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Intracerebral hemorrhage in COVID-19: A narrative review

      Highlights

      • ICH is a rare manifestation with high mortality rate in patients with COVID-19.
      • ICH due to COVID-19 can be explained by the pathophysiology of the disease.
      • ICHs were mainly lobar, even though 52% of the cases had a history of arterial HTN.
      • ICU admission and thromboprophylaxis/ anticoagulation seem related with ICH.

      Abstract

      Coronavirus Disease 19 (COVID-19) pandemic affects the worldwide healthcare system and our understanding of this disease grows rapidly. Although COVID-19 is a mainly respiratory disease, neurological manifestations are not uncommon. The aim of this review is to report on the etiology, clinical profile, location, and outcome of patients with intracerebral hemorrhage (ICH) and COVID-19. This review includes 36 studies examining ICH in the clinical presentation of COVID-19. Overall, 217 cases with intracranial hemorrhage, of which 188 ICHs, were reported. Generally, a low incidence of both primary and secondary ICH was found in 8 studies [106 (0.25%) out of 43,137 hospitalized patients with COVID-19]. Available data showed a median age of 58 years (range: 52–68) and male sex 64%, regarding 36 and 102 patients respectively. Furthermore, 75% of the patients were on prior anticoagulation treatment, 52% had a history of arterial hypertension, and 61% were admitted in intensive care unit. Location of ICH in deep structures/basal ganglia was ascertained in only 7 cases making arterial hypertension an improbable etiopathogenetic mechanism. Mortality was calculated at 52.7%. Disease related pathophysiologic mechanisms support the hypothesis that SARS-CoV2 can cause ICH, however typical ICH risk factors such as anticoagulation treatment, or admission to ICU should also be considered as probable causes. Physicians should strongly suspect the possibility of ICH in individuals with severe COVID-19 admitted to ICU and treated with anticoagulants. It is not clear whether ICH is related directly to COVID-19 or reflects expected comorbidity and/or complications observed in severely ill patients.

      Keywords

      1. Introduction

      1.1 Pathophysiology and transmission of COVID-19

      Coronavirus disease (COVID-19) has become the most difficult challenge for modern medicine, as it has manifested into a worldwide pandemic by infecting over 61 million people as of November 24, 2020. The etiological factor is coronavirus 2 (SARS-CoV2), which infects the host cells by binding through the surface spike protein (mediated by transmembrane serine protease 2) to the human angiotensin converting receptor (ACE 2) [
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      ].
      SARS-CoV2 entry in cells causes cellular injury and finally cellular death. Subsequently, the formation of damage associated molecular patterns (DAMP’s) extracellularly and pathogen associated molecular patterns (PAMP’s) intracellularly leads to DAMP and PAMP recognition by pattern recognition receptors on endothelial cells and alveolar macrophages, thus triggering the induction of proinflammatory cytokine transcription factors [
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      ]. This leads to a pulmonary recruitment of macrophages and dendritic cells which phagocytose SARS-CoV2 and migrate to secondary lymphoid organs further propagating cytokine release. Increased cytokine levels are associated with more severe disease [
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      Transmission of SARS-CoV2 occurs through both direct or indirect means. Human to human transmission via inhalation of mucosalivary droplets which can remain intact, contagious and airborne for at least 3 h is considered the direct mechanism of transmission [
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      ]. Contact with contaminated objects and then with mucous membranes can indirectly transmit the disease. SARS-CoV2 can also be transmitted from asymptomatic carriers without any radiological finding or patients who are in the incubation period [
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      1.2 Clinical characteristics of COVID-19

      COVID-19 disease is characterized by a variety of clinical manifestations ranging from asymptomatic state to Acute Respiratory Distress Syndrome (ARDS) and multiorgan failure, but primary involves the respiratory system. Initial symptoms typically include fever, dry cough, sore throat, headache, fatigue, myalgia and shortness of breath [
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      ]. Confusion, diarrhea, nausea and vomiting, rhinorrhea and skin rash, as well as conjunctivitis have also been reported in COVID-19 [
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      ]. Anosmia and dysgeusia are the most common early neurological symptoms of COVID-19 (occurring to up to 80% of patients) [
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      ], whilst encephalopathy is common in critically ill patients [
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      ]. Ischemic and hemorrhagic strokes have also been reported and must be taken into consideration when assessing COVID-19 patients with known vascular risk factors [
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      ]. Other neurological manifestations include Guillain-Barré syndrome and its variants, meningoencephalitis, acute disseminated encephalomyelitis, acute hemorrhagic necrotizing encephalopathy [
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      ], generalised myoclonus, ataxia [
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      ], posterior reversible encephalopathy syndrome, and seizures [
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      Abnormal coagulation parameters have also been observed and are associated with poor prognosis [
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      ]. Additionally, SARS-CoV2 can cause liver dysfunction, acute kidney failure, acute myocarditis, heart failure and shock [
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      Extra-respiratory manifestations of COVID-19.
      ]. In patients who demonstrate an extreme rise in cytokines by the end of the first week, the disease can progress to pneumonia, ARDS, multisystem failure, and finally death [
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      The immune system and COVID-19: Friend or foe?.
      ].

      1.3 Intracerebral hemorrhage in patients with COVID-19

      Intracerebral hemorrhage (ICH) is a very rare but well documented complication of COVID-19. Primary ICH could occur in the absence or presence of known risk factors, such as arterial hypertension (HTN) or anticoagulation therapy (pre-treatment of unrelated disease or COVID-19 thromboprophylaxis). ICH may also be secondary to hemorrhagic transformation of an acute ischemic stroke or to complications of revascularization procedures; cerebral sinus thrombosis can also cause brain hemorrhage. Symptoms are usually focal, depending on the affected cerebral region but can also be non-specific. Patients with ICH typically present with severe headache, hemiparesis, eye deviation and impaired levels of consciousness. Brain imaging such as a rapid computed tomography (CT) is mandatory and must be performed urgently in order to distinguish between ICH and ischemic stroke [

      Rordorf G, McDonald C, Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis. UptoDate. 2020. Available at: https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-pathogenesis-clinical-features-and-diagnosis. Accessed November 21, 2020.

      ]. CT angiography is a highly specific test and is suitable for bleeding source detection. Other options include brain magnetic resonance imaging and angiography [
      • van Asch C.J.
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      ]. Treatment usually involves hemodynamic and neurological stabilization, management of the underlying conditions and, in selected cases, neurosurgical intervention [
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      ].

      2. Methodology

      Pubmed and Google Scholar were used as search tools to identify relevant studies and articles, with the last search being performed on November 20th 2020. Keywords include: “COVID-19”, “Intracerebral”, “Cerebral” and “Hemorrhage”. Inclusion criteria parameters include: All article types written in English language and published in the last year that examine COVID-19 in combination with ICH. Articles excluded from the review were not written in English language and/or did not provide a full-text publication. Our initial search yielded 2365 search results out of which 36 original studies met our inclusion criteria.
      The aim of this narrative review is to report on the etiology, clinical profile, location, and outcome of patients with ICH and COVID-19.

      3. Results

      Thirty-six original studies, case series and reports, reported a total of 217 cases with intracranial hemorrhage, of which 188 were ICHs (Table 1) [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,
      • Shahjouei S.
      • Naderi S.
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      • Khan A.
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      • Farahmand G.
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      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
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      • Barbella-Aponte R.A.
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      Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description.
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      Acute cerebrovascular events in hospitalized COVID-19 patients.
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      Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.
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      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Behzadnia H.
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      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,

      Varatharaj A, Thomas N, Ellul MA, Davies N, Pollak TA, Tenorio EL ,et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study [published correction appears in Lancet Psychiatry. 2020 Jul 14;:]. Lancet Psychiatry. 2020;7(10):875-882.

      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
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      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
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      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
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      • Zhao Q.
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      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
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      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ]. However, in some reports intracranial hemorrhage was used as a broader term co-reporting ICH with other types of brain hemorrhage (subarachnoid hemorrhage (SAH), primary intraventricular, subdural hemorrhage).
      Table 1Reviewed studies and findings (n = 36).
      n = number, ICH: Intracerebral Hemorrhage, SAH: Subarachnoid hemorrhage, SD: Standard Deviation, HTN: Hypertension, HT: Hemorrhagic Transformation, NR: Not Reported, IV: Intravenous, UFH: Unfractionated Heparin, LMWH: Low Molecular Weight Heparin, ECMO: Extracorporeal Membrane Oxygenation.
      StudyNumber of intracranial hemorrhages/total number of cases with COVID-19 (n of ICH)Sex (male) nAge in yearsHistory of HTN nICU admission prior to hemorrhageAnticoagulation therapy at the time of ICH nHemorrhage location nEtiology of hemorrhageDays from COVID-19 to stroke diagnosis Median (range)Other Findings
      Dogra et al.

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      33/3824 (33 ICH)26Median (range): 62 (37 – 83)16NR22 (15 UFH, 3 on UFH + LMWH, 3 UFH + argatroban, 1 enoxaparin) 3 (type of drug NR) + 2 long term (warfarin and dabigatran)NR7 Primary ICH, 26 Secondary to HT of ischemic stroke17 (8–23)Long-term treatment prior to ICH: 7 on aspirin, 2 aspirin + clopidogrel, 1 on cilostazol, 1 clopidogrel ICH score median: 2

      (range: 1–2)Mortality: 42.4%

      (14/33)
      Siegler et al.

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      28/14,483 (20 ICH)1818NRNR13 supratentorial ICHs

      7 infratentorial ICHs

      8 other types of intracranial hemorrhage
      Primary ICHs3,5 (1 – 7)ICH score median: 3 (range: 1–3) NIHSS score median: 22

      (7 – 25)Mortality:16/28

      (58,3%)
      Shahjouei et al
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      27 / 17,799 (25 ICH)19Mean (SD)

      62,5 (15.3)
      NRNRNRICHs NR, 2 SAHPrimary ICHs1 (0–5)NIHSS score median: 13 (8 – 17) ICH score median: 3

      (2 – 4)
      Kvernland et al.

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      19/4071 (16 ICH)15Median (range): 60 (51–63)81617 (13 heparin, 2 enoxaparin, 2 long-term warfarin)6 lobar intraparenchymal (IPH) ICHs

      4 multifocal cortical, 1 multifocal IPH, 1 subcortical, 2 cortical, 2 cerebellar

      3 SAH
      Primary ICHsNRMortality: 11/19 (57.9%) at follow-up

      15 with HT of ischemic stroke were excluded from this study

      In 1 patient heparin was changed to argatroban.
      Hernández-Fernández et al.
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      5 ICH/16834Mean (SD): 62,6 (7.2)433 (type NR)3 lobar ICHs (1 left frontal,1 left frontal with SAH expansion, 1 left temporal)

      1 basal ganglia ICH

      1 focal cortico-subcortical ICH with SAH involvement
      Primary ICHsNRMortality: 2/5
      Rothstein et al.
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      8/ 844 (5 ICH)4Mean (SD)57

      (7.0)
      667 (type NR}5 lobar ICHs

      3 SAH
      Primary ICHs25 (17–29)4/7 treated with anticoagulants on simultaneous antiplatelet drugs

      6/8 patients died in-hospital
      Li et al.
      • Li Y.
      • Li M.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.
      1 ICH/ 219NR601NRNRNRPrimary ICHs10Died 13 days after ICH
      Ling Mao et al.
      • Mao L.
      • Jin H.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      1 ICH/ 214NRNRNRNRNRNRPrimary ICHsNRCause of death: respiratory failure
      Behzandia et al.
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      23 ICH11Mean (SD)69.4

      (9.8)
      88NR16 lobar ICHs

      7 non-lobar ICHs
      Primary ICHsNR
      Nawabi et al.

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      18 (6 ICH)9Median (range): 49,5 (39.5 – 62.8)1088 (type NR)6 ICHs (4 lobar, 1 deep, 1 infratentorial)

      2 primary intraventricular

      9 SAH

      1 subdural hematoma
      Primary ICHs1.5 (0 – 3)1 case, ICH was diagnosed as a first manifestation of COVID-19.

      1 patient on antiplatelets
      Varathatraj et al.

      Varatharaj A, Thomas N, Ellul MA, Davies N, Pollak TA, Tenorio EL ,et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study [published correction appears in Lancet Psychiatry. 2020 Jul 14;:]. Lancet Psychiatry. 2020;7(10):875-882.

      9 ICHNRNRNRNRNRNRPrimary ICHsNR
      Argiro et al.

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      6 ICH3Median (range)

      64,5 (58.75 – 75)
      NR45 - LMWH6 lobar ICHs (4 parietal, 1 temporal

      1 parieto-occipital and temporal)
      Secondary to Cerebral Vein ThrombosisNR
      Benger et al.
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      5 ICH3Median (range)52

      (45,5 – 59)
      445 (2 LMWH, 2 IV heparin, 1 warfarin)3 lobar ICHs, 1 multi-lobar ICH

      1 basal ganglia ICH
      Primary ICHs32 (14–38)Patients with HTN developed lobar and multilobar ICHs whereas the patient with no history of HTN developed basal ganglia hemorrhage
      Usman et al.
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      4 (3 ICH)3Mean (range)53.7

      (50,5–58,25)
      244 (3 UFH, 1 UFH + argatroban)3 lobar ICHs (1 frontal with SAH expansion, 1 frontal-temporal, 1 temporal with intraventricular expansion)

      1 SAH
      Primary ICH5,5 (3 – 18) from ECMO administrationAll 4 on ECMO.

      All 3 patients with ICHs died.
      Goncalves et al.
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      3 ICH156, 40s, 60s033 (2 enoxaparin, 1 UFH)1 cerebellar

      1 multifocal (frontal and occipital lobes, thalamus)

      1 multifocal (basal ganglia, frontal & occipital lobes)
      2 Primary

      1 due to cerebral vein thrombosis
      15 (15, 16, 15)Mortality: 3/3
      Bihlmaier et al.
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      3 ICH2Medium age (56.6)23NR3 multifocalPrimary ICHNR3 patients on ECMO and 1 on long-term acetylsalicylic acid.

      Mortality: 3/3
      Fayed et al.
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      2 ICH157, 71221 - heparin, 1 NR2 lobar ICHs(1 frontal, 1 occipital)Primary ICHs201/2 patients died, following complications of ICH (cerebral circulatory arrest)
      Morassi et al.
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      2 ICH257 (both cases)121 - enoxaparin2 lobar ICHs (1 Bilateral, 1 Frontal extending to ventricles)Primary ICHs14 & 17One patient only on dual antiplatelet therapy

      Both died on the same day of ICH diagnosis
      Ghani et al.
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      2 ICH159 (both cases)NR22 (1 IV UFH and 1 apixaban switched to enoxaparin)Locations NR (1 with SAH expansion, and 1 intraventricular expansion)Primary ICHsNR
      Agarwal et al.
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      2 ICH256, 721NRNR1 pontine with intraventricular expansion

      1 multifocal
      Primary ICH0 & NRMortality: 1/2
      Sharifi-Razavi et al.

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

      1 ICHMale79NRNRNR1 right hemisphere, accompanied by intraventricular and subarachnoid hemorrhagePrimary ICH3Patient admitted for ICH and later confirmed COVID-19 infection, though mild symptoms of infection were already present
      Bao et al.
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      1 ICHMale38NR1NRLobar ICH extending to basal ganglia.Primary ICH0The diagnosis of COVID-19 was made 7 days after admission with positive PCR test results; subsequent PCR tests were found negative. No COVID-19 symptoms prior admission
      Motoie et al.
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      1 ICHmale50NR11 - IV UFHMultifocalSecondary ICH to HT of an ischemic stroke10Patient on ECMO.

      Patient in hypercoagulable state prior to ICH. The patient died 8 days after ICH onset.
      Al – Olama et al.
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      1 ICHMale36NR0NR1 lobar ICH (frontal with subdural extension)Secondary ICH to COVID-19 encephalitis6Radiologically ICH was attributed to viral encephalitis
      Kim et al.
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      1 ICHFemale5300NR1 basal ganglia ICH (external capsule and putamen with intraventricular expansion)Primary ICH5Patient was positive for COVID-19 but was asymptomatic until the development of ICH.

      30 days after admission ICH symptoms started improving
      Khattar et al.
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      1 ICHMale42111 - IV heparinmulti-loculated centered in the lentiform nucleusPossibly secondary due to HT of ischemic stroke29ICH was diagnosed 8 days after IV heparin was first administered due to hypercoagulable state.
      Thu et al.
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      1 ICHMale72NR10Lobar ICH (olfactory gyrus)Primary ICHNR
      Gogia et al.

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      1 ICHMale75111 - Enoxaparin/ also on aspirin and clopidogrelMultifocalPrimary ICH17 days post admission.Clinical course was complicated by herniation due to ICH and patient deceased on the same day of ICH diagnosis.
      Daci et al.
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      1 ICHFemale60s000Bilateral basal ganglia ICH with effacement of lateral ventriculesPrimary ICH2Patient died 13 days after COVID-19 was diagnosed.
      Haddadi et al.
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      1 ICHFemale54100Bilateral basal ganglia ICHPrimary ICH5
      Flores et al.

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      1 ICHMale40100Midbrain and Pons with intraventricular extensionPrimary ICHNR
      Fraiman et al.

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      1 ICHFemale38NR0NRFrontal lobePrimary ICH0Prior MRI showed microbleeds.
      Rajdev et al.

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      1 ICHMale62111 - HeparinNRPossibly secondary due to HT of ischemic stroke.12Patient expired after 27 days of hospitalization
      Hussain et al.
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      1 ICHFemale69NR11 - LMWHNRPrimary ICH24Patient also had aortic vavle endocarditis

      Patient expired 18 days after admission
      Krett et al.

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      1 ICHMale6911NRMultifocalSecondary to encephalopathy17Patient gradually recovered.
      Dixon et al.
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      1 ICHFemale59NR1NRLobar (occipital lobe and later brain stem and amygdalae)Secondary to acute necrotizing encephalopathy10History of transfusion dependent aplastic anemia
      a n = number, ICH: Intracerebral Hemorrhage, SAH: Subarachnoid hemorrhage, SD: Standard Deviation, HTN: Hypertension, HT: Hemorrhagic Transformation, NR: Not Reported, IV: Intravenous, UFH: Unfractionated Heparin, LMWH: Low Molecular Weight Heparin, ECMO: Extracorporeal Membrane Oxygenation.

      3.1 Incidence

      Data from 8 studies [

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,
      • Mao L.
      • Jin H.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ] including 43,137 hospitalized patients with COVID-19 reported a total number of 122 (0.28%) cases of intracranial hemorrhage, of which 106 (0.25%) were ICHs. Of the 106 reported ICH cases, 80 (75.5%) were considered primary, whilst the remaining 26 were all secondary to hemorrhagic transformation of ischemic stroke. The remaining 16 cases developed other type of intracranial hemorrhage (8 were SAH and 8 could not be identified).

      3.2 Age and sex

      Four studies [
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ] reported 63 hospitalized patients with intracranial hemorrhage with a mean age that ranged from 57 (±7.0) to 69.4 (±9.8) years; a median age that ranged from 49.5 (range: 39.5 – 62.8) to 62 (range: 37 – 83) was reported in 3 studies regarding 70 patients [

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ]. A median age of 58 years (range: 52–68) was calculated in 36 cases of ICH regarding 23 studies [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,
      • Li Y.
      • Li M.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ].
      Male sex was reported in 134 (65%) out of 206 patients with intracranial hemorrhages, [
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ] and 65 (64%) out of 102 patients with ICH [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ].

      3.3 History of arterial hypertension and prior use of anticoagulants

      History of arterial HTN was reported in 89 (54%) out of 164 patients with intracranial hemorrhage, [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,
      • Li Y.
      • Li M.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.
      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ] and in 45 (52%) out of 87 patients with ICH [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Li Y.
      • Li M.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ].
      Anticoagulation prior to onset of brain hemorrhage was administered in 88 (75%) out of the 118 patients with intracranial hemorrhage [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ], and 54 (75%) of the 72 patients with ICH [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ]. The type of anticoagulation treatment was reported in 67 cases with intracranial hemorrhages; in 62 of them anticoagulation treatment was initiated in-hospital (39 received unfractionated heparin (UFH), 16 low molecular weight heparin (LMWH), 4 heparin & argatroban, 3 heparin switched to LWMH), and 5 have been on long term anticoagulant treatment (3 were receiving warfarin, and 2 warfarin/dabigatran) [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ].

      3.4 Intensive care unit admission prior to intracranial hemorrhage

      ICU admission prior to brain hemorrhage was reported in 73 (64%) of the 115 patients who subsequently developed intracranial hemorrhage, [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ] and 42 (61%) of the 69 who subsequently developed ICH [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ].

      3.5 Time from COVID-19 symptoms to diagnosis of hemorrhage

      Median time from COVID-19 symptoms to diagnosis of brain hemorrhage ranged from 1 to 32 days amongst 6 reviewed studies [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ].

      3.6 Etiology and location of ICH

      Out of 188 ICHs, 149 (79%) were primary, [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,
      • Kim C.
      • Kwak Y.
      • Hwang J.
      • Eun M.Y.
      Spontaneous intracerebral hemorrhage in a patient with asymptomatic 2019 novel coronavirus disease.
      ,
      • Hussain A.
      • Roberts N.
      • Oo A.
      Prosthetic aortic valve endocarditis complicated by COVID-19 and hemorrhage.
      ,

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,
      • Li Y.
      • Li M.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study.
      ,
      • Mao L.
      • Jin H.
      • Wang M.
      • Hu Y.
      • Chen S.
      • He Q.
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,

      Varatharaj A, Thomas N, Ellul MA, Davies N, Pollak TA, Tenorio EL ,et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study [published correction appears in Lancet Psychiatry. 2020 Jul 14;:]. Lancet Psychiatry. 2020;7(10):875-882.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
      • Bnà C.
      • et al.
      Stroke in patients with SARS-CoV-2 infection: case series.
      ,
      • Ghani M.U.
      • Kumar M.
      • Ghani U.
      • Sonia F.
      • Abbas S.A.
      Intracranial hemorrhage complicating anticoagulant prophylactic therapy in three hospitalized COVID-19 patients.
      ,
      • Agarwal A.
      • Vishnu V.Y.
      • Vibha D.
      • et al.
      Intracerebral hemorrhage and SARS-CoV-2: association or causation.
      ,

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

      ,
      • Bao Y.
      • Lin S.Y.
      • Cheng Z.H.
      • Xia J.
      • Sun Y.P.
      • Zhao Q.
      • et al.
      Clinical features of COVID-19 in a young man with massive cerebral hemorrhage-case report [published online ahead of print, 2020 May 23]. SN Compr.
      ,
      • Thu S.S.
      • Matin N.
      • Levine S.R.
      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
      Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019.
      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ] including those with or without known risk factors such as arterial HTN, prior use of anticoagulants or extracorporeal membrane oxygenation (ECMO); 29 ICHs were secondary to hemorrhagic transformation of ischemic stroke, [

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,
      • Motoie R.
      • Akai M.
      • Kitahara T.
      • Imamura H.
      • Tanabe T.
      • Sarazawa K.
      • et al.
      Coronavirus disease 2019 complicated by multiple simultaneous intracerebral hemorrhages.
      ,
      • Khattar N.K.
      • Sharma M.
      • McCallum A.P.
      • Oxford B.G.
      • Zeb H.
      • Suliman S.A.
      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,

      Rajdev K, Lahan S, Klein K, Piquette CA, Thi M. Acute Ischemic and Hemorrhagic Stroke in COVID-19: Mounting Evidence. Cureus. 2020;12(8):e10157. Published 2020 Aug 31.

      ] 7 to cerebral vein thrombosis, [

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ] and 3 to encephalitis/encephalopathy [
      • Al-Olama M.
      • Rashid A.
      • Garozzo D.
      COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.
      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ].
      Location of ICH was reported in 114 cases; 64 (56%) were located at lobar regions, 7 at deep/basal-ganglia, 13 supratentorial (not specified in detail), 13 infratentorial (1 midbrain & pons, 1 pons, 3 cerebellar, 8 not specified in detail), 7 non-lobar (not specified in detail) and 10 were reported as multifocal [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ,
      • Behzadnia H.
      • Omrani S.N.
      • Nozari-Golsefid H.
      • Moslemi S.
      • Alijani B.
      • Reyhanian Z.
      • et al.
      Ischemic stroke and intracerebral hemorrhage in patients with COVID-19.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ,

      Krett JD, Jewett GAE, Elton-Lacasse C, et al. Hemorrhagic encephalopathy associated with COVID-19 [published online ahead of print, 2020 Jul 14]. J Neuroimmunol. 2020;346:577326.

      ,
      • Dixon L.
      • Varley J.
      • Gontsarova A.
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ,

      Argirò R, Cirelli C, Sgreccia A, Del Sette B, Da Ros V. Cerebral hemorrhage related to vein thrombosis in Covid-19 patients in different Italian hospitals: View point for clinical and imaging implications [published online ahead of print, 2020 Jul 10]. J Neurol Sci. 2020;416:117023.

      ,
      • Usman A.A.
      • Han J.
      • Acker A.
      • Olia S.E.
      • BermudezC Cucchiara B
      • et al.
      A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19.
      ,
      • Gonçalves B.
      • Righy C.
      • Kurtz P.
      Thrombotic and hemorrhagic neurological complications in critically Ill COVID-19 patients.
      ,
      • Bihlmaier K.
      • Coras R.
      • Willam C.
      • et al.
      Disseminated multifocal intracerebral bleeding events in three coronavirus disease 2019 patients on extracorporeal membrane oxygenation as rescue therapy.
      ,
      • Fayed I.
      • Pivazyan G.
      • Conte A.G.
      • Chang J.
      • Mai J.C.
      Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.
      ,
      • Morassi M.
      • Bagatto D.
      • Cobelli M.
      • D'Agostini S.
      • Gigli G.L.
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      ,

      Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect. 2020;35:100669. Published 2020 Mar 27.

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      ,
      • Kim C.
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      ,
      • Khattar N.K.
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      • et al.
      Intracranial hemorrhage in a young COVID-19 patient.
      ,
      • Thu S.S.
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      Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection.
      ,

      Gogia B, Fang X, Rai P. Intracranial Hemorrhage in a Patient With COVID-19: Possible Explanations and Considerations. Cureus. 2020;12(8):e10159. Published 2020 Aug 31.

      ,
      • Daci R.
      • Kennelly M.
      • Ferris A.
      • Azeem M.U.
      • Johnson M.D.
      • Hamzei-Sichani F.
      • et al.
      Bilateral basal ganglia hemorrhage in a patient with confirmed COVID-19.
      ,
      • Haddadi K.
      • Ghasemian R.
      • Shafizad M.
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      ,

      Flores G, Kumar JI, Pressman E, Sack J, Alikhani P. Spontaneous Brainstem Hemorrhagic Stroke in the Setting of Novel Coronavirus Disease 2019 - A Case Report. Cureus. 2020;12(10):e10809. Published 2020 Oct 5.

      ,

      Fraiman P, Freire M, Moreira-Neto M, Godeiro-Junior C. Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?. eNeurologicalSci. 2020;21:100274.

      ].

      3.7 Mortality

      Available data from 5 studies with known in-hospital mortality in patients with intracranial hemorrhage, showed that 49 (52.7%) out of 93 patients deceased [

      Dogra S, Jain R, Cao M, Bilaloglu S, Zagzag, D, Hochman, et al. Hemorrhagic stroke and anticoagulation in COVID-19. J Stroke Cerebrovasc Dis. 2020;29(8):104984.

      ,

      Siegler JE, Cardona P, Arenillas JF, Talavera B, Guillen AN, Chavarría-Miranda A ,et al. Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19 Multinational Registry [published online ahead of print, 2020 Sep 30]. Int J Stroke. 2020;1747493020959216.

      ,

      Kvernland A, Kumar A, Yaghi S, Raz E, Frontera J, Lewis A, et al. Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System [published online ahead of print, 2020 Aug 24]. Neurocrit Care. 2020;1-12.

      ,
      • Hernández-Fernández F.
      • Sandoval Valencia H.
      • 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.
      ,
      • Rothstein A.
      • Oldridge O.
      • Schwennesen H.
      • Do D.
      • Cucchiara B.L.
      Acute cerebrovascular events in hospitalized COVID-19 patients.
      ].

      4. Discussion

      ICH is an infrequent but life-threatening complication of COVID-19. In our current literature review, incidence ranged from 0.14% to 0.86% in hospitalised patients with COVID-19. This rate is clearly higher than the worldwide incidence of ICH which is 24,6/100.000 person-years or 0,0246% per person-year [
      • van Asch C.J.
      • Luitse M.J.
      • Rinkel G.J.
      • van der Tweel I.
      • Algra A.
      • Klijn C.J.
      Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.
      ] Even though COVID-19 equally affects both genders, European studies have shown a 3-fold to 4-fold higher incidence of ICU admission in male patients [
      • Gebhard C.
      • Regitz-Zagrosek V.
      • Neuhauser H.K.
      • Morgan R.
      • Klein S.L.
      Impact of sex and gender on COVID-19 outcomes in Europe.
      ]. The fact that 61% of ICH cases were developed in ICU care, may explain the predominance of males.

      4.1 Potential mechanisms of SARS-CoV-2 mediated cerebrovascular injury

      A proposed mechanism of ICH is through a virus related direct and indirect endothelial injury. The virus can directly invade host’s cells (in this case endothelial cells) via ACE2 receptor connection, causing cellular death. The indirect mechanism involves systemic factors such as inflammatory cytokine production, prothrombotic factors, activation of coagulation cascades, and complement-mediated microvascular thrombosis [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ]. This thrombotic state has the potential of inducing ICH [
      • Román G.C.
      • Spencer P.S.
      • Reis J.
      • Buguet A.
      • Faris M.
      • Katrak S.M.
      • et al.
      The neurology of COVID-19 revisited: a proposal from the environmental neurology specialty group of the world federation of neurology to implement international neurological registries.
      ]. Finally, dysfunction of the blood–brain-barrier via tight junction complex disruption will occur leading to intracerebral hemorrhage [

      P.T. Ronaldson, T.P. Davis Mechanisms of endothelial injury and blood–brain barrier dysfunction in stroke. InPrimer on Cerebrovascular Diseases, Academic Press. 2017:220-226.

      ].

      4.2 Risk factors for intracerebral hemorrhage regardless of COVID-19 infection

      The majority of patients with COVID-19 who developed ICH, had one or more risk factors such as arterial HTN, anticoagulation therapy or admission to the ICU due to severe disease. Acute spontaneous ICH is a common cause of critical illness and death among patients admitted to the ICU (regardless of COVID-19), making admission to the ICU a clearly important risk marker for the development of ICH [

      Zhou YT, Tong DM, Wang SD, Ye S, Xu BW, Yang CX. Acute spontaneous intracerebral hemorrhage and traumatic brain injury are the most common causes of critical illness in the ICU and have high early mortality. BMC Neurol. 2018;18(1):127. Published 2018 Aug 27.

      ]. Furthermore, SARS-CoV-2 can cause thrombotic events by both enhancing coagulation and weakening anticoagulation/fibrinolysis pathways [

      Haimei MA. Pathogenesis and Treatment Strategies of COVID-19-Related Hypercoagulant and Thrombotic Complications. Clin Appl Thromb Hemost. 2020;26:1076029620944497.

      ]. Prothrombotic mechanisms have also been implied in the etiopathogenesis of ischemic strokes and are also observed in such patients; [

      Haimei MA. Pathogenesis and Treatment Strategies of COVID-19-Related Hypercoagulant and Thrombotic Complications. Clin Appl Thromb Hemost. 2020;26:1076029620944497.

      ] with incidence ranging from 0,2% [

      Katsanos AH, Palaiodimou L, Zand R, et al. The Impact of SARS‐CoV‐2 on Stroke Epidemiology and Care: A Meta‐analysis. Ann Neurol. Accepted Author Manuscript 2020.

      ] to 1,4% [
      • Nannoni S.
      • de Groot R.
      • Bell S.
      • Markus H.S.
      Stroke in COVID-19: a systematic review and meta-analysis.
      ]. Use of anticoagulants in acute ischemic stroke increases the risk of hemorrhagic transformation, which in our review was observed in 29 out of 188 ICHs.
      The hypercoagulable state of SARS-CoV-2 combined with the high risk of thrombotic complications in critically ill patients admitted to ICU [
      • Klok F.A.
      • Kruip M.J.H.A.
      • van der Meer N.J.M.
      • Arbous M.S.
      • Gommers D.
      • Kant K.M.
      • et al.
      Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.
      ] makes pharmacological thromboprophylaxis or anticoagulation imperative in such cases; [

      Ma A, Kase CS, Shoamanesh A, Abdalkader M, Pikula A, Sathya A ,et al. Stroke and Thromboprophylaxis in the Era of COVID-19 [published online ahead of print, 2020 Oct 9]. J Stroke Cerebrovasc Dis. 2020;30(1):105392.

      ] mainly with the use of unfractionated heparin, LMWH, or fondaparinux; [

      Ejaz A, Ahmed MM, Tasleem A, Rafay Khan Niazi M, Ahsraf MF, Ahmad I ,et al. Thromboprophylaxis in Intensive Care Unit Patients: A Literature Review. Cureus. 2018;10(9):e3341.

      ] furthermore, anticoagulation therapy appears to be independently associated with ICH [

      Melmed KR, Cao M, Dogra S, Zhang R, Yaghi S, Lewis ,et al. Risk factors for intracerebral hemorrhage in patients with COVID-19 [published online ahead of print, 2020 Sep 24]. J Thromb Thrombolysis. 2020;1-8.

      ]. Lastly, ECMO, which can be applied in severe refractory COVID-19 pneumonia, may be a contributing factor to the development of ICH [

      Melmed KR, Cao M, Dogra S, Zhang R, Yaghi S, Lewis ,et al. Risk factors for intracerebral hemorrhage in patients with COVID-19 [published online ahead of print, 2020 Sep 24]. J Thromb Thrombolysis. 2020;1-8.

      ,
      • Morotti Andrea
      • Goldstein Joshua N.
      Anticoagulant-associated intracerebral hemorrhage.
      ].
      Arterial HTN can cause deep perforator arteriopathy/ hypertensive arteriolosclerosis, and is the most common cause of primary ICH located in deep brain structures [
      • Ikram M.A.
      • Wieberdink R.G.
      • Koudstaal P.J.
      International epidemiology of intracerebral hemorrhage.
      ,
      • Fisher C.M.
      Pathological observations in hypertensive cerebral hemorrhage.
      ]. In our review, arterial HTN does not appear to be the main cause of ICH as only 7 out of 114 hemorrhages were located in deep brain structures indicating etiopathogenetic mechanisms other than arterial HTN, at least for the majority of cases.
      Other risk factors for ICH should be accounted for, but were not reported by the studies that we reviewed. For instance, brain hemorrhage in COVID-19 has been associated with an unusual pattern of cerebral microbleeds in critically ill patients [

      Fitsiori A, Pugin D, Thieffry C, Lalive P, Vargas MI. COVID-19 is Associated with an Unusual Pattern of Brain Microbleeds in Critically Ill Patients. J Neuroimaging. 2020;30(5):593-597. ] [Gupta NA, Lien C, Iv M. Critical illness-associated cerebral microbleeds in severe COVID-19 infection. Clin Imaging. 2020;68:239-241.

      ,
      • Vattoth S.
      • Abdelhady M.
      • Alsoub H.
      • Own A.
      • Elsotouhy A.
      Critical illness-associated cerebral microbleeds in COVID-19.
      ,
      • Cannac O.
      • Martinez-Almoyna L.
      • Hraiech S.
      Critical illness-associated cerebral microbleeds in COVID-19 acute respiratory distress syndrome.
      ,
      • Wang S.
      • Lv Y.
      • Zheng X.
      • Qiu J.
      • Chen H.S.
      The impact of cerebral microbleeds on intracerebral hemorrhage and poor functional outcome of acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis.
      ]. Small vessel disease (most commonly cerebral amyloid angiopathy), aneurysms, arteriovenous malformations, brain tumors, alcohol abuse and genetic contribution could also be considered as contributing factors [
      • An S.J.
      • Kim T.J.
      • Yoon B.W.
      Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: an Update.
      ].

      4.3 Clinical presentation of intracerebral hemorrhage

      Time between onset of COVID-19 symptoms and development of ICH diagnosis varied; a median time of 1 or 1.5 days was observed in some studies [
      • Shahjouei S.
      • Naderi S.
      • Li J.
      • Khan A.
      • Chaudhary D.
      • Farahmand G.
      • et al.
      Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study.
      ,

      Nawabi J, Morotti A, Wildgruber M, Boulouis G, Kraehling H, Schlunk F, et al. Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage. J Clin Med. 2020;9(8):2543. Published 2020 Aug 6.

      ] and up to 32 in other [
      • Benger M.
      • Williams O.
      • Siddiqui J.
      • Sztriha L.
      Intracerebral haemorrhage and COVID-19: Clinical characteristics from a case series.
      ]. This variability could be partly explained by the deep sedation of patients admitted in ICU, which masks the typical symptoms of ICH. Physicians should strongly suspect the possibility of ICH in individuals with severe COVID-19 admitted to ICU and treated with anticoagulants.

      4.4 Outcome

      Typically, non-traumatic ICH is life-threatening emergency. Mortality reaches 40% at the first month and can rise up to 54% at 12 months [
      • An S.J.
      • Kim T.J.
      • Yoon B.W.
      Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: an Update.
      ,
      • Fridman S.
      • Bullrich M.B.
      • Jimenez-Ruiz A.
      • Costantini P.
      • Shah P.
      • Just C.
      • et al.
      Stroke Risk, phenotypes, and death in COVID-19: Systematic review and newly reported cases.
      ]. Mortality in patients with ICH and COVID19 has not been reported in detail; data from our review show an in-hospital mortality of 52.7%; unfortunately no data are available for longer term follow–up. Of note, COVID-19 mortality in patients admitted in ICU is high (up to 49%) regardless of ICH development [
      • Grasselli G.
      • Greco M.
      • Zanella A.
      • Albano Giovanni
      • Antonelli Massimo
      • Bellani Giacomo
      • et al.
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in lombardy, Italy. JAMA.
      ]. Finally, it is unclear whether ICH is related directly to COVID-19 or reflects expected comorbidity and/or complications observed in severely ill patients.

      4.5 Limitations

      Intracranial hemorrhage was used as a broader term in some reports and these patients could not be classified more specifically. Thus, SAH and other types of brain hemorrhage (i.e. primary intraventricular, subdural) are considered a confounding factor in our review. Publication bias was also an issue.

      5. Conclusion

      ICH is a rare clinical manifestation with high mortality rate in patients with COVID-19. Beyond typical risk factors for ICH, pathophysiologic involvement of SARS-CoV-2 can also be implicated. Although almost half of the reported cases had a history of arterial HTN, ICHs were mainly lobar, indicating other mechanism than hypertensive arteriolosclerosis. Admission to the ICU due to critical illness and the concomitant medical thromboprophylaxis or anticoagulation treatment seem clearly related with ICH. Still, it is unclear whether ICH is related directly to COVID-19 or reflects expected comorbidity and/or complications observed in severely ill patients. More original studies are needed in order to establish a clear relationship between ICH and COVID-19.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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