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Intracranial hemorrhage in critically ill patients hospitalized for COVID-19

  • Islam Fayed
    Affiliations
    MedStar Georgetown University Hospital, Department of Neurosurgery, 3800 Reservoir Road NW, 7PHC, Washington, DC 20007, USA

    MedStar Washington Hospital Center, Department of Neurosurgery, 110 Irving Street NW, Washington, DC 20010, USA
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  • Gnel Pivazyan
    Affiliations
    MedStar Georgetown University Hospital, Department of Neurosurgery, 3800 Reservoir Road NW, 7PHC, Washington, DC 20007, USA

    MedStar Washington Hospital Center, Department of Neurosurgery, 110 Irving Street NW, Washington, DC 20010, USA
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  • Anthony G. Conte
    Affiliations
    MedStar Georgetown University Hospital, Department of Neurosurgery, 3800 Reservoir Road NW, 7PHC, Washington, DC 20007, USA

    MedStar Washington Hospital Center, Department of Neurosurgery, 110 Irving Street NW, Washington, DC 20010, USA
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  • Jason Chang
    Affiliations
    MedStar Washington Hospital Center, Department of Critical Care Medicine, 110 Irving Street NW, Washington, DC 20010, USA
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  • Jeffrey C. Mai
    Correspondence
    Corresponding author at: MedStar Washington Hospital Center, Department of Neurosurgery, 110 Irving Street NW, Washington, DC 20010, USA.
    Affiliations
    MedStar Georgetown University Hospital, Department of Neurosurgery, 3800 Reservoir Road NW, 7PHC, Washington, DC 20007, USA

    MedStar Washington Hospital Center, Department of Neurosurgery, 110 Irving Street NW, Washington, DC 20010, USA
    Search for articles by this author
Published:August 18, 2020DOI:https://doi.org/10.1016/j.jocn.2020.08.026

      Highlights

      • Intracranial hemorrhage occurs in COVID-19 patients with prolonged hospitalization.
      • SARS-CoV-2 binds to the endothelial lining of the cerebral vasculature via ACE-II.
      • Direct endothelial injury, pro-thrombotic states and DIC lead to hemorrhagic events.
      • We advocate heightened vigilance for intracerebral hemorrhage in COVID-19 patients.

      Abstract

      In this study, we report three cases of spontaneous intracranial hemorrhage in patients who were initially hospitalized at our tertiary care center in Washington, DC with symptoms of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed in all three patients, who were critically ill, requiring intubation and ventilatory support. During their protracted hospitalizations, subsequent imaging disclosed intracranial hemorrhages, including intracerebral and subarachnoid hemorrhages, in the context of anticoagulation and coagulopathy. We believe this is related to the tropism of SARS-CoV-2 to the endothelial lining of the cerebral vasculature via their angiotensin-converting enzyme (ACE) II receptors. Given our findings, we advocate heightened vigilance for intracerebral hemorrhage events, and scanning when practicable, in COVID-19 patients which have prolonged ventilatory support and depressed neurologic examinations.

      Keywords

      We report three cases of spontaneous intracranial hemorrhage in patients who were initially hospitalized at our tertiary care center in Washington, DC with symptoms of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed in all three patients, who were critically ill, requiring intubation and ventilatory support. During their protracted hospitalizations, subsequent imaging disclosed intracranial hemorrhages, including intracerebral and subarachnoid hemorrhages, in the context of anticoagulation and coagulopathy.
      Our first patient was a 57-year-old woman with past medical history of hypertension, obesity, sleep apnea, and asthma who presented to our emergency department (ED) with shortness of breath and fever. After testing positive for SARS-CoV-2, she was initially admitted to the floor and subsequently escalated to the intensive care unit (ICU) and intubated for hypoxic respiratory failure. She developed acute renal insufficiency, requiring continuous veno-venous hemofiltration under coverage of a heparin drip. Following two weeks of mechanical ventilation, a computed tomography (CT) scan of the head was performed given persistent encephalopathy, revealing a subacute lobar right frontal intracerebral hemorrhage (ICH) (Fig. 1A). No coagulation or platelet dyscrasias were uncovered. Repeat CT imaging was stable, and following negative PCR testing for SARS-CoV-2, she was able to undergo contrasted magnetic resonance imaging (MRI), which did not disclosed an underlying pathology for the original ICH and revealed interval development of ICH in the left frontal lobe, despite being off heparization at that time (Fig. 1B and C). Interestingly, it also revealed significant inflammation of the sphenoid sinus – a putative mechanism for neuro-invasion by the virus (Fig. 1D). The patient was subsequently discharged to an acute rehabilitation facility one week later.
      Figure thumbnail gr1
      Fig. 1A: Axial computed tomography (CT) of the head demonstrating a 3.5 × 3.4 × 3.2 cm acute intraparenchymal hematoma with inferior frontal midline shift. B,C: Axial magnetic resonance imaging (MRI) gradient echo (GRE) sequence demonstrating stable 3.2 cm right frontal intraparenchymal hematoma (B) with additional 0.6 cm left frontal intraparenchymal hematoma (C). D: Sagittal post-contrast T1 MRI with evidence of inflammation in the sphenoid sinus, a possible conduit for neuro-invasion by the virus. E, F: Axial (E) and coronal (F) non-contrast CT head demonstrating massive subarachnoid hemorrhage distributed throughout the basal cisterns with effacement of normal sulcal-gyri pattern. G,H: Axial (G) and sagittal (H) non-contrast CT head demonstrating a 2.2 × 2.2 cm intraparenchymal hemorrhage with surrounding hypodensity, suspicious for hemorrhagic transformation of a right-sided posterior cerebral artery (PCA) infarction.
      The second patient is a 54-year-old female with past medical history of hypertension, obesity, and bilateral mastectomy in 2016 for BRCA2 mutant breast cancer who presented to our ED with four days of myalgia and fever. After testing positive for SARS-CoV-2, she was discharged to home, but was admitted two days later with dyspnea and hypoxia necessitating mechanical ventilation. She continued to deteriorate, entering vasodilatory shock requiring vasopressors and epoprostenol treatment with prone positioning. She had a transient thrombocytopenia and was placed on a heparin drip for thromboembolic protection. At 24 h following cessation of heparin drip, at one week post-intubation, the patient developed dilated and non-reactive pupils on hourly neurologic checks and CT images of the head disclosed diffuse subarachnoid hemorrhage with intraventricular extension and sulcal effacement (Fig. 1E and F). She progressed to brain death and expired due to asystole four days later (Table 1).
      Table 1Clinical Characteristics of Three COVID+ Patients who Developed Intracranial Hemorrhages.
      Case 1Case 2Case 3
      Age – years575471
      GenderFemaleFemaleMale
      Medical HistoryObesity

      Sleep Apnea

      Asthma
      Hypertension

      Bilateral Mastectomy (BRCA2 mutant breast cancer)
      Hypertension

      Type II Diabetes Mellitus

      Chronic Kidney Disease

      B-Cell Lymphoma (In Remission)
      Relevant MedicationsAspirin 81 mgAspirin 81 mg

      Placebo vs Sarilumab

      Epoprostenol

      Desmopressin
      N/A
      Presenting COVID SymptomsShortness of Breath

      Fever
      Body Aches

      Fever

      Hypoxia
      Shortness of Breath

      Dizziness
      Hospital Stay Prior to ICH – days20820
      Duration of Intubation Prior to ICH – days18815
      Prone Positioning+++
      Other Critical Care NeedsVasopressors

      Continuous Veno-Venous Hemofiltration
      VasopressorsVasopressors
      Anticoagulation (Duration)Heparin drip (6 days)Heparin drip (30 h)N/A
      Symptom Prompting Head ImagingPersistent EncephalopathyFixed and Dilated PupilsPersistent Encephalopathy
      Type and location of ICHRight Frontal Lobar Intracerebral HemorrhageDiffuse Subarachnoid HemorrhageRight PCA distribution infarct

      with hemorrhagic conversion
      Imaging Studies PerformedCT and MRICT and Nuclear Medicine StudyCT
      Laboratory Values – At Presentation/At Time of ICH/Minimum-Maximum
      White Blood Cell Count – per mm310,700/24,800/8800–91,0008300/17,300/5200–18,20010,200/9300/5300–18,600
      Platelet Count – per mm3200,000/181,000/159,00–506,000135,000/123,000/17,000–137,000207,000/354,000/64,000–360,000
      Prothrombin Time – seconds13.2/13.9/13.2–15.713.0/14.5/13.0–14.813.5/20.3/13.2–20.3
      Activated Partial-Thromboplastin Time – seconds33.2/20.8/20.8–40.925.1/48.2/25.1–48.2N/A/57.3/57.3–65.7
      International Normalized Ratio1.0/1.1/1.0–1.21.0/1.1/1.0–1.21.0/1.7/1.0–1.7
      Anti-Xa – IU/mLN/A/N/A/0.23–1.10N/A/0.26/0.97–1.10N/A
      Fibrinogen – mg/dLN/A/638/382–1214630/308/308–788672/1276/672–1276
      D-dimer – mcg/mL1.06/14.08/1.06–18.630.52/13.79/0.52–20.001.44/9.55/1.44–9.88
      OutcomeAcute rehabilitationCerebral circulatory arrest

      confirmed by nuclear medicine study
      Palliative extubation
      ICH: intracranial hemorrhage; CT: computed tomography; MRI: magnetic resonance imaging; PCA: posterior cerebral artery.
      The third patient is a 71-year-old gentleman with past medical history of hypertension, type II diabetes, chronic kidney disease, and B-cell lymphoma in remission who presented to the ED with acute onset shortness of breath and dizziness. After testing positive for SARS-CoV-2, the patient was admitted, progressing from a 15-liter supplement oxygen requirement to intubation, prone positioning, and vasopressor support within 5 days of admission. At two weeks post-intubation, persistent encephalopathy promoted a surveillance head CT, which disclosed a right occipital ICH with surrounding edema suggestive of hemorrhagic conversion of an infarct (Fig. 1G and H). D-dimer and fibrinogen were elevated to 3.2mcg/mL (normal range 0–0.72 mcg/mL) and 1018 mg/dL (normal range 213–536 mg/dL), respectively, indicating a hypercoagulable state. While international normalized ratio (INR) and platelet counts were within normal range prior to the hemorrhage, they subsequently became profoundly hypercoagulable and thrombocytopenic afterwards, suspicious for disseminated intravascular coagulation (DIC). While the ICH remained stable on repeat imaging, the patient ultimately succumbed to multi-system organ failure one week later.
      These cases support the predisposition of COVID-19 patients to the development of intracranial hemorrhage during critical illness. The pathophysiology is unclear, but the tropism of SARS-CoV-2 to the endothelial lining of the cerebral vasculature via their angiotensin-converting enzyme (ACE) II receptors, remains a possibility [
      • Guzik T.J.
      • Mohiddin S.A.
      • Dimarco A.
      • Patel V.
      • Savvatis K.
      • Marelli-Berg F.M.
      • et al.
      COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.
      ,
      • Sharifi-Razavi A.
      • Karimi N.
      • Rouhani N.
      COVID-19 and intracerebral haemorrhage: causative or coincidental?.
      ], and a recent pathology study The Lancet demonstrated the presence of virus particles within endothelial cells and an accumulation of inflammatory cells, leading to endothelial cell death [
      • Varga Z.
      • Flammer A.J.
      • Steiger P.
      • Haberecker M.
      • Andermatt R.
      • Zinkernagel A.S.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ]. Furthermore, a recent Italian review of animal studies suggests a higher neuro-invasive property of SARS-CoV-2 compared to other coronaviruses [
      • Natoli S.
      • Oliveira V.
      • Calabresi P.
      • Maia L.F.
      • Pisani A.
      Does SARS-Cov-2 invade the brain? Translational lessons from animal models.
      ]. Zhou et al were able to detect SARS-CoV-2 RNA in human cerebrospinal fluid, and neurologic sequelae have been observed in an estimated 36% of COVID-19 patients [
      • Roe K.
      Explanation for COVID-19 infection neurological damage and reactivations.
      ,
      • Zhou Z.
      • Kang H.
      • Li S.
      • Zhao X.
      Understanding the neurotropic characteristics of SARS-CoV-2: from neurological manifestations of COVID-19 to potential neurotropic mechanisms.
      ,
      • Tsai S.-T.
      • Lu M.-K.
      • San S.
      • Tsai C.-H.
      The neurologic manifestations of coronavirus disease 2019 pandemic: a systemic review.
      ]. Postmortem brain studies have also shown direct invasion of neurons and glial cells [
      • Md Noh M.S.F.
      COVID-19 and cerebral hemorrhage: proposed mechanisms.
      ,
      • Aghagoli G.
      • Gallo Marin B.
      • Katchur N.J.
      • Chaves-Sell F.
      • Asaad W.F.
      • Murphy S.A.
      Neurological involvement in COVID-19 and potential mechanisms: a review.
      ]. Several studies have suggested a pro-thrombotic state in these patients, possibly related to antiphospholipid antibodies, which may lead to ischemic complications related to occlusion of the cerebral vasculature [
      • Zhang Y.
      • Xiao M.
      • Zhang S.
      • Xia P.
      • Cao W.
      • Jiang W.
      • et al.
      Coagulopathy and antiphospholipid antibodies in patients with Covid-19.
      ,
      • Oxley T.J.
      • Mocco J.
      • Majidi S.
      • Kellner C.P.
      • Shoirah H.
      • Singh I.P.
      • et al.
      Large-vessel stroke as a presenting feature of Covid-19 in the young.
      ,

      Li Y, Li M, Wang M, Zhou Y, Chang J, Xian Y, et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vascular Neurol 2020:svn-2020-000431. https://doi.org/10.1136/svn-2020-000431.

      ,
      • Hernández-Fernández F.
      • Valencia H.S.
      • Barbella-Aponte R.A.
      • Collado-Jiménez R.
      • Ayo-Martín Ó.
      • Barrena C.
      • et al.
      Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description.
      ,
      • Reddy S.T.
      • Garg T.
      • Shah C.
      • Nascimento F.A.
      • Imran R.
      • Kan P.
      • et al.
      Cerebrovascular disease in patients with COVID-19: a review of the literature and case series.
      ,
      • Hanafi R.
      • Roger P.-A.
      • Perin B.
      • Kuchcinski G.
      • Deleval N.
      • Dallery F.
      • et al.
      COVID-19 neurologic complication with CNS vasculitis-like pattern.
      ]. Additionally, numerous reports of ICH in COVID-19 have begun to accumulate in the literature [
      • Li J.
      • Long X.
      • Zhu C.
      • Hu S.
      • Lin Z.
      • Li J.
      • et al.
      A case of COVID-19 pneumonia with cerebral hemorrhage.
      ,
      • Krett J.D.
      • Jewett G.A.E.
      • Elton-Lacasse C.
      • Fonseca K.
      • Hahn C.
      • Au S.
      • et al.
      Hemorrhagic encephalopathy associated with COVID-19.
      ,
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: clinical characteristics from a case series.
      ,
      • García-García S.
      • Cepeda S.
      • Arrese I.
      • Sarabia R.
      Letter: Hemorrhagic conditions affecting the central nervous system in COVID-19 patients.
      ,
      • Dong S.
      • Liu P.
      • Luo Y.
      • Cui Y.
      • Song L.
      • Chen Y.
      Pathophysiology of SARS-CoV-2 infection in patients with intracerebral hemorrhage.
      ]. Collectively, these findings corroborate the possibility of direct cerebrovascular endothelial injury, vascular injury, and DIC leading to cerebral hemorrhagic events, exacerbated by concomitant anticoagulation therapy in two instances.
      The ability to identify and treat these patients is hindered by the strict isolation and precautions mandated by COVID-19 infection. Given our findings, we advocate heightened vigilance for intracerebral hemorrhage events, and scanning when practicable, in COVID-19 patients which have prolonged ventilatory support and depressed neurologic examinations.

      Acknowledgments

      None.

      Statement of ethics

      This study did not require approval by our institution’s Institutional Review Board and did not require patient consent due to the retrospective nature of the analysis.

      Disclosure statement

      The authors certify that this manuscript is a unique submission and is not being considered for publication, in part or in full, with any other source in any medium. Each named author has substantially contributed to conducting the underlying research and drafting this manuscript. Additionally, to the best of our knowledge, the named authors have no conflict of interest, financial or otherwise.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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