key: cord-0752787-77ln4lw8
authors: He, Yuanyuan; Bai, Xiaojie; Zhu, Tiantian; Huang, Jialin; Zhang, Hong
title: What can the neurological manifestations of COVID-19 tell us: a meta-analysis
date: 2021-08-23
journal: J Transl Med
DOI: 10.1186/s12967-021-03039-2
sha: ea2a991f7e43095cc846dd295ab529e739a71b7d
doc_id: 752787
cord_uid: 77ln4lw8

BACKGROUND: Covid-19 became a global pandemic in 2019. Studies have shown that coronavirus can cause neurological symptoms, but clinical studies on its neurological symptoms are limited. In this meta-analysis, we aimed to summarize the various neurological manifestations that occurred in COVID-19 patients and calculate the incidence of various neurological manifestations. At the same time, we further explored the mechanism of nervous system injury and prognosis in COVID-19 patients in combination with their nervous system manifestations. This study provides a reference for early clinical identification of COVID-19 nervous system injury in the future, so as to achieve early treatment and reduce neurological sequelae. METHODS: We systematically searched all published English literature related to the neurological manifestations of COVID-19 from January 1, 2020, to April 30, 2021, in Pubmed, Embase, and Cochrane Library. The keywords used were COVID-19 and terminology related to the nervous system performance. All included studies were selected by two independent reviewers using EndNote and NoteExpress software, any disagreement was resolved by consensus or by a third reviewer, and the selected data were then collected for meta-analysis using a random-effects model. RESULTS: A total of 168 articles (n = 292,693) were included in the study, and the meta-analysis showed that the most common neurological manifestations of COVID-19 were myalgia(33%; 95%CI 0.30–0.37; I(2) = 99.17%), smell impairment(33%; 95%CI 0.28–0.38; I(2) = 99.40%), taste dysfunction(33%; 95%CI 0.27–0.39; I(2) = 99.09%), altered mental status(32%; 95%CI 0.22–0.43; I(2) = 99.06%), headache(29%; 95%CI 0.25–0.33; I(2) = 99.42%), encephalopathy(26%; 95%CI 0.16–0.38; I(2) = 99.31%), alteration of consciousness(13%; 95%CI 0.08–0.19; I(2) = 98.10%), stroke(12%; 95%CI 0.08–0.16; I(2) = 98.95%), dizziness(10%; 95%CI 0.08–0.13; I(2) = 96.45%), vision impairment(6%; 95%CI 0.03–0.09; I(2) = 86.82%), intracerebral haemorrhage(5%; 95%CI 0.03–0.09; I(2) = 95.60%), seizure(4%; 95%CI 0.02 -0.05; I(2) = 98.15%), encephalitis(2%; 95%CI 0.01–0.03; I(2) = 90.36%), Guillan-Barré Syndrome (GBS) (1%; 95%CI 0.00–0.03; I(2) = 89.48%). CONCLUSIONS: Neurological symptoms are common and varied in Covid-19 infections, and a growing number of reports suggest that the prevalence of neurological symptoms may be increasing. In the future, the role of COVID-19 neurological symptoms in the progression of COVID-19 should be further studied, and its pathogenesis and assessment methods should be explored, to detect and treat early neurological complications of COVID-19 and reduce mortality.

At the end of December 2019, an epidemic of COVID-19 occurred in Wuhan, Hubei Province, China. As the epidemic has spread, cases have been found in many countries. At the time of writing, it has spread to more than 200 countries and regions, with a total of 187,637,579 confirmed cases and 4,066,292 death. Coronavirus has caused two fatal outbreaks in the past, the first in China in 2003, with a 10 percent mortality rate; The second outbreak was Middle East Respiratory Syndrome (MERS) in Saudi Arabia in 2012, with a mortality rate of 35% [1, 2] . Novel Coronavirus was named severe acute respiratory syndrome coronavirus Type 2 (SARS-COV-2). Sars-Cov-2 is a single-stranded RNA coronavirus, belonging to the same -coronavirus branch as SARS-COV and MERS-CoV. Its genome sequence is 89.1% similar to the nucleotide sequence of a group of SARS-like coronaviruses. Studies have found that the viral structure and receptor binding domain of SARS-COV-2 is similar to that of SARS-COV, and both of them enter human cells by binding to ACE2 receptors [3, 4] . To evaluate the genetic variation of SARS-COV-2, 86 complete or nearly complete genomes were genetically analyzed, and many mutations and deletions were found in both coding and non-coding regions [5] . At present, the biological characteristics and genetic variation of SARS-COV-2 are still not very clear and deserve further study.

Although COVID-19 is typically characterized by respiratory symptoms, numerous clinical studies have shown that patients infected with SARS-COV-2 are associated with acute injuries to external pulmonary organs, including the heart, digestive tract, liver, kidney, and nervous system [6, 7] . More and more clinical evidence indicates that SARS-COV-2 may invade the central nervous system. A retrospective analysis of 214 patients with COVID-19 found that 78 (36.4%) had nervous system involvement, and 28.2% of them had severe central nervous system injury [8] . Studart-Neto A et al. retrospectively analyzed 1208 patients with COVID-19 and found that 89 (7.4%) presented neurological manifestations, including encephalopathy (44.4%), stroke (16.7%), epilepsy (9.0%), neuromuscular disease (5.6%), another acute brain injury (3.4%), and other mild non-specific diseases (11.2%) [9] . Takeshi et al. detected SARS-COV-2 RNA in cerebrospinal fluid specimens, providing direct evidence for the nervous invasiveness of SARS-COV-2 [10] . There are three main types of COVID-19 nervous system involvement: (1) central nervous system involvement, such as dizziness, headache, disturbance of consciousness, acute cerebrovascular disease, and epilepsy;

(2) peripheral nervous system involvement, including anosmia, decreased taste, decreased vision, and neuralgia; (3) skeletal muscle injury [11, 12] .COVID-19 possible mechanisms include: nerve injury by angiotensin-converting enzyme (ACE2) receptor function, blood and break through the blood-brain barrier, through the way such as the olfactory nerve attack the nervous system [13, 14] .

Since nervous system manifestations are an important part of COVID-19 patients' clinical manifestations, early detection and treatment of nerve injury in COVID-19 patients is of great significance for their prognosis and reduction of neurological sequelae. This study aims to further summarize the incidence and characteristics of various nervous system manifestations in COVID-19 patients, and explore the mechanism and prognosis of nervous system injury in combination with nervous system manifestations, so as to provide positive clinical significance for better epidemic prevention and control and clinical diagnosis and treatment in the future.

We searched the following electronic databases for literature published between 1 January 2020 and April 30, 2021: Pubmed, Embase and the Cochrane Library. The search terms used include: ((severe acute respiratory syndrome coronavirus 2) OR (SARS-CoV-2) OR (2019-nCoV) OR (2019 novel coronavirus) OR (COVID- 19) OR (coronavirus) OR (novel coronavirus pneumonia) OR (NCP)) AND ((neurologic manifestations) OR (neurological manifestations) OR (neurologic manifestation) OR (neurologic signs and symptoms) OR (neurological manifestation) OR (neurologic deficits) OR (neurologic deficit) OR (neurologic symptoms) OR (neurologic symptom) OR (neurologic findings) OR (neurologic finding) OR (neurologic signs) OR (neurologic sign) OR (neurologic dysfunction) OR (neurologic dysfunctions) OR (nervous system diseases) OR (nervous system disease) OR (neurologic disorders) OR (neurologic disorder) OR (neurological disorders) OR (neurological disorder) OR (nervous system disorders) OR (nervous system disorder) OR (neurological complication) OR (neurological complications) OR (nerve function injury)).

The inclusion criteria for this study are as follows: all English literature from 1 January 2020 solstices 30 April 2021 that has been published reporting neurological manifestations of COVID-19 patients. Studying types include case-control studies, cohort studies, cross-sectional studies, and case series. Only those subjects who were diagnosed with SARS-COV-2 infection by realtime reverse transcription-polymerase chain reaction or by high-throughput sequencing of swab samples were included in the study. Only those studies whose results included specific neurological manifestations were included.

Exclusion criteria included: (1) no clinical manifestations of related neurological symptoms and lack relevant data; (2) Age < 18 years old; (3) Repeated studies; (4)

Our study synthesizes the results of several similar studies to provide a quantitative summary. The extracted data details and instructions are presented in tables and figures. We used Stata (version 15.1) for the meta-analysis. I 2 was calculated to assess the level of heterogeneity and can be divided into four categories: maybe unimportant (0-40%), may represent moderate heterogeneity (30-60%), may represent significant heterogeneity (50-90%) and significant heterogeneity (75-100%) . In this study, a fixed-effect model or random-effect model was used to calculate the comprehensive prevalence rate and 95% confidence interval. When there was no heterogeneity, the fixed effect model was selected; when there was heterogeneity, a random effect model was selected. Forest maps are used to visually indicate the magnitude of the effects that the study summarizes and their 95% confidence intervals. Funnel plot and Egger's test were used to assess the publication bias of all literature, and P < 0.05 was considered statistically significant.

A total of 8812 studies were selected from the database, including 5789 in Pubmed, 2971 in Embase, and 52 in the Cochrane Library. After eliminating duplicate studies (n = 1916), 6896 studies met the preliminary screening criteria based on titles and abstracts. After excluding review, mata analysis, case report, age < 18, animal experiment and literature with inconsistent research contents (n = 6483), the remaining 413 articles were screened according to the inclusion and exclusion criteria. After the full-text screening, 168 articles (N = 292,693) were included in the meta-analysis. Figure 1 shows the details and characteristics of the 16 included studies divided into severe and non-severe groups. Included studies had good methodological quality (Figs. 2, 3, 4, 5 ).

According to our meta-analysis, the most common neurological manifestations of COVID-19 patients were myalgia (33%), smell impairment (33%), taste dysfunction (33%) and altered mental status (32%). It can be seen that both the central nervous system and peripheral nervous system will be involved after patients are infected with SARS-CoV-2. At the same time, considering the difference between symptoms and diseases, our study can conclude that the most common central nervous system symptoms are altered mental status (32%), headache (29%), alteration of consciousness (13%), and dizziness (10%). The most common central nervous system (CNS) disorders were encephalopathy (26%), stroke (12%), intracerebral haemorrhage (5%), seizure (4%), and encephalitis (2%). The most common symptoms of peripheral nervous system (PNS) impairment were myalgia (33%), smell impairment (33%), taste dysfunction (33%) and vision impairment (6%). Guillan-Barre Syndrome (GBS) occurs in approximately 1% of peripheral nervous system disorder.

In addition, COVID-19 involvement in the peripheral nervous system includes other manifestations, such as cranial neuropathy and neuromuscular joint disease, etc. However, since only a few studies have reported such cases, and most of these studies were case reports, these less frequent COVID-19 peripheral nervous system manifestations were not included in this study. In the future, as more and more of these studies are reported, we can conduct further research.

Among 168 studies that were finally included in the meta-analysis, 123 studies discussed the incidence of headache, 106 studies discussed smell impairment, 86 studies discussed myalgia, and 80 studies discussed taste dysfunction. In our opinion, this also indirectly indicates that COVID-19 patients have symptoms of headache, smell impairment, myalgia and smell impairment earlier and have more cases, which is worthy of further study and discussion, to provide a diagnosis and treatment direction for early intervention in the future.

In 16 of the included studies, patients were divided into severe and non-severe groups for detailed analysis according to the severity of COVID-19 infection in patients. We found that the most studied neurological manifestations in this literature were headache, dizziness, seizure, myalgia, smell impairment and taste dysfunction. Our results showed that there was no significant difference in the incidence of headache between the two groups, both at 16%; the incidence of dizziness and seizure in the severe COVID-19 group was higher than that in the non-severe group (12% VS 9%, 3% VS 1%, respectively). The incidence of myalgia, smell impairment and taste dysfunction in the severe COVID-19 group was lower than that in the non-severe group, which was 21% VS 24%, 8% VS 13%, 9% VS 14%, respectively. However, considering that the severity of COVID-19 disease is not classified the same according to different prevalence periods of COVID-19 and its prevalence in different countries, our statistical data may be biased to a certain extent, and the statistical results may lack a certain scientific nature. At the same time, there are still limited studies on various neurologic characteristics of COVID-19 under different severity, which deserves more research and exploration.

We also found that altered mental status, encephalopathy, and alteration of consciousness were reported separately, but they may be related to each other. Through reading different literature, we found that different researchers have different definitions of the above three aspects. Josef Anrather et al. [181] argue that altered mental status (e.g., confusion, disorientation, emotional restlessness and lethargy) can be collectively referred to as encephalopathy. Emad Nader Eskandar et al. [130] suggested that if there was evidence of cognitive impairment (e.g., confusion, disorientation, agitation or delirium) or impaired arousal (e.g., lethargy or dullness), the patient can be included in the altered mental status cohort. In another study, altered mental status was defined as including personality, behavior, cognition, and consciousness changes; encephalopathy, encephalitis; catatonia, mania, anxiety or depression, etc. [131] . We recognize that there may be overlapped parts among altered mental status, encephalopathy and alteration of consciousness, but they can all indicate that the central nervous system of patients is damaged, so their clinical reference value is not affected.

ACE2 has been proved to be a functional receptor of SARS-CoV-2, which binds to the ACE2 receptor through its Spike (S) protein C-terminal domain (CTD) [182] . The expression profile of ACE2 is very extensive, and it is expressed in various regions of the human brain, such as the ventricle, motor cortex and posterior cingulum gyrus, middle temporal gyrus, substantial nigra, olfactory bulb, contralateral medulla oblongata, nucleus solitaries, vagus nerve, neurons, astrocytes, microglia and oligodendroglia, etc. [183, 184] . Therefore, the nervous system is at risk of SARS-COV-2 infection. The mechanism of nervous system injury in COVID-19 patients includes cross-neuronal hypothesis, homogenous transmission and BBB transmission, hypoxia, inflammatory response and hypercoagulability and immune mechanism as well.

In the following sections, we will analyze and discuss the relationship between the neurological manifestations we have studied and the corresponding mechanisms of neurological damage.

The altered mental status and alteration of consciousness of COVID-19 patients may be a systemic consequence of the over-activation of the body's immune response or may be caused by the direct invasion of the nerves by SARS-COV2 [185, 186] . Hypoxia, organ dysfunction, the need for large doses of sedatives, and prolonged isolation may also contribute to consciousness changes [181] .

Headaches and dizziness can be caused by a variety of causes. One reason may be the large and rapid increase of inflammatory cytokines, including IL-1, IL-6, and TNFα, after infection. It can also cause pain if the virus invades the nervous system directly and damages the nerve. Hypoxia leads to the accumulation of acid in brain cells, swelling, and interstitial edema, resulting in cerebral vasodilation or cerebral blood flow obstruction, etc., which is also considered as one of the potential mechanisms of causing headache [185] .

Because there are ACE2 receptors in skeletal muscle [187] , direct cytotoxicity caused by the interaction between SARS-CoV-2 and ACE2 in skeletal muscle should be considered. Secondly, muscle injury may be related to the harmful immune response mediated by infection and the increase of pro-inflammatory cytokines [8] . Elevated concentrations of C-reactive protein and D-dimer in the blood may induce the expression of a strong immune response, leading to direct immune-mediated nerve and muscle injury [188] . At the same time, prolonged mechanical ventilation or the use of neuromuscular blockers in patients with severe COVID-19 infection is also closely related to the progression of critical myopathy [189] .

Studies have shown that the anosmia of most COVID-19 patients has nothing to do with rhinorrhea or nasal obstruction, and may be related to the transmission of the virus through olfactory nerve epithelial cells and further invasion of the olfactory bulb and central nervous system [43, 190] . It has been reported that higher levels of angiotensin can induce the apoptosis effect of neural stem cells [191] , reducing the number of nerve cells migrating to the olfactory bulb, resulting in reduced replacement of 19:363 new neurons in the olfactory bulb, and interference with the smell. Animal experiments have shown that SARS-CoV-2 may invade the brain retrograde along with taste and trigeminal nerve pathways in the early stage of infection, causing lesions such as taste disturbance [192] .

Patients with COVID-19 may develop many types of encephalopathy. The combination of SARS-CoV-2 virus and ACE2 receptor increases peripheral vascular resistance, leading to a significant and rapid increase in blood pressure, triggering a cascade reaction that leads to the destruction of blood-brain barrier integrity, cerebral hyperperfusion, and cerebral edema, leading to the development of hypertensive encephalopathy [193, 194] . Hypoxia, insufficient energy supply, or overall insufficiency after severe brain injury can progress to hypoxicischemic encephalopathy. Steatosis, liver function damage, or cardiovascular dysfunction after COVID-19 infection may induce the occurrence of hepatic encephalopathy, which may be related to direct liver damage of SARS-CoV-2 or the side effects of some drugs [195, 196] .

In addition, recent studies have found an increased incidence of acute renal damage after SARS-CoV-2, and the pathophysiological mechanism remains unclear, which may also be caused by an inflammatory response, ACE/ ACE2 imbalance, or dysfunction of other organs (such as the heart). When patients have renal insufficiency, the body cannot completely discharge toxins and regulate the concentration of cytokines normally, and the brain homeostasis will be destroyed, leading to uremic encephalopathy [197] . When SARS-CoV-2 enters the human body through ACE2, the human body immediately generates an immune response. When the virus invades the brain, it will cause immune damage and lead to the attack of encephalitis [198] . Encephalitis may also be associated with blood-brain barrier disruption and cytokine surges [199] .

SARS-CoV-2 directly invades the nerve through ACE2 receptors and deregulation of blood pressure is the potential mechanism of COVID-19 stroke [200, 201] . Continuous hypoxia in COVID-19 patients will eventually lead to disorders in neurotransmitter metabolism and mitochondrial failure, causing irreversible nerve damage and increasing the risk of stroke [202] . Studies have shown that increased inflammatory markers such as IL-2, IL-6, macrophage inflammatory protein 1-α or coagulation dysfunction in patients with severe COVID-19 may increase the likelihood of stroke compared with moderate patients [200] . After the SARS-CoV-2 virus binds to the ACE2 receptor, it can lead to increased blood pressure, which may lead to hypertensive crisis in severe cases and increase the risk of intracranial hemorrhage [188] .

The process of SARS-CoV-2 virus replication in host cells disrupts neuronal function and manifests as seizures, convulsions, and loss of consciousness [203] . The increase of pro-inflammatory mediators may contribute to epileptic seizures, which in turn enhance the production of cytokines such as IL-1B and TNFα [204] . After the destruction of the blood-brain barrier, inflammatory factors and viral particles flood into the central nervous system, leading to brain damage that can lead to epileptic seizures [188] .

Guillain-Barre syndrome (GBS) is an increasing occurrence in patients with COVID-19, a typical viral autoimmune nervous system disease caused by a strong immune response, which includes a range of polyneuropathy characterized by acute motor weakness, mild to moderate paresthesia, cranial nerve involvement, and muscle or nerve root pain [205] . At present, large sample studies on GBS are still lacking, and most researchers express their views in the form of case reports.

A prospective study showed that total Tau, GFAP, and NFL protein levels in cerebrospinal fluid were elevated in 63, 37, and 16% of patients, respectively, and NFL protein was associated with disease severity, duration of intensive care, and level of consciousness [206] . Multiple studies on COVID-19 patients with ischemic stroke have shown that the neutrophil-lymphocyte ratio (NLR) is increased in 90% of the patients [207] , CRP is increased in over 90% of the patients [208] , and serum ferritin is also increased [209] , in which serum ferritin can also predict the degree of nerve injury in patients with acute ischemic stroke [210] . There was a significant correlation between the decrease of interleukin-6 level and the improvement of olfaction and taste function in COVID-19 patients [211] . Elevated serum nerve filament light chain (SNFL) levels in critically ill patients with COVID-19 are closely associated with poor prognosis [212] .

In our study, stroke incidence was 12%, intracerebral hemorrhage 5%, encephalopathy 26% and encephalitis 2%. Studies have shown that patients with COVID-19 with acute neuroimaging abnormalities are more likely to have an ischemic stroke. Neuroimaging features of these patients are not invariable but are predominated by acute ischemic infarction, intracranial hemorrhage, and leukoencephalopathy [81] . COVID-19 is an independent risk factor for acute ischemic stroke and a valid indicator of poor prognosis. Meningitis and encephalitis are not very common [213, 214] . In one study, continuous EEG monitoring was performed in 11 of 16 patients with COVID-19, most of whom presented with nonspecific encephalopathy [215] . At the same time, some studies also found significant structural changes in the olfactory nerve, olfactory bulb, olfactory cortex and other olfactory pathways in MRI examination of COVID-19 patients, suggesting that SARS-CoV-2 may enter the central nervous system through the olfactory bulb mediated crossneuronal pathway [94, 95] . The relationship between COVID-19 imaging changes and neurological symptoms requires more research.

Nervous system damage is closely associated with the mortality of SARS-COV-2 infection, and whether the neurological symptoms are reversible is not yet clear. Patients with COVID-19 who require ICU admission for neurological problems or develop neurological dysfunction in the ICU have significantly increased mortality [216] .

In one animal study, 4 out of 14 infected mice developed significant respiratory distress and neurological symptoms 2 days after infection, and only the mice showing neurological symptoms died, suggesting that neurological involvement may be a cause of death [217] . Some studies have confirmed that recovery from acute SARS-CoV-2 infection does not completely clear the virus, and has been found to have a higher potential risk for long-term residual neuropsychiatric and neuroscientist impairments, including depression, obsessive-compulsive disorder, psychosis, Parkinson's disease and Alzheimer's disease [218] . An experimental animal study has also shown that coronavirus can persist in the central nervous system of its host [219] . The study results of Helms et al. showed that 36% of severe COVID-19 survivors developed Dysfunction Syndrome [220] , and some studies also reported that patients with severe dysfunction after the acute phase had significant recovery after active neurological rehabilitation [221] . In a prospective study, 68.33% of patients developed neurological symptoms during infection with SARS-CoV-2, and 50% recovered 3 months after infection but still had neurological symptoms [213] . Imaging results of 60 patients after recovery of COVID-19 neurological symptoms suggest that the microstructure and functional brain integrity of the brain may be damaged during the rehabilitation phase, which may require long-term neurological and neuroimaging follow-up [214] .

Our meta-analysis included 168 articles (n = 292,693) detailing the various neurologic symptoms common in COVID-19 patients and providing a comprehensive view of the neurologic symptoms of COVID-19. The results were comprehensive. We started the discussion of the clinical manifestations and analyzed the evidence, possible mechanism and prognosis of the nervous system injury caused by SARS-CoV-2. We also discussed the biomarkers and examination methods of nervous system injury caused by SARS-COV-2, providing some valuable suggestions for early identification, monitoring, screening, diagnosis and follow-up of nervous system injury and poor prognosis in patients with COVID-19 and potential targets for future clinical intervention strategies. This study also has some limitations. Firstly, most of the included literature was retrospective studies, which may cause some potential bias. Secondly, this study failed to provide an analysis of the correlation between various neurological manifestations and disease severity and mortality. The question of which neurological manifestations are the most insidious and which are the most difficult to recover from is currently unanswered, and more findings will be needed in the future. Finally, the high degree of heterogeneity in our study may be due to differences in patient race selection, disease severity, comorbidities, only a few studies specifically assessed neurological symptoms, differences in the number of patients in different studies, or differences in publication bias and study methodology.

In conclusion, our study suggests that nervous system expression in COVID-19 is diverse and pervasive but easily underestimated. Therefore, the long-term pathophysiological results of SARS-COV-2 neuropathy should be of serious concern to us. At the same time, summarizing the entire symptom spectrum, biomarkers and examination methods of the disease is conducive to predicting the severity of neurological impairment and providing better suggestions for preventing misdiagnosis, early diagnosis, preventing disease transmission, early intervention treatment, evaluation of therapeutic effect and follow-up. In the future, more clinical and experimental studies should be carried out to provide strong evidence to support clinical practice, and further, explore the role of nervous system symptoms in the incidence of COVID-19 and its possible mechanism, to reduce mortality, reduce disease severity, control disease progression and prevent possible long-term nervous system complications.

Proteomics. Tissue-based map of the human proteome

COVID-19: a global threat to the nervous system

Understanding the neurotropic characteristics of SARS-CoV-2: from neurological manifestations of COVID-19 to potential neurotropic mechanisms

Neurological insights of COVID-19 pandemic

Genetic diversity and evolution of SARS-CoV-2

Extra-respiratory manifestations of COVID-19

Neuropathogenesis of SARS-CoV-2 infection

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan

Neurological consultations and diagnoses in a large, dedicated COVID-19 university hospital

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

Neurologic involvement in COVID-19: radiologists' perspective

Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) Outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention

Neurological associations of COVID-19

Taste and smell dysfunction in COVID-19 patients

Demographic characteristics and neurological comorbidity of patients with COVID-19

Neurological manifestations in 404 COVID-19 patients in Washington State

Relationship between anosmia and hospitalisation in patients with coronavirus disease 2019: an otolaryngological perspective

Olfactory and oral manifestations of COVID-19: sex-related symptomsa potential pathway to early diagnosis

Main symptoms in patients presenting in the COVID-19 period

Headache: a striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution

Prevalence and recovery from olfactory and gustatory dysfunctions in Covid-19 infection: a prospective multicenter study

Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study

Acute cerebrovascular events in hospitalized COVID-19 patients

Cerebrovascular events and outcomes in hospitalized patients with COVID-19: The SVIN COVID-19

Multinational Registry

Brain MRI findings in severe COVID-19: a retrospective observational study

Early neurological manifestations of hospitalized COVID-19 patients

Cerebrospinal fluid findings in neurological diseases associated with COVID-19 and insights into mechanisms of disease development

Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019

Characteristics, onset, and evolution of neurological symptoms in patients with COVID-19

Clinical and neuroimaging correlation in patients with COVID-19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

COVID-19 and stroke: incidence and etiological description in a high-volume center

A Prospective study of neurologic disorders in hospitalized patients with COVID-19 in

Features of anosmia in COVID-19

Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19

Frequency and type of red flags in patients with Covid-19 and headache: a series of 104 hospitalized patients

Frequency of neurological presentations of coronavirus disease in patients presenting to a tertiary care hospital during the 2019 coronavirus disease pandemic

The frequency of neurological symptoms in COVID-19 patients at a tertiary care hospital in Pakistan

Headache associated with COVID-19: frequency, characteristics and association with anosmia and ageusia

Imaging of neurologic disease in hospitalized patients with COVID-19: an Italian multicenter retrospective observational study

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients

Loss of smell and taste in 2013 European patients with mild to moderate COVID-19

Nervous system: subclinical target of SARS-CoV-2 infection

Subjective neurological symptoms frequently occur in patients with SARS-CoV2 infection

Neurological features in SARS-CoV-2-infected patients with smell and taste disorder

Neurological implications of non-critically ill patients with coronavirus disease 2019 in a Fangcang Shelter Hospital in Wuhan

Neurologic manifestations associated with COVID-19: a multicentre registry

Neurological predictors of clinical outcomes in hospitalized patients with COVID-19

Neurological symptoms as initial manifestation of Covid-19-an observational study

Remote psychophysical evaluation of olfactory and gustatory functions in early-stage coronavirus disease 2019 patients: the Bologna experience of 300 cases

Self-reported anosmia and dysgeusia as key symptoms of coronavirus disease 2019

Neurosensory dysfunction: a diagnostic marker of early COVID-19

New loss of smell and taste: uncommon symptoms in COVID-19 patients on Nord Franche-Comte cluster

New onset neurologic events in people with COVID-19 in 3 regions in China

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study

Prevalence and duration of acute loss of smell or taste in COVID-19 patients

A prospective clinical study of detailed neurological manifestations in patients with COVID-19

Self-reported loss of smell and taste in SARS-CoV-2 patients: primary care data to guide future early detection strategies

Objective evaluation of anosmia and ageusia in COVID-19 patients: single-center experience on 72 cases

Smell and taste disorders during COVID-19 outbreak: cross-sectional study on 355 patients

Symptom profiles and risk factors for hospitalization in patients with SARS-CoV-2 and COVID-19: a large cohort from South America

Time course of anosmia and dysgeusia in patients with mild SARS-CoV-2 infection

gustatory and olfactory dysfunctions in patients with COVID-19

Acute olfactory loss is specific for COVID-19 at the emergency department

Acute-onset smell and taste disorders in the context of COVID-19: a pilot multicentre polymerase chain reaction based case-control study

Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection

Evaluation of the clinical profile, laboratory parameters and outcome of two hundred COVID-19 patients from a tertiary centre in India. Monaldi Arch Chest Dis

Assessment of neurological manifestations in hospitalized patients with COVID-19

Ear nose throat-related symptoms with a focus on loss of smell and/or taste in COVID-19 patients

Characteristics, complications and outcomes among 1549 patients hospitalised with COVID-19 in a secondary hospital in Madrid, Spain: a retrospective case series study

Clinical characteristics of laboratory confirmed positive cases of SARS-CoV-2 infection in Wuhan, China: a retrospective single center analysis

Clinical features of COVID-19 and influenza: a comparative study on Nord Franche-Comte cluster

COVID-19)-associated encephalopathies and cerebrovascular disease: the New Orleans Experience

Altered mental status in 71 deaths due to COVID-19

Anosmia and dysgeusia associated with SARS-CoV-2 infection: an age-matched case-control study

Anosmia in COVID-19 patients

Anosmia as a prominent symptom of COVID-19 infection

Assessment of brain injury using portable, low-field magnetic resonance imaging at the bedside of critically ill patients

Association of chemosensory dysfunction and COVID-19 in patients presenting with influenza-like symptoms

Brain and lung imaging correlation in patients with COVID-19: could the severity of lung disease reflect the prevalence of acute abnormalities on neuroimaging? A global multicenter observational study

Brain imaging use and findings in COVID-19: a single academic center experience in the epicenter of disease in the United States

Brain imaging of patients with COVID-19: findings at an academic institution during the height of the outbreak in New York City

Cerebrospinal fluid features in patients with coronavirus disease 2019 and neurological manifestations: correlation with brain magnetic resonance imaging findings in 58 patients

Characteristics and outcomes of 100 consecutive patients with acute stroke and COVID-19

Chemosensory dysfunction in COVID-19: prevalences, recovery rates, and clinical associations on a large Brazilian sample

Clinical and radiological characteristics of acute cerebrovascular diseases among egyptian patients with COVID-19 in upper Egypt

Clinical characteristics and outcomes of covid-19 cohort patients in Daegu Metropolitan City outbreak in 2020

The clinical characteristics and prognosis of COVID-19 patients with cerebral stroke: a retrospective study of 113 cases from one single-centre

Clinical characteristics of asymptomatic and symptomatic patients with mild COVID-19

Clinical characteristics, symptoms and outcomes of 1054 adults presenting to hospital with suspected COVID-19: a comparison of patients with and without SARS-CoV-2 infection

Clinical description of the broad range of neurological presentations of COVID-19: a retrospective case series

Clinical manifestations and factors associated with mortality from COVID-19 in older adults: retrospective population-based study with 9807 older Brazilian COVID-19 patients

Clinical presentation and outcomes of the first patients with COVID-19 in Argentina: results of 207079 cases from a national database

Clinical, cerebrospinal fluid, and neuroimaging findings in COVID-19 encephalopathy: a case series

Contribution of anosmia and dysgeusia for diagnostic of COVID-19 in outpatients

Coronavirus disease 2019: new things to know

The coronavirus disease 2019: the prevalence, prognosis, and recovery from olfactory dysfunction (OD)

COVID-19 impact on consecutive neurological patients admitted to the emergency department

Covid-19 in outpatients-Is fever a useful indicator for SARS-CoV-2 infection?

Coronavirus positive patients presenting with stroke-like symptoms

COVID-19 respiratory illness and subsequent cerebrovascular events, the initial iranian experience

COVID-19 viral load in the severity of and recovery from olfactory and gustatory dysfunction

COVID-19 symptoms predictive of healthcare workers' SARS-CoV-2 PCR results

COVID-19 with and without anosmia or dysgeusia: a case-control study

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New-onset anosmia and ageusia in adult patients diagnosed with SARS-CoV-2 infection

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Olfactory and gustatory dysfunctions as a clinical manifestation of Coronavirus Disease 2019 in a Malaysian Tertiary Center

Olfactory and gustatory outcomes in COVID-19: a prospective evaluation in nonhospitalized subjects

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Olfactory dysfunction in COVID-19 patients: findings from a tertiary rural centre

Otolaryngological manifestations of hospitalised patients with confirmed COVID-19 infection

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Objective olfactory evaluation of self-reported loss of smell in a case series of 86 COVID-19 patients

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Presenting symptoms of COVID-19 and clinical outcomes in hospitalised older adults

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Quantitative detection of SARS-CoV-2 RNA in nasopharyngeal samples from infected patients with mild disease

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Symptomatology of COVID-19 from the otorhinolaryngology perspective: a survey of 223 SARS-CoV-2 RNA-positive patients

Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China

Smell and taste alterations in COVID-19: a cross-sectional analysis of different cohorts

Smell and taste dysfunction in COVID-19 is associated with younger age in ambulatory settings: a multicenter cross-sectional study

Strong associations and moderate predictive value of early symptoms for SARS-CoV-2 test positivity among healthcare workers, the Netherlands

A structural equation model to examine the clinical features of mild-to-moderate COVID-19: a multicenter Italian study

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Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID-19

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SARS-CoV-2 and stroke in a New York healthcare system

COVID-19 presenting as stroke

Biological signatures of brain damage associated with high serum ferritin levels in patients with acute ischemic stroke and thrombolytic treatment

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ZH and HY proposed the research idea. HY completed the data analysis and paper writing and was a major contributor in writing the manuscript.BX and ZT were responsible for literature retrieval and data extraction.HJ finished the quality evaluation. All authors read and approved the final manuscript.

"Prevention, control, and treatment" three-ring linkage, major emergency rescue medical team construction research. Health soft science research key project of Anhui province in 2020.

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The authors declare that they have no competing interests.