Introduction

Severe acute respiratory syndrome namely corona-virus 2019 (nCoV-2019) pandemic has changed the understanding and viewpoint of viral infection and given a cause to think more critically in the management of viral infection. β-type SARS-CoV-2 is the version 7.0 of corona virus familyCOVID-19 may be asymptomatic or have mild to severe pneumonia like syndrome1,2. Several researches have recommended that 2019-nCoV is one of the predominant viruses that specifically target the human respiratory system. SARS, MERS and COVID-19 essentially exhibit as respiratory distress, which can manifest as mild respiratory symptoms to serious respiratory distress syndrome (ARDS) and incidentally adjunct to gastrointestinal appearances2, cardiovascular and neurological involvement3. Neurological potentiality is never been studies in any of the published literatures as a primary or secondary objective. If we see the history of the corona virus family and its pandemic situations, it appeared in 2002 as SARS and MERS in 2012. Current ongoing high mortality rate of the present nCoV-2019 as compared to the other counterparts signifies that the pathogenesis is likely completely different from its old counterparts and yet to be understood4.

The common symptoms of nCoV-2019 infection starts in 4–5 days with mild fever, mild to moderate cough, running nose and fatigue whereas some other 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 failure4.

Presently as on June 5, 2020 the total number of coronavirus cases world wide were 6,720,550, with 393,542 deaths (5.85%) and nearly 3,264,238 have recovered till now (48.57%)5. This suggests that COVID-19 pandemic is one of the major world public health issue which World Health Organization (WHO) formally declared as pandemic on 11 March 2020 and named as, COVID-19 outbreak6. Studies reporting nCoV-2019 infections have found related neurological manifestations (e.g., febrile seizures, convulsions, change in mental status, and encephalitis)7,8,9. Very few reports have described the neurotropic and neuro invasive abilities of corona viruses to humans, which suggest that nasal nCoV-2019 infection, get access to CNS through the olfactory bulb leading to inflammation and demyelination in the bulb10. Therefore, current systematic review and meta-analysis aimed to congregate proof on the incidence of CNS/PNS involvement and neurological manifestations in population with COVID-19.

Methods

Objectives

Incidence of the neurological manifestations in nCoV-2019 and prevailing prevalence in the context of previous CoV-SARS. Therefore, present study reserves the objectives to find out;

  1. 1.

    Prevalence of neurological outcome in 2019-nCoV infected patients.

  2. 2.

    Correlation of events in SARS, MERS and 2019-nCoV infection.

  3. 3.

    Prevalence of CNS/PNS symptoms in all the corona pandemics.

  4. 4.

    Network analysis of case reports of SARS, MERS and COVID-19.

Search methods

The manuscript search was from complete possible online sources. Out of total 2615articles, finally we included 31 articles for the systematic review and meta-analysis. The analysis was made in the two sections, one which is the current nCoV-2019 outbreak for the neurological manifestations and another is cumulative outcome of 2002 and 2012 SARS and MERS outbreak respectively.

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 keywords 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 were obtained and evaluated as per neurological sign and symptoms in nCoV-2019 positive 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.

Selection criteria

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) were followed to analyze and report systematic review and meta-analysis (Fig. 1). The registration of the review protocol was not previously done. The thorough search engine was used to collect all possible studies through Google scholar, MEDLINE (PubMed), EMBASE, OVID, Cochrane Central Library, CNKI, MedRixv and BioRixv and Scopus till June 5, 2020.

Figure 1
figure 1

PRISMA chart2,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 showing study section criteria and process.

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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-square test. We used network analysis to correlate with the different pandemics namely SARS-2002, MERS-2012 and COVID-19. “MedCalc Statistical Software version 19.2.6 (MedCalc Software bv, Ostend, Belgium; https://www.medcalc.org; 2020)” was used to analyze the data. The fixed and random effect model were used to obtain pooled prevalence. Heterogeneity was investigated (standard χ2 test) and represented as I2 for the degree of inconsistency. Analyzed report showed both fixed effect and random effect model as necessary as an indication of the variability in the studies. The significant 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 criteria of studies Total 2615 articles were found in databases search and after removing duplicates, 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 31articles were included in the final review (Fig. 1).

Data collection and analysis2,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 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 final review. The PRISMA flowchart37 of the study is shown in Fig. 1, 215 articles were excluded after full-text screen (Not related to neurological manifestation = 32, Reports (incomplete data) = 78, In silico /in vitro study = 30, Management of SARS, MERS or COVID-19 = 55 incomplete epidemiological study = 20). Details of studies with neurological manifestation in SARS-2002, MERS-2012 and COVID-19 summarized in Tables 1, 2 and 3.

Table 1 Published observational/cross sectional studies which reported the neurological manifestation to the COVID-19 positive patients.
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Table 2 Published case reports of neurological manifestations in COVID-19 positive patients.
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Prevalence of nervous system complication/manifestations in COVID-19 positive patients

Overall prevalence of central and peripheral nervous system (CNS/PNS) symptoms

A total of 09 studies (total 11,147 patients) reported occurrence of CNS-PNS combined symptoms in COVID-19 positive patients, the proportion was 48.278%, 45.718% by fixed and random effect size model, respectively. As there was significant heterogeneity 96.00%, (95% CI for I2 94.08–97.29), we used random effect model. The forest plot is showed in Fig. 2a. No significant publication bias was seen (Fig. 2b).

Figure 2
figure 2

(a) Forest plot showed pooled prevalence of CNS-PNS combined among patients with COVID-19 patients. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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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% and 34.890% by fixed and random effect size model, respectively. As there was significant heterogeneity 95.32%, (95% CI for I2 92.75–96.98) (P < 0.0001), we used random effect model. The forest plot is showed in Fig. 3a. Publication bias was seen, may be due to a smaller number of publications (Fig. 3b).

Figure 3
figure 3

(a) Forest plot showed pooled prevalence of CNS complication among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Overall prevalence of peripheral nervous system (PNS) symptoms

A total of 08 studies (total 11,009 patients) reported occurrence of PNS symptoms in COVID-19 positive patients, the proportion 41.366% and 48.386% by random and fixed effect size model, respectively. As there was significant heterogeneity 98.82% (95% CI for I2 98.43–99.11) (P < 0.0001), we used random effect model. The forest plot is showed in Fig. 4a. No significant publication bias was seen (Fig. 4b).

Figure 4
figure 4

(a) Forest plot showed pooled prevalence of PNS complications among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Prevalence of ANOSMIA/HYPOSMIA as symptoms

A total of 3 studies (total 10,769 patients) reported occurrence of anosmia/hyposmia symptoms in COVID-19 positive patients, the proportion 48.547%, 37.270% by random and fixed effect size model, respectively. As there was significant heterogeneity 99.47% (95% CI for I2 99.26–99.61), we used random effect model. The forest plot is showed in Fig. 5a. Publication bias was seen, may be due to very a smaller number of publications. (Fig. 5b).

Figure 5
figure 5

(a) Forest plot showed pooled prevalence of anosmia/hyposmia complications among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Overall prevalence of Myalgia

A total of 2 studies (total 77 patients) reported occurrence of Myalgia in COVID-19 positive patients, the proportion 21.279%, 19.994% by random and fixed effect size model, respectively. As there was significant heterogeneity 95.40% (95% CI for I2 86.48–98.44), we used random effect model. The forest plot is showed in Fig. 6a. No significant publication bias was seen (Fig. 6b).

Figure 6
figure 6

(a) Forest plot showed pooled prevalence of Myalgia among patients with COVID-19. Incidence of Myalgia symptoms. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Overall prevalence of fatigue

A total of 2 studies (total 135patients) reported occurrence of fatigue in COVID-19 positive patients, the proportion 24.674% and 30.810% by fixed and random effect size model, respectively. As there was significant heterogeneity 91.33% (95% CI for I2 69.43–97.54) (P = 0.0007), we used random effect model. The forest plot is showed in Fig. 7a. No significant publication bias was seen (Fig. 7b).

Figure 7
figure 7

(a) Forest plot showed pooled prevalence of Fatigue among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Overall prevalence of dyspnea

A total of 5 studies (total 731 patients) reported occurrence of Dyspnea symptoms in COVID-19 positive patients, the proportion 15.419% and 26.131% by fixed and random effect size model, respectively. As there was significant heterogeneity 95.48% (95% CI for I2 92.01–97.44) (P < 0.0001), we used random effect model. The forest plot is showed in Fig. 8a. No significant publication bias was seen (Fig. 8b).

Figure 8
figure 8

(a) Forest plot showed pooled prevalence of Dyspnea among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Overall prevalence of headache

A total of 3 studies (total 629patients) reported occurrence of Headache in COVID-19 positive patients, the proportion 10.263%, 9.727% by random and fixed effect size model, respectively. As there was not significant heterogeneity 52.06% (95% CI for I2 0.00–86.21), we used random effect model. The forest plot is showed in Fig. 9a. No significant publication bias was seen (Fig. 9b).

Figure 9
figure 9

(a) Forest plot showed pooled prevalence of Headache among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Overall prevalence of impaired consciousness

A total of 2 studies (total 629patients) reported occurrence of Impaired Consciousness in COVID-19 positive patients, the proportion 9.471%, 13.580% by random and fixed effect size model, respectively. As there was significant heterogeneity 83.49% (95% CI for I2 31.48–96.02), we used random and fixes effect model. The forest plot is showed in Fig. 10a. No significant publication bias was seen (Fig. 10b).

Figure 10
figure 10

(a) Forest plot showed pooled prevalence/incidence of Impaired Consciousness among patients with COVID-19. (b) Funnel plot showed publication bias among studies evaluating neurological complications of COVID-19.

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Network analysis of neurological manifestations

The network analysis of case reports (n = 103) showed that the neurological manifestation of COVID-19 and other CoV infection is proportionate with each other, whereas, analysis showed that COVID-19 pandemic has more neurological manifestations as compared with other SARS and MERS pandemics in 2002 and 2012 respectively (Fig. 11). The number of studies reported in previous SARS-CoV and MERS-CoV infections were minimal as compared to the COVID-19. The individual neurological manifestation of CNS or PNS ranges from simple headache to the seizure or GBS and even myalgia reported by Lau et al.32 and Al-Hameed et al., 2017 reported of GTC (Seizure)37 by intracerebral hemorrhage. Kim et al.36 reported Guillain–Barré syndrome (GBS), confusion and seizure of several patients. However, recent nCoV-2019 pandemic showed more neurological involvement of meningoencephalitis reported by Duong et al.18 and Moriguchi et al.21 and Guillain–Barré syndrome was reported by Scheidl et al.23, Sedaghat et al.24, Toscano et al.26, Virani et al.27 and Zhao et al.28. (Tables 2, 3; Fig. 12).

Figure 11
figure 11

Overall Network analysis which showed the relationship with three main pandemics i.e., SARS-2002, MERS-2012 and COVID-19 with the CNS, PNS or combined manifestations. Note: The size of node defines the degree of relation with the individual neurological symptoms and increased number of edges give the increased relation with the respective nodes. (Edges showing directed association, Node size depicts degree of nodes).

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Table 3 Published case reports of previous SARS-CoV and MERS patients of neurological manifestations/ outcomes.
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Figure 12
figure 12

Network analysis showed the impact of neurological manifestation as per described symptoms in case report as well as observational studies. Note: The size of node defines the degree of relation with the individual neurological symptoms and increased number of edges give the increased relation with the respective nodes. (Edges showing directed association, Node size depicts degree of nodes).

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Gutiérrez-Ortiz et al.45 reported the single case of Miller Fisher Syndrome and polyneuritis cranialis, depicting the absence of immune response during COVID-19.

Discussion

The present systematic review and meta-analysis revealed that the pattern of neurological manifestations of nCoV-2019 is related to the previous two ancestral pandemics i.e., SARS-2002 and MERS-2012. The main clinical manifestations of SARS and MERS were fever, chills, dry cough, and difficulty breathing which is related to nCoV-2019 symptoms as well. In moderate to severe cases, respiratory failure associated with multiple organ involvement may occur32. In addition, some of these patients developed neurological manifestations such as encephalitis, polyneuropathy, and aortic ischemic stroke38. Autopsy revealed overall deteriorating findings namely infiltration of monocytes and lymphocytes in the vessel wall, ischemic changes of neurons, demyelization of nerve fibers to the cerebral edema and meningeal vasodilation in patients.

Present systematic review and meta-analysis aimed to access the neurological manifestation of nCoV-2019 infection, which can further be classified into 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 studied15,46.

Ina study by Hung et al.30 showed SARS positivity in CSF sample of SARS-CoV and genome sequences of SARS in brain sample. MERS outbreak in 2012–13 also reported delirium, neuropathy and acute cerebrovascular disease34,36whereas Saad et al.20 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.21, showed patients with SARS-CoV-2 suffered from meningitis/encephalitis which were confirmed by RT-PCR detection in cerebrospinal fluid.

The exact reason is unclear, however, few described in the literature are, development of focal meningitis/encephalitis affecting the rhino- or gustatory-cortex or sub-cortical ascending/descending tracts in the CoV positive patients is one of the reasons which may be easily detect viral-RNA in the cerebrospinal fluid (CSF) of infected patients15,21. In our network study meningitis/encephalitis, seizure and confusion were well connected to the SARS, MERS and COVID-19 pandemics.

PNS symptoms appeared due to involvement of peripheral nerves, including the cranial nerves which further associate to cranial nerves I, VII, IX, and X by SARS–CoV246. Our study, reported common neurological signs and symptoms were dyspnea (15.419% and 26.131%), fatigue (24.674% and 30.810%), myalgia (19.994–21.279%), loss of consciousness (9.471–13.580%) and agnosia (37.270–48.547%). However, few case reports have reported even more severe neurological manifestations like seizure, GBS or meningitis/encephalopathy (Figs. 11, 12). However, none of the studies observed the viral neurotropism but few authors have reported that the patients with neurological manifestations have the positive-CSF of COVID-1939. Therefore, it is very early to explain whether neurological dysfunction is due to direct viral injury or systemic disease.

The other school of thought is that the neurotropism of CoV family occur mainly through two pathways, i.e., the hematogenous and retrograde route through respiratory infection. An experimental study showed that MERS-CoV tissue pantropism occurs after the viral entry into blood stream through endothelial infection in the choroid plexus7,22.

High mortality and fast spread of the CoV-family viruses occurs due to the high fusion of these virus and rapid replication involving angiotensin converting enzyme-2 (ACE-2) receptor which is present throughout the vital organs16. Therefore, presence of ACE 2 receptor in brain is an important factor and link to study the neurological manifestations in 2019-nCoV infection. Patel AB, 202040 described that there is evidence for a major involvement of excessive brain ACE/Ang II/ AT-1R axis leading to increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration and other brain disorders44. At last, the probable chance of neurological manifestation may be due to the cytokines overload and reduced immunity. Immuno-inflammation plays an important role in viral infection and which leads to the systemic inflammatory response syndrome (SIRS)41. In vitro study suggested that primary glial cells release large number of inflammatory cytokines namely IL-6, IL-12, IL-15, and TNF-α after being infected with SARS-CoV42. Further, study suggests that virus-induced SIRS or SIRS-like immune disorders may cause mortality due to involvement of macrophages, microglia, and astrocytes in the CNS43.

Concluding remarks

The nCoV-2019 infection starts with mild flu-like symptoms to the late neurological manifestations in moderate to severely COIVD-19 positive patients. However, patients with comorbid conditions namely lung diseases, diabetes, obesity, hypertension, cardiac or kidney disease are more prone to exacerbation of disease or neurological manifestations or death. Further, studies suggested that the involvement of both peripheral and central nervous systems, also suggested of neurotropism of nCoV-2019. Therefore, we need more studies to conclude the neuro-invasion in brain and affected areas for the management of patients, worldwide.

Limitations of the study

In the present study, meta-analysis is restricted to the evaluations of observational and case report studies which was available at the earliest during the synthesis of the current study in the scientific community. Limited studies and rapid spreading nCoV-2019 pandemic restrict the evidence-based studies like randomized control trial (RCT)/double blind studies during the pandemics. Currently, there is other variant new strain is also identified and being studied. Therefore, there may chances of some new neurological symptoms to be reported. The good designed studied during pandemic is the major limitations of systematic analysis or meta-analysis study.