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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 98-108

Central nervous system sequelae in patients with coronavirus disease 19: A systematic review and meta-analysis of cohort studies

1 College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
2 College of Medicine and Medical Sciences, Arabian Gulf University; Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, Manama, Kingdom of Bahrain
3 College of Medicine and Medical Sciences, Arabian Gulf University; Ministry of Health, Manama, Kingdom of Bahrain
4 Department of Medicine, College of Medicine, University Sleep Disorders Center, King Saud University; The Strategic Technologies Program of the National Plan for Sciences and Technology and Innovation in the Kingdom of Saudi Arabia, Riyadh, Saudi Arabia

Date of Submission08-Apr-2021
Date of Decision06-Dec-2021
Date of Acceptance16-Jan-2022
Date of Web Publication28-Apr-2022

Correspondence Address:
Ghada Al-Kafaji
College of Medicine and Medical Sciences, Arabian Gulf University, Manama; Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, Manama
Kingdom of Bahrain
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jnsm.jnsm_39_21

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Study Objectives: This systematic review and meta-analysis was conducted to identify the neurological sequelae and consequences in patients infected with coronavirus disease 19 (COVID-19), as well as to explore the impact of COVID-19 infection on the central nervous system, and the contributing risk factors to the neurological sequelae associated with the disease. Methodology: The World Health Organization COVID-19 database, which included data from 31 multiple databases, was used in February 2021. Exclusion of noncohort studies was conducted as well as the exclusion of studies with pediatric age groups (<18 years of age). There was an English language restriction. The random-effect models meta-analysis model was used with the DerSimonian and Laird methodology. Results: Nineteen papers, involving a total of 45,181 participants, were judged relevant and contributed to the systematic review and meta-analysis of neurological sequelae in patients with COVID-19. The overall event rate of any given neurological sequelae among all studies was 7.6% (95% confidence interval [CI], 3.0%–17.6%). Meta-regression showed an increase of overall neurological sequelae in relation to age, as well as an increased occurrence in females. Stroke had an event rate of 1.8% (95% CI, 0.9%–3.3%). Headache had an event rate of 6.7% (95% CI, 1.9%–20.7%). Delirium had an event rate of 25.2% (95% CI, 13.9%–41.4%). Intracerebral hemorrhage (ICH) had an event rate of 1.0% (95% CI, 0.4%–2.8%). Conclusions: The prevalence of stroke and ICH was higher than that of the global prevalence. Delirium showed a similar prevalence to the global prevalence. Headache was found to have a lower prevalence compared to the global prevalence.

Keywords: Central nervous system disorders, neurology, outcome, severe acute respiratory syndrome coronavirus 2

How to cite this article:
Alhamad MO, Alkhlofi SA, AbuIdrees TS, Ahmed AM, Taheri SK, Alrowaiei RA, Ali ML, Al-Kafaji G, Jahrami HA, BaHammam AS. Central nervous system sequelae in patients with coronavirus disease 19: A systematic review and meta-analysis of cohort studies. J Nat Sci Med 2022;5:98-108

How to cite this URL:
Alhamad MO, Alkhlofi SA, AbuIdrees TS, Ahmed AM, Taheri SK, Alrowaiei RA, Ali ML, Al-Kafaji G, Jahrami HA, BaHammam AS. Central nervous system sequelae in patients with coronavirus disease 19: A systematic review and meta-analysis of cohort studies. J Nat Sci Med [serial online] 2022 [cited 2023 Mar 27];5:98-108. Available from: https://www.jnsmonline.org/text.asp?2022/5/2/98/344208

  Introduction Top

Coronavirus disease 19 (COVID-19) is a clinical disease caused by a new genus of the coronaviridae subfamily, coining the name severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] It was first identified in the Wuhan district of the People's Republic of China after multiple reports of a new virus. The outbreak spanned over 223 countries, areas, and territories with confirmed cases of SARS-Cov-2. COVID-19 was given a pandemic status or public health emergency of international concern by the World Health Organization (WHO).[2] COVID-19 causes a cluster of symptoms including fever, dry cough, fatigue, and to a lesser extent, loss of taste and smell, sore throat, headaches, GI symptoms, arthralgia, and muscle pain, and chills or dizziness; the primary presenting symptomatology falling into the category of respiratory symptoms. In some cases, patients with COVID-19 continue to experience some symptoms, including fatigue, respiratory, and some level of neurological symptoms. While about 80% of patients with COVID-19 go through recovery without the need to receive medical care or perhaps can be managed on an outpatient basis; 15% develop a more severe condition and require medical care, and about 5% become critically ill and require intensive medical care in a tertiary hospital center with an equipped intensive care unit.

COVID-19 has been associated with several complications, including respiratory failure, ARDS, sepsis and septic shock, multi-organ failure, as well as cardiac, renal, and hepatic injuries.[3] It has been well documented that SARS-Cov-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors to enter the cells.[4],[5] ACE2 receptors are widely expressed in various human body tissues, of specific relevance, the brain's glial cells, and neurons, granting the virus its neurotropic features. Besides the presence of SARS-CoV-2 in cerebrospinal fluid.[6],[7]

It is also hypothesized that respiratory failure, a major cause of mortality, is due to neurogenic origins.[8] In a study conducted to compare the neurological sequelae of SARS-CoV-2 infection during acute disease and at follow-up after 3 months, it was discovered that persistence of neurological anomalies was common. Neurological symptoms at 3 months follow-up were found in a sixth of the patients participating in said study, with the most common persistent neurological symptom being hyposmia/anosmia.[9] SARS-CoV-2 infection is proposed to be associated with neurotoxicity, causing delirium and neurological symptoms, leading to a longer stay in the ICU and an increased risk of mortality and morbidity.[10] However, there is much uncertainty associated with neurological outcomes concerning whether they occur during or after SARS-CoV-2 infection. The aim of this systematic review and meta-analysis is to identify the neurological sequelae and consequences in patients with COVID-19, the impact of SARS-CoV-2 on the central nervous system (CNS), and the contributing risk factors to the neurological sequelae associated with COVID-19.

Specifically, this review addresses the following questions: (1) What are the main neurological sequelae in patients infected with COVID-19 and those who recovered from the disease? (2) What are the common risk factors presenting throughout various populations? (3) What are the specific risk factors presenting in certain populations that lead to a CNS impact? and (4) whether SARS-CoV-2 infection leads to the first-time occurrence of these neurological consequences or as an exacerbation of a neurological disease that already presents.

  Methodology Top


A systematic review was conducted, taking into consideration methodological guidelines.[11] To standardize the review procedure, the PRISMA tool and flow chart were utilized. The literature was systematically taken through the following key phases: (1) Formulating study questions; (2) A specific set of keywords was formed and utilized and identifying the electronic databases; (3) Identifying original research investigating the neurological outcomes of patients with COVID-19 followed by selecting only those studies, (4) Charting the data from the articles, summarizing, and reporting the results.

Eligibility criteria

All studies about COVID-19 that have been conducted in relation to patients that have developed neurological sequelae following or during primary infection would be included in this review. In further detail, studies included must have been: (1) Observational (prospective and retrospective) cohort studies regardless of sample size with original research merit (2) Targeting a specific sample of adult patients seeking medical attention at a healthcare facility, and (3) Included the relationship between COVID-19 and a neurological outcome would be included. Both published and accepted articles that were already published solely online were incorporated into the study. Studies that have included pediatric age groups as part of the sample have been excluded due to differences in multiple aspects about the focus of the review, which is adult COVID-19 patients, including differences in presenting symptomatology and severity, as shown by Milani et al.[12] Studies that included both adult and pediatric age groups were also excluded for the same reasoning above, in addition to an inability to extract adult-only data from some studies. Therefore, a decision was made to exclude the mixed adult and pediatric age group studies. Non-English language studies were excluded.


The endpoints that were sought after in this review and have been examined were stroke, headache, hyposmia/anosmia, delirium, intracerebral hemorrhage (ICH), encephalitis, and seizures. The definitions of these endpoints are listed below:

  1. Stroke is defined as “Rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 h or longer or leading to death, with no apparent cause other than of vascular origin”[13]
  2. Headache is defined as “Pain located in the head, above the orbitomeatal line and/or nuchal ridge”[14]
  3. Hyposmia was defined as the “decrease of the olfactory function and anosmia the total loss of any olfactory function”[15]
  4. Delirium is defined as “Acute confusional state, characterized by an alteration of consciousness and cognition with reduced ability to focus, sustain or shift attention”[16]
  5. ICH is defined as “A subtype of stroke, where a hematoma is formed within the brain parenchyma with or without blood extension into the ventricles”[17]
  6. Encephalitis, or Viral Encephalitis is defined as “an inflammation of the brain, caused by any one of a number of viruses”[18]
  7. Seizures are defined as “The uncontrolled, abnormal electrical activity of the brain that may cause changes in the level of consciousness, behavior, memory, or feelings.”[19]

Database search

In February 2021, an inclusive electronic search was carried out independently by three members without a date restriction in the WHO COVID-19 database, which includes data from 31 multiple databases, including MEDLINE (99487), WHO COVID (63358), medRxiv (10172), ICTRP (7874), ELSEVIER (5032), SSRN (3279), bioRxiv (2914), LILACS (Americas) (1861), ChemRxiv (410), SciFinder (379), WPRIM (Western Pacific) (297), PubMed (124), PREPRINT-SCIELO (105), Centers for Disease Control and Prevention (67), ProQuest Central (45), CAplus (39), ArXiv (20), Other Preprints (11), Embase (6), F1000Research (6), Web of Science (3), CAB Abstracts (2), LIS (2), PMC (2), WHO (2), Biomed Central (1), Embase MEDLINE (1), PsyArXiv (1), Scopus (1).

We applied an English language restriction, as well as a study type restriction, including only prognostic and incidence studies that meet eligibility criteria. Grey literature was excluded. Certain search criteria were developed to gather articles that were related to neurological sequelae and outcomes in patients with COVID-19. Search terms were used in combinations into the following sets: “COVID-19 Neurological Outcomes cohort.” The final search results were exported into an Excel sheet to be refined and remove duplicates.

Screening, reviewing process, and data extraction

The titles and abstracts of the identified articles were examined by one author then cross-reviewed by another author to confirm relevance to the review and the inclusion criteria. Any reasons for the article omission were documented. Following this, eligible studies underwent a review and appraisal of the evidence by two independent reviewers, charting the data and discussing the results throughout the process. Any discrepancies in article selection were discussed in a meeting between the authors and reviewers before inclusion into the review. Data were then extracted in Microsoft Excel 2019 using the following variables categorization. Extracted data included: title, authors, DOI (citation), document type, date of publication, country, sample size, event rate (by endpoint), mean age, proportion of male gender participants, tool utilized (clinical, investigation, imaging), other comorbid multi-system problem, and the setting in which the study was conducted.

Quality evaluation

Two reviewers (AMA and RAA) independently assessed the methodological quality of the studies using the Newcastle–Ottawa Scale. The Newcastle–Ottawa Scale checklist contains 7 questions, which we divided into three domains: Participants selection (questions 1–4), comparability (question 5), and outcome and statistics (questions 6 and 7). Scores range from 0 to 10. Details of the items used in the Newcastle–Ottawa Scale and score interpretations are presented in [Supplemental Table S1]. Quality assessment was also performed in parallel with data extraction.

Data synthesis and analysis

Data were synthesized for the meta-analysis using the random-effects model according to the DerSimonian–Laird method. We reported the results of the overall prevalence rate and corresponding 95% confidence intervals (CIs). We performed a detailed analysis of the heterogeneity using I2, Cochran (Q) statistic test, H test, tau, and tau2 (τ2). A jackknife sensitivity analysis was performed by iteratively removing one study at a time to confirm that our findings were not driven by any single study. Funnel plots are a visual tool for examining publication bias in meta-analysis. All data analyses were performed using R software for Statistical Computing. The packages “meta” and “metafor” were used for all analytics.

  Results Top

Literature search

The preliminary search in the WHO COVID-19 electronic database yielded a total of 184 citations, of which 56 were duplicates and deleted, leaving a total of 128 studies. The initial screening of the remaining 128 citations excluded a total of 89 studies, which were unrelated to the topic of the analysis, generating a total list of 39 studies to be critically appraised. Twenty studies were excluded based on not meeting the analysis eligibility criteria; most of which did not discuss neurological diseases as outcomes of COVID-19 infection or included a pediatric age group. Finally, the remaining studies that met the inclusion criteria were 19 studies. This process is illustrated in full detail as Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram in [Figure 1]. Summary of all included studies is shown in [Table 1].
Figure 1: Preferred reporting items for systematic reviews and meta-analyses flow diagram of study inclusion

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Table 1: Selected characteristics, methods, and individual event rates of the included studies in this review about neurological sequelae in patients with coronavirus disease-2019

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The analysis included all the endpoints, with emphasis on the endpoints of stroke, headache, delirium, and ICH (K = 19). The total participant population was 45181, with an event rate of 7.6% (95% C. I. 3.0%–17.6%) for any endpoint, with individual event rates ranging from 0.5% to 69.3%. The studies were considerably heterogeneous with an I2 = 99.7%, tau = 2.1208, tau2 = 4.4977 and H = 17.91. The results were statistically significant with a P value of 0, which is reflected in [Figure 2]. There appears to be no publication bias in the included studies, as seen in [Supplemental Figure 1]. Meta-regression showed an apparent increase in the event rate of neurological sequelae about an increase in age and a relatively increased occurrence in females than in males, as seen in [Supplemental Figure 2] and [Supplemental Figure 3].
Figure 2: Overall neurological sequelae forest plot

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Out of the total 19 studies included in the analysis, 10 studies (53%) of the total included studies (K = 19), dealt with stroke as an endpoint in patients infected with COVID-19. Of those studies, a total of 31773 represented the sample for the stroke endpoint with an individual rate ranging between 0.4% and 26.6% and an overall event rate of 1.8% (95% C. I. 0.9%–3.3%). The studies showed considerable heterogeneity with the I2 = 96.4%, tau = 1.0039, tau2 = 1.0078, and H = 5.26, as shown in [Figure 3]. A publication bias was exhibited, with two outlying studies, as shown in [Supplemental Figure 4]. Meta-regression exhibits an increase in the occurrence of stroke in patients infected with COVID-19, in relation to an increase in age, as well as an increased occurrence in males than in females, as shown in [Supplemental Figure 5] and [Supplemental Figure 6], respectively.
Figure 4: Forest plot for the headache endpoint

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As shown in [Figure 4] (26%) of the overall studies examined headache as an endpoint in patients infected with COVID-19. The overall event rate was 6.7% (95% C. I. 1.94%–20.67%), with individual event rates recorded between 0.2% and 26.7%, as shown in [Figure 4]. About quantifying heterogeneity, the results showed considerable heterogeneity with the tau2 = 1.964, tau = 1.4014, I2 = 94.7%, and H = 4.33. Two studies were shown to have possible publication biases, as [Supplemental Figure 7]. Meta-regression showed an increase in the occurrence of headache in patients infected with COVID-19 in relation to an increase in age, as well as an increased occurrence in females than in males, as seen in [Supplemental Figure 8] and [Supplemental Figure 9], respectively.{Figure 4}


As shown in [Figure 5] (32%) of the 19 studies assessed delirium as an endpoint of those patients infected with COVID-19. The event rate of delirium was 25.2% (95% CI 13.9%–41.4%) on a total sample of 5299 across the included studies (K = 19, N = 5299), with individual study event rates ranging from 0.8% to 69.3%. On heterogeneity analysis of the included papers, the I2 = 99%, and tau = 0.906, and tau2 = 0.821, H = 10.23, showing considerable heterogeneity, which may be owed to differences in sample size and the settings in which these studies have taken place. Meta-regression showed that there is an apparent increase in the event rate of delirium about an increase in age, as well as an increased occurrence in males than in females, as shown in [Supplemental Figure 10] and [Supplemental Figure 11], respectively. Furthermore, there appears to be no publication bias in the included studies that have looked at delirium as an outcome, as shown in [Supplemental Figure 12].
Figure 5: Forest plot for the delirium endpoint

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Intracerebral hemorrhage

Five (26%) studies of all included studies (K = 19) dealt with ICH as an endpoint in patients infected with COVID-19. The total sample size was 23,767 participants. The overall event rate was 1% (95% C. I. 0.4%–2.8%), with individual event rates ranging between 0.2% and 5.8%. The studies showed considerable heterogeneity, where I2 = 96%, tau = 1.1026, tau2 = 1.2157, and H = 4.94, as shown in [Figure 6]. [Supplemental Figure 13] demonstrates a publication bias, with two outlying studies. Meta-regression shows a decrease in the occurrence of ICH in patients infected with COVID-19 about an increase in age, contrary to the previous endpoints and the overall meta-regression, however, there is an increased occurrence in females than in males, as shown in [Supplemental Figure 14] and [Supplemental Figure 15], respectively.
Figure 6: Forest plot for the intracerebral hemorrhage endpoint

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  Discussion Top

The current review aimed to identify the neurological sequelae and consequential in patients with COVID-19, the impact of SARS-CoV-2 on the CNS, and the contributing risk factors to the neurological sequelae associated with COVID-19. The studies in the analysis mainly explored hospitalized patients as the populations, with some looking at nonhospitalized patients as well. The results showed that the overall event rates of the endpoints, which included stroke, headache, delirium, and ICH, were 1.8%, 6.7%, 25.2%, and 1%, respectively. Comparing these results to the global incidence of the endpoints above, we found that stroke had a global incidence of 0.25%,[20] headache had a global prevalence of 50%,[21] and ICH had a global prevalence of 0.024%,[22] illustrating that stroke and ICH had higher event rates than the global incidence. However, the global prevalence of headache was higher than in our analysis, possibly due to underreporting in the included studies.

Stroke is considered a disease of old age in which most affected people are over the age of 65, as well as a higher lifetime incidence in males, but a higher prevalence in females,[23] owing to increased life expectancy, which was consistent with the results of our analysis. In addition, females have a higher risk of developing migraines, while there is an equal sex ratio in the prevalence of tension headaches,[24] which shows similar consistency as the results of our analysis. Concerning the incidence of ICH,[25] it has been shown that ICH increases with age, and this was contrary to our results in the current review. However, Beyrouti et al. demonstrated that ICH associated with COVID-19 seems to affect younger (median age: 60), more frequently male (64%), and less often hypertensive (53%) population, and appears to more often be lobar, multifocal, and associated with the use of anticoagulants drugs. All of these observations by Beyrouti et al. suggest that ICH associated with COVID-19 potentially has different characteristics and mechanisms as compared to ICH unassociated with COVID-19[26] and this might be the reason for our results in the context of age.

Looking at delirium in the context of those affected with COVID-19 as well as the intensive care unit setting, our results showed an event rate of 25.2% in individuals affected with COVID-19 compared to an overall incidence of delirium in the ICU patients of 28.1%. The study by Kyle Hendrie et al.,[27] which looked at the incidence and prevalence of delirium in the intensive care unit setting, suggested a similar rate of delirium occurrence to that found in our analysis. In a multicenter study, Pun et al.[28] investigated the prevalence of delirium in critically ill patients and reported a prevalence of 54.9%, whereas a study by Paola Rebora et al.[29] looked at delirium in the context of acute medical wards and reported a 14.1% overall prevalence of delirium at admission. These observations possibly outline the relationship between the severity of COVID-19 and delirium development as one of the endpoints in our analysis.

In our meta-analysis, heterogeneity refers to the differences in research outcomes between studies. The I2 statistic indicates how much variance between research is attributable to heterogeneity rather than chance. This variance is best explained by the patient's characteristics not available at meta-analysis level, for example, underlying medical conditions or risk factors for each of the endpoints.

Vasilevskis et al.[47] discussed the risk factors for developing delirium across an array of medical settings, highlighting multiple risk factors, which could be applied in the same context to those that develop delirium as a consequence of COVID-19, including increasing age and infections, such as pneumonia.

Stroke and ICH were viewed in the context of anticoagulant use as a concomitant risk factor to COVID-19 infection. The utilities used in relation to the anticoagulant use in stroke and ICH are clinical, including the National Institutes of Health Stroke Scale (NIHSS), Diffusion-Weighted Imaging–Alberta Stroke Program, Burden Clot Score (DWI-ASPECTS), and the use of neuroimaging modalities such as computed tomography and magnetic resonance imaging. In a study conducted by Escalard et al.,[48] COVID-19 patients had more severe strokes on the NIHSS score but a lower burden clot score and a lower DWI-ASPECTS, suggesting that COVID-19 patients had a higher mortality rate. It is hypothesized that coagulation disorders and endothelial dysfunction are followed by systemic inflammation supported by microvascular immunothrombosis. Beyrouti et al.[26] and Moores et al.[49] discussed the use of anticoagulants in thromboembolic events in patients with severe SARS-Cov-2 infection. In these studies, anticoagulation has been shown to be effective but also could be considered as a serious etiology for ICH. Moreover, patients at higher risk of developing ICH have accompanying comorbidities such as hypertension and diabetes. Moreover, the proportion of ICH COVID-19 patients related to hypertensive angiopathy and coagulopathy is high in those who received anticoagulant therapy more frequently.[26]

It is postulated that dysfunction ACE2 receptors in the brain lead to the disturbances of autoregulation, resulting in high blood pressure and arterial wall rupture.[50] In addition, coagulopathy may occur in patients with COVID-19, which further increases the risk of secondary cerebral hemorrhages.[51] It has been shown that COVID-19 infection produces a cytokine storm, which has been postulated as one of the triggers for the development of cerebrovascular disease and stroke.[52] Furthermore, severe infection with COVID-19 is associated with increased levels of D-dimers and a decreased platelets, which may predispose them to thrombosis.[53]

The Coronaviridae family is known to affect multiple organs; of particular interest in this review is the CNS. This feature is shared between viruses of this family, most notably the pandemic-causing agents SARS-CoV, MERS-CoV, and SARS-CoV-2.[54],[55],[56],[57] Indeed, there is a similarity in the pattern of neurological manifestation associated with all of the viruses above, with frequent reports of encephalitis and stroke complications. For instance, a retrospective study conducted by Saad et al.[58] exploring MERS-CoV in Saudi Arabia and involving 70 patients has found that 18 (25.7%) patients developed confusion, 9 (12.7%) developed a headache, and 6 (8.6%) experienced a seizure. Interestingly, the results of our meta-analysis review showed relatively similar results for SARS-CoV-2. On the other hand, a retrospective study conducted by Kim et al.[59] in South Korea focusing on the neurological complications of MERS-CoV found that these complications are often delayed by 2–3 weeks after respiratory symptoms, giving a possible reason for under-diagnosis of neurological sequelae. Another prospective study conducted by Umapathi et al.[60] in Singapore during the SARS-CoV outbreak in 2003 showed that out of 206 patients, 5 (2.43%) developed stroke. This finding correlates with the results of our analysis.

In addition the association of CNS involvement in influenza viruses has also been documented. For instance, Toovey[61] found that febrile seizures are most frequently associated with influenza, whereas influenza-associated encephalitis and encephalopathy are less common. Moreover, a study by Cárdenas et al.[52] on the neurological complications of influenza, A H1N1 virus involving 1349 cases showed a wide spectrum of complications including stroke, myelitis, and encephalitis.

Our review has certain limitations, which may influence the results. One of these limitations is the follow-up period in the analyzed studies is too short for specific chronic and progressive neurologic deficits to present in COVID-19. In addition, the exclusion of the pediatric age group, as well as non-English language studies, may also affect our analysis. Finally, some studies have investigated the presence/absence of SARS-Cov-2 infection without eliciting the severity, which may be a limiting factor in determining the true occurrence of neurological deficits following infection. In addition, the analysis of headaches mainly took into account unclassified headaches, limiting the interpretation of the endpoint, in addition to the inclusion of unexplained headaches in studies, such as in the study conducted by Xiong et al.

  Conclusions Top

The analysis found that the incidence of ICH and stroke was greater than their incidence in the general population, perhaps indicating a different pathophysiology in their occurrence, whereas the incidence of delirium was similar to that of the general population. Finally, headaches had a lower incidence than the general population.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.[62]

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

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