.
      • McGary H.A.
      • Khan J.A.
      • Razmpour R.
      • Hale J.F.
      • Galie P.A.
      • Potula R.
      • Andrews A.M.
      • Ramirez S.H.
      The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier.
      The heterogeneity of barrier function within the CNS may additionally explain some of the variability of neurologic manifestations of COVID-19.

      Neurologic Manifestations of SARS-CoV-2 Infection

      Patients with severe respiratory disease are reported to have multiple neurologic manifestations. In a case study of 509 consecutive patients admitted with confirmed COVID-19 in Chicago, IL, a significantly higher risk of neurologic complications was seen in patients with severe symptoms of COVID-19.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      Many of the coronaviruses discovered to date have similar structures and infection mechanisms as well as similar neuro-invasive potential.
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      ,
      • Li Y.C.
      • Bai W.Z.
      • Hashikawa T.
      The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.
      The neuro-invasiveness of SARS-CoV has been established previously, and because of the similarities between the two coronaviruses, a similar risk of neuro-invasiveness may be extrapolated to SARS-CoV-2.
      • Paniz-Mondolfi A.
      • Bryce C.
      • Grimes Z.
      • Gordon R.E.
      • Reidy J.
      • Lednicky J.
      • Sordillo E.M.
      • Fowkes M.
      Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
      ,
      • Reddy S.T.
      • Garg T.
      • Shah C.
      • Nascimento F.A.
      • Imran R.
      • Kan P.
      • Bowry R.
      • Gonzales N.
      • Barreto A.
      • Kumar A.
      • Volpi J.
      • Misra V.
      • Chiu D.
      • Gadhia R.
      • Savitz S.I.
      Cerebrovascular disease in patients with COVID-19: a review of the literature and case series.
      • Ghoush M.S.A.
      • ElBashari M.
      • Alzaabi A.
      • Aboelnaga M.
      COVID-19 vasculitis: a case report with complicated course.
      • Hanafi R.
      • Roger P.-A.
      • Perin B.
      • Kuchcinski G.
      • Deleval N.
      • Dallery F.
      • Michel D.
      • Hacein-Bey L.
      • Pruvo J.-P.
      • Outteryck O.
      • Constans J.-M.
      COVID-19 neurologic complication with CNS vasculitis-like pattern.
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      • Antinone S.E.
      • Smith G.A.
      Retrograde axon transport of herpes simplex virus and Pseudorabies virus: a live-cell comparative analysis.
      • Bougakov D.
      • Podell K.
      • Goldberg E.
      Multiple neuroinvasive pathways in COVID-19.
      ,
      • Baig A.M.
      • Sanders E.C.
      Potential neuroinvasive pathways of SARS-CoV-2: deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19).
      ,
      • Li Y.C.
      • Bai W.Z.
      • Hashikawa T.
      The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.
      The coronavirus family, including SARS-CoV-2, has been associated with seizures, status epilepticus, encephalitis, acute disseminated encephalomyelitis, Guillan-Barre syndrome, leukoencephalopathy, and critical illness neuromyopathy.
      • Zhao H.
      • Shen D.
      • Zhou H.
      • Liu J.
      • Chen S.
      Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence?.
      ,
      • Yu S.
      • Yu M.
      Severe acute respiratory syndrome coronavirus 2-induced neurological complication.
      More recently (in 2003), SARS-CoV was detected in the cerebrospinal fluid of a patient with SARS.
      • Hung E.C.
      • Chim S.S.
      • Chan P.K.
      • Tong Y.K.
      • Ng E.K.
      • Chiu R.W.
      • Leung C.B.
      • Sung J.J.
      • Tam J.S.
      • Lo Y.M.
      Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome.
      ,
      • Lau K.K.
      • Yu W.C.
      • Chu C.M.
      • Lau S.T.
      • Sheng B.
      • Yuen K.Y.
      Possible central nervous system infection by SARS coronavirus.
      Although coronaviruses, including SARS-CoV-2, have been isolated from brain tissue in autopsy specimens, the presence of neutralizing antibodies in patient serum and cerebrospinal fluid has also been detected.
      • Paniz-Mondolfi A.
      • Bryce C.
      • Grimes Z.
      • Gordon R.E.
      • Reidy J.
      • Lednicky J.
      • Sordillo E.M.
      • Fowkes M.
      Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
      ,
      • Alexopoulos H.
      • Magira E.
      • Bitzogli K.
      • Kafasi N.
      • Vlachoyiannopoulos P.
      • Tzioufas A.
      • Kotanidou A.
      • Dalakas M.C.
      Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: studies in 8 stuporous and comatose patients.
      ,
      • Burks J.S.
      • DeVald B.L.
      • Jankovsky L.D.
      • Gerdes J.C.
      Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients.
      Multiple neurologic manifestations, varying from non-specific to specific symptoms, have been reported with SARS-CoV-2 infection.
      • Pinzon R.T.
      • Wijaya V.O.
      • Buana R.B.
      • Al Jody A.
      • Nunsio P.N.
      Neurologic characteristics in coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.
      Mild neurologic symptoms include headache, dizziness, hypogeusia, hyposmia, and neuralgia.
      • Lechien J.R.
      • Chiesa-Estomba C.M.
      • De Siati D.R.
      • Horoi M.
      • Le Bon S.D.
      • Rodriguez A.
      • Dequanter D.
      • Blecic S.
      • El Afia F.
      • Distinguin L.
      • Chekkoury-Idrissi Y.
      • Hans S.
      • Delgado I.L.
      • Calvo-Henriquez C.
      • Lavigne P.
      • Falanga C.
      • Barillari M.R.
      • Cammaroto G.
      • Khalife M.
      • Leich P.
      • Souchay C.
      • Rossi C.
      • Journe F.
      • Hsieh J.
      • Edjlali M.
      • Carlier R.
      • Ris L.
      • Lovato A.
      • De Filippis C.
      • Coppee F.
      • Fakhry N.
      • Ayad T.
      • Saussez S.
      Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.
      ,
      • Uygun Ö.
      • Ertaş M.
      • Ekizoğlu E.
      • Bolay H.
      • Özge A.
      • Orhan E.K.
      • Çağatay A.A.
      • Baykan B.
      Headache characteristics in COVID-19 pandemic-a survey study.
      The underlying mechanisms of these neurologic effects are likely numerous, including direct viral transmission through the olfactory nerve,
      • Meinhardt J.
      • Radke J.
      • Dittmayer C.
      • Franz J.
      • Thomas C.
      • Mothes R.
      • et al.
      Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.
      hypoxic brain injury, or immune mediated, via disruption of the blood-brain barrier.
      • Buzhdygan T.P.
      • DeOre B.J.
      • Baldwin-Leclair A.
      • Bullock T.A.
      • McGary H.A.
      • Khan J.A.
      • Razmpour R.
      • Hale J.F.
      • Galie P.A.
      • Potula R.
      • Andrews A.M.
      • Ramirez S.H.
      The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier.
      The likely early symptoms of COVID-19 include a fever and headache, with approximately 11% of emergency departments presenting patients experiencing headache.
      • Pinzon R.T.
      • Wijaya V.O.
      • Buana R.B.
      • Al Jody A.
      • Nunsio P.N.
      Neurologic characteristics in coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.
      As headaches are a common neurologic response to many daily concerns, including stress, tension, and dehydration,
      • Bolay H.
      • Gül A.
      • Baykan B.
      COVID-19 is a real headache!.
      the presentation of this symptom is widely variable and cannot be considered in isolation, although poor response to common analgesics is common.
      • Uygun Ö.
      • Ertaş M.
      • Ekizoğlu E.
      • Bolay H.
      • Özge A.
      • Orhan E.K.
      • Çağatay A.A.
      • Baykan B.
      Headache characteristics in COVID-19 pandemic-a survey study.
      Patients have reported headaches as pulsating, stabbing, or pressing, which normally indicates different headache types, such as migraine or tension. In the context of COVID-19, headache is likely to occur in conjunction with gastrointestinal symptoms.
      • Uygun Ö.
      • Ertaş M.
      • Ekizoğlu E.
      • Bolay H.
      • Özge A.
      • Orhan E.K.
      • Çağatay A.A.
      • Baykan B.
      Headache characteristics in COVID-19 pandemic-a survey study.
      These dual symptoms of gastrointestinal tract involvement with headache are linked to the gut-brain axis, which is affected by significant cytokine release, common in COVID-19 patients,
      • Moore J.B.
      • June C.H.
      Cytokine release syndrome in severe COVID-19.
      ,
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      ,
      • Hojyo S.
      • Uchida M.
      • Tanaka K.
      • Hasebe R.
      • Tanaka Y.
      • Murakami M.
      • Hirano T.
      How COVID-19 induces cytokine storm with high mortality.
      including tumor necrosis factor-α, ILs, and calcitonin gene-related peptide, a neuropeptide significantly linked to trigeminovascular activation, which leads to headache.
      • Uygun Ö.
      • Ertaş M.
      • Ekizoğlu E.
      • Bolay H.
      • Özge A.
      • Orhan E.K.
      • Çağatay A.A.
      • Baykan B.
      Headache characteristics in COVID-19 pandemic-a survey study.
      Further neurologic complications and cerebrovascular events include cerebrovascular accident, Guillian-Barre syndrome, acute transverse myelitis, and, although difficult to detect, acute encephalitis.
      • Haider A.
      • Siddiqa A.
      • Ali N.
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      ,
      • Zhao H.
      • Shen D.
      • Zhou H.
      • Liu J.
      • Chen S.
      Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence?.
      Encephalitis, or inflammation of the brain, is known to occur after some viral infections, including varicella zoster and influenza A viruses.
      • Kennedy P.G.E.
      Viral encephalitis: causes, differential diagnosis, and management.
      Coronaviruses have been detected in both the cerebrum and cerebrospinal fluid of individuals with seizures, encephalitis, and encephalomyelitis. The first case of encephalitis associated with SARS-CoV-2 infection was reported in May 2020 in a 24-year-old man,
      • Moriguchi T.
      • Harii N.
      • Goto J.
      • Harada D.
      • Sugawara H.
      • Takamino J.
      • Ueno M.
      • Sakata H.
      • Kondo K.
      • Myose N.
      • Nakao A.
      • Takeda M.
      • Haro H.
      • Inoue O.
      • Suzuki-Inoue K.
      • Kubokawa K.
      • Ogihara S.
      • Sasaki T.
      • Kinouchi H.
      • Kojin H.
      • Ito M.
      • Onishi H.
      • Shimizu T.
      • Sasaki Y.
      • Enomoto N.
      • Ishihara H.
      • Furuya S.
      • Yamamoto T.
      • Shimada S.
      A first case of meningitis/encephalitis associated with SARS-coronavirus-2.
      and since then, many more cases have been identified.
      • Mondal R.
      • Ganguly U.
      • Deb S.
      • Shome G.
      • Pramanik S.
      • Bandyopadhyay D.
      • Lahiri D.
      Meningoencephalitis associated with COVID-19: a systematic review.
      The higher risk of neurologic complications in patients with severe symptoms is caused primarily by a higher frequency of encephalopathy, especially in older patients.
      • Haider A.
      • Siddiqa A.
      • Ali N.
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      ,
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      Patients diagnosed with encephalitis have demonstrated signs of immune-mediated small-vessel damage, leading to altered integrity of the blood-brain barrier and brain edema.
      • Conte G.
      • Avignone S.
      • Carbonara M.
      • Meneri M.
      • Ortolano F.
      • Cinnante C.
      • Triulzi F.
      COVID-19–associated PRES–like encephalopathy with perivascular gadolinium enhancement.
      Secondary CNS vasculitis is a rare condition characterized by inflammation of the blood vessels in the brain or spine caused by viral infection, leading to varied symptoms, including confusion and significant forgetfulness.
      • Vaschetto R.
      • Cena T.
      • Sainaghi P.P.
      • Meneghetti G.
      • Bazzano S.
      • Vecchio D.
      • Pirisi M.
      • Brustia D.
      • Barini M.
      • Cammarota G.
      • Castello L.
      • Della Corte F.
      Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia.
      Because of its rarity, few patients diagnosed with COVID-19 have exhibited symptoms and been included in case studies as confirmed vasculitis patients. The condition often presents as multiple ischemic small-vessel lesions and hyperdense blood areas, with scans showing injury to the intracranial microvasculature.
      • Hanafi R.
      • Roger P.-A.
      • Perin B.
      • Kuchcinski G.
      • Deleval N.
      • Dallery F.
      • Michel D.
      • Hacein-Bey L.
      • Pruvo J.-P.
      • Outteryck O.
      • Constans J.-M.
      COVID-19 neurologic complication with CNS vasculitis-like pattern.
      ,
      • Vaschetto R.
      • Cena T.
      • Sainaghi P.P.
      • Meneghetti G.
      • Bazzano S.
      • Vecchio D.
      • Pirisi M.
      • Brustia D.
      • Barini M.
      • Cammarota G.
      • Castello L.
      • Della Corte F.
      Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia.
      The pattern seen on the scans is characteristic of disease processes that progress from endoluminal, vessel wall (vasculitis), or perivascular (leukoencephalopathy) cellular proliferation.
      • Hanafi R.
      • Roger P.-A.
      • Perin B.
      • Kuchcinski G.
      • Deleval N.
      • Dallery F.
      • Michel D.
      • Hacein-Bey L.
      • Pruvo J.-P.
      • Outteryck O.
      • Constans J.-M.
      COVID-19 neurologic complication with CNS vasculitis-like pattern.
      Of the few case studies available, patients were treated with steroids and immunoglobulin (Ig), as well as IL inhibitors, with varied outcomes for the patients.
      • Ghoush M.S.A.
      • ElBashari M.
      • Alzaabi A.
      • Aboelnaga M.
      COVID-19 vasculitis: a case report with complicated course.
      ,
      • Vaschetto R.
      • Cena T.
      • Sainaghi P.P.
      • Meneghetti G.
      • Bazzano S.
      • Vecchio D.
      • Pirisi M.
      • Brustia D.
      • Barini M.
      • Cammarota G.
      • Castello L.
      • Della Corte F.
      Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia.
      ,
      • Dixon L.
      • Coughlan C.
      • Karunaratne K.
      • Gorgoraptis N.
      • Varley J.
      • Husselbee J.
      • Mallon D.
      • Caroll R.
      • Jones B.
      • Boynton C.
      • Pritchard J.
      • Youngstein T.
      • Mason J.
      • Gabriel C.
      Immunosuppression for intracranial vasculitis associated with SARS-CoV-2: therapeutic implications for COVID-19 cerebrovascular pathology.
      An increased rate of ischemic stroke and intracerebral hemorrhage has been reported among COVID-19 patients.
      • Kaneko N.
      • Satta S.
      • Komuro Y.
      • Muthukrishnan S.D.
      • Kakarla V.
      • Guo L.
      • An J.
      • Elahi F.
      • Kornblum H.I.
      • Liebeskind D.S.
      • Hsiai T.
      • Hinman J.D.
      Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.
      ,
      • Helms J.
      • Kremer S.
      • Merdji H.
      • Clere-Jehl R.
      • Schenck M.
      • Kummerlen C.
      • Collange O.
      • Boulay C.
      • Fafi-Kremer S.
      • Ohana M.
      • Anheim M.
      • Meziani F.
      Neurologic features in severe SARS-CoV-2 infection.
      Cerebrovascular accident (alias stroke) is associated with COVID-19 diagnosis, across all age ranges, but is especially concerning in younger patients (aged <50 years) without the expected risk factors.
      • Altable M.
      • De La Serna J.M.
      Cerebrovascular disease in COVID-19: is there a higher risk of stroke?.
      Viral infections cause strokes by increasing the risks for embolism.
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • Sapozhnikov S.
      • Dandu V.
      • Toom S.
      • Glaser A.
      • Elsayegh D.
      COVID-19 presenting as stroke.
      ,
      • Grau A.J.
      • Buggle F.
      • Becher H.
      • Zimmermann E.
      • Spiel M.
      • Fent T.
      • Maiwald M.
      • Werle E.
      • Zorn M.
      • Hengel H.
      • Hacke W.
      Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia.
      Hypercoagulopathy, resulting from viral effects on systemic and CNS coagulation pathways, has been a growing concern, and anticoagulant administration is associated with decreased mortality in COVID-19 patients. In a case study of 32 critically ill patients, 8 had severe CNS involvement. Three patients were imaged with vessel wall sequence magnetic resonance imaging and showed contrast enhancement, suggesting large-vessel pathologies with an inflammatory component; however CSF samples were negative for SARS-CoV-2.
      • Keller E.
      • Brandi G.
      • Winklhofer S.
      • Imbach L.L.
      • Kirschenbaum D.
      • Frontzek K.
      • Steiger P.
      • Dietler S.
      • Haeberlin M.
      • Willms J.
      • Porta F.
      • Waeckerlin A.
      • Huber M.
      • Abela I.A.
      • Lutterotti A.
      • Stippich C.
      • Globas C.
      • Varga Z.
      • Jelcic I.
      Large and small cerebral vessel involvement in severe COVID-19.
      There have since been reports that PCR analysis of the CSF may be not reliable for the diagnosis because SARS-CoV-2 dissemination in the brain can be transient and its CSF titer may be extremely low.
      • Ye M.
      • Ren Y.
      • Lv T.
      Encephalitis as a clinical manifestation of COVID-19.
      Across the published articles available by mid-2020, it was calculated that between 0.2% and 1% of those infected with COVID-19 develop ischemic strokes.
      • Keller E.
      • Brandi G.
      • Winklhofer S.
      • Imbach L.L.
      • Kirschenbaum D.
      • Frontzek K.
      • Steiger P.
      • Dietler S.
      • Haeberlin M.
      • Willms J.
      • Porta F.
      • Waeckerlin A.
      • Huber M.
      • Abela I.A.
      • Lutterotti A.
      • Stippich C.
      • Globas C.
      • Varga Z.
      • Jelcic I.
      Large and small cerebral vessel involvement in severe COVID-19.
      This compares with annual rates of roughly 0.1% of the population in the United Kingdom and 0.2% of the population in the United States. Both the presentation and outcome are generally worse in stroke associated with a COVID-19 diagnosis compared with other strokes.
      • Altable M.
      • De La Serna J.M.
      Cerebrovascular disease in COVID-19: is there a higher risk of stroke?.
      Patients whose symptoms include severe pneumonia and multiorgan failure are more likely to additionally develop stroke, and the outcome for these patients is poor.
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • Vogrig A.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Abou-Ismail M.Y.
      • Diamond A.
      • Kapoor S.
      • Arafah Y.
      • Nayak L.
      The hypercoagulable state in COVID-19: incidence, pathophysiology, and management.
      Reported cerebrovascular events are predominantly found in older patients; however, acute mental state alterations, although represented in all age groups, are considered to be disproportionately found in younger patients.
      • Liotta E.M.
      • Batra A.
      • Clark J.R.
      • Shlobin N.A.
      • Hoffman S.C.
      • Orban Z.S.
      • Koranic I.J.
      Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients.
      ,
      • Varatharaj A.
      • Thomas N.
      • Ellul M.A.
      • Davies N.
      • Pollak T.A.
      • Tenorio E.L.
      • Sultan M.
      • Easton A.
      • Breen G.
      • Zandi M.
      • Coles J.P.
      • Manji H.
      • Al-Shahi Salman R.
      • Menon D.K.
      • Nicholson T.R.
      • Benjamin L.A.
      • Carson A.
      • Smith C.
      • Turner M.R.
      • Solomon T.
      • Kneen R.
      • Pett S.L.
      • Galea I.
      • Thomas R.H.
      • Michael B.D.
      Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study.
      Additional, long-term studies are required, but there is also speculation that COVID-19 infection may have long-term negative implications on the incidence of Alzheimer disease within the population.
      • de Erausquin G.A.
      • Snyder H.
      • Carrillo M.
      • Hosseini A.A.
      • Brugha T.S.
      • Seshadri Sl
      The chronic neuropsychiatric sequelae of COVID-19: the need for a prospective study of viral impact on brain functioning.
      Disrupted cardiorespiratory function causes metabolic dysfunction that may increase risk for future Alzheimer disease and related dementia, whereas the extreme inflammatory response to the infection causes the release of ILs and tumor necrosis factor-α.
      • Daugherty A.M.
      • Chopra T.
      • Korzeniewski S.J.
      • Levy P.
      COVID-19 as a risk factor for Alzheimer's disease and related dementia: a perspective from Detroit, MI.
      Proinflammatory cytokine expression promotes oxidative stress, which, if unchecked, degrades mitochondria, causes DNA mutations, and accelerates apoptosis.
      • Raz N.
      • Daugherty A.M.
      Pathways to brain aging and their modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) model - a mini-review.
      This cell death may lead to neural dysfunction and an acceleration in neural decline over time.
      • Daugherty A.M.
      • Chopra T.
      • Korzeniewski S.J.
      • Levy P.
      COVID-19 as a risk factor for Alzheimer's disease and related dementia: a perspective from Detroit, MI.
      These data on the impact of the CNS insult to patients support the fact that the neurologic complications from SARS-CoV-2 infection may have longer-lasting consequences, and in fact be more debilitating, than the initial respiratory symptoms of the disease.
      • Ghoush M.S.A.
      • ElBashari M.
      • Alzaabi A.
      • Aboelnaga M.
      COVID-19 vasculitis: a case report with complicated course.

      Blood Vessels in SARS-CoV-2 Infection

      As COVID-19 mainly presents as a respiratory disease, it is not surprising that post-mortem studies in patients with COVID-19 identified diffuse alveolar damage in patients with severe disease, indicating pulmonary epithelial cell involvement.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      However, several studies also describe severe endothelial damage and coagulopathic features in the pulmonary microvasculature (Figure 1).
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      ,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      Human brain microvascular endothelial cells are known to be infected by several virus types, including HIV, polio, and SARS-CoV-2.
      • Kaneko N.
      • Satta S.
      • Komuro Y.
      • Muthukrishnan S.D.
      • Kakarla V.
      • Guo L.
      • An J.
      • Elahi F.
      • Kornblum H.I.
      • Liebeskind D.S.
      • Hsiai T.
      • Hinman J.D.
      Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.
      ,
      • Verma S.
      • Lo Y.
      • Chapagain M.
      • Lum S.
      • Kumar M.
      • Gurjav U.
      • Luo H.
      • Nakatsuka A.
      • Nerurkar V.R.
      West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier.
      • Moses A.V.
      • Bloom F.E.
      • Pauza C.D.
      • Nelson J.A.
      Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism.
      • Coyne C.B.
      • Kim K.S.
      • Bergelson J.M.
      Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2.
      Viral migration into the brain occurs in several ways, including tight junction modulation,
      • Verma S.
      • Lo Y.
      • Chapagain M.
      • Lum S.
      • Kumar M.
      • Gurjav U.
      • Luo H.
      • Nakatsuka A.
      • Nerurkar V.R.
      West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier.
      receptor activation,
      • Coyne C.B.
      • Kim K.S.
      • Bergelson J.M.
      Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2.
      hematogenous dissemination,
      • Desforges M.
      • Le Coupanec A.
      • Brison E.
      • Meessen-Pinard M.
      • Talbot P.J.
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      ,
      • Engelhardt B.
      • Liebner S.
      Novel insights into the development and maintenance of the blood-brain barrier.
      and direct endothelial cell infection.
      • Moses A.V.
      • Bloom F.E.
      • Pauza C.D.
      • Nelson J.A.
      Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism.
      Like many other viruses, the mechanisms underlying cerebral endothelial susceptibility and individual patient neurologic responses to SARS-CoV-2 are unknown.
      • van den Pol A.N.
      Viral infection leading to brain dysfunction: more prevalent than appreciated?.
      ,
      • Kaneko N.
      • Satta S.
      • Komuro Y.
      • Muthukrishnan S.D.
      • Kakarla V.
      • Guo L.
      • An J.
      • Elahi F.
      • Kornblum H.I.
      • Liebeskind D.S.
      • Hsiai T.
      • Hinman J.D.
      Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.
      Figure thumbnail gr1
      Figure 1Comparison of normal blood vessels versus potential disease states of blood vessels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. The figure was generated with Biorender.com (BioRender, Toronto, ON, Canada).
      Endothelial cells in a healthy environment are able to prevent coagulation, inhibit inflammation, and control blood flow and the passage of proteins from blood into tissues by modulation of vascular permeability.
      • Pober J.S.
      • Sessa W.C.
      Evolving functions of endothelial cells in inflammation.
      ,
      • Teuwen L.-A.
      • Geldhof V.
      • Pasut A.
      • Carmeliet P.
      COVID-19: the vasculature unleashed.
      Evidence based on COVID-19 risk factors, which include old age, obesity, hypertension, and diabetes mellitus, indicates a link between endothelial cells and COVID-19, as all of the above are characterized by pre-existing vascular dysfunction.
      • Teuwen L.-A.
      • Geldhof V.
      • Pasut A.
      • Carmeliet P.
      COVID-19: the vasculature unleashed.
      As endothelial cells play a crucial role in maintaining hemostasis and vessel wall integrity, localized dysfunction of pulmonary microvascular cells is likely to be a key component in the thromboinflammatory processes that result in COVID-19 vasculopathy.
      • McGonagle D.
      • O'Donnell J.S.
      • Sharif K.
      • Emery P.
      • Bridgewood C.
      Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.
      Evidence from autopsies indicates direct viral tissue injury and localized cytokine release induce microvascular inflammation, which triggers endothelial activation.
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      This is seen in several organs, including the lungs
      • Tian S.
      • Hu W.
      • Niu L.
      • Liu H.
      • Xu H.
      • Xiao S.-Y.
      Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer.
      and kidneys.
      • Su H.
      • Yang M.
      • Wan C.
      • Yi L.-X.
      • Tang F.
      • Zhu H.-Y.
      • Yi F.
      • Yang H.-C.
      • Fogo A.B.
      • Nie X.
      • Zhang C.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China - Kidney International.
      The lungs of COVID-19 autopsy patients have features of severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      ,
      • Tian S.
      • Hu W.
      • Niu L.
      • Liu H.
      • Xu H.
      • Xiao S.-Y.
      Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer.
      The lungs have also been found to contain widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      whereas the kidneys show evidence of vasodilation and prothrombotic conditions,
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      as well as cell swelling and capillary occlusion.
      • Su H.
      • Yang M.
      • Wan C.
      • Yi L.-X.
      • Tang F.
      • Zhu H.-Y.
      • Yi F.
      • Yang H.-C.
      • Fogo A.B.
      • Nie X.
      • Zhang C.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China - Kidney International.
      There is also significant evidence of heart damage, seen in upwards of one-third of hospitalized COVID-19 patients.
      • Bois M.C.
      • Boire N.A.
      • Layman A.J.
      • Aubry M.C.
      • Alexander M.P.
      • Roden A.C.
      • Hagen C.E.
      • Quinton R.A.
      • Larsen C.
      • Erben Y.
      • Majumdar R.
      • Jenkins S.M.
      • Kipp B.R.
      • Lin P.T.
      • Maleszewski J.J.
      COVID-19–associated nonocclusive fibrin microthrombi in the heart.
      Comorbidities of severe COVID-19, which are linked to vascular endothelial damage, such as atherosclerosis, cause significant damage to the endothelial glycocalyx, whereas SARS-CoV-2 can induce cytokine release, also leading to systemic degradation of the vascular endothelial glycocalyx.
      • Yamaoka-Tojo M.
      Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19.
      This causes microvascular leakage and initiates changes in the coagulation cascade.
      • Yamaoka-Tojo M.
      Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19.
      ,
      • Okada H.
      • Yoshida S.
      • Hara A.
      • Ogura S.
      • Tomita H.
      Vascular endothelial injury exacerbates coronavirus disease 2019: the role of endothelial glycocalyx protection.
      Microthrombosis of the small-vessel myocardial vasculature is a relatively common finding in COVID-19 patients and may persist even after viral clearance.
      • Bois M.C.
      • Boire N.A.
      • Layman A.J.
      • Aubry M.C.
      • Alexander M.P.
      • Roden A.C.
      • Hagen C.E.
      • Quinton R.A.
      • Larsen C.
      • Erben Y.
      • Majumdar R.
      • Jenkins S.M.
      • Kipp B.R.
      • Lin P.T.
      • Maleszewski J.J.
      COVID-19–associated nonocclusive fibrin microthrombi in the heart.
      Further evidence of vascular cell involvement in coagulopathy, most obviously seen in thrombi formation in the lungs and in ischemic strokes, is also visible in the blood vessels of the skin. Rashes, described as livedoid and purpuric, are visible manifestations of a suspected underlying pulmonary thrombotic state in COVID-19 patients.
      • Droesch C.
      • Do M.H.
      • DeSancho M.
      • Lee E.
      • Magro C.
      • Harp J.
      Livedoid and purpuric skin eruptions associated with coagulopathy in severe COVID-19.
      These rashes have been noted to occur in patients already receiving therapeutic dose anticoagulation therapies to stave off suspected pulmonary embolism.
      • Droesch C.
      • Do M.H.
      • DeSancho M.
      • Lee E.
      • Magro C.
      • Harp J.
      Livedoid and purpuric skin eruptions associated with coagulopathy in severe COVID-19.
      These symptoms are associated with occlusive vascular disease,
      • Galván-Casas C.
      • Català A.
      • Carretero-Hernández G.
      • Rodríguez-Jiménez P.F.-N.D.
      • Rodríguez-Villa A.
      • Navarro-Fernández I.
      • Ruiz-Villaverde R.
      • Falkenhain-López D.
      • Llamas Velasco M.
      • García-Gavín J.
      • Baniandrés O.
      • González-Cruz C.
      • Morillas-Lahuerta V.
      • Cubiró X.
      • Figueras-Nart I.
      • Selda-Enriquez G.
      • Romaní J.
      • Fustà-Novell X.
      • Melian-Olivera A.
      • Roncero-Riesco M.
      • Burgos-Blasco P.
      • Sola-Ortigosa J.
      • Feito-Rodriguez M.
      • García-Doval I.
      Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.
      especially as punch biopsies indicated pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, and/or arterioles in conjunction with significantly elevated D-dimer levels. In these cases, patients were not believed to be experiencing alternate conditions resulting in thrombi formation, including disseminated intravascular coagulation (DIC), because of their normal levels of fibrinogen.
      • Droesch C.
      • Do M.H.
      • DeSancho M.
      • Lee E.
      • Magro C.
      • Harp J.
      Livedoid and purpuric skin eruptions associated with coagulopathy in severe COVID-19.
      Disruption of the endothelial cells is not an end point in itself, but rather a component of a thromboinflammatory feedback loop within small vessels, wherein disruption, cytokine release, and coagulation cascade activation lead to a comparably hypoxic environment that exacerbates the aforementioned factors.
      • McGonagle D.
      • O'Donnell J.S.
      • Sharif K.
      • Emery P.
      • Bridgewood C.
      Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.
      Although, in the lungs, thrombotic complications are likely to relate, at least in part, to endothelial inflammation and injury, its in the cerebrovascular system is currently limited.
      • Dixon L.
      • Coughlan C.
      • Karunaratne K.
      • Gorgoraptis N.
      • Varley J.
      • Husselbee J.
      • Mallon D.
      • Caroll R.
      • Jones B.
      • Boynton C.
      • Pritchard J.
      • Youngstein T.
      • Mason J.
      • Gabriel C.
      Immunosuppression for intracranial vasculitis associated with SARS-CoV-2: therapeutic implications for COVID-19 cerebrovascular pathology.

      Mechanisms of Vascular Damage in SARS-CoV-2 Infection

      Cytokine release syndrome, also described as cytokine storm, is of serious concern in COVID-19 patients as it has been linked to increased patient mortality.
      • Channappanavar R.
      • Perlman S.
      Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.
      ,
      • Moore J.B.
      • June C.H.
      Cytokine release syndrome in severe COVID-19.
      ,
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      ,
      • Hojyo S.
      • Uchida M.
      • Tanaka K.
      • Hasebe R.
      • Tanaka Y.
      • Murakami M.
      • Hirano T.
      How COVID-19 induces cytokine storm with high mortality.
      Viral infection leads to the release of antiviral cytokines, such as interferon-αβ.
      • Channappanavar R.
      • Perlman S.
      Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.
      This leads to the release of proinflammatory cytokines, such as tumor necrosis factor-α and IL-6 and IL-1β, as well as chemokines, including vascular endothelial growth factor, monocyte chemoattractant protein-1, and CXCL10.
      • Channappanavar R.
      • Perlman S.
      Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.
      ,
      • Moore J.B.
      • June C.H.
      Cytokine release syndrome in severe COVID-19.
      ,
      • Hojyo S.
      • Uchida M.
      • Tanaka K.
      • Hasebe R.
      • Tanaka Y.
      • Murakami M.
      • Hirano T.
      How COVID-19 induces cytokine storm with high mortality.
      Although the relative levels of these cytokines are well below those found in acute respiratory distress syndrome patients,
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      they are far above normal and their presence in COVID-19 patients is now being used as biomarkers and predictors of future care.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      ,
      • Herold T.
      • Jurinovic V.
      • Arnreich C.
      • Lipworth B.J.
      • Hellmuth J.C.
      • von Bergwelt-Baildon M.
      • Klein M.
      • Weinberger T.
      Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.
      For example, IL-6 expression is significantly higher in fatal outcomes compared with survivors and is also used an indicator of the need for mechanical ventilation.
      • Herold T.
      • Jurinovic V.
      • Arnreich C.
      • Lipworth B.J.
      • Hellmuth J.C.
      • von Bergwelt-Baildon M.
      • Klein M.
      • Weinberger T.
      Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.
      The activated phenotype of endothelial cells, which is induced by inflammatory cytokines and chemokines, promotes adhesions and infiltration of neutrophils, which produce large amounts of histotoxic mediators, including neutrophil extracellular traps, which leads to endothelial cell injury.
      • Teuwen L.-A.
      • Geldhof V.
      • Pasut A.
      • Carmeliet P.
      COVID-19: the vasculature unleashed.
      These activated endothelial cells initiate coagulation by expressing fibrinogen, among others, leading to platelet binding, fibrin production, and thrombus formation.
      • Perico L.
      • Benigni A.
      • Casiraghi F.
      • Ng L.F.P.
      • Renia L.
      • Remuzzi G.
      Immunity, endothelial injury and complement-induced coagulopathy in COVID-19.
      The microvascular inflammation caused by release of inflammatory and apoptosis-inducing mediators, followed by endothelial activation, leads to increased patient mortality.
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      The main SARS-CoV-2 cellular receptor, ACE2, has regional variability within the human brain but is poorly expressed by human brain endothelial cells.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      ,
      • Kaneko N.
      • Satta S.
      • Komuro Y.
      • Muthukrishnan S.D.
      • Kakarla V.
      • Guo L.
      • An J.
      • Elahi F.
      • Kornblum H.I.
      • Liebeskind D.S.
      • Hsiai T.
      • Hinman J.D.
      Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.
      Up-regulation of ACE2 in the brain is linked to oxidative stress, apoptosis, and neurodegeneration.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      ACE2 expression can be triggered in vitro in a flow-dependent manner, which indicates that cerebral vessels are susceptible to SARS-CoV-2 infection.
      • Kaneko N.
      • Satta S.
      • Komuro Y.
      • Muthukrishnan S.D.
      • Kakarla V.
      • Guo L.
      • An J.
      • Elahi F.
      • Kornblum H.I.
      • Liebeskind D.S.
      • Hsiai T.
      • Hinman J.D.
      Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.
      However, the question remains as to whether the pathobiology and neuroinfectiveness of SARS-CoV-2 mean that damage occurs from direct effects of the virus on the CNS tissue, or whether damage occurs as a secondary insult, triggered by hypoxia, immune response cytokine release, or clotting cascades.
      • DeKosky S.T.
      • Kochanek P.M.
      • Valadka A.B.
      • Clark R.
      • Chou S.H.
      • Au A.K.
      • Horvat C.
      • Jha R.M.
      • Mannix R.
      • Wisniewski S.R.
      • Wintermark M.
      • Rowell S.E.
      • Welch R.D.
      • Lewis L.
      • House S.
      • Tanzi R.E.
      • Smith D.R.
      • Vittor A.Y.
      • Denslow N.D.
      • Davis M.D.
      • Glushakova O.Y.
      • Hayes R.L.
      Blood biomarkers for detection of brain injury in COVID-19 patients.
      Within the CNS, one proposed route of infection is direct infection of cerebral vascular endothelial cells due to leukocyte tethering and trafficking,
      • Drevets D.A.
      • Leenen P.J.
      Leukocyte-facilitated entry of intracellular pathogens into the central nervous system.
      which allows immediate passage across the BBB into the CNS.
      • Swanson P.A.I.
      • McGavern D.B.
      Viral diseases of the central nervous system.
      ,
      • Pober J.S.
      Endothelial activation: intracellular signaling pathways.
      Autopsied patients have SARS-CoV-2–infected frontal lobe microvascular endothelial cells and tissue damage, characterized by cell lysis and dysfunction, as well as evidence of localized cytokine release,
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      ,
      • Teuwen L.-A.
      • Geldhof V.
      • Pasut A.
      • Carmeliet P.
      COVID-19: the vasculature unleashed.
      a probable cause of the prevalence of vessel inflammation seen in scans.
      • Keller E.
      • Brandi G.
      • Winklhofer S.
      • Imbach L.L.
      • Kirschenbaum D.
      • Frontzek K.
      • Steiger P.
      • Dietler S.
      • Haeberlin M.
      • Willms J.
      • Porta F.
      • Waeckerlin A.
      • Huber M.
      • Abela I.A.
      • Lutterotti A.
      • Stippich C.
      • Globas C.
      • Varga Z.
      • Jelcic I.
      Large and small cerebral vessel involvement in severe COVID-19.
      Interestingly, although ACE2 receptor is required for SARS-CoV-2 to bind and gain access to the cell, this binding reduces ACE2 enzyme activity, activating the kallikrein-bradykinin pathway, and increasing vascular permeability.
      • Teuwen L.-A.
      • Geldhof V.
      • Pasut A.
      • Carmeliet P.
      COVID-19: the vasculature unleashed.
      This increased permeability leads to the release of inflammatory cytokines such as ILs and tumor necrosis factor-α, whose downstream mediators promote fluid retention, leading to increased vascular leakage.
      • Pober J.S.
      • Sessa W.C.
      Evolving functions of endothelial cells in inflammation.
      ,
      • Teuwen L.-A.
      • Geldhof V.
      • Pasut A.
      • Carmeliet P.
      COVID-19: the vasculature unleashed.
      Likely cofactors remain a mystery, however, in our understanding of the association of SARS-CoV-2 infection with cerebrovascular events.
      Although considered a mild symptom, headache caused by SARS-CoV-2 infection is attributed to a possible pathophysiological mechanism involving the peripheral trigeminal nerve endings. This occurs either by direct viral activation or through vasculopathy caused by increased circulating proinflammatory cytokines and hypoxia.
      • Uygun Ö.
      • Ertaş M.
      • Ekizoğlu E.
      • Bolay H.
      • Özge A.
      • Orhan E.K.
      • Çağatay A.A.
      • Baykan B.
      Headache characteristics in COVID-19 pandemic-a survey study.
      ,
      • Bolay H.
      • Gül A.
      • Baykan B.
      COVID-19 is a real headache!.
      With regard to the rare neurologic symptoms, including encephalitis and vasculitis, immune-mediated small-vessel damage, leading to altered integrity of the blood-brain barrier, followed by brain edema, is the proposed mechanism.
      • Conte G.
      • Avignone S.
      • Carbonara M.
      • Meneri M.
      • Ortolano F.
      • Cinnante C.
      • Triulzi F.
      COVID-19–associated PRES–like encephalopathy with perivascular gadolinium enhancement.
      In patients with vasculitis, this immune-mediated small-vessel damage leads to ischemic lesions, as well as hyperdense blood areas, due to intracranial microvasculature injury.
      • Hanafi R.
      • Roger P.-A.
      • Perin B.
      • Kuchcinski G.
      • Deleval N.
      • Dallery F.
      • Michel D.
      • Hacein-Bey L.
      • Pruvo J.-P.
      • Outteryck O.
      • Constans J.-M.
      COVID-19 neurologic complication with CNS vasculitis-like pattern.
      ,
      • Vaschetto R.
      • Cena T.
      • Sainaghi P.P.
      • Meneghetti G.
      • Bazzano S.
      • Vecchio D.
      • Pirisi M.
      • Brustia D.
      • Barini M.
      • Cammarota G.
      • Castello L.
      • Della Corte F.
      Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia.
      Immune-related COVID-19 pathology in pediatric populations was recently described in the United States and in Europe. These children developed a Kawasaki-like syndrome, believed to be associated with COVID-19.
      • Jones V.G.
      • Mills M.
      • Suarez D.
      • Hogan C.A.
      • Yeh D.
      • Segal J.B.
      • Nguyen E.L.
      • Barsh G.R.
      • Maskatia S.
      • Mathew R.
      COVID-19 and Kawasaki disease: novel virus and novel case.
      Kawasaki disease is characterized by a high fever and systemic vasculitis and may result in neurologic complications.
      • Bougakov D.
      • Podell K.
      • Goldberg E.
      Multiple neuroinvasive pathways in COVID-19.
      In patients diagnosed with COVID-19, both ischemic and hemorrhagic strokes are possible, although hemorrhagic strokes are less likely.
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • Vogrig A.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Spence D.J.
      • de Freitas G.R.
      • Pettigrew C.L.
      • Ay H.
      • Liebeskind D.S.
      • Kase C.S.
      • Del Brutto O.H.
      • Hankey G.J.
      • Venketasubramanian N.
      Mechanisms of stroke in COVID-19.
      The rate of patients experiencing ischemic stroke is significantly elevated over the normal population.
      • Zhao H.
      • Shen D.
      • Zhou H.
      • Liu J.
      • Chen S.
      Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence?.
      Hypotheses as to the mechanism of action for both ischemic and hemorrhagic stroke onset include disseminated intravascular coagulation (alias consumption coagulopathy)
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      as well as significantly increased levels of D-dimer.
      • Leisman D.E.
      • Deutschman C.S.
      • Legrand M.
      Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
      ,
      • Leisman D.E.
      • Ronner L.
      • Pinotti R.
      • Taylor M.D.
      • Sinha P.
      • Calfee C.S.
      • Hirayama A.V.
      • Mastroiani F.
      • Turtle C.J.
      • OHarhay M.
      • Legrand M.
      • Deutschmann C.S.
      Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
      Rates of COVID-19 complicated by disseminated intravascular coagulation have been reported as 0.6% for survivors and 71.4% for nonsurvivors.
      • Tang N.
      • Li D.
      • Wang X.
      • Sun Z.
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      Although most patients experience ischemic stroke, some patients experience secondary hemorrhagic transformations of ischemic strokes.
      • Spence D.J.
      • de Freitas G.R.
      • Pettigrew C.L.
      • Ay H.
      • Liebeskind D.S.
      • Kase C.S.
      • Del Brutto O.H.
      • Hankey G.J.
      • Venketasubramanian N.
      Mechanisms of stroke in COVID-19.
      ,
      • Fatehi P.
      • Hesam-Shariati N.
      • Abouzaripour M.
      • Fathi F.
      • Hesam-Shariati M.B.
      Acute ischemic and hemorrhagic stroke and COVID-19: case series.
      ,
      • Valderrama E.V.
      • Humbert K.
      • Lord A.
      • Frontera J.
      • Yaghi S.
      Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke.
      This transition is indicative of serious malfunctions in both the clotting cascade, possibly due to disseminated intravascular coagulation, as well as lack of integrity of the vessel walls caused by endothelial damage.
      • Spence D.J.
      • de Freitas G.R.
      • Pettigrew C.L.
      • Ay H.
      • Liebeskind D.S.
      • Kase C.S.
      • Del Brutto O.H.
      • Hankey G.J.
      • Venketasubramanian N.
      Mechanisms of stroke in COVID-19.
      ,
      • Valderrama E.V.
      • Humbert K.
      • Lord A.
      • Frontera J.
      • Yaghi S.
      Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke.
      This immune-driven endothelial damage is likely a large contributor to the increased risk of ischemic and hemorrhagic stroke seen in COVID-19 patients.
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • Vogrig A.
      Stroke in patients with SARS-CoV-2 infection: case series.
      In addition, hypercoagulability and vasculitis due to intracranial cytokine storm, leading to macrothrombi and microthrombi formation in the vessels, are also proposed as mechanisms.
      • Keller E.
      • Brandi G.
      • Winklhofer S.
      • Imbach L.L.
      • Kirschenbaum D.
      • Frontzek K.
      • Steiger P.
      • Dietler S.
      • Haeberlin M.
      • Willms J.
      • Porta F.
      • Waeckerlin A.
      • Huber M.
      • Abela I.A.
      • Lutterotti A.
      • Stippich C.
      • Globas C.
      • Varga Z.
      • Jelcic I.
      Large and small cerebral vessel involvement in severe COVID-19.
      ,
      • Avula A.
      • Nalleballe K.
      • Narula N.
      • Sapozhnikov S.
      • Dandu V.
      • Toom S.
      • Glaser A.
      • Elsayegh D.
      COVID-19 presenting as stroke.
      ,
      • Elkhider H.
      • Ibrahim F.
      • Sharma R.
      • Sheng
      • Sen
      • Jasti M.
      • Lotia M.
      • Kapoor N.
      • Onteddu S.
      • Mueed S.
      • Allam H.
      • Nalleballe K.
      COVID-19 and stroke, a case series and review of literature.

      Conclusion

      The large number of studies relating to COVID-19 (an early January 2021 PubMed search returned >85,000 COVID-19 hits) indicate the urgency in the scientific community to determine the factors causing increased patient mortality. Although improving patient survival rates is of the utmost importance, the impact of the endothelium-linked CNS insult to COVID-19 patients cannot be overstated. Research articles discussing long COVID and post–COVID-19 neurological syndrome have been recently published.
      • Wijeratne T.
      • Crewther S.
      Post-COVID 19 neurological syndrome (PCNS); a novel syndrome with challenges for the global neurology community.
      ,
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • Brown J.S.
      • Denneny E.K.
      • Hare S.S.
      • Heightman M.
      • Hillman T.E.
      • Jacob J.
      • Jarvis H.C.
      • Lipman M.C.I.
      • Naidu S.B.
      • Nair A.
      • Porter J.C.
      • Tomlinson G.S.
      • Hurst J.R.
      “Long-COVID”: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      As the pandemic is still ongoing, it is too early to describe the future clinical needs of these patients. However, current evidence indicates that the long-term neurologic complications from SARS-CoV-2 infection may be more debilitating than the initial respiratory symptoms of the disease.
      • Ghoush M.S.A.
      • ElBashari M.
      • Alzaabi A.
      • Aboelnaga M.
      COVID-19 vasculitis: a case report with complicated course.
      ,
      • de Erausquin G.A.
      • Snyder H.
      • Carrillo M.
      • Hosseini A.A.
      • Brugha T.S.
      • Seshadri Sl
      The chronic neuropsychiatric sequelae of COVID-19: the need for a prospective study of viral impact on brain functioning.
      ,
      • Daugherty A.M.
      • Chopra T.
      • Korzeniewski S.J.
      • Levy P.
      COVID-19 as a risk factor for Alzheimer's disease and related dementia: a perspective from Detroit, MI.
      ,
      • Wijeratne T.
      • Crewther S.
      Post-COVID 19 neurological syndrome (PCNS); a novel syndrome with challenges for the global neurology community.

      Acknowledgments

      We thank Michel Plantevin and Andrew Firger for supporting publication. H.A.B.W. thanks the Consular Information Unit and the Nonimmigrant Visa Unit at the US Embassy in London, UK, for assistance in obtaining a National Interest Exemption Waiver to allow her return to the United States during the COVID-19 pandemic to work on this project. L.A.K. thanks Dr. Nahyoung Grace Lee for support.

      References

        • Wu Z.
        • McGoogan J.M.
        Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
        JAMA. 2020; 323: 1239-1242
        • Leisman D.E.
        • Deutschman C.S.
        • Legrand M.
        Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation.
        Intensive Care Med. 2020; 46: 1105-1108
        • Huang C.
        • Wang Y.
        • Li X.
        • Ren L.
        • Zhao J.
        • Hu Y.
        • Zhang L.
        • Fan G.
        • Xu J.
        • Gu X.
        • Cheng Z.
        • Yu T.
        • Xia J.
        • Wei Y.
        • Wu W.
        • Xie X.
        • Yin W.
        • Li H.
        • Liu M.
        • Xiao Y.
        • Gao H.
        • Guo L.
        • Xie J.
        • Wang G.
        • Jiang R.
        • Gao Z.
        • Jin Q.
        • Wang J.
        • Cao B.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        Lancet. 2020; 395: 30183-30185
        • Al-Sharif E.
        • Strianese D.
        • AlMadhi N.H.
        • D'Aponte A.
        • dell'Omo R.
        • DiBenedetto R.
        • Costagliola C.
        Ocular tropism of coronavirus (CoVs): a comparison of the interaction between the animal-to-human transmitted coronaviruses (SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, NL63, OC43, HKU1) and the eye.
        Int Ophthalmol. 2021; 41: 349-362
        • Yin Y.
        • Wunderink R.G.
        MERS, SARS and other coronaviruses as causes of pneumonia.
        Respirology. 2018; 23: 130-137
        • Wu A.
        • Peng Y.
        • Huang B.
        • Ding X.
        • Wang X.
        • Niu P.
        • Meng J.
        • Zhu Z.
        • Zhang Z.
        • Wang J.
        • Sheng J.
        • Quan L.
        • Xia Z.
        • Tan W.
        • Cheng G.
        • Jiang T.
        Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
        Cell Host Microbe. 2020; 27: 325-328
        • De Wit E.
        • Van Doremalen N.
        • Falzarano D.
        • Munster V.J.
        SARS and MERS: recent insights into emerging coronaviruses.
        Nat Rev Microbiol. 2016; 14: 523-534
        • Channappanavar R.
        • Perlman S.
        Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.
        Semin Immunopathol. 2017; 39: 529-539
        • Tzotzos S.J.
        • Fischer B.
        • Fischer H.
        • Zeitlinger M.
        Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey.
        Crit Care. 2020; 24: 516
        • Su H.
        • Yang M.
        • Wan C.
        • Yi L.-X.
        • Tang F.
        • Zhu H.-Y.
        • Yi F.
        • Yang H.-C.
        • Fogo A.B.
        • Nie X.
        • Zhang C.
        Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China - Kidney International.
        Kidney Int. 2020; 98: 219-227
        • Keller E.
        • Brandi G.
        • Winklhofer S.
        • Imbach L.L.
        • Kirschenbaum D.
        • Frontzek K.
        • Steiger P.
        • Dietler S.
        • Haeberlin M.
        • Willms J.
        • Porta F.
        • Waeckerlin A.
        • Huber M.
        • Abela I.A.
        • Lutterotti A.
        • Stippich C.
        • Globas C.
        • Varga Z.
        • Jelcic I.
        Large and small cerebral vessel involvement in severe COVID-19.
        Stroke. 2020; 51: 3719-3722
        • Altable M.
        • De La Serna J.M.
        Cerebrovascular disease in COVID-19: is there a higher risk of stroke?.
        Brain Behav Immun Health. 2020; 6: 100092
        • Avula A.
        • Nalleballe K.
        • Narula N.
        • Sapozhnikov S.
        • Dandu V.
        • Toom S.
        • Glaser A.
        • Elsayegh D.
        COVID-19 presenting as stroke.
        Brain Behav Immun. 2020; 87: 115-119
        • Haider A.
        • Siddiqa A.
        • Ali N.
        • Dhallu M.
        COVID-19 and the brain: acute encephalitis as a clinical manifestation.
        Cureus. 2020; 12: e10784
        • Libby P.
        • Lüscher T.
        COVID-19 is, in the end, an endothelial disease.
        Eur Heart J. 2020; 41: 3038-3044
        • Siddiqi H.K.
        • Libby P.
        • Ridker P.M.
        COVID-19 - a vascular disease.
        Trends Cardiovasc Med. 2021; 31: 1-5
        • Moore J.B.
        • June C.H.
        Cytokine release syndrome in severe COVID-19.
        Science. 2020; 368: 473-474
        • Leisman D.E.
        • Ronner L.
        • Pinotti R.
        • Taylor M.D.
        • Sinha P.
        • Calfee C.S.
        • Hirayama A.V.
        • Mastroiani F.
        • Turtle C.J.
        • OHarhay M.
        • Legrand M.
        • Deutschmann C.S.
        Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.
        Lancet Respir Med. 2020; 8: 1233-1244
        • van den Pol A.N.
        Viral infection leading to brain dysfunction: more prevalent than appreciated?.
        Neuron. 2009; 64: 17-20
        • Swanson P.A.I.
        • McGavern D.B.
        Viral diseases of the central nervous system.
        Curr Opin Virol. 2015; 11: 44-54
        • Hocke A.C.
        • Becher A.
        • Knepper J.
        • Peter A.
        • Holland G.
        • Tönnies M.
        • Bauer T.T.
        • Schneider P.
        • Neudecker J.
        • Muth D.
        • Wendtner C.M.
        • Rückert J.C.
        • Drosten C.
        • Gruber A.D.
        • Laue M.
        • Suttorp N.
        • Hippenstiel S.
        • Wolff T.
        Emerging human Middle East respiratory syndrome coronavirus causes widespread infection and alveolar damage in human lungs.
        Am J Respir Crit Care Med. 2013; 188: 882-886
        • Paniz-Mondolfi A.
        • Bryce C.
        • Grimes Z.
        • Gordon R.E.
        • Reidy J.
        • Lednicky J.
        • Sordillo E.M.
        • Fowkes M.
        Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
        J Med Virol. 2020; 92: 699-702
        • DeKosky S.T.
        • Kochanek P.M.
        • Valadka A.B.
        • Clark R.
        • Chou S.H.
        • Au A.K.
        • Horvat C.
        • Jha R.M.
        • Mannix R.
        • Wisniewski S.R.
        • Wintermark M.
        • Rowell S.E.
        • Welch R.D.
        • Lewis L.
        • House S.
        • Tanzi R.E.
        • Smith D.R.
        • Vittor A.Y.
        • Denslow N.D.
        • Davis M.D.
        • Glushakova O.Y.
        • Hayes R.L.
        Blood biomarkers for detection of brain injury in COVID-19 patients.
        J Neurotrauma. 2020; 38: 1-43
        • Liotta E.M.
        • Batra A.
        • Clark J.R.
        • Shlobin N.A.
        • Hoffman S.C.
        • Orban Z.S.
        • Koranic I.J.
        Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients.
        Ann Clin Transl Neurol. 2020; 7: 2221-2230
        • Reddy S.T.
        • Garg T.
        • Shah C.
        • Nascimento F.A.
        • Imran R.
        • Kan P.
        • Bowry R.
        • Gonzales N.
        • Barreto A.
        • Kumar A.
        • Volpi J.
        • Misra V.
        • Chiu D.
        • Gadhia R.
        • Savitz S.I.
        Cerebrovascular disease in patients with COVID-19: a review of the literature and case series.
        Case Rep Neurol. 2020; 12: 199-209
        • Ghoush M.S.A.
        • ElBashari M.
        • Alzaabi A.
        • Aboelnaga M.
        COVID-19 vasculitis: a case report with complicated course.
        Am J Med Case Rep. 2020; 8: 428-430
        • Hanafi R.
        • Roger P.-A.
        • Perin B.
        • Kuchcinski G.
        • Deleval N.
        • Dallery F.
        • Michel D.
        • Hacein-Bey L.
        • Pruvo J.-P.
        • Outteryck O.
        • Constans J.-M.
        COVID-19 neurologic complication with CNS vasculitis-like pattern.
        Am J Neuroradiol. 2020; 41: 1384-1387
        • Desforges M.
        • Le Coupanec A.
        • Brison E.
        • Meessen-Pinard M.
        • Talbot P.J.
        Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
        Adv Exp Med Biol. 2014; 807: 75-96
        • Antinone S.E.
        • Smith G.A.
        Retrograde axon transport of herpes simplex virus and Pseudorabies virus: a live-cell comparative analysis.
        J Virol. 2010; 84: 1504-1512
        • Bougakov D.
        • Podell K.
        • Goldberg E.
        Multiple neuroinvasive pathways in COVID-19.
        Mol Neurobiol. 2021; 58: 564-575
        • Lukiw W.J.
        • Pogue A.
        • Hill J.M.
        SARS-CoV-2 infectivity and neurological targets in the brain.
        Cell Mol Neurobiol. 2020; (, [Epub ahead of print] doi:10.1007/s10571-020-00947-7)
        • Buzhdygan T.P.
        • DeOre B.J.
        • Baldwin-Leclair A.
        • Bullock T.A.
        • McGary H.A.
        • Khan J.A.
        • Razmpour R.
        • Hale J.F.
        • Galie P.A.
        • Potula R.
        • Andrews A.M.
        • Ramirez S.H.
        The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood–brain barrier.
        Neurobiol Dis. 2020; 146: 105131
        • Alexopoulos H.
        • Magira E.
        • Bitzogli K.
        • Kafasi N.
        • Vlachoyiannopoulos P.
        • Tzioufas A.
        • Kotanidou A.
        • Dalakas M.C.
        Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: studies in 8 stuporous and comatose patients.
        Neurol Neuroimmunol Neuroinflam. 2020; 7: e893
        • Engelhardt B.
        • Liebner S.
        Novel insights into the development and maintenance of the blood-brain barrier.
        Cell Tissue Res. 2014; 355: 687-699
        • Liebner S.
        • Dijkhuizen R.M.
        • Reiss Y.
        • Plate K.H.
        • Agalliu D.
        • Constantin G.
        Functional morphology of the blood-brain barrier in health and disease.
        Acta Neuropathol. 2018; 135: 311-336
        • Baig A.M.
        • Sanders E.C.
        Potential neuroinvasive pathways of SARS-CoV-2: deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19).
        J Med Virol. 2020; 92: 1845-1857
        • Sisó S.
        • Jeffrey M.
        • González L.
        Sensory circumventricular organs in health and disease.
        Acta Neuropathol. 2010; 120: 689-705
        • Wilhelm I.
        • Nyúl-Tóth Á.
        • Suciu M.
        • Hermenean A.
        • Krizbai I.A.
        Heterogeneity of the blood-brain barrier.
        Tissue Barriers. 2016; 4: e1143544
        • Keyhanian K.
        • Umeton R.P.
        • Mohit B.
        • Davoudi V.
        • Hajighasemi F.
        • Ghasemi M.
        SARS-CoV-2 and nervous system: from pathogenesis to clinical manifestation.
        J Neuroimmunol. 2021; 350: e577436
        • Meinhardt J.
        • Radke J.
        • Dittmayer C.
        • Franz J.
        • Thomas C.
        • Mothes R.
        • et al.
        Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.
        Nat Neurosci. 2021; 24: 168-175
        • De Santis G.
        SARS-CoV-2: a new virus but a familiar inflammation brain pattern.
        Brain Behav Immun. 2020; 87: 95-96
        • Zwijnenburg P.J.
        • van der Poll T.
        • Roord J.J.
        • van Furth A.M.
        Chemotactic factors in cerebrospinal fluid during bacterial meningitis.
        Infect Immun. 2006; 74: 1445-1451
        • Drevets D.A.
        • Leenen P.J.
        Leukocyte-facilitated entry of intracellular pathogens into the central nervous system.
        Microbes Infect. 2000; 2: 1609-1618
        • Pober J.S.
        Endothelial activation: intracellular signaling pathways.
        Arthritis Res. 2002; 4: S109-S116
        • Li Y.C.
        • Bai W.Z.
        • Hashikawa T.
        The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.
        J Med Virol. 2020; 92: 552-555
        • Zhao H.
        • Shen D.
        • Zhou H.
        • Liu J.
        • Chen S.
        Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence?.
        Lancet Neurol. 2020; 19: 383-384
        • Yu S.
        • Yu M.
        Severe acute respiratory syndrome coronavirus 2-induced neurological complication.
        Front Cell Dev Biol. 2020; 8: e605972
        • Hung E.C.
        • Chim S.S.
        • Chan P.K.
        • Tong Y.K.
        • Ng E.K.
        • Chiu R.W.
        • Leung C.B.
        • Sung J.J.
        • Tam J.S.
        • Lo Y.M.
        Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome.
        Clin Chem. 2003; 49: 2108-2109
        • Lau K.K.
        • Yu W.C.
        • Chu C.M.
        • Lau S.T.
        • Sheng B.
        • Yuen K.Y.
        Possible central nervous system infection by SARS coronavirus.
        Emerg Infect Dis. 2004; 10: 342-344
        • Burks J.S.
        • DeVald B.L.
        • Jankovsky L.D.
        • Gerdes J.C.
        Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients.
        Science. 1980; 209: 933-934
        • Pinzon R.T.
        • Wijaya V.O.
        • Buana R.B.
        • Al Jody A.
        • Nunsio P.N.
        Neurologic characteristics in coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.
        Front Neurol. 2020; 11: e565
        • Lechien J.R.
        • Chiesa-Estomba C.M.
        • De Siati D.R.
        • Horoi M.
        • Le Bon S.D.
        • Rodriguez A.
        • Dequanter D.
        • Blecic S.
        • El Afia F.
        • Distinguin L.
        • Chekkoury-Idrissi Y.
        • Hans S.
        • Delgado I.L.
        • Calvo-Henriquez C.
        • Lavigne P.
        • Falanga C.
        • Barillari M.R.
        • Cammaroto G.
        • Khalife M.
        • Leich P.
        • Souchay C.
        • Rossi C.
        • Journe F.
        • Hsieh J.
        • Edjlali M.
        • Carlier R.
        • Ris L.
        • Lovato A.
        • De Filippis C.
        • Coppee F.
        • Fakhry N.
        • Ayad T.
        • Saussez S.
        Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.
        Eur Arch Otorhinolaryngol. 2020; 277: 2251-2261
        • Uygun Ö.
        • Ertaş M.
        • Ekizoğlu E.
        • Bolay H.
        • Özge A.
        • Orhan E.K.
        • Çağatay A.A.
        • Baykan B.
        Headache characteristics in COVID-19 pandemic-a survey study.
        J Headache Pain. 2020; 21: 1-10
        • Bolay H.
        • Gül A.
        • Baykan B.
        COVID-19 is a real headache!.
        Headache. 2020; 60: 1415-1421
        • Hojyo S.
        • Uchida M.
        • Tanaka K.
        • Hasebe R.
        • Tanaka Y.
        • Murakami M.
        • Hirano T.
        How COVID-19 induces cytokine storm with high mortality.
        Inflamm Regen. 2020; 40: e30
        • Kennedy P.G.E.
        Viral encephalitis: causes, differential diagnosis, and management.
        J Neurol Neurosurg Psychiatry. 2004; 75: 10-15
        • Moriguchi T.
        • Harii N.
        • Goto J.
        • Harada D.
        • Sugawara H.
        • Takamino J.
        • Ueno M.
        • Sakata H.
        • Kondo K.
        • Myose N.
        • Nakao A.
        • Takeda M.
        • Haro H.
        • Inoue O.
        • Suzuki-Inoue K.
        • Kubokawa K.
        • Ogihara S.
        • Sasaki T.
        • Kinouchi H.
        • Kojin H.
        • Ito M.
        • Onishi H.
        • Shimizu T.
        • Sasaki Y.
        • Enomoto N.
        • Ishihara H.
        • Furuya S.
        • Yamamoto T.
        • Shimada S.
        A first case of meningitis/encephalitis associated with SARS-coronavirus-2.
        Int J Infect Dis. 2020; 94: 55-58
        • Mondal R.
        • Ganguly U.
        • Deb S.
        • Shome G.
        • Pramanik S.
        • Bandyopadhyay D.
        • Lahiri D.
        Meningoencephalitis associated with COVID-19: a systematic review.
        J Neurovirol. 2021; 27: 12-25
        • Conte G.
        • Avignone S.
        • Carbonara M.
        • Meneri M.
        • Ortolano F.
        • Cinnante C.
        • Triulzi F.
        COVID-19–associated PRES–like encephalopathy with perivascular gadolinium enhancement.
        Am J Neuroradiol. 2020; 41: 2206-2208
        • Vaschetto R.
        • Cena T.
        • Sainaghi P.P.
        • Meneghetti G.
        • Bazzano S.
        • Vecchio D.
        • Pirisi M.
        • Brustia D.
        • Barini M.
        • Cammarota G.
        • Castello L.
        • Della Corte F.
        Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia.
        J Clin Neurosci. 2020; 79: 71-73
        • Dixon L.
        • Coughlan C.
        • Karunaratne K.
        • Gorgoraptis N.
        • Varley J.
        • Husselbee J.
        • Mallon D.
        • Caroll R.
        • Jones B.
        • Boynton C.
        • Pritchard J.
        • Youngstein T.
        • Mason J.
        • Gabriel C.
        Immunosuppression for intracranial vasculitis associated with SARS-CoV-2: therapeutic implications for COVID-19 cerebrovascular pathology.
        J Neurol Neurosurg Psychiatry. 2021; 92: 103-104
        • Kaneko N.
        • Satta S.
        • Komuro Y.
        • Muthukrishnan S.D.
        • Kakarla V.
        • Guo L.
        • An J.
        • Elahi F.
        • Kornblum H.I.
        • Liebeskind D.S.
        • Hsiai T.
        • Hinman J.D.
        Flow-mediated susceptibility and molecular response of cerebral endothelia to SARS-CoV-2 infection.
        Stroke. 2021; 52: 260-270
        • Helms J.
        • Kremer S.
        • Merdji H.
        • Clere-Jehl R.
        • Schenck M.
        • Kummerlen C.
        • Collange O.
        • Boulay C.
        • Fafi-Kremer S.
        • Ohana M.
        • Anheim M.
        • Meziani F.
        Neurologic features in severe SARS-CoV-2 infection.
        N Engl J Med. 2020; 382: 2268-2270
        • Grau A.J.
        • Buggle F.
        • Becher H.
        • Zimmermann E.
        • Spiel M.
        • Fent T.
        • Maiwald M.
        • Werle E.
        • Zorn M.
        • Hengel H.
        • Hacke W.
        Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia.
        Neurology. 1998; 50: 196-203
        • Ye M.
        • Ren Y.
        • Lv T.
        Encephalitis as a clinical manifestation of COVID-19.
        Brain Behav Immun. 2020; 88: 945-946
        • Morassi M.
        • Bagatto D.
        • Cobelli M.
        • D'Agostini S.
        • Gigli G.L.
        • Bnà C.
        • Vogrig A.
        Stroke in patients with SARS-CoV-2 infection: case series.
        J Neurol. 2020; 267: 2185-2192
        • Abou-Ismail M.Y.
        • Diamond A.
        • Kapoor S.
        • Arafah Y.
        • Nayak L.
        The hypercoagulable state in COVID-19: incidence, pathophysiology, and management.
        Thromb Res. 2020; 194: 101-115
        • Varatharaj A.
        • Thomas N.
        • Ellul M.A.
        • Davies N.
        • Pollak T.A.
        • Tenorio E.L.
        • Sultan M.
        • Easton A.
        • Breen G.
        • Zandi M.
        • Coles J.P.
        • Manji H.
        • Al-Shahi Salman R.
        • Menon D.K.
        • Nicholson T.R.
        • Benjamin L.A.
        • Carson A.
        • Smith C.
        • Turner M.R.
        • Solomon T.
        • Kneen R.
        • Pett S.L.
        • Galea I.
        • Thomas R.H.
        • Michael B.D.
        Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study.
        Lancet Psychiatry. 2020; 7: 875-882
        • de Erausquin G.A.
        • Snyder H.
        • Carrillo M.
        • Hosseini A.A.
        • Brugha T.S.
        • Seshadri Sl
        The chronic neuropsychiatric sequelae of COVID-19: the need for a prospective study of viral impact on brain functioning.
        Alzheimer Demen. 2021; 17: 1056-1065
        • Daugherty A.M.
        • Chopra T.
        • Korzeniewski S.J.
        • Levy P.
        COVID-19 as a risk factor for Alzheimer's disease and related dementia: a perspective from Detroit, MI.
        Psychiatry Res. 2020; 294: e113557
        • Raz N.
        • Daugherty A.M.
        Pathways to brain aging and their modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) model - a mini-review.
        Gerontology. 2018; 64: 49-57
        • Ackermann M.
        • Verleden S.E.
        • Kuehnel M.
        • Haverich A.
        • Welte T.
        • Laenger F.
        • Vanstapel A.
        • Werlein C.
        • Stark H.
        • Tzankov A.
        • Li W.W.
        • Li V.W.
        • Mentzer S.J.
        • Jonigk D.
        Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
        N Engl J Med. 2020; 383: 120-128
        • Verma S.
        • Lo Y.
        • Chapagain M.
        • Lum S.
        • Kumar M.
        • Gurjav U.
        • Luo H.
        • Nakatsuka A.
        • Nerurkar V.R.
        West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier.
        Virology. 2009; 385: 425-433
        • Moses A.V.
        • Bloom F.E.
        • Pauza C.D.
        • Nelson J.A.
        Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism.
        Proc Natl Acad Sci U S A. 1993; 90: 10474-10478
        • Coyne C.B.
        • Kim K.S.
        • Bergelson J.M.
        Poliovirus entry into human brain microvascular cells requires receptor-induced activation of SHP-2.
        EMBO J. 2007; 26: 4016-4028
        • Pober J.S.
        • Sessa W.C.
        Evolving functions of endothelial cells in inflammation.
        Nat Rev Immunol. 2007; 7: 803-815
        • Teuwen L.-A.
        • Geldhof V.
        • Pasut A.
        • Carmeliet P.
        COVID-19: the vasculature unleashed.
        Nat Rev Immunol. 2020; 20: 389-391
        • McGonagle D.
        • O'Donnell J.S.
        • Sharif K.
        • Emery P.
        • Bridgewood C.
        Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.
        Lancet Rheumatol. 2020; 2: e437-e445
        • Tian S.
        • Hu W.
        • Niu L.
        • Liu H.
        • Xu H.
        • Xiao S.-Y.
        Pulmonary pathology of early-phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer.
        J Thorac Oncol. 2020; 15: 700-704
        • Bois M.C.
        • Boire N.A.
        • Layman A.J.
        • Aubry M.C.
        • Alexander M.P.
        • Roden A.C.
        • Hagen C.E.
        • Quinton R.A.
        • Larsen C.
        • Erben Y.
        • Majumdar R.
        • Jenkins S.M.
        • Kipp B.R.
        • Lin P.T.
        • Maleszewski J.J.
        COVID-19–associated nonocclusive fibrin microthrombi in the heart.
        Circulation. 2021; 143: 230-243
        • Yamaoka-Tojo M.
        Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19.
        Biomed J. 2020; 43: 399-413
        • Okada H.
        • Yoshida S.
        • Hara A.
        • Ogura S.
        • Tomita H.
        Vascular endothelial injury exacerbates coronavirus disease 2019: the role of endothelial glycocalyx protection.
        Microcirculation. 2020; e12654: 1-7
        • Droesch C.
        • Do M.H.
        • DeSancho M.
        • Lee E.
        • Magro C.
        • Harp J.
        Livedoid and purpuric skin eruptions associated with coagulopathy in severe COVID-19.
        JAMA Dermatol. 2020; 156: 1-3
        • Galván-Casas C.
        • Català A.
        • Carretero-Hernández G.
        • Rodríguez-Jiménez P.F.-N.D.
        • Rodríguez-Villa A.
        • Navarro-Fernández I.
        • Ruiz-Villaverde R.
        • Falkenhain-López D.
        • Llamas Velasco M.
        • García-Gavín J.
        • Baniandrés O.
        • González-Cruz C.
        • Morillas-Lahuerta V.
        • Cubiró X.
        • Figueras-Nart I.
        • Selda-Enriquez G.
        • Romaní J.
        • Fustà-Novell X.
        • Melian-Olivera A.
        • Roncero-Riesco M.
        • Burgos-Blasco P.
        • Sola-Ortigosa J.
        • Feito-Rodriguez M.
        • García-Doval I.
        Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.
        Br J Dermatol. 2020; 183: 71-77
        • Herold T.
        • Jurinovic V.
        • Arnreich C.
        • Lipworth B.J.
        • Hellmuth J.C.
        • von Bergwelt-Baildon M.
        • Klein M.
        • Weinberger T.
        Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.
        J Allergy Clin Immunol. 2020; 146: 128-136
        • Perico L.
        • Benigni A.
        • Casiraghi F.
        • Ng L.F.P.
        • Renia L.
        • Remuzzi G.
        Immunity, endothelial injury and complement-induced coagulopathy in COVID-19.
        Nat Rev Nephrol. 2021; 17: 46-64
        • Jones V.G.
        • Mills M.
        • Suarez D.
        • Hogan C.A.
        • Yeh D.
        • Segal J.B.
        • Nguyen E.L.
        • Barsh G.R.
        • Maskatia S.
        • Mathew R.
        COVID-19 and Kawasaki disease: novel virus and novel case.
        Hosp Pediatr. 2020; 10: 537-540
        • Spence D.J.
        • de Freitas G.R.
        • Pettigrew C.L.
        • Ay H.
        • Liebeskind D.S.
        • Kase C.S.
        • Del Brutto O.H.
        • Hankey G.J.
        • Venketasubramanian N.
        Mechanisms of stroke in COVID-19.
        Cerebrovasc Dis. 2020; 49: 451-458
        • Tang N.
        • Li D.
        • Wang X.
        • Sun Z.
        Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
        J Thromb Haemost. 2020; 18: 844-847
        • Fatehi P.
        • Hesam-Shariati N.
        • Abouzaripour M.
        • Fathi F.
        • Hesam-Shariati M.B.
        Acute ischemic and hemorrhagic stroke and COVID-19: case series.
        SN Compr Clin Med. 2020; : 1-6
        • Valderrama E.V.
        • Humbert K.
        • Lord A.
        • Frontera J.
        • Yaghi S.
        Severe acute respiratory syndrome coronavirus 2 infection and ischemic stroke.
        Stroke. 2020; 51: e124-e127
        • Elkhider H.
        • Ibrahim F.
        • Sharma R.
        • Sheng
        • Sen
        • Jasti M.
        • Lotia M.
        • Kapoor N.
        • Onteddu S.
        • Mueed S.
        • Allam H.
        • Nalleballe K.
        COVID-19 and stroke, a case series and review of literature.
        Brain Behav Immun Health. 2020; 9: e100172
        • Wijeratne T.
        • Crewther S.
        Post-COVID 19 neurological syndrome (PCNS); a novel syndrome with challenges for the global neurology community.
        J Neurol Sci. 2020; 419: e117179
        • Mandal S.
        • Barnett J.
        • Brill S.E.
        • Brown J.S.
        • Denneny E.K.
        • Hare S.S.
        • Heightman M.
        • Hillman T.E.
        • Jacob J.
        • Jarvis H.C.
        • Lipman M.C.I.
        • Naidu S.B.
        • Nair A.
        • Porter J.C.
        • Tomlinson G.S.
        • Hurst J.R.
        “Long-COVID”: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
        Thorax. 2021; 76: 396-398