Central nervous system manifestations in COVID‐19 patients: A systematic review and meta‐analysis

Abstract Background At the end of December 2019, a novel respiratory infection, initially reported in China, known as COVID‐19 initially reported in China, and later known as COVID‐19, led to a global pandemic. Despite many studies reporting respiratory infections as the primary manifestations of this illness, an increasing number of investigations have focused on the central nervous system (CNS) manifestations in COVID‐19. In this study, we aimed to evaluate the CNS presentations in COVID‐19 patients in an attempt to identify the common CNS features and provide a better overview to tackle this new pandemic. Methods In this systematic review and meta‐analysis, we searched PubMed, Web of Science, Ovid, EMBASE, Scopus, and Google Scholar. Included studies were publications 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 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 presentations as remarkable manifestations that happen. Hence, understanding the CNS characteristics of COVID‐19 can help us for better diagnosis and ultimately prevention of worse outcomes.


| INTRODUC TI ON
At the end of December 2019, a novel respiratory syndrome, known as COVID-19, was reported in Wuhan city, Hubei province, China.
Hence, the COVID-19 outbreak was officially considered as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) Emergency Committee (Mackenzie & Smith, 2020;WHO, 2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoonotic pathogen and can transmit from infected animals (such as bats and snakes) to humans eventually leading to epidemics and pandemics through human-to-human transmission (Hassan et al., 2020;Mackenzie & Smith, 2020). Most cases of COVID-19 have shown respiratory symptoms ranging from cough to dyspnea and respiratory failure as well as the typical signs and symptoms of infection such as fever and fatigue (Cascella et al., 2020;Young et al., 2020).
However, a growing number of COVID-19 patients are presenting with different combinations of the central nervous system (CNS) manifestations (Asadi-Pooya & Simani, 2020;Mao et al., 2020;Montalvan et al., 2020). Several case reports have indicated the presence of various CNS complications, including encephalitis, stroke, meningitis, and encephalopathy in COVID-19 patients (Co et al., 2020;Filatov et al., 2020;Moriguchi et al., 2020;Zhou, Zhang, et al., 2020). Furthermore, a large observational study carried out by Mao et al. shows the prevalence of the CNS presentations such as dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure . Therefore, awareness of the different aspects of the short-and long-term effects of this virus on the central nervous system could decently guide scientists.
In this systematic review and meta-analysis, we assessed the CNS manifestations in COVID-19 cases.

Conclusions:
The growing number of studies has reported COVID-19, CNS presentations as remarkable manifestations that happen. Hence, understanding the CNS characteristics of COVID-19 can help us for better diagnosis and ultimately prevention of worse outcomes.

K E Y W O R D S
consciousness disorders, COVID-19, dizziness, headache, nervous system diseases, SARS-CoV-2 infection country, and gender limitations included for quantitative synthesis. The preprint studies, interventional studies, systematic reviews, case reports, conferences, commentaries, letters, editorial, author responses, correspondence articles, in vitro, animal studies, children population, articles without full text, or unreliable data were excluded. In addition, the reference list of the eligible studies was searched to prevent missing publication and include all related literature. The data were independently extracted

| Data analysis and quality assessment
The desired data were recorded using an excel spreadsheet form that included the title, first author, year and month of publication, type of study, country, total sample size, the sample size of male and female, study design, demographic characteristics, exposure history, clinical manifestation, CNS symptoms, and any reported comorbidity. We

| Meta-analysis
Data from included studies were extracted for the number of events and total patients to perform a meta-analysis (S.D). Cochrane's Q test and the I 2 index were used to assess heterogeneity among selected studies. Heterogeneity was categorized as low (below 25%), moderate (25%-75%), and high (above 75%) (Higgins & Thompson, 2002). Also, data adjusted by Freeman-Tukey double arcsine transformation and their 95% CIs were calculated by the Clopper-Pearson method (Clopper & Pearson, 1934). We calculate mean and standard deviations from median and quartiles by using Wan method (Wan et al., 2014).
For continuous data, we estimate pooled results of means and their respective 95% CI by the inverse variance method. All analyses were performed using STATA statistical software, version 13 (StataCorp).

| D ISCUSS I ON
Recently, the world has encountered an emergent outbreak posed by the novel coronavirus 2019, officially known as COVID-19. This infection has become a global threat, endangering millions of lives worldwide. Hence, many experts, researchers, scientists, and clinicians are attempting to investigate various aspects of this new infection to find useful solutions for coping with COVID-19. One of the various aspects of COVID-19 is its impact on the CNS, as reported in a growing number of studies (Baig, 2020). In addition to the common symptoms in COVID-19, several CNS symptoms such as headache and impaired consciousness have been observed in infected patients .

F I G U R E 1
The process of surveying, screening, and selecting the articles for this systematic review and meta-analysis based on PRISMA guideline TA B L E 1 Demographics and baseline characteristics of included studies with COVID-19-infected patients presenting CNS symptoms reported that the headache may also be related to the elevated level of inflammatory mediators and reduced cerebral blood flow in response to hypoxia (Jasti et al., 2020), but further studies are needed.
There are two main routes of CNS entry of COVID-19 (hematogenous and peripheral nerves route) leading to CNS infection. In the hematogenous route, the virus infecting respiratory tracts can reach the CNS through the bloodstream via overcoming a strict obstacle known as the blood-brain barrier (BBB) (Desforges et al., 2014(Desforges et al., , 2020Román et al., 2020;Sepehrinezhad et al., 2020;Swanson and McGavern, 2015). They also may enter the CNS through circumventricular organs, those CNS organs lacking the BBB (Chigr et al., 2020).
The second route, a peripheral nerve, can provide the virus with a retrograde route in to access the CNS via an axonal transport machinery Desforges et al., 2014Desforges et al., , 2020Román et al., 2020;Sepehrinezhad et al., 2020;Swanson and McGavern, 2015). In accordance with this finding, some previous studies on other types of coronaviruses indicate that coronaviruses can reach the brain via cranial nerves (e.g., olfactory, trigeminal nerve terminals in the nasal cavity) (Desforges et al., 2020;Li et al., 2016;Natoli et al., 2020;Netland et al., 2008).
Furthermore, SARS-CoV-2 can have indirect effects on the CNS (Zhou, Kang, et al., 2020). Cytokine storm as an immune system response during COVID-19 infection could lead to the breakdown of the blood-brain barrier (BBB) (Liguori et al., 2020;Poyiadji et al., 2020). Infection of airway tissues by COVID-19 in severe cases leads to impaired gas exchange, subsequently causing CNS hypoxia resulting in neural dysfunction (Abboud et al., 2020). More precisely, both cytokine storm and hypoxia which are frequently present in the severe condition of infection can contribute to making the BBB more permeable to the virus (Kaur & Ling, 2008;Zhou, Kang, et al., 2020).
Hence, ACE2 may be a potential target of COVID-19 upon the entrance into the CNS, triggering its effects on CNS tissue . The presence of the virus in the central nervous system is also supported by some evidence reporting COVID-19 in the CSF of the infected cases (Moriguchi et al., 2020;Zhou, Zhang, et al., 2020).
In our meta-analysis, the mortality rate of COVID-19 cases with at least one CNS symptom was 10.47%, which is much higher than the mortality rate of the general infected population ( patients. This may be due to the effect of COVID-19 on the brain stem and suppression of the cardiorespiratory control centers causing respiratory failure and death . Moreover, recent studies have shown that COVID-19 can accelerate the formation of the blood clot in the blood vessels, increasing the risk of cerebrovascular diseases in COVID-19 patients Hess et al., 2020). Hence, because the brain is nourished with increased severity and mortality . Not only respiratory system dysfunction, but also impairment of respiratory control centers in the CNS (brain stem) can induce acute respiratory failure (Carvalho et al., 2011;Li, Bai, et al., 2020). Therefore, considering all effective factors, it can provide clinicians to choose the best way in an attempt to manage this pandemic more efficiently.

| LI M ITATI O N S
There are several limitations in our systematic review and metaanalysis. Since in this ongoing pandemic, most of the investigations have conducted on typical signs and symptoms of COVID-19. Thus, the number of studies on the atypical complications of COVID-19, such as CNS presentations, is partially low. Moreover, there exist many COVID-19 preprint papers that have not yet undergone peer review. Additionally, five studies included in our meta-analysis reported headache and/or dizziness as one symptom in COVID-19 cases. Because we were not sure that headache and/or dizziness is resulted from headache or is a consequence of the dizziness, it would be challenging to categorize headache and/or dizziness in the subgroup of dizziness or headache. Hence, in our meta-analysis, it was not reported as a CNS manifestation and is implied as a separate symptom (Table 3).

| CON CLUS ION
COVID-19 is a global problem that currently affects millions of people. This highly pathogenic virus can affect various parts of the human body. Although the respiratory tract has been mainly targeted by COVID-19, the central nervous system can be affected significantly.
In addition, patients with more severe illness showed more CNS symptoms, which may bring on worsen clinical conditions. This study achieved an important estimation for the incidence of neurological

ACK N OWLED G M ENTS
Dr. Katayoun Alikhani for her supports and comments.

CO N FLI C T O F I NTE R E S T
None.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.2025.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly available.