Acute Ischemic Stroke in COVID-19: A Case-Based Systematic Review

 You don't want to get a stroke from COVID-19 so get treated immediately upon diagnosis. Don't tough it out at home or wait until it is severe.

Seventy five percent of the patients with COVID-19 and Acute Ischemic Stroke died or are still severely disabled.

Acute Ischemic Stroke in COVID-19: A Case-Based Systematic Review

Tissa Wijeratne^1,2,3*, Carmela Sales⁴, Leila Karimi^2,5 and Sheila Gillard Crewther^2,4

• ¹Neurology & Stroke, Australian Institute for Musculoskeletal Science, Melbourne Medical School, Sunshine Hospital, The University of Melbourne, Parkville, VIC, Australia
• ²School of Psychology and Public Health, College of Science, Health and Engineering, La Trobe University, Melbourne, Parkville, VIC, Australia
• ³Department of Medicine and Dean's Office, Rajarata University of Sri Lanka, Anuradhapura, Sri Lanka
• ⁴Department of Neurology, Australian Institute for Musculoskeletal Science, Level Three, Western Centre for Health Research and Education, Sunshine Hospital, Western Health & University Melbourne, St Albans, VIC, Australia
• ⁵Faculty of Social and Political Sciences, Tbilisi State University, Tbilisi, Georgia

Corona virus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) is recognized as a global pandemic by WHO 2020 with 5,934 936 infections, 367,166 deaths and affecting over 200 countries as of 30th May 2020. Acute Ischemic Stroke (AIS) in brain is also emerging as an important neurovascular/neurological complication of COVID-19, associated with extreme immune responses leading to dysregulated coagulation system and generalized thrombo-embolic status and increased risk of AIS especially among usually less vulnerable younger adults in this cohort. Thus, in early June 2020, we aimed to review the clinical data on all published cases of COVID-19 and concomitant AIS, with a view to understanding the pertinent clinical, laboratory and imaging features. The neutrophil-lymphocyte ratio (NLR) at time of hospital admission for COVID infection correlates positively with the duration of time before onset of clinical features of AIS. Higher NLR, C-Reactive protein, serum ferritin, D-dimer and fibrinogen levels are associated with poor prognosis of AIS in COVID-19 with 75% of patients dying or being severely disabled at present. Currently it is too early to comment on the long-term outcomes for survivors.

Key Findings

• Acute ischemic stroke is an important, but an under recognized complication of SARS-CoV2 infection, that leaves most recovered patients with significant disabilities as of present stage July 2020 of the pandemic.

• Hypercoagulation markers such as D-dimer are substantially elevated among all patients early in the disease progression.

• Neutrophil to lymphocyte ratio, C-Reactive protein, and Serum Ferritin levels appear to be prognostic markers.

• Patients with higher admission neutrophil-lymphocyte ratios demonstrate a shorter interval between infective symptoms of COVID-19 and the clinical manifestation of Acute Ischemic Stroke.

• Large vessel occlusion is the main etiologic subtype, with only a minority of patients receiving standard of care treatment.

• Seventy five percent of the patients with COVID-19 and Acute Ischemic Stroke died or are still severely disabled.

• The COVID-19 pandemic has created a unique opportunity to advance the whole field of neurorehabilitation based on a better biological and scientific underpinning of precision neurorehabilitation protocols.

Introduction

In December 2019, a novel corona virus associated with a series of acute, atypical respiratory diseases was first detected in Wuhan China. Since then the virus, now known as SARS-CoV2 (Severe Acute Respiratory Syndrome coronavirus two), has spread to over 200 countries and is now recognized as a major world pandemic (1). As of May 30th 2020, the mortality rate of COVID-19 was reported with the number of confirmed deaths with recorded cases worldwide. Since the pathogenesis of SARS-CoV2 first began to emerge, numerous other clinical system manifestations have been identified.

Neurological manifestations of SARS-CoV 2 infection were first reported in a series of patients in Wuhan, China by Zhou et al. (2). Acute ischemic stroke (AIS) was diagnosed in 5% of the cases (2). However, a much lower rate of only 0.9% imaging confirmed AIS i.e., 32/3,556 total patients case number with COVID-19 was reported in New York USA (3). Subsequent retrospective reports from Europe have also confirmed AIS as a common neurovascular complications of SARS-CoV2 (4, 5). Interestingly Oxley et al. noted an increased occurrence of younger SARS CoV2 virus-infected patients with no significant traditional risk factors for AIS, presenting with large vessel occlusion (6). Putative mechanisms suggested as inducing AIS in association with SARS CoV2 have included systemic inflammation, inflammatory cytokine storm, hyper-coagulability, and imbalances in the classical and alternative Renin Angiotensin System (RAS) in relation to SARS-CoV-2 spike glycoprotein-ACE2 binding related molecular mechanisms (3, 7–19). The RAS system comprises both a plasma-based RAS regulating cardiovascular system and tissue-based RAS regulating long term changes via a complex hormonal system, endocrine, paracrine, and autocrine in action. Thus, the RAS controls renal, adrenal and cardiovascular systems with important implications on blood pressure control as well as fluid/electrolyte control which are critically important to maintain life being very susceptible to damage by SARS-CoV 2. The inflammatory pathway is core to the various clinical manifestations of SARS-CoV2 infection. Also referred to as the “cytokine storm,” it triggers an upsurge of various inflammatory cytokines such as IL-2, IL-7, IL-10 (20, 21), induces a state of lymphocytopenia (22–24) and also activates a spike of acute phase reactants such as CRP and ferritin (25, 26).

Various parameters have been proposed to predict prognosis and outcomes among patients with COVID, including the neutrophil to lymphocyte ratio (NLR) (27–30). A metanalysis of six studies involving 1,141 patients has demonstrated that an elevated NLR is associated with severe disease manifestation (28). The same meta-analysis has also revealed that along with ESR and IL-6, CRP was correlated with increased severity among patients with SARS-CoV2 infection (28). The role of ferritin as a predictor of mortality among confirmed SARS-CoV2, has also been confirmed in another metanalysis of 10 studies involving more than 1,400 subjects (31). Furthermore, elevated D-dimer and hyperfibrinogenemia, which are both biomarkers of inflammation and hypercoagulable state, have also been shown to predict the severity of the said infection (31, 32). Interestingly, similar biomarkers predict outcomes in stroke (33–39). In particular, it is known that patients who show elevated NLR, ferritin, CRP, D-dimer and fibrinogen have a higher risk for stroke and equate to potentially poorer clinical outcomes (33–39).

To date, despite the theoretical association of inflammatory and procoagulable states linking stroke and SARS-CoV2 infection, there is limited published literature on the actual co-occurrence of both. There is also limited information on the biological markers which may be associated with poor neurological outcomes. Thus, this study aims to describe the clinical characteristics of patients with acute ischemic stroke and concomitant SARS-CoV2 infection. By further analysis of available laboratory data, this will look at the trend of inflammatory biomarkers such as NLR, CRP, serum ferritin, fibrinogen and D-dimer and hospital discharge outcomes.

Currently, there is limited information about the clinical characteristics and specific neurorehabilitation issues of AIS patients with SARS-CoV 2 infection (40–43). However, it is expected that the surge in patient numbers, on-going issues with personal protective equipment (PPE) shortages, and associated health care workers anxiety and stress about the potential of getting infected with COVID-19 (and actual infection of health care workers and mandatory self isolation for 14 days even if these members are demonstrating minimum or no symptoms) will create a significant challenge to traditional neurorehabilitation practices and pathways, at least during the pandemic, possibly for a long time to come. Thus, these circumstances argue a strong case for converting the catastrophe [Complex rearrangement of hospital facilities as part of the preparation for the pandemic has also occasioned significant problems and added resource problems for health care systems across the world (44–50) into an opportunity for revamping of rehabilitation protocols]. Currently evidence is emerging for further expansion of telemedicine type paradigms, with incorporation of tablet based remote monitoring technology (Melbourne Rapid Field visual fields, wearable devices and artificial intelligence) suggesting as the way forward in neurorehabilitation of AIS in COVID19 pandemic era, at least for the foreseeable future (43, 51–53).

Thus, this systematic review aims to identify and collate the clinical and laboratory features, acute and long term treatment, and outcomes of all published reports on patients with concomitant diagnosis of confirmed SARS-CoV 2 infection and acute ischemic stroke and with a special emphasis on clinical and laboratory features.

Purpose

The present study was conducted to provide a systematic review of AIS and COVID-19 with respect to definition, prevalence, pathophysiology, clinical characteristics, acute, subacute features, prognostic markers outcomes.