Central Nervous System Manifestations in COVID‐19 Patients
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Received: 30 July 2020 | Revised: 23 November 2020 | Accepted: 20 December 2020 DOI: 10.1002/brb3.2025 REVIEW Central nervous system manifestations in COVID-19 patients: A systematic review and meta-analysis Shahrzad Nazari1 | Amirhossein Azari Jafari2 | Seyyedmohammadsadeq Mirmoeeni2 | Saeid Sadeghian3 | Mohammad Eghbal Heidari4 | Siavash Sadeghian5 | Farhad Assarzadegan6 | Seyed Mahmoud Puormand7 | Hamid Ebadi8 | Davood Fathi9,10 | Sahar Dalvand11 1Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran 2Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran 3Department of Paediatric Neurology, Golestan Medical, Educational, and Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 4Students Scientific Research Center, Tehran University Medical Science, Tehran, Iran 5Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 6Department of Neurology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran 7Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran 8Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada 9Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran 10Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran 11Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran Correspondence Sahar Dalvand, Functional Neurosurgery Abstract Research Center, Shohada Tajrish Background: At the end of December 2019, a novel respiratory infection, initially Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of reported in China, known as COVID-19 initially reported in China, and later known Medical Sciences, Tehran, Iran. as COVID-19, led to a global pandemic. Despite many studies reporting respiratory Email: [email protected] infections as the primary manifestations of this illness, an increasing number of in- Davood Fathi, Brain and Spinal Cord Injury vestigations have focused on the central nervous system (CNS) manifestations in Research Center, Neuroscience Institute, Tehran University of Medical Sciences, COVID-19. In this study, we aimed to evaluate the CNS presentations in COVID-19 Tehran, Iran. patients in an attempt to identify the common CNS features and provide a better Email: [email protected] overview to tackle this new pandemic. Funding information Methods: In this systematic review and meta-analysis, we searched PubMed, Web of The author(s) received no financial support for the research, authorship, and/or Science, Ovid, EMBASE, Scopus, and Google Scholar. Included studies were publica- publication of this article. tions that reported the CNS features between 1 January 2020 and 20 April 2020. The data of selected studies were screened and extracted independently by four reviewers. Extracted data analyzed by using STATA statistical software. The study protocol registered with PROSPERO (CRD42020184456). Results: Of 2,353 retrieved studies, we selected 64 studies with 11,687 patients after screening. Most of the studies were conducted in China (58 studies). The most This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC Brain and Behavior. 2021;00:e02025. wileyonlinelibrary.com/journal/brb3 | 1 of 14 https://doi.org/10.1002/brb3.2025 2 of 14 | NAZARI ET AL. common CNS symptom of COVID-19 was headache (8.69%, 95%CI: 6.76%–10.82%), dizziness (5.94%, 95%CI: 3.66%–8.22%), and impaired consciousness (1.90%, 95%CI: 1.0%–2.79%). Conclusions: The growing number of studies has reported COVID-19, CNS presenta- tions as remarkable manifestations that happen. Hence, understanding the CNS char- acteristics of COVID-19 can help us for better diagnosis and ultimately prevention of worse outcomes. KEYWORDS consciousness disorders, COVID-19, dizziness, headache, nervous system diseases, SARS- CoV-2 infection 1 | INTRODUCTION 2 | METHOD At the end of December 2019, a novel respiratory syndrome, known 2.1 | Search strategy and selection criteria as COVID-19, was reported in Wuhan city, Hubei province, China. The first sign of this infection (2019-nCoV, COVID-19) was pneumo- We performed this systematic review and meta-analysis based nia (Adhikari et al., 2020; WHO, 2020; Shi, Qin, et al., 2020; Velavan on Preferred Reporting Items for Systematic Reviews and Meta- & Meyer, 2020; Wang, Hu, et al., 2020; Wang, Wang, et al., 2020; Analyses (PRISMA) guidelines (Moher et al., 2009), and our study Wu, Chen, et al., 2020). This new pandemic rapidly spread world- protocol is submitted to PROSPERO (ID: CRD42020184456). We wide, and an increasing number of infected cases and deaths have systematically searched six databases including Google Scholar, been reported globally (Jiang et al., 2020; Sohrabi et al., 2020). Scopus, PubMed, Web of science, Ovid, and EMBASE for all pub- Hence, the COVID-19 outbreak was officially considered as a Public lished articles from 1 January 2020 until 20 April 2020 using the Health Emergency of International Concern (PHEIC) by the World following Medical Subject Heading terms (MESH terms): Health Organization (WHO) Emergency Committee (Mackenzie (“Wuhan coronavirus” OR “Wuhan seafood market pneumonia & Smith, 2020; WHO, 2020). Severe acute respiratory syndrome virus” OR “COVID19 virus” OR “COVID-19 virus” OR “coronavirus coronavirus 2 (SARS-CoV-2) is a zoonotic pathogen and can transmit disease 2019 virus” OR “SARS-CoV-2” OR “SARS2” OR “2019-nCoV” from infected animals (such as bats and snakes) to humans eventu- OR “2019 novel coronavirus” OR “2019-nCoV infection” OR “2019 ally leading to epidemics and pandemics through human-to-human novel coronavirus disease” OR “2019-nCoV disease” OR “corona- transmission (Hassan et al., 2020; Mackenzie & Smith, 2020). Most virus disease-19” OR “coronavirus disease 2019” OR “2019 novel cases of COVID-19 have shown respiratory symptoms ranging coronavirus infection” OR “COVID19” OR “COVID-19” OR “severe from cough to dyspnea and respiratory failure as well as the typical acute respiratory syndrome coronavirus 2” OR “coronavirus*”) AND signs and symptoms of infection such as fever and fatigue (Cascella (“Manifestation, Neurologic” OR “Neurological Manifestations” et al., 2020; Chen, Zhou, et al., 2020; Wang, Hu, et al., 2020; Young OR “Neurologic Manifestation” OR “Neurological Manifestation” et al., 2020). OR “Neurologic Symptom” OR “CNS” OR “brain” OR “neuro*” OR However, a growing number of COVID-19 patients are present- “headache” OR “dizziness” OR “ataxia” OR “epilepsy” OR “seizure” ing with different combinations of the central nervous system (CNS) OR “migraine*” OR “CSF” OR “Cerebrospinal Fluids” OR “Fluid, manifestations (Asadi-Pooya & Simani, 2020; Mao et al., 2020; Cerebrospinal” OR “Fluids, Cerebrospinal” OR “Cerebro Spinal Fluid” Montalvan et al., 2020). Several case reports have indicated the OR “Cerebro Spinal Fluids” OR “Fluid, Cerebro Spinal” OR “Fluids, presence of various CNS complications, including encephalitis, Cerebro Spinal” OR “Spinal Fluid, Cerebro” OR “Spinal Fluids, stroke, meningitis, and encephalopathy in COVID-19 patients (Co Cerebro” OR “stroke” OR “vertigo” OR “consciousness” OR “Impaired et al., 2020; Filatov et al., 2020; Moriguchi et al., 2020; Zhou, Zhang, consciousness” OR “coma” OR “cerebrovascular disease” OR “acute et al., 2020). Furthermore, a large observational study carried out by cerebrovascular disease” OR “encephalitis”) alone or in combination Mao et al. shows the prevalence of the CNS presentations such as with OR and AND operators. dizziness, headache, impaired consciousness, acute cerebrovascular After removing the duplicated records, articles were screened disease, ataxia, and seizure (Mao et al., 2020). Therefore, awareness based on their titles and abstracts by two authors (S.S and M.H) of the different aspects of the short- and long-term effects of this independently. The full texts of eligible publications were exam- virus on the central nervous system could decently guide scientists. ined for inclusion and exclusion criteria (A.AJ, S.M, S.S, and M.H). In this systematic review and meta-analysis, we assessed the CNS Observational studies reported at least one of the related CNS manifestations in COVID-19 cases. symptoms in COVID-19 patients without any language, race, NAZARI ET AL. | 3 of 14 country, and gender limitations included for quantitative synthe- articles, 41 preprints, 6 case reports, 1 case controls, 4 reports, 4 pa- sis. The preprint studies, interventional studies, systematic re- pers with specific children population, one study with specific preg- views, case reports, conferences, commentaries, letters, editorial, nant population, and 13 publications such as Commentary, editorial author responses, correspondence articles, in vitro, animal stud- or Correspondence letters were excluded. Finally, 64 studies (Barrasa ies, children population, articles without full text, or unreliable et al., 2020; Chen, Chen, et al., 2020; Chen, Qi, et al., 2020; Chen, data were excluded. In addition,