key: cord-0791019-h0c01w2l authors: Deng, Xiao; Lo, Yew-Long; Tan, Eng -King title: Comparing COVID-19-linked neurological complications with other viral infections date: 2020-12-09 journal: J Transl Med DOI: 10.1186/s12967-020-02633-0 sha: e2c8e91c1b2620c5cdb91cf8c7e7c367461ddb53 doc_id: 791019 cord_uid: h0c01w2l nan There are increasing reports of multi-system involvement in coronavirus disease 2019 (COVID-19). Among these, cerebrovascular diseases (CVD) in COVID patients have been highlighted to be associated with varied features and prognosis. COVID-19 may possess the similar mechanism and clinical characteristics as SARS, as the viruses causing them are under the same category and share highly homological genetic sequence. Influenza H1N1 and COVID-19 are comparable in terms of outbreak size as Influenza H1N1 also bring about global pandemic. However, to date, a detailed systematic comparison of neurological complications among COVID-19, SARS-CoV-1 and Influenza H1N1 infections has not been carried out. To address this gap in knowledge, we compared the frequency, presentation and prognosis of neurological complications in COVID-19 with SARS and Influenza H1N1 infection (Tables 1, 2 ). This may provide further mechanistic insights into potential differences between COVID-19 and other viral infections. We searched PubMed from January, 2020 to June, 2020. The following key words were included: "COVID-19", "SARS", "influenza", "cerebrovascular disease", "neurological symptoms", "neurological manifestations". Two review authors (EK-T, XD) independently reviewed the included studies and extracted study characteristics. About 3% of COVID-19 patients reported acute CVD in a study from Wuhan [1] , comparable to the reported frequency of 2.42% for SARS reported in Singapore [2] . Neurologic manifestations occurred both early and late stage in the course of the COVID-19 [3] , with more clinical variability than SARS and H1N1 infections. The most common severe neurologic manifestations in COVID-19 patients included acute CVD, impaired consciousness, and skeletal muscle injury, which appeared slightly higher than SARS and H1N1 patients [1, 2, 4, 5] . Acute symptomatic seizures or status epilepticus were not seen commonly in COVID-19 patients [6] . More children with H1N1 than adults suffered neurologic injury with poor outcome [7] , whereas paediatric patients with COVID-19 were more likely to have better outcome than adults [8] ( Table 1) . For CVD in COVID-19, we noticed that a number of them were relatively young (less than 50 years and of male gender) ( Table 2 ). There was no consistent pattern to the types of strokes, with reports of involvement in small, medium or large vessels [3, 9] (Table 2 ). The blockages of these vessels led to infarcts and in some cases frank bleeding. The prognosis depended on the severity of the strokes at presentations and associated complications. Not surprisingly, vascular risk factors such as hyperlipidaemia, diabetes and hypertension were present especially in the older group of patients [10] . These risk factors were not different from the common stroke patients seen during non-COVID-19 period. Several patients in one series [3] have been reported to have a positive lupus anticoagulant, which may have predisposed them to the disease. However, it is not clear if these patients were more susceptible to Journal of Translational Medicine COVID-19 or if there was a complex interplay of the factors involved. It is possible that proinflammatory cytokines contributed to the blockage of the vessels [3] . For those stroke patients who were disabled, long term data on the final recovery outcomes were still not available. The infection of SARS-CoV can affect brains, especially the brainstem mainly mediated by a cellular receptor angiotensin-converting enzyme 2 (ACE2) [11] , which can be expressed in human airway epithelia, lung parenchyma, vascular endothelia. The similarity of severe neurological manifestations in COVID-19 and in SARS patients indicate that ACE2 may also play a role in the underlying mechanism. In addition, the respiratory failure in COVID-19 patients may result from the neuroinvasive potential of SARS-CoV2 [11] . Different from the possible mechanisms of SARS-CoV-1 and SARS-CoV-2 infections, H1N1 infection might be due to direct infection, hypoxia and metabolite dysfunction [12] . To summarise, based on current data, the frequency of CVD in COVID-19 appeared slightly more than SARS and H1N1 patients. COVID-19 had more variability than SARS and H1N1 patients in terms of the onset of neurologic manifestations. Longitudinal studies to further clarify the chronic neurological burden could be particularly useful to stratify COVID-19 patients and guide the medical recourse allocation. It could be particularly useful to guide strategic planning for current and future pandemics. Functional studies to decipher the pathophysiologic mechanism, in particular the role of the COVID-19 in vessel wall inflammation, blockage and secondary cytokine response will be warranted. Possible mechanism The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure [11] ACE2 [11] and immune injury may play a role Direct infection, hypoxia and metabolite dysfunction may be more significant [12] Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan China Large artery ischaemic stroke in severe acute respiratory syndrome (SARS) Characteristics of ischaemic stroke associated with COVID-19 The neurological manifestations of H1N1 influenza infection; diagnostic challenges and recommendations Neuromuscular disorders in severe acute respiratory syndrome New-onset acute symptomatic seizure and risk factors in Corona virus disease2019: a retrospective multicenter study Pediatric neurological complications of 2009 pandemic influenza A (H1N1) Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study Large-vessel stroke as a presenting feature of covid-19 in the young Multimorbidity in older adults with cardiovascular disease The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Influenza A virus (H1N1) triggers a hypoxic response by stabilizing hypoxia-inducible factor-1alpha via inhibition of proteasome Neurologic features in severe SARS-CoV-2 infection Neurological associations of COVID-19 Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations The authors thank the National Medical Research Council (STaR Award and Translational Clinical Research Programme in PD). Authors' contributions E-KT and XD: study concept and design; E-KT and XD drafting the manuscript; E-KT and Y-LL: revising the manuscript. All authors read and approved the final manuscript. None. Not applicable. Not applicable. Not applicable. Received: 23 May 2020 Accepted: 27 November 2020