key: cord-253201-r6vsa0pw
authors: Nazari, S.; Azari Jafari, A.; Mirmoeeni, S.; Sadeghian, S.; Heidari, M. E.; Asarzadegan, F.; Puormand, S. M.; Alikhani, K.; Ebadi, H.; Fathi, D.; Dalvand, S.
title: Central Nervous System Manifestations in COVID-19 Patients: A Systematic Review and Meta-analysis
date: 2020-07-22
journal: nan
DOI: 10.1101/2020.07.21.20158691
sha: 
doc_id: 253201
cord_uid: r6vsa0pw

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 January 1st, 2020, to April 20th, 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 2353 retrieved studies, we selected 64 studies with 11282 patients after screening. Most of the studies were conducted in China (58 studies). The most common CNS symptom of COVID-19 were Headache (8.69%, 95%CI: 6.76%-10.82%), Dizziness (5.94%, 95%CI: 3.66%-8.22%), and Impaired consciousness (1.9%, 95%CI: 1%-2.79%). Conclusions: The growing number of studies have 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.

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At the end of December 2019, a novel respiratory syndrome, currently known as COVID-19, was reported in Wuhan city, Hubei province, China, and the first sign of this 2019 novel coronavirus infection (2019-nCoV, COVID-19) was pneumonia [1] [2] [3] [4] [5] [6] [7] . This new infection rapidly spread worldwide, and an increasing number of infected cases and deaths have been reported globally [8, 9] . 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 [10, 11] . 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 [11, 12] . 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 [7, [13] [14] [15] .

However, a growing number of COVID-19 patients are presenting with different combinations of the central nervous system (CNS) manifestations [16] [17] [18] . Several case reports have indicated the presence of various CNS complications, including encephalitis, stroke, meningitis, and encephalopathy in COVID-19 patients [19] [20] [21] [22] . Furthermore, a large observational study carried out by Mao et al. show the prevalence of the CNS presentations such as dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure [16] . 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.

("Wuhan coronavirus" OR "Wuhan seafood market pneumonia virus" OR "COVID19 virus" OR "COVID-19 virus" OR "coronavirus disease 2019 virus" OR "SARS-CoV-2" OR "SARS2" OR "2019-nCoV" OR "2019 novel coronavirus" OR "2019-nCoV infection" OR "2019 novel coronavirus disease" OR "2019-nCoV disease" OR "coronavirus disease-19" OR "coronavirus disease 2019" OR "2019 novel coronavirus infection" OR "COVID19" OR "COVID-19" OR "severe acute respiratory syndrome coronavirus 2" OR "coronavirus*") AND ("Manifestation, Neurologic" OR "Neurological Manifestations" OR "Neurologic Manifestation" OR "Neurological Manifestation" OR "Neurologic Symptom" OR "CNS" OR "brain" OR "neuro*"

OR "headache" OR "dizziness" OR "ataxia" OR "epilepsy" OR "seizure" OR "migraine*" OR "CSF" OR "Cerebrospinal Fluids" OR "Fluid, Cerebrospinal" OR "Fluids, Cerebrospinal" OR "Cerebro Spinal Fluid" OR "Cerebro Spinal Fluids" OR "Fluid, Cerebro Spinal" OR "Fluids, Cerebro Spinal" OR "Spinal Fluid, Cerebro" OR "Spinal Fluids, Cerebro" OR "stroke" OR "vertigo" OR "consciousness" OR "Impaired consciousness" OR "coma" OR "cerebrovascular disease" OR "acute cerebrovascular disease" OR "encephalitis") alone or in combination with OR and AND operators. 

The desired data was 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 assessed the quality of included studies (A.AJ. S.M, S.S, S.S, and M.H), based on the NIH quality assessment tool for observational cohort and case series studies [24] . This instrument   assessed the quality of included studies based on the research question, study population, the   participation rate of eligible persons, inclusion and exclusion criteria, sample size justification, analyses, reasonable timeframe, exposure, outcome measures, outcome assessors and, loss to follow-up.

Data from included studies were extracted for the number of events and total patients to perform a meta-analysis. 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 All analysis were performed using STATA statistical software, version 13 (StataCorp).

As illustrated in (figure 1), a total of 2353 studies were retrieved after a systematic search in the aforementioned databases. (Table 2) , the proportion of . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 22, 2020. . https://doi.org/10.1101/2020.07.21.20158691 doi: medRxiv preprint patients with travel history to Wuhan, Wuhan related exposure, and Living in Wuhan was 30.43%, 3.83%, and 4.74%, respectively. In addition, the proportion of patients with travel history to other infected areas and contact with patients was 1.17% and 13.33%, respectively. Mortality was assessed in 25 studies with a pooled incidence rate of 10.47%. The incidence rate of positive females and males were 46.4% (95% CI: 43%-49.8%) and 49.5% (95% CI: 45.7%-53.3%), respectively. 36.1% (95% CI: 27.9%-44.8%) of infected patients were in the severe, critical, or Intensive care unit condition. In addition, the incidence rate of mortality and survival were 10.47% (95% CI: 5%-17.3%) and 81.43% (95% CI: 65.7%-93.2%), respectively.

Based on the results shown in (Table 3 and The highest incidence rate among CNS symptoms of COVID-19 patients was for headache (8.69% with 95% CI: 6.76%-10.82%), followed by Dizziness (5.94%, 95%CI: 3.66%-8.22%), and Impaired consciousness (1.9% with 95% CI: 1%-2.79%). Table 4 ) shows comorbidities that were reported in 60 studies including 6959 patients. The highest incidence rate in comorbidities were hypertension with 23.54% (95% CI: 19.14%-27.94%), diabetes mellitus (11.68% with 95% CI, 0.98%-13.57%), cardiovascular disease (11.66% with 95% CI: 0.89%-14.35%), and cerebrovascular diseases (3.47% with 95% CI: 2.29%-4.85%). (Table 4) 

reported in a growing number of studies [87] . In addition to the common symptoms in COVID-19, several CNS symptoms such as headache and impaired consciousness have been observed in infected patients [16] .

While most investigated the respiratory symptoms of COVID-19, Mao et al. specifically examined the prevalence of neurological manifestations ranging from CNS to peripheral nervous system (PNS) and neuromuscular symptoms in an observational study on COVID-19 patients [16] . They demonstrated CNS presentations ranging from dizziness and headache to impaired consciousness, acute cerebrovascular disease, ataxia, and seizure [16] . Based on the possible neuroinvasive potential of COVID-19, in this systematic review and meta-analysis, we analyzed those evidence indicating the involvement of CNS. We assessed 11687 COVID-19 adult patients from six countries. We reported that COVID-19 patients commonly showed CNS symptoms, including headache, dizziness, and impaired consciousness. Headache (8.69%) were the most common CNS symptoms, followed by dizziness (5.94%) and impaired consciousness (1.9%).

There are two main routes of CNS entry of COVID-19 (hematogenous and peripheral nerves route) leading to CNS infection and inducing various symptoms such as meningitis and encephalitis. 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) [18, [88] [89] [90] [91] [92] [93] . They also may enter the CNS through circumventricular organs, those CNS organs lacking the BBB [94] . The second route, a peripheral nerve, can provide the virus with a retrograde route in to access the CNS via an axonal transport machinery [18, [88] [89] [90] [91] [92] [93] . In accordance with this finding, some previous studies on other types of coronaviruses indicating that coronaviruses can reach the brain via cranial nerves (e.g., olfactory, trigeminal nerve terminals in the nasal cavity) [88, [95] [96] [97] . Such a neuroinvasive propensity is supported by reporting of patients exhibiting smell impairment, as a hallmark of COVID-19 infection due to the involvement of the olfactory nerve [16, 87] .

The COVID-19 infection mechanism requires the virus attaching to its receptor called angiotensin-converting enzyme 2 (ACE2) expressed in various tissues ranging from endothelial cells of the cardiovascular system, airway epithelia, kidney cells, small intestine, and lung parenchyma [98] [99] [100] . There exists a wealth of evidence that supports the expression and distribution of the ACE2 in the CNS [100] [101] [102] [103] [104] [105] [106] . Hence, ACE2 may be a potential target of COVID-19 upon the entrance into the CNS, triggering its effects on CNS tissue [92] . The . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . 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 [19, 21] .

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 [107] .

Such a mortality rate can indicate the importance of careful monitoring of CNS manifestations in COVID-19 patients. Moreover, in Mao's study, the prevalence of CNS manifestations were higher in severe cases of the illness associated with higher mortality [16] . Although, this can be due to the effect of COVID-19 on the brain stem and suppression of the cardiorespiratory control centers causing respiratory failure and death [108] , other possible reasons such as cytokine storm and hypoxia have been suggested to explain the high mortality rate in cases with CNS manifestations. Cytokine storm as an immune system response during COVID-19 infection could enhance the permeability of the blood brain-barrier (BBB) [109, 110] . Infection of airway tissues by COVID-19 in severe infection leads to impaired gas exchange, subsequently causing CNS hypoxia resulting in neural dysfunction [111] . This hypoxic condition associated with severe infection disrupts the BBB through elevation of some factors like nitric oxide (NO) and inflammatory cytokines [112] . More precisely, all of these factors mentioned above may contribute to making the BBB more permeable to the virus. Therefore, in the severe condition of infection, COVID-19 easily enters the CNS via disrupted BBB and puts the brain at risk leading to the manifestation of CNS features [113] [114] [115] [116] .

Furthermore, 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 [117, 118] . Hence, because the brain is nourished by a network of blood vessels, this could be indicative of the importance of cerebral vasculature investigations on the CNS symptoms in the COVID-19 infection.

In a nutshell, attention to the CNS aspects of COVID-19 infection has outstanding benefits for clinician's understanding of a very serious complication of this infection. At this point in time, researchers have mainly focused on finding medicinal treatments for respiratory symptoms of COVID-19. However, it is necessary to investigate the various CNS manifestations of COVID-19 since they are associated with increased severity and mortality [16] . Not only respiratory system dysfunction, but also impairment of respiratory control centers in the CNS (brain stem)

can induce acute respiratory failure [108, 119] . Therefore, considering all effective factors, it can provide clinicians to choose the best way in an attempt to manage this pandemic more efficiently.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . https://doi.org/10.1101/2020.07.21.20158691 doi: medRxiv preprint

There are several limitations in our systematic review and meta-analysis. 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 are 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 are implied as a separate symptom (table 3).

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 

Abbreviation . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . https://doi.org/10.1101/2020.07.21.20158691 doi: medRxiv preprint CNS: Central nervous system; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; PHEIC: Public health emergency of international concern; WHO: World health organization; PRISMA: Preferred reporting items for systematic reviews and meta-analyses; PNS: Peripheral nervous system; BBB: Blood brain barrier; ACE2:

Angiotensin-converting enzyme 2; CI: Confidence interval . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . https://doi.org/10.1101/2020.07.21.20158691 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . https://doi.org/10.1101/2020.07.21.20158691 doi: medRxiv preprint Figure 1 . The process of surveying, screening, and selecting the articles for this systematic review and meta-analysis based on PRISMA guideline . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. .

Created with BioRender.com)

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2020. . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 22, 2020. . https://doi.org/10.1101/2020.07.21.20158691 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 22, 2020. .

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