nCoV-2019 infection induces neurological outcome and manifestation, linking its historical ancestor SARS-CoV & MERS-CoV: A systematic review and meta-analysis

Importance: The �rst systematic review and meta-analysis to help clinician to identify early the sign and symptoms of neurological manifestation in COVID-19 positive patients which further help in early management of patients. Objective: Present systematic review and meta-analysis aimed to discuss the prevalence of neurological involvement of the 2019-nCoV patients and assess the symptomatic trend of events as compared to the 2002 “SARS” and 2012 “MERS” pandemics. Methods: The articles were systematically screened through several search engine and databases. The articles published or in preprint were included in the study till 15 th May 2020. The systematic review done as per the published literatures which included 31 cross sectional, observational studies and case reports which revealed neural sign and symptoms in SARS-COV-2 disease. For meta-analysis, we included 09 observational and cross sectional studies which included COVID-19 positive patients and assessed the predominance of various neurological sign and symptoms in COVID-19 patients relation to SARS-2002 and MERS-2012. Data were analyzed by using the “MedCalc Statistical Software version 19.2.6 and reported as pooled prevalence. Heterogeneity was investigated (standard I 2 test). Results: We have collected and screened about a total 2615 articles, �nally we have included 31 articles for the systematic review and 09 for meta-analysis as per the inclusion/exclusion criteria. The analysis was made as per the prevalence rate of neurological symptoms during the COVID-19 positive patients. The cumulative neurological outcome of SARS-2002 and MERS-2012 was assessed to get the trends which is next tried to correlate the events with the current pandemic. During the analysis severity and outcome of neurological manifestations range from simple headache to vague non-focal complaints to severe neurologic impairment associated with seizure or meningitis. Conclusion & Relevance: Central and peripheral nervous system (CNS/PNS) manifestations were seen during the SARS-2002, MERS-2012 and COVID-19. However, none of the publication found with the primary or secondary objective of �nding the neurological manifestation in the COVID-19 patients and their mechanism which strengthen the importance to start more precise clinical trials.

Interpretation: The prevalence of neurological sign and symptoms were taken as primary objective.Thereafter, the prevalence of each CNS/PNS symptoms was categorized and their prevalence studied.The selection of Bagheri et al 2020 may be discussed because they have done the cross sectional study with the neurological nding and correlated the data with prevalence of the COVID-19 positive patients.The proportion of patients presenting with neurological outcome and clinical/PCR positivity were done, however we had searched and followed all the possible ndings available on online/web source, therefore, the data collection process may remain a limitation of work.Due to lack of data of SARS-CoV and MERS-CoV we have included the case reports, MERS and COVID-19 in CNS/PNS manifestations.

Background
Severe acute respiratory syndrome namely corona-virus 2 (2019-nCoV) pandemic has changed the understanding and viewpoint of viral infection and given a cause to think more critically in the management of viral infection.SARS-CoV-2 is said to be the version 7.0 of corona virus family and of β-type.COVID-19 may be asymptomatic or have mild to severe pneumonia like syndrome. 1,2Several research recommended that 2019-nCoV is one of the predominant virus that speci cally target the human respiratory system.SARS, MERS and COVID-19 essentially exhibit as respiratory distress, which represented through slight respiratory problem to a serious respiratory distress syndrome (ARDS) and incidentally adjunct to gastrointestinal appearances 2 , cardiovascular and neurological conditions 3 .If we see the neurological capabilities is never been studies in any of the published literatures as a primary or secondary objectives.If we see the history of the corona virus family and its pandemic situations it came earlier in 2002 as SARS and MERS in 2012.But logically speaking the mortality rate worldwide indicate the prevailing high risk of the present 2019-nCoV compared to the other counterparts is more. 5e present systematic review and meta-analysis aimed to the evidence based its neurological manifestations and The common symptoms of nCoV-2019 infection start in 4-5 days with mild fever, mild to moderate cough, running nose and fatigue whereas other most common symptoms namely headache, hemoptysis, and dyspnea were reported in several studies.Moderate to severe cases of nCoV-2019 infection may worsen with the development of pneumonia, acute respiratory distress syndrome, acute cardiac problems, and multiorgan failure.5 Presently as on June 5, 2020 the complete Coronavirus Cases is 6,720,550, which precipitated 393,542 Deaths (5.85%) and nearly 3,264,238 recovered (48.57%) 6 .This suggests that COVID-19 pandemic is one of major world public health issue which World Health Organization (WHO) formally think about as a world pandemic on 11 March 2020 and named as, COVID-19 outbreak 7 .Studies suggesting about the nCoV-2019 infections may have related neurological manifestations (e.g., febrile seizures, convulsions, change in mental status, and encephalitis) 8,9 .Very few reports have described the neurotropic and neuroinvasive abilities of corona viruses to humans, which suggest that nasal nCoV-2019 infection, get access to CNS thru the olfactory bulb inflammation and demyelination 10 .Therefore, in the current systematic review, we will talk about the proof on the incidence of CNS involvement and neurological manifestations in population with COVID-19.Search methods: The manuscript search is depending on the complete possible online sources.Out of total 1651 articles, nally we have included 32 articles for the systematic review and meta-analysis.The analysis were made in the two sections, one which is the current 2019-nCoV outbreak for the neurological/CNS manifestation and another is cumulative outcome of 2002 and 2012 SARS and MERS outbreak respectively.

Objectives
Database search: Three independent reviewers AJ, HM and PS searched the Google Scholar, MEDLINE (Pubmed), EMBASE, OVID, Scopus, Science Direct and unpublished data were screened through Medrixv and BioRixv.The search strategy included both keyword and Medical Subject Headings (MeSH) terms.The keywords used were: "Neuro", "CNS", Central nervous System, "anxiety", "depression'', "seizure", "agitation", "neurological", "2019-nCov", 2019 "novel corona virus", COVID-19, corona virus disease-2019, OR infarction for the corona virus -2 however, all previous studies for SARS-2002 and MERS-2012 where searched with the key words "corona virus-SARS" OR SARS OR SARS--CoV AND "corona virus-MERS OR MERS OR MERS-CoV".During the screening process we have kept no language restrictions and for articles written in languages other than English, google translate was used to obtain relevant information and extract data if possible, otherwise it was excluded from the analysis.In cases in which the translation cannot work out we have collected data only from the abstract (if it is in English).We retrieved the full text article of the potentially eligible study after screening the title, summary/ abstract and type of study as described by search result which met the eligibility criteria for current systematic review and meta-analysis.Databases were systematically searched thoroughly and duplicates were independently screened by authors (DP, NB, AB and HM).In the next phase articles were selected as per the titles/abstracts published and have the relevance as neurological outcome in COVID-19.For relevant articles, the full texts was obtained and evaluated as per neurological sign and symptoms in nCoV-19 infected patients.BM, MM, MG and AP were consulted for any discrepancy or confusion.Four authors (HS, DP, RS and NB) have extracted data independently by using pre-tested Cochrane data extraction form.After independently verifying by BM, MM, MG and AP, the data was entered into MedCalc software and analyzed.
Selection criteria: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Metaanalysis of Observational Studies in Epidemiology (MOOSE) were followed to analyze and report systematic review and meta-analysis (Figure . 1).The registration of the review protocol was not previously done.The thorough search engine were used to collect all possible studies through Google scholar, MEDLINE (Pub Med), EMBASE, OVID, Cochrane Central Library, CNKI, Medrixv and BioRixv and Scopus till May 15, 2020.
Statistical analysis: To analyze the differences in neurological impact, levels of anosmia/hyposmia, dyspnea, headache, headache and loss of consciousness were calculated according to the number of respondents per response to the number of total patients as categorical variables.Differences categorical variables were analyzed for proportion analysis by chi-squared test.We used network analysis to correlate with the different pandemics namely SARS-2002, MERS-2012 and COVID-19.Data were analyzed by using the "MedCalc Statistical Software version 19.2.6 (MedCalc Software bv, Ostend, Belgium; https://www.medcalc.org;2020)" and reported as pooled prevalence using a xed and random effect model.Heterogeneity was investigated (standard χ2 test) and represented as I 2 for the degree of inconsistency.Analyzed report showed both xed effect and random effect model as necessary as an indication of the variability in the studies.The signi cant level set at p < 0•05 and prevalence range were represented as 95% CI.
Publication bias in the selected study was evaluated by plotting the funnel plot and done the analysis accordingly.

Results
Inclusion/exclusion of studies: Total 2615 articles were found in databases search and after duplicate, title and summary screening articles reduced to 1651, thereafter, a total of 1459 articles were excluded.Full-text screening of the remaining 1156 articles was done.Among these studies, after full-text screening, a total of 31 articles were included in the nal review.(Figure 1) Data collection and analysis: A total of 1651 articles were found after preliminary screening of the databases.After title and abstract screening, a total of 495 articles were excluded.Full-text screening of the remaining 1156 articles was done.Among these studies, after full-text screening, a total of 247 articles were included in the nal review.The PRISMA owchart of the study is shown in Figure 1 2a.No signi cant publication bias was seen (Figure 2b).

Overall prevalence of nervous system symptoms (CNS)
A total of 08 studies (total 1078 patients) reported occurrence of CNS symptoms in COVID-19 positive patients, the proportion was 25.184 % & 34.890 % by xed and random effect size model, respectively.As there was signi cant heterogeneity 95.32 %, (95% CI for I 2 92.75 to 96.98)(P < 0.0001), we used random effect model.The forest plot is showed in Figure 3a.Publication bias was seen, may be due to less number of publication.(Figure 3b).
Overall prevalence of peripheral nervous system (PNS) symptoms A total of 08 studies (total 11009 patients) reported occurrence of PNS symptoms in COVID-19 positive patients, the proportion 41.366 % & 48.386 % by random and xed effect size model, respectively.As there was signi cant heterogeneity 98.82 % (95% CI for I 2 98.43 to 99.11) (P < 0.0001), we used random effect model.The forest plot is showed in Figure 4a.No signi cant publication bias was seen (Figure 4b).
Prevalence of ANSOMIA/HYPOSMIA as symptoms A total of 3 studies (total 10769 patients) reported occurrence of ANSOMIA/HYPOSMIA symptoms in COVID-19 positive patients, the proportion 48.547%, 37.270% by random and xed effect size model, respectively.As there was signi cant heterogeneity 99.47% (95% CI for I 2 99.26 to 99.61), we used random effect model.The forest plot is showed in Figure 5a.Publication bias was seen, may be due to very less number of publication.(Figure 5b).
Overall prevalence of nervous system symptoms (Myalgia)  6a.No signi cant publication bias was seen (Figure 6b).
Overall prevalence of nervous system symptoms (Fatigue) A total of 2 studies (total 135 patients) reported occurrence of Fatigue symptoms in COVID-19 positive patients, the proportion 24.674% & 30.810% by xed and random effect size model, respectively.As there was signi cant heterogeneity 91.33% (95% CI for I 2 69.43 to 97.54) (P = 0.0007), we used random effect model.The forest plot is showed in Figure 7a.No signi cant publication bias was seen (Figure 7b).
Overall prevalence of nervous system symptoms (Dyspnea)  8a.No signi cant publication bias was seen (Figure 8b).
Overall prevalence of nervous system symptoms (Headache) A total of 3 studies (total 629 patients) reported occurrence of Headache symptoms in COVID-19 positive patients, the proportion 10.263%, 9.727% by random and xed effect size model, respectively.As there was not signi cant heterogeneity 52.06% (95% CI for I 2 0.00 to 86.21), we used random effect model.The forest plot is showed in Figure 9a.No signi cant publication bias was seen (Figure 9b).
Overall prevalence of nervous system symptoms (Impaired Consciousness) A total of 2 studies (total 629 patients) reported occurrence of Impaired Consciousness symptoms in COVID-19 positive patients, the proportion 9.471%, 13.580% by random and xed effect size model, respectively.As there was signi cant heterogeneity 83.49% (95% CI for I 2 31.48 to 96.02), we used random and xes effect model.The forest plot is showed in Figure 10a.No signi cant publication bias was seen (Figure 10b).

Network analysis of neurological manifestations
The network analysis of case reports (n=103) showed the neuronal manifestation of COVID-19 and other CoV infection is widely correlated with each other, whereas , analysis showed that the COVID-19 pandemic have more degree of neuronal manifestation as compared with other SARS and MERS pandemics in 2002 and 2012 respectively.(Figure 11) The number of study reported in previous SARS-CoV and MERS-CoV infection were minimal as compared to the COVID-  39 reported Guillain-Barré syndrome (GBS), confusion and seizure of several patients.However, in the recent nCoV-2019 pandemic it was seen more neurological involvement i.e.Duong L et al, 2020 19 and Moriguchi T, et al, 2020 22 have reported about the meningoencephalitis, Scheidl et al, 2020 24 , Sedaghat Z et al, 2020 25 , Toscano G, et al 2020 27 , Virani A et al, 2020 28 and Zhao H et al, 2020 29 have reported of Guillain-Barré syndrome.(Table 2 & 3; Figure 12) Gutiérrez-Ortiz C et al, 2020 46 reported the single event of Miller Fisher Syndrome and polyneuritis cranialis as neurological manifestations, proposed the absence of immune response during COVID-19.

Discussion
The present systematic review and meta-analysis revealed that the pattern of neurological manifestation of nCoV-2019 is related to the previous two pandemics i.e.SARS-2002 and MERS-2012.The main clinical manifestations of SARS and MERS were fever, chills, dry cough, and di culty breathing which is related to the 2019-nCoV symptoms as well.In moderate to severe cases, respiratory failure associated with multiple organ involvement may occur 33 .In addition, these patients found to be neurological manifestations such as encephalitis, polyneuropathy, and aortic ischemic stroke 38 .An autopsy sample revealed overall deteriorating ndings namely in ltration of monocytes and lymphocytes in the vessel wall, ischemic changes of neurons, demyelization of nerve bers to the cerebral edema and meningeal vasodilation in patients.
Present systematic review and metaanalysis aimed to access the neurological manifestation of nCoV-2019 infection were further classi ed as central nervous system (CNS) symptoms namely dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and epilepsy and peripheral nervous system (PNS) symptoms like hypoplasia, hyposmia, neuralgia, and hypogeusia were studied 16 .
In Study by Hung EC et al, 2003 31 showed SARS positive evidenced in CSF sample of SARS-CoV and genome sequences of SARS in brain sample (Guetal., 2005; Zhangetal.,2003).MERS outbreak in 2012-13 also reported delirium, neuropathy and acute cerebrovascular disease 35,37 where as Saad et al, 2014 21 reported confusion and seizures in 18 and 6 of the participants, respectively out of 70 MERS patients.Therefore, published literature showed the indication of neurotropism by the CoV-family.Recent study by Moriguchi, et al. 2020 22 , showed patients with SARS-CoV-2 suffered from meningitis / encephalitis which were con rmed by RT-PCR detection in cerebrospinal uid.The exact reason is unclear, but the few described in the literature are, development of focal meningitis/encephalitis affecting the rhino-or gustatory-cortex representations or appropriate sub-cortical ascending/descending tracts in the CoV positive patients is one of the reason which may be easily detect viral-RNA in the cerebrospinal uid (CSF) of infected patients 16,22 .In our network study meningitis/encephalitis, seizure and confusion were well connected to the MERS and COVID-19.
The symptoms of PNS appeared due to involvement of peripheral nerves, including the cranial nerves which further associate to cranial nerves I, VII, IX, and X by SARS-CoV 2 47 .Our study study reported common neurological sign and symptoms were dyspnea (15.419 % & 26.131% ), fatigue, myalgia (19.994%-21.279), loss of counciousness (9.471% to 13.580% ) and agnosia.However, few case reports have reported even more severe neurological manifestation like seizure, GBS or meningitis/encephalopathy. (Figure 11, 12) However, none of the studies observed the viral neurotropism but few author have reported that the patients with neurological manifestation have the positive CSF of COVID-19 39 .Therefore, it is very early to explain the event whether neurological dysfunction is due to direct viral injury or systemic disease.
The other school of thought showed that the neurotropism of CoV family occur mainly through two pathways, i.e. the hematogenous and neuronal retrograde courses of CNS infection through respiratory infection.An animal study showed MERS-CoV tissue pantropism occur after the viral entry into blood stream through endothelial infection in the choroid plexus 23,40 .
High mortality and fast spread of the CoV-family namely SARS, MERS and 2019-nCoV infection due to the high fusion of these virus and rapid replication involved angiotensin-converting enzyme 2 (ACE2) receptor which is present throughout the vital organs 17 .Therefore, the presence of ACE 2 receptor in brain is an important factor and link to study the neurological manifestation and management in 2019-nCoV infection.Patel AB, 2020 41 Incidence of the neurological manifestation in 2019-nCoV and prevailing prevalence in the context of previous CoV-SARS.Therefore y-the objective of the paper 1. Prevalence of neurological outcome in 2019-nCoV infected patients 2. Correlation of events in SARS, MERS and 2019-nCoV infection 3. Prevalence of CNS/PNS symptoms in all the corona pandemics 4. Network analysis of case reports of SARS, MERS and COVID-19

2 ;Figure 1 PRISMA chart showing study section criteria and process Figure 2 a:
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Prevalence of nervous system complication/manifestations in COVID-19 positive patientsOverall prevalence of central and peripheral nervous system (CNS/PNS) symptoms A total of 09 studies (total 11147 patients) reported occurrence of CNS-PNS combined symptoms in COVID-19 positive patients, the proportion was 48.278 %, 45.718% by xed and random effect size model, respectively.As there was signi cant heterogeneity 96.00%, (95% CI for I 2 94.08 to 97.29), we used random effect model.The forest plot is showed in Figure total of 5 studies (total 731 patients) reported occurrence of Dyspnea symptoms in COVID-19 positive patients, the proportion 15.419 % & 26.131% by xed and random effect size model, respectively.As there was signi cant heterogeneity 95.48 % (95% CI for I 2 92.01 to 97.44) (P < 0.0001), we used random effect model.The forest plot is showed in Figure 33 reporting.The individual neuronal manifestation of CNS or PNS nature ranges from simple headache to the Seizure or GBS and even Lau KK et al, 200433reported Myalgia and Al-Hameed FM et al, 2017 reported of GTC (Seizure) 38 by Intracerebral hemorrhage.Kim JE et al, 2017