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Table of Contents
Year : 2020  |  Volume : 17  |  Issue : 5  |  Page : 2-5

COVID-19 and stroke – Updated review

1 Institute of Neurosciences, Indraprastha Apollo Hospitals, Saket, New Delhi, India
2 Department of Critical Care, Max Hospital, Saket, New Delhi, India

Date of Submission09-Jul-2020
Date of Acceptance30-Jul-2020
Date of Web Publication07-Aug-2020

Correspondence Address:
Pushpendra Nath Renjen
C-85, Anand Niketan, New Delhi - 110 021
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_89_20

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Although the precise incidence is not known, stroke is emerging as a complication of the COVID-19 pandemic. The clinical course of COVID-19 is most severe in elderly patients, in men, and in patients with comorbidities such as hypertension, diabetes, heart disease, and obesity, all risk factors for stroke. Severe acute respiratory syndrome coronavirus infection is linked to a prothrombotic state causing venous and arterial thromboembolism and elevated D-dimer levels. The occurrence of acute ischemic stroke at the time of this pandemic poses a great challenge regarding emergency treatment (particularly administering thrombolysis and performing thrombectomy) of acute stroke patients. In this article, we will review the pathophysiology and challenges in the management of COVID-19 infection-associated stroke.

Keywords: COVID-19, severe acute respiratory syndrome coronavirus 2, stroke, novel coronavirus, thrombolysis

How to cite this article:
Renjen PN, Chaudhari DM, Mishra A, Bukhari I. COVID-19 and stroke – Updated review. Apollo Med 2020;17, Suppl S1:2-5

How to cite this URL:
Renjen PN, Chaudhari DM, Mishra A, Bukhari I. COVID-19 and stroke – Updated review. Apollo Med [serial online] 2020 [cited 2021 Nov 30];17, Suppl S1:2-5. Available from: https://www.apollomedicine.org/text.asp?2020/17/5/2/291738

  Introduction Top

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) virus, was declared a pandemic by the World Health Organization on March 11, 2020. This was just 2½ months after the first case was reported on December 2019 in Wuhan, China. This just demonstrates the rapid human transmissibility of this virus which has spread across continents in such a brief time.[1] Although the precise incidence is not known, stroke is emerging as a complication of the COVID-19 pandemic. The clinical course of COVID-19 is most severe in elderly patients, in men, and in patients with comorbidities such as hypertension, diabetes, heart disease, and obesity, all risk factors for stroke.[2] Neurological symptoms are common in COVID-19 including anosmia and hypogeusia, seizures, and strokes. In a retrospective study of 214 hospitalized COVID-19 patients from Wuhan, China, 5.7% of the severe patients suffered a stroke.[3]

  Corona Virus Top

Coronaviruses are a large family of viruses which may cause disease in animals or humans.[4] Seven coronaviruses can produce infection in people around the world but commonly people get infected with these four human coronaviruses: 229E, NL63, OC43, and HKU1. They usually cause a respiratory infection ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome and SARS and the most recently discovered coronavirus (COVID-19) causes infectious disease.[4] This zoonotic disease caused by SARS-CoV-2. The WHO originally called this infectious disease Novel Coronavirus-Infected Pneumonia and the virus had been named 2019 novel coronavirus (2019-nCoV).[5] The standard tool of diagnosis is by reverse transcription polymerase chain reaction (rRT-PCR) from a throat swab or nasopharyngeal swab. The infection can also be diagnosed from a combination of symptoms, risk factors, and a chest computerized tomography (CT) scan showing features of pneumonia.[6]

  Covid-19 and Cerebrovascular Disease Top

Although 80% of patients infected with the virus remain nonhospitalized, in full form, COVID-19 is a SARS caused by a novel coronavirus now named SARS CoV-2.[7] In the past few weeks, it has become clear that patients infected with the SARS-CoV-2 virus may present in a number of ways, including with neurological symptoms that are coincident with, or could potentially precede, pulmonary symptoms, and fever. In recent studies from three hospitals in Wuhan, China, up to 36% of COVID-19 patients manifest neurological symptoms.[3],[8] The most common neurological manifestations were dizziness (16.8%), headache (13.1%), and encephalopathy (2.8%). The most common peripheral signs and symptoms were anosmia (5.1%), dysgeusia (5.6%), and muscle injury (10.1%, detected by elevated creatine kinase). Stroke complicated COVID-19 infection in 5.9% of patients at median 10 days after symptom onset. Stroke patients were older, had more cardiovascular comorbidities, and more severe pneumonia. Stroke mechanisms may vary and could include hypercoagulability from critical illness and cardioembolism from virus-related cardiac injury.[9]

A single-center study of 221 consecutive hospitalized patient with COVID-19 infection reported that 11 (5%) developed acute ischemic stroke, 1 (0.5%) cerebral venous sinus thrombosis, and 1 (0.5%) cerebral hemorrhage.[8] The mean age of patients who developed stroke (72 years) was higher (52 years) and the stroke group had higher frequency of hepatic and renal dysfunction. The frequency of hypertension, diabetes mellitus, and previous history of cerebrovascular disease were higher among those who developed stroke. Of the 11 patients with ischemic stroke, five were related to large artery disease, three small artery disease, and three cardioembolic events. The fibrin D-dimer levels were 12-fold higher in patients who developed stroke indicating a hypercoagulable state.[8]

While dealing with stroke in COVID-19, the stroke team may be involved in evaluation of three categories of patients:

Stroke patients with known COVID-19 infection

The current data suggest that patients with COVID-19 infection developed stroke in advanced stages of COVID-19 infection. The median duration from first symptoms of COVID-19 to the development of stroke was 10 days in one study.[8] Therefore, whether the patients are being evaluated in the emergency department (ED) or within the hospital, the institutional screening protocols would have already identified COVID-19 infection in these patients.[7]

Stroke patients with suspected COVID-19 infection

The time constraints for confirming a COVID-19 infection need to be understood. Confirmation of COVID-19 infection requires the detection of unique sequences of virus RNA using real-time rRT-PCR from nasopharyngeal and oropharyngeal swab, endotracheal aspirate, or bronchoalveolar lavage. The time required to get the results vary depending on what kit is being used (5 min to 8 h for rRT-PCR and 3 days for serological enzyme-linked immunosorbent assays) and whether the specimen has to be sent to a laboratory outside the hospital. One of the challenges in identifying COVID-19 infection in acute stroke patients is an inability to get an accurate history of clinical symptoms due to underlying aphasia, dysarthria, and confusion.[7]

Stroke patients with undiagnosed COVID-19 infection

Acute stroke patients may be asymptomatic carriers, in the prodromal period, or neurological deficits is the first manifestation. The possibility of isolated neurological symptoms as presenting symptoms in COVID-19-infected patient such as confusion (8%), headache (8%–13%), and dizziness (17%) may prompt a stroke evaluation.[3] The viral load that was detected in the asymptomatic patients was similar to that in the symptomatic patients, highlighting the transmission potential of asymptomatic or minimally symptomatic patients.[10]

  Pathological Characteristics of Ischemic Stroke Associated With Covid-19 Top

SARS-CoV-2 infection is associated with coagulopathy causing venous and arterial thrombosis. SARS-CoV-2 infection is linked to a prothrombotic state causing venous and arterial thromboembolism and elevated D-dimer levels.[11] Severe COVID-19 is associated with pro-inflammatory cytokines which induce endothelial and mononuclear cell activation with expression of tissue factor leading to coagulation activation and thrombin generation. Circulation of free thrombin, uncontrolled by natural anticoagulants, can activate platelets and lead to thrombosis.[11]

  Pro-Inflammatory Markers Top

Studies on the various pathogenic mechanisms of COVID-19 have demonstrated role of a pro-inflammatory cascade with higher levels of CRP, interleukin 6, D-dimer, and multiple other cytokines in these patients.[12] The higher levels of these pro-inflammatory markers among COVID-19 patients have been associated with more severe manifestations, poorer outcomes, and a greater occurrence of neurological manifestations. Thus, a plausible unifying hypothesis could be a procoagulant state induced by the pro-inflammatory milieu, leading to a greater chance of vascular thrombosis among individuals who are already harboring traditional stroke risk factors.[1] The occurrence of venous thromboembolism in up to 31% cases in a case series of 184 intensive care unit (ICU) patients with severe COVID-19 pneumonia also supports a hypercoagulable state due to an excessive inflammatory response among COVID-19.[13]

  Antiphospholipid Antibodies Top

Antiphospholipid antibodies (aPL)

were reported in 3 COVID-19 patients. aPL are antibodies directed to phosphoproteins and associated with both arterial and venous thrombotic events. All three patients suffered multiple cerebral infarcts and one had multiple limb ischemia. All had elevated IgA anticardiolipin antibodies and elevated IgA and IgG beta 2 glycoprotein I antibodies with prolonged activated partial thromboplastin times and prothrombin times but no lupus anticoagulant. Two of the three patients had thrombocytopenia and all had high C-reactive protein levels. It is not clear if the strokes and thrombotic events were related to SIC or the aPL.[14]

  Angiotensin Converting Enzyme 2 Receptors Top

Another possible mechanism could be the role of angiotensin converting enzyme 2 (ACE2) receptor. ACE2 has now been recognized as the receptor through which virus binds to the host cells.[15] ACE and its receptors are present in the lungs, gastrointestinal tracts, nervous system, skeletal muscles, and in the cerebral endothelial cells. Interestingly, these are some of the major target organs of this virus. ACE2 converts angiotensin II into a heptapeptide (angiotensin [1–7]) having vasodilatory, antioxidant, and anti-inflammatory actions. There have been studies regarding downregulation of ACE2 postbinding by COVID-19 to host cell membranes. Therefore, ACE2 downregulation might lead to vasoconstriction, pro-inflammatory effects leading to increased risk of hypertension and strokes.[1] Since ACE2 is expressed by brain endothelium and neurons, it is likely that viral-mediated depletion of ACE2 impairs endothelial function and predisposes to or worsens acute stroke [Figure 1].[16]
Figure 1: Angiotensin converting enzyme 2 is expressed in human brain endothelium. Severe acute respiratory syndrome coronavirus 2 binds angiotensin converting enzyme 2, depleting angiotensin converting enzyme 2 on the endothelium[16]

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  Management of Stroke Patients With Covid-19 Top

The occurrence of acute ischemic stroke at the time of this pandemic poses a great challenge regarding emergency treatment (particularly administering thrombolysis and performing thrombectomy) of acute stroke patients. From the time, the patient arrives in the emergency, it would be pertinent to do a quick screen for respiratory symptoms and travel history. Quick transportation for CT scan through fast tracked low traffic corridors with prior communication to the radiology colleagues is of utmost importance as well. The presence of concomitant COVID-19 infection in stroke patients is not a contraindication for thrombolysis per se.[1]

Stroke care often involves networks of hospitals; commonly a comprehensive “hub” with multiple smaller hospitals or “spoke” sites which transfer stroke patients to the hub of the spoke for care for higher level of care such as ET, or ICU care for massive infarcts with cerebral edema or for intracerebral hemorrhage (ICH). Tele-stroke should be encouraged to evaluate patients and to prevent unnecessary transfers. For acute ischemic stroke, neuroimaging including arterial imaging should be obtained at the spoke site, and should be reviewed both by local radiologists as well as the tele-stroke physician to aid in appropriate patient selection for transfer.[17] Due to COVID-19 outbreak, self-presentation in emergency room (ER) is highly discouraged because of a potential risk of infection; highly suspected for infection or COVID-19 positive (COVID+) patients should be pretriaged in a separate box. The approach to patients referred to ER should focus on early recognition of suspected COVID-19-positive cases that require immediate isolation and infection control measures.[18]

Several factors in patients with COVID-19 infection have been established which can identify the patients at risk for in-hospital mortality such as older age, high sequential organ failure assessment (SOFA) score, cardiovascular diseases, secondary infections, ARDS, acute renal injury, and laboratory findings of lymphopenia and elevated hepatic enzymes, C-reactive protein, ferritin, creatinine phosphokinase, and fibrin D-dimers.[2] Therefore, the assessment of dysfunction in other organs using validated systems such as SOFA appears to be important to provide overall prognosis prior to determining the appropriate acute stroke treatment. The SOFA assesses respiration (PaO2/FiO2 ratio), coagulation (platelet count strata), hepatic enzymes (bilirubin concentration strata), cardiovascular (hypotension and treatment), neurological function (Glasgow Coma Scale/score strata), renal (serum creatinine/urine output strata), and sepsis (present/absent) and assigns a score of 0–4.[7] The mortality rates range from 3.2% in patients without organ failure to 91.3% in patients with failure of all the six organs analyzed in patients with sepsis.[19]

  Intravenous Recombinant Tissue Plasminogen Activator Top

Intravenous recombinant tissue plasminogen activator (rt-PA) is recommended for selected patients who may be treated within 3 h and for highly selected patients who can be treated within 3 and 4.5 h of symptom onset or last known well. The relatively high prevalence of elevated concentration of inflammation and hypercoagulability markers such as leukocytosis, and C reactive protein and D dimers in patients with COVID-19 infection need to be recognized. While none of these laboratory abnormalities are a contraindication to intravenous rt-PA, previous studies conducted in patients with acute ischemic stroke but without COVID-19 infection demonstrated a higher rate of death or disability and postthrombolytic ICH.[7]

  Mechanical Thrombectomy Top

With regards to mechanical thrombectomy, there must be adequate information provided beforehand to the neurointervention team if a stroke patient is demonstrating any respiratory symptoms, so that adequate PPE can be donned. There is mechanistically no difference in the technique of thrombectomy to be performed apart from high-risk prognosis for those with COVID-19 and respiratory distress. The site of postthrombolysis or thrombectomy care would be of utmost importance to prevent the spread of infection to other neurological patients. Hence, a dedicated COVID-19 stroke ward/ICU would be ideal for isolating these patients while imparting optimal care.[1]

Given the complexities associated with performing invasive procedures in patients with suspected or confirmed COVID-19 infection, a stringent policy is required to select acute ischemic stroke patients for mechanical thrombectomy. Although decisions need to be made on a case-by-case basis, the highest rates of favorable outcomes are expected in those who meet inclusion criteria used in clinical trials and when procedures can be initiated and performed rapidly.[7]

  Decontamination Top

At the end of the intervention, the undressing of the staff must take place inside the angio-suite and near an exit door (preferably a different door from the one used for the patient's exit); near this door, a dedicated garbage must be set up for the collection of contaminated waste.

  Conclusions Top

  1. Strokes are being reported as a complication of COVID-19. Binding to and depletion of ACE2 may tip the RAS balance in favor of the ACE-1-angiotensin II-AT1 axis and contribute to endothelial dysfunction, organ damage, and stroke
  2. Neurologists need to be aware and should have a high index of suspicion of COVID-19 among stroke cases especially at the peak of this pandemic
  3. Given the significant impact of the COVID- 19 pandemic on the health-care system and the rapid depletion of its resources, urgent steps should be taken while managing acute stroke patients to prevent the spread of the disease, to protect both patients and staff, and to minimize the uses of already strained resources
  4. Patients with COVID-19 infection carry a high risk of developing acute stoke especially in those with multiple organ dysfunctions
  5. If a stroke patient is suspected to have COVID-19 infection, pulmonary imaging using chest CT scan and/or radiograph may be helpful in identifying radiological abnormalities suggestive of COVID-19 infection.

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Conflicts of interest

There are no conflicts of interest.

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