Advertisement

Frequency and burden of neurological manifestations upon hospital presentation in COVID-19 patients: Findings from a large Brazilian cohort

Published:November 02, 2022DOI:https://doi.org/10.1016/j.jns.2022.120485

      Highlights

      • Ageusia, anosmia and headaches were the most commonly reported symptoms.
      • Acute encephalopathy, coma and seizures were the most common neurological syndromes.
      • Septic shock and ICU admission were more frequent in cases with neurological syndromes.
      • In-hospital death was more common in COVID-19 patients with neurological syndromes.Neurological syndromes are a risk for morbidity in COVID-19 patients.

      Abstract

      Background

      Scientific data regarding the prevalence of COVID-19 neurological manifestations and prognosis in Latin America countries is still lacking. Therefore, the study aims to understand neurological manifestations of SARS-CoV 2 infection and outcomes in the Brazilian population.

      Methods

      This study is part of the Brazilian COVID-19 Registry, a multicentric cohort, including data from 37 hospitals. For the present analysis, patients were grouped according to the presence of reported symptoms (i.e., headache; anosmia and ageusia; syncope and dizziness) vs. clinically-diagnosed neurological manifestations (clinically-defined neurological syndrome: neurological signs or diagnoses captured by clinical evaluation) and matched with patients without neurological manifestations by age, sex, number of comorbidities, hospital of admission, and whether or not patients had underlying neurological disease.

      Results

      From 6,635 hospitalized patients with COVID-19, 30.8% presented reported neurological manifestations, 10.3% were diagnosed with a neurological syndrome and 60.1% did not show any neurological manifestations. In patients with reported symptoms, the most common ones were headache (20.7%), ageusia (11.1%) and anosmia (8.0%). In patients with neurological syndromes, acute encephalopathy was the most common diagnosis (9.7%). In the matched analysis, patients with neurological syndromes presented more cases of septic shock (17.0 vs. 13.0%, p = 0.045), intensive care unit admission (45.3 vs. 38.9%, p = 0.023), and mortality (38.7 vs. 32.6%, p = 0.026; and 39.2 vs. 30.3%, p < 0.001) when compared to controls.

      Conclusion

      COVID-19 in-hospital patients with clinically defined neurological syndromes presented a higher incidence of septic shock, ICU admission and death when compared to controls.

      Keywords

      University Hospital, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena, 110 Room 107. Ala Sul., Santa Efigênia – Belo Horizonte – MG. Brazil, CEP 30130–100.

      1. Introduction

      The coronavirus disease 19 (COVID-19) pandemic has affected millions of people worldwide. Clinical signs of upper respiratory tract infection such as nasal congestion and cough, alongside systemic symptoms like fatigue and fever usually precede lung involvement [
      • SeyedAlinaghi S.
      • Mirzapour P.
      • Dadras O.
      • Pashaei Z.
      • Karimi A.
      • MohsseniPour M.
      • Soleymanzadeh M.
      • Barzegary A.
      • Afsahi A.M.
      • Vahedi F.
      • Shamsabadi A.
      • Behnezhad F.
      • Saeidi S.
      • Mehraeen E.
      • Jahanfar Shayesteh
      Characterization of SARS-CoV-2 different variants and related morbidity and mortality: a systematic review.
      ]. Besides the severity of respiratory symptoms, risk factors associated with worse clinical outcomes include, older age, male sex, baseline comorbidities (e.g. diabetes mellitus, chronic kidney disease, cerebrovascular disease, hypertension and obesity), and abnormal laboratory biomarkers [
      • Shi C.
      • Wang L.
      • Ye J.
      • Gu Z.
      • Wang S.
      • Xia J.
      • Xie Y.
      • Li Q.
      • Xu R.
      • Lin N.
      Predictors of mortality in patients with coronavirus disease 2019: a systematic review and meta-analysis.
      ,
      • Marcolino M.S.
      • Pires M.C.
      • Ramos L.E.F.
      • Silva R.T.
      • Oliveira L.M.
      • Carvalho R.L.R.
      • et al.
      ABC2-SPH risk score for in-hospital mortality in COVID-19 patients: development, external validation and comparison with other available scores.
      ]. Also, previous studies have associated the presence of neurological comorbidities, such as epilepsy and dementia, to a poorer COVID-19 prognosis [
      • Muccioli L.
      • Zenesini C.
      • Taruffi L.
      • Licchetta L.
      • Mostacci B.
      • Di Vito L.
      • Pasini E.
      • Volpi L.
      • Riguzzi P.
      • Ferri L.
      • Baccari F.
      • Nonino F.
      • Michelucci R.
      • Tinuper P.
      • Vignatelli L.
      • Bisulli F.
      Risk of hospitalization and death for COVID-19 in persons with epilepsy over a 20-month period: the EpiLink Bologna cohort, Italy.
      ,
      • Cascini S.
      • Agabiti N.
      • Marino C.
      • Acampora A.
      • Balducci M.
      • Calandrini E.
      • Davoli M.
      • Bargagli A.M.
      Incidence and outcomes of SARS-CoV-2 infection in older adults living with dementia: A population-based cohort study.
      ].
      COVID-19 can also evolve with cardiac, renal, ophthalmologic, skin, and other manifestations. Several reports have described a series of neurological manifestations associated with COVID-19 [
      • Johansson A.
      • Mohamed M.S.
      • Moulin T.C.
      • Schiöth H.B.
      Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms.
      ]. Both peripheral and central nervous systems may be affected, with a wide range of symptoms, signs and syndromes [
      • Johansson A.
      • Mohamed M.S.
      • Moulin T.C.
      • Schiöth H.B.
      Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms.
      ,
      • Collantes M.E.V.
      • Espiritu A.I.
      • Sy M.C.C.
      • Anlacan V.M.M.
      • Jamora R.D.G.
      Neurological manifestations in COVID-19 infection: A systematic review and Meta-analysis.
      ,
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ]. Importantly, the presence of neurological signs and/or syndromes, such as delirium and coma, has been associated with up to five times higher risk of in-hospital death, but this finding has not been consistent across studies [
      • Chou S.H.
      • Beghi E.
      • Helbok R.
      • Moro E.
      • Sampson J.
      • Altamirano V.
      • Mainali S.
      • Bassetti C.
      • Suarez J.I.
      • McNett M.
      • GCS-NeuroCOVID Consortium and ENERGY Consortium
      Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium.
      ,
      • Misra S.
      • Kolappa K.
      • Prasad M.
      • Radhakrishnan D.
      • Thakur K.T.
      • Solomon T.
      • Michael B.D.
      • Winkler A.S.
      • Beghi E.
      • Guekht A.
      • Pardo C.A.
      • Wood G.K.
      • Hsiang-Yi Chou S.
      • Fink E.L.
      • Schmutzhard E.
      • Kheradmand A.
      • Hoo F.K.
      • Kumar A.
      • Das A.
      • Srivastava A.K.
      • Agarwal A.
      • Dua T.
      • Prasad K.
      Frequency of neurologic manifestations in COVID-19: A systematic review and Meta-analysis.
      ]. General alterations in the patient's mental status during COVID-19 have been associated with in-hospital mortality [
      • García-Azorín D.
      • Trigo J.
      • Martínez-Pías E.
      • Hernández-Pérez I.
      • Valle-Peñacoba G.
      • Talavera B.
      • Simón-Campo P.
      • de Lera M.
      • Chavarría-Miranda A.
      • López-Sanz C.
      • Gutiérrez-Sánchez M.
      • Martínez-Velasco E.
      • Pedraza M.
      • Sierra Á.
      • Gómez-Vicente B.
      • Guerrero Á.
      • Arenillas J.F.
      Neurological symptoms in Covid-19 patients in the emergency department.
      ]. Meanwhile, the presence of mild neurological symptoms, such as anosmia and ageusia, have been associated with a better disease prognosis [
      • Chou S.H.
      • Beghi E.
      • Helbok R.
      • Moro E.
      • Sampson J.
      • Altamirano V.
      • Mainali S.
      • Bassetti C.
      • Suarez J.I.
      • McNett M.
      • GCS-NeuroCOVID Consortium and ENERGY Consortium
      Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium.
      ,
      • Misra S.
      • Kolappa K.
      • Prasad M.
      • Radhakrishnan D.
      • Thakur K.T.
      • Solomon T.
      • Michael B.D.
      • Winkler A.S.
      • Beghi E.
      • Guekht A.
      • Pardo C.A.
      • Wood G.K.
      • Hsiang-Yi Chou S.
      • Fink E.L.
      • Schmutzhard E.
      • Kheradmand A.
      • Hoo F.K.
      • Kumar A.
      • Das A.
      • Srivastava A.K.
      • Agarwal A.
      • Dua T.
      • Prasad K.
      Frequency of neurologic manifestations in COVID-19: A systematic review and Meta-analysis.
      ,
      • García-Azorín D.
      • Trigo J.
      • Martínez-Pías E.
      • Hernández-Pérez I.
      • Valle-Peñacoba G.
      • Talavera B.
      • Simón-Campo P.
      • de Lera M.
      • Chavarría-Miranda A.
      • López-Sanz C.
      • Gutiérrez-Sánchez M.
      • Martínez-Velasco E.
      • Pedraza M.
      • Sierra Á.
      • Gómez-Vicente B.
      • Guerrero Á.
      • Arenillas J.F.
      Neurological symptoms in Covid-19 patients in the emergency department.
      ,
      • Talavera B.
      • García-Azorín D.
      • Martínez-Pías E.
      • Trigo J.
      • Hernández-Pérez I.
      • Valle-Peñacoba G.
      • Simón-Campo P.
      • de Lera M.
      • Chavarría-Miranda A.
      • López-Sanz C.
      • Gutiérrez-Sánchez M.
      • Martínez-Velasco E.
      • Pedraza M.
      • Sierra Á.
      • Gómez-Vicente B.
      • Guerrero Á.
      • Arenillas J.F.
      Anosmia is associated with lower in-hospital mortality in COVID-19.
      ]. Headache, for instance, is frequently associated with a lower duration of COVID-19 symptoms and low risk of in-hospital mortality [
      • Caronna E.
      • Ballvé A.
      • Llauradó A.
      • Gallardo V.J.
      • Ariton D.M.
      • Lallana S.
      • López Maza S.
      • Olivé Gadea M.
      • Quibus L.
      • Restrepo J.L.
      • Rodrigo-Gisbert M.
      • Vilaseca A.
      • Hernandez Gonzalez M.
      • Martinez Gallo M.
      • Alpuente A.
      • Torres-Ferrus M.
      • Pujol Borrell R.
      • Alvarez-Sabin J.
      • Pozo-Rosich P.
      Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution.
      ,
      • Trigo J.
      • García-Azorín D.
      • Planchuelo-Gómez Á.
      • Martínez-Pías E.
      • Talavera B.
      • Hernández-Pérez I.
      • Valle-Peñacoba G.
      • Simón-Campo P.
      • de Lera M.
      • Chavarría-Miranda A.
      • López-Sanz C.
      • Gutiérrez-Sánchez M.
      • Martínez-Velasco E.
      • Pedraza M.
      • Sierra Á.
      • Gómez-Vicente B.
      • Arenillas J.F.
      • Guerrero Á.L.
      Factors associated with the presence of headache in hospitalized COVID-19 patients and impact on prognosis: a retrospective cohort study.
      ,
      • Gonzalez-Martinez A.
      • Fanjul V.
      • Ramos C.
      • Serrano Ballesteros J.
      • Bustamante M.
      • Villa Martí A.
      • Álvarez C.
      • García Del Álamo Y.
      • Vivancos J.
      • Gago-Veiga A.B.
      Headache during SARS-CoV-2 infection as an early symptom associated with a more benign course of disease: a case-control study.
      ]. Additionally, some manifestations are related to persistent disability, potentially associated with long-term care needs and high health, social, and economic costs [
      • Ellul M.A.
      • Benjamin L.
      • Singh B.
      • Lant S.
      • Michael B.D.
      • Easton A.
      • Kneen R.
      • Defres S.
      • Sejvar J.
      • Solomon T.
      Neurological associations of COVID-19.
      ]. Despite the epidemiological and clinical relevance of the matter, data on the prevalence of those manifestations and their prognosis in Latin American patients is still lacking.
      Therefore, this study aimed: (i) to characterize the spectrum of neurological manifestations among Brazilian patients hospitalized with COVID-19; and (ii) to investigate the potential association between neurological manifestations and clinical outcomes, specifically in-hospital mortality.

      2. Methods

      2.1 Study design and subjects

      This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline [
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gøtzsche P.C.
      Vandenbroucke JP; STROBE initiative. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ]. This was an urgent public health research study in response to a Public Health Emergency of International Concern. Methods were performed in accordance with guidelines and regulations [
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • Pocock S.J.
      • Gøtzsche P.C.
      Vandenbroucke JP; STROBE initiative. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ].
      Patients were selected from the Brazilian COVID-19 Registry, a retrospective multicenter cohort project with 37 participant hospitals in 17 cities from five Brazilian states (Minas Gerais, Pernambuco, Rio Grande do Sul, Santa Catarina, São Paulo). Details of the cohort were published elsewhere [
      • Marcolino M.S.
      • Ziegelmann P.K.
      • Souza-Silva M.V.R.
      • Nascimento I.J.B.
      • Oliveira L.M.
      • Monteiro L.S.
      • Sales T.L.S.
      • Ruschel K.B.
      • Martins K.P.M.P.
      • Etges A.P.B.S.
      • Molina I.
      • Polanczyk C.A.
      Brazilian COVID-19 registry investigators. Clinical characteristics and outcomes of patients hospitalized with COVID-19 in Brazil: results from the Brazilian COVID-19 registry.
      ]. The study was approved by the National Commission for Research Ethics (CAAE 30350820.5.1001.0008). Individual informed consent was waived by the National Commission for Research Ethics owing to the pandemic situation and the use of deidentified data, based on medical chart review only.
      The cohort study included consecutive adult patients (aged 18 or older) with confirmed COVID-19 diagnosis through real time polymerase-chain reaction (RT-PCR) or serologic testing (symptoms and positive test; diagnosis based only on typical clinical symptoms was not accepted), according to World Health Organization guidance, who were hospitalized in one of the participating centers from March 1st to September 30th, 2020, during the first wave of the COVID-19 pandemic in Brazil [
      • World Health Organization
      Diagnostic testing for SARS-CoV-2. Interim guidance. Online.
      ]. Patients who developed their first COVID-19 symptoms while hospitalized for other conditions, or those who were admitted on mechanical ventilation, unable to perform the complete neurological exam and collection of clinical history were not included in this analysis.

      2.2 Data collection

      Study data were collected by trained hospital staff using Research Electronic Data Capture (REDCap) tools [
      • Harris P.A.
      • Taylor R.
      • Minor B.L.
      • Elliott V.
      • Fernandez M.
      • O’Neal L.
      • McLeod L.
      • Delacqua G.
      • Delacqua F.
      • Kirby J.
      • Duda S.N.
      • REDCap Consortium
      The REDCap consortium: building an international community of software platform partners.
      ], hosted at the Telehealth Center, University Hospital, Universidade Federal de Minas Gerais [
      • Marcolino M.S.
      • Alkmim M.B.M.
      • Assis T.G.P.
      • Palhares D.M.F.
      • da Silva G.A.
      • Cunha L.R.
      • Sousa L.
      • de Abreu M.P.
      • Figueira R.M.
      • Ribeiro A.L.
      A Rede de Teleassistência de Minas Gerais e suas contribuições para atingir os princípios de universalidade, equidade e integralidade do SUS – relato de experiência.
      ]. Medical records were reviewed by trained health professionals or interns, to collect data on patients' demographic and clinical characteristics, including age, sex, pre-existing medical conditions and home medications; COVID-19 symptoms at hospital presentation; clinical assessment upon hospital presentation, and upon ICU admission (if admission was required); laboratory, imaging, electrocardiographic data; inpatient medications, treatment and outcomes. A detailed data management plan (DMP) was developed and provided to all participating centers (Supplementary File 1).
      Stages of disease severity were defined based on WHO classification, as follows:
      i. Critical COVID-19: presence of acute respiratory distress syndrome, sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies, such as mechanical ventilation or vasopressor therapy.
      ii. Severe COVID-19: any of: (i) oxygen saturation < 90% on room air; (ii) signs of severe respiratory distress (accessory muscle use, inability to complete full sentences, respiratory rate > 30 breaths per minute), in addition to the signs of pneumonia.
      iii. Non-severe COVID-19: absence of any criteria for severe or critical COVID-19.

      2.3 Neurological manifestations

      Neurological manifestations were assessed upon hospital presentation, ie., when the patient sought care at the emergency department and had his/her first clinical assessment. They were categorized as: (1) reported symptoms (i.e., headache; anosmia and ageusia; syncope and dizziness) and (2) clinically-defined neurological syndrome: neurological signs or diagnoses captured by clinical evaluation (i.e., acute encephalopathy; stroke; coma; seizure and/or status epilepticus; aphasia; abnormal brainstem reflexes; involuntary movements; motor and sensory deficits), as proposed by Chou et al. (2021) [
      • Chou S.H.
      • Beghi E.
      • Helbok R.
      • Moro E.
      • Sampson J.
      • Altamirano V.
      • Mainali S.
      • Bassetti C.
      • Suarez J.I.
      • McNett M.
      • GCS-NeuroCOVID Consortium and ENERGY Consortium
      Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium.
      ]. The controls were enrolled COVID-19 patients with no neurological manifestations/syndromes (for more details see Statistical analysis section).

      2.4 Primary and secondary outcomes

      The primary outcome was all-cause in-hospital mortality. Secondary outcomes included hospital stay, admission and time to the intensive care unit (ICU), mechanical ventilation, acute kidney injury (AKI), septic shock, nosocomial infection, dialysis, acute heart failure, vascular thrombosis and laboratory parameters.

      2.5 Statistical analysis

      Categorical data were presented as absolute numbers and proportions, and continuous variables were expressed as medians and interquartile ranges. Fisher Exact test was used to compare the distribution of categorical variables, and Wilcoxon-Mann–Whitney or Kruskal-Wallis tests were used for continuous variables. Missing data were not imputed.
      First, we compared clinical features and laboratory findings at hospital presentation among patients with reported symptoms, clinically-defined neurological syndrome and no neurological manifestations using the whole sample (unmatched). Bonferroni correction was undertaken for multiple testing, by dividing the critical p-value (0.05) by the number of comparisons.
      When analyzing for primary and secondary outcomes, as categorizing patients according to the presence of neurological manifestations would lead to groups with different distribution of age, sex and number of comorbidities, treating hospital and presence of underlying neurological disease, and given the fact that these variables may be prognostic factors in COVID-19, a propensity score analysis through nearest neighbor matching (within 0.25 standard deviations of the logit of the propensity score, on a scale from 0 to 1.00) was used to control for confounding, by balancing those variables across the groups. Propensity score model was estimated by a logistic regression model, using the MatchIt package in R software. There were six different matchings:
      i. Patient with at least one clinically-defined neurological syndrome, were matched with patients with no clinically-defined neurological syndrome, taking into account sex, age, number of comorbidities, admitting hospital, and past history of neurological disease;
      ii. Patient with at least one clinically-defined neurological syndrome, were matched with patients with no clinically-defined neurological syndrome, taking into account sex, age, number of comorbidities, and admitting hospital, withou taking into account past history of neurological disease;
      iii. Patient with any neurological manifestation (clinically-defined neurological syndrome or reported neurological symptom) were matched with patients with no neurological manifestation, taking into account sex, age, number of comorbidities (hypertension, diabetes mellitus, obesity, coronary artery disease, heart failure, atrial fibrillation or flutter, cirrhosis, chronic obstructive pulmonary disease, cancer, and previous stroke), admitting hospital, and past history of neurological disease;
      iv. Patient with any neurological manifestation (clinically-defined neurological syndrome or reported neurological symptom) were matched with patients with no neurological manifestation, taking into account sex, age, number of comorbidities (hypertension, diabetes mellitus, obesity, coronary artery disease, heart failure, atrial fibrillation or flutter, cirrhosis, chronic obstructive pulmonary disease, cancer, and previous stroke), and admitting hospital, without taking into account past history of neurological disease;
      v. Patient with a reported neurological symptom (and no clinically-defined neurological syndrome) were matched with patients with no neurological manifestation, taking into account sex, age, number of comorbidities (hypertension, diabetes mellitus, obesity, coronary artery disease, heart failure, atrial fibrillation or flutter, cirrhosis, chronic obstructive pulmonary disease, cancer, and previous stroke), admitting hospital, and past history of neurological disease;
      vi. Patient with a reported neurological symptom (and no clinically-defined neurological syndrome) were matched with patients with no neurological manifestation, taking into account sex, age, number of comorbidities (hypertension, diabetes mellitus, obesity, coronary artery disease, heart failure, atrial fibrillation or flutter, cirrhosis, chronic obstructive pulmonary disease, cancer, and previous stroke), admitting hospital, without taking into account past history of neurological disease.
      A prespecified sample size was not calculated. All patients who had the inclusion criteria and no excluding factors were included. All statistical analysis was performed with R software (version 4.0.2).

      3. Results

      This study involved 6635 patients (Fig. 1). The median age was 60.0 (47.0–72.0) years, 54.3% were men, and COVID-19 confirmation was through RT-PCR in 96.7% of them. Neurological manifestations were present in 39.9% of the patients, of which 30.8% were subjects with reported neurological manifestations, and 10.3% were subjects with clinically-defined neurological syndrome.
      Fig. 1
      Fig. 1Flowchart of COVID-19 patients included in the study.
      Headache was the most common reported neurological symptom (20.7%), followed by ageusia (11.1%) and anosmia (8.0%). Regarding clinically-defined neurological syndromes, acute encephalopathy was the most commonly diagnosed, affecting 9.7% of patients. Other neurological syndromes were much less frequent (Table 1).
      Table 1Neurologic manifestations at hospital presentation in the study population (n = 6635).
      CharacteristicsPatients n (%)
      Any neurological manifestation2645 (39.86%)
      Reported neurological symptoms2042 (30.8%)
       Headache1371 (20.7%)
       Ageusia739 (11.1%)
       Anosmia529 (8.0%)
       Syncope or dizziness91 (1.4%)
      Neurological diagnoses captured by clinical evaluation679 (10.3)
       Acute encephalopathy645 (9.7%)
       Coma34 (0.5%)
       Seizures25 (0.5%)
       Stroke14 (0.2%)
       Peripheral neuropathy3 (0.04%)
      Table S1 shows clinical features and laboratory findings stratified by each category of neurological manifestations for the original sample, and Table S2 shows the p-value for each comparison, with Bonferroni correction. When comparing patients with a clinically-defined neurological syndrome to those with reported neurological symptoms and those with no neurological symptoms, the first group was older and had a higher prevalence of all comorbidities assessed, except for obesity, which was lower than the other groups. They also had higher frequency of inotropes requirement, lower SF ratio, lower hemoglobin, higher leucocytes count, lactate, C-reactive protein, urea, creatinine and sodium at hospital presentation, as well as a higher frequency of several and critical diseases, when compared to both groups (Tables S1 and S2). When comparing patients with a reported neurological manifestation with those with no manifestations, the first group had a lower frequency to all assessed comorbidities, except for obesity.

      3.1 Matched analysis

      3.1.1 Patients with any neurological manifestation vs. patients with no neurological manifestation (Table 2)

      When comparing patients with any neurological manifestations to matched controls, there was no significant difference in the incidence of acute kidney injury, acute heart failure, septic shock, nosocomial infection, dialysis, acute heart failure and/or vascular thrombosis, as well as need for invasive mechanical ventilation support, intensive care unit admission and mortality.
      Table 2Clinical outcomes when comparing patients with any neurological manifestation with paired controls, taking or not account underlying neurological diseases.
      Any neurological manifestation
      CharacteristicsTaking into account underlying neurological diseaseWithout taking into account underlying neurological disease
      CasesControls
      Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      p-valueCasesControls
      Matched by age, gender, number of comorbidities and hospital.
      p-value
      n = 2564
      Matched by age, gender, number of comorbidities and hospital.
      ,
      Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      n = 2564n = 2587
      Matched by age, gender, number of comorbidities and hospital.
      ,
      Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      n = 2587
      Age (years)59.0 (46.0, 72.0)60.0 (47.0, 71.0)0.71559.0 (46.0, 73.0)60.0 (47.0, 71.0)0.770
      Men1328 (51.8%)1300 (50.7%)0.4511318 (50.9%)1300 (50.3%)0.636
      Hospital stay7.0 (4.0, 13.0)8.0 (4.0, 13.0)0.0167.0 (4.0, 13.0)8.0 (4.0, 13.0)0.013
      ICU834 (32.6%)875 (34.2%)0.252836 (32.4%)890 (34.5%)0.118
      Mechanical ventilation556 (22.2%)596 (23.7%)0.204558 (22.0%)581 (23.0%)0.445
      AKI498 (23.2%)551 (25.0%)0.175504 (23.2%)551 (24.8%)0.208
      Septic shock260 (10.1%)269 (10.5%)0.717261 (10.1%)266 (10.3%)0.854
      Nosocomial infection232 (9.1%)226 (8.8%)0.803233 (9.0%)215 (8.3%)0.401
      Dialysis206 (8.1%)225 (8.8%)0.372207 (8.0%)230 (8.9%)0.269
      Acute heart failure64 (2.5%)62 (2.4%)0.92664 (2.5%)60 (2.3%)0.785
      Vascular thrombosis103 (4.0%)118 (4.6%)0.337103 (4.0%)129 (5.0%)0.093
      Death428 (16.7%)437 (17.1%)0.785434 (16.8%)890 (34.5%)0.911
      Numbers are presented as median (IQR) or n (%).
      Cases: patients with any neurological manifestation upon hospital presentation; controls: matched patients who did not have any neurological manifestation upon hospital presentation.
      AKI: acute kidney injury. ICU: intensive care unit.
      low asterisk Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      low asterisklow asterisk Matched by age, gender, number of comorbidities and hospital.

      3.1.2 Patients with a reported neurological symptom (and no clinically-defined neurological syndrome) vs. patients with no neurological manifestation (Table 3)

      Mortality was lower in patients with reported neurological symptoms when compared to controls, in both comparisons (taking and not taking account underlying neurological diseases to select matched controls). When underlying neurological diseases (previously diagnosed neurological comorbidities) were taken into account to select matched controls, they also had a lower incidence of need for invasive mechanical ventilation support.
      Table 3Clinical outcomes when comparing patients with reported neurological symptoms with paired controls, taking or not account underlying neurological diseases.
      Reported neurological symptoms
      CharacteristicsTaking into account underlying neurological diseaseWithout taking into account underlying neurological disease
      CasesControls
      Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      p-valueCasesControls
      Matched by age, gender, number of comorbidities and hospital.
      p-value
      n = 1933
      The total number of patients with reported neurological symptoms is 1966, but in propensity score analysis we opt not to force the model to find a pair that does not meet all the pre-specified requirements, to avoid comparing to a sample that is not similar enough. That is also the reason for the different numbers when taking account or not underlying neurological disease.
      n = 1933n = 1933
      The total number of patients with reported neurological symptoms is 1966, but in propensity score analysis we opt not to force the model to find a pair that does not meet all the pre-specified requirements, to avoid comparing to a sample that is not similar enough. That is also the reason for the different numbers when taking account or not underlying neurological disease.
      n = 1933
      Age (years)54.0 (43.0, 65.0)53.0 (41.0, 65.0)0.26554.0 (43.0, 65.0)54.0 (41.0, 65.0)0.467
      Men996 (51.5%)1022 (52.9%)0.4211001 (51.8%)1030 (53.3%)0.367
      Hospital stay7.0 (4.0, 11.0)7.0 (4.0, 12.0)0.0126.0 (4.0, 11.0)7.0 (4.0, 12.0)0.021
      ICU546 (28.3%)610 (31.6%)0.028547 (28.3%)590 (30.6%)0.141
      Mechanical ventilation359 (18.9%)387 (20.3%)0.299359 (18.9%)387 (20.4%)0.274
      AKI312 (19.5%)321 (19.6%)0.980312 (19.5%)336 (20.5%)0.515
      Septic shock150 (7.8%)159 (8.2%)0.635149 (7.7%)171 (8.8%)0.220
      Nosocomial infection162 (8.4%)152 (7.9%)0.596162 (8.4%)152 (7.9%)0.596
      Dialysis139 (7.2%)129 (6.7%)0.566139 (7.2%)130 (6.7%)0.613
      Acute heart failure28 (1.4%)29 (1.5%)>0.99928 (1.4%)35 (1.8%)0.446
      Vascular thrombosis82 (4.2%)94 (4.9%)0.39682 (4.2%)94 (4.9%)0.396
      Death177 (9.2%)229 (11.9%)0.008177 (9.2%)234 (12.1%)0.004
      Numbers are presented as median (IQR) or n (%).
      Cases: patients with any neurological manifestation upon hospital presentation; controls: matched patients who did not have any neurological manifestation upon hospital presentation.
      AKI: acute kidney injury. ICU: intensive care unit.
      low asterisk Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      low asterisklow asterisk Matched by age, gender, number of comorbidities and hospital.
      low asterisklow asterisklow asterisk The total number of patients with reported neurological symptoms is 1966, but in propensity score analysis we opt not to force the model to find a pair that does not meet all the pre-specified requirements, to avoid comparing to a sample that is not similar enough. That is also the reason for the different numbers when taking account or not underlying neurological disease.

      3.1.3 Patients with clinically-defined neurological syndrome vs. patients with no clinically-defined neurological syndrome (Table 4)

      Patients presenting with clinically-defined neurological syndromes had higher mortality when compared to controls, in both comparisons (taking and not taking into account underlying neurological diseases to select matched controls). In the comparison which took into account underlying neurological diseases, they also had a higher frequency of ICU admission (45.3% vs. 38.9%, p = 0.02). When underlying neurological diseases were not taken into account, they had a higher frequency of septic shock (17.0 vs. 13.0, p = 0.045).
      Table 4Clinical outcomes when comparing patients with clinically-defined neurological syndromes with paired controls, taking or not account underlying neurological diseases.
      Clinically-defined neurological syndromes
      CharacteristicsTaking into account underlying neurological diseaseWithout taking into account underlying neurological disease
      CasesControls
      Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      p-valueCasesControls
      Matched by age, gender, number of comorbidities and hospital.
      p-value
      n = 648
      The total number of patients with clinically-defined neurological syndromes is 679, but in propensity score analysis we opt not to force the model to find a pair that does not meet all the pre-specified requirements, to avoid comparing to a sample that is not similar enough. That is also the reason for the different numbers when taking account or not underlying neurological disease.
      n = 648n = 672
      The total number of patients with clinically-defined neurological syndromes is 679, but in propensity score analysis we opt not to force the model to find a pair that does not meet all the pre-specified requirements, to avoid comparing to a sample that is not similar enough. That is also the reason for the different numbers when taking account or not underlying neurological disease.
      n = 672
      Age (years)78.0 (66.8, 84.0)77.0 (66.0, 84.0)0.78578.0 (67.0, 85.0)77.0 (66.0, 85.0)0.719
      Men325 (50.2%)322 (49.7%)0.912333 (49.6%)350 (52.1%)0.383
      Hospital stay10.0 (5.0, 16.0)9.0 (5.0, 16.0)0.4989.5 (5.0, 16.0)9.0 (5.0, 15.0)0.249
      ICU292(45.3%)251 (38.9%)0.023295 (44.2%)264 (39.6%)0.101
      Mechanical ventilation203 (32.4%)180 (28.4%)0.135204 (31.4%)191 (29.2%)0.437
      AKI188 (33.2%)206 (36.0%)0.341193 (32.9%)208 (35.4%)0.389
      Septic shock111 (17.2%)93 (14.4%)0.191114 (17.0%)87 (13.0%)0.045
      Nosocomial infection72 (11.1%)66 (10.2%)0.64673 (10.9%)78 (11.6%)0.737
      Dialysis68 (10.6%)74 (11.5%)0.65669 (10.3%)78 (11.1%)0.472
      Acute heart failure33 (5.1%)21 (3.2%)0.12534 (5.1%)25 (3.7%)0.284
      Vascular thrombosis22 (3.4%)37 (5.7%)0.06322 (3.3%)28 (4.2%)0.474
      Death249 (38.7%)210 (32.6%)0.026262 (39.2%)202 (30.3%)<0.001
      Numbers are presented as median (IQR) or n (%).
      Cases: patients with clinically-defined neurological syndromes upon hospital presentation; controls: matched patients who did not have any clinically-defined neurological syndrome upon hospital presentation.
      AKI: acute kidney injury. ICU: intensive care unit.
      low asterisk Matched by age, gender, number of comorbidities, hospital and underlying neurological disease.
      low asterisklow asterisk Matched by age, gender, number of comorbidities and hospital.
      low asterisklow asterisklow asterisk The total number of patients with clinically-defined neurological syndromes is 679, but in propensity score analysis we opt not to force the model to find a pair that does not meet all the pre-specified requirements, to avoid comparing to a sample that is not similar enough. That is also the reason for the different numbers when taking account or not underlying neurological disease.

      4. Discussion

      To the best of our knowledge, this is the first cohort study to systematically investigate COVID-19-related acute neurological manifestations and their impact in a representative sample of hospitalized patients from Brazil/Latin America. It is also the first study that associates, in a large sample, the presence of reported neurological symptoms, such as anosmia and ageusia to a better COVID-19 prognosis. Previous Brazilian and Latin American studies have reported cross-sectional case series, usually focusing on specific neurological manifestations and investigating pathophysiological processes instead of assessing the whole picture and the prognostic impact [
      • AMB Matos
      • Dahy F.E.
      • JVL Moura
      • RMN Marcusso
      • ABF Gomes
      • FMM Carvalho
      • GBP Fernandes
      • Felix A.C.
      • Smid J.
      • Vidal J.E.
      • NAF Frota
      • Casseb J.
      • Easton A.
      • Solomon T.
      • Witkin S.S.
      • Malta Romano C.
      • ACP Oliveira
      • NeuroCovBR Study Group
      Subacute cognitive impairment in individuals with mild and moderate COVID-19: A case series.
      ,
      • Espíndola O.M.
      • Gomes Y.C.P.
      • Brandão C.O.
      • Torres R.C.
      • Siqueira M.
      • Soares C.N.
      • Lima M.A.S.D.
      • Leite A.C.C.B.
      • Venturotti C.O.
      • Carvalho A.J.C.
      • Torezani G.
      • Araujo A.Q.C.
      • Silva M.T.T.
      Inflammatory cytokine patterns associated with neurological diseases in coronavirus disease 2019.
      ,
      • World Health Organization
      Coronavirus Dashboard.
      ]. Our results showed that approximately 40% of the patients admitted to a hospital due to COVID-19 presented reported or clinically-diagnosed neurological symptoms and/or syndromes upon hospital presentation. More importantly, the presence of clinically-defined neurological symptoms was associated with worse clinical outcomes, including the need for ICU admission, septic shock and death.
      Previous studies comprising case series and/or cohorts using different definitions and clinical samples led to very diverse incidence estimates of COVID-related neurological manifestations. To provide more reliable and/or generalizable information on the incidence, type, and outcomes of neurological manifestations among patients, a recent systematic review analyzed 350 studies, involving 145,721 patients, which is currently the largest meta-analysis on the topic [
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ]. When considering only the subanalysis of hospitalized patients, the observed incidence of ageusia and anosmia in our study was inside the confidence interval (10.4 vs. 13% [95% CI 8 to 19%], and 7.4 vs. 11% [95% CI 8 to 15%], respectively); while the frequency of headache was higher than the authors observed in the pooled analysis (19.3 vs.11% [95%CI 10 to 12%]) [
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ].
      It has been hypothesized that patients with severe COVID-19 might not be able to provide a clear history regarding smell or taste impairment [
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ]. This could have impacted our results, especially when taking into account that the overall mortality previously observed in our cohort (22.0%) was observed to be higher than what was observed in other countries [
      • Marcolino M.S.
      • Ziegelmann P.K.
      • Souza-Silva M.V.R.
      • Nascimento I.J.B.
      • Oliveira L.M.
      • Monteiro L.S.
      • Sales T.L.S.
      • Ruschel K.B.
      • Martins K.P.M.P.
      • Etges A.P.B.S.
      • Molina I.
      • Polanczyk C.A.
      Brazilian COVID-19 registry investigators. Clinical characteristics and outcomes of patients hospitalized with COVID-19 in Brazil: results from the Brazilian COVID-19 registry.
      ]. Ageusia and anosmia have been regarded as independent positive prognostic factors of a less severe COVID-19 infection [
      • Aziz M.
      • Goyal H.
      • Haghbin H.
      • Lee-Smith W.M.
      • Gajendran M.
      • Perisetti A.
      The association of “loss of smell” to COVID-19: A systematic review and Meta-analysis.
      ,
      • Porta-Etessam J.
      • Núñez-Gil I.J.
      • González García N.
      • Fernandez-Perez C.
      • Viana-Llamas M.C.
      • Eid C.M.
      • Romero R.
      • Molina M.
      • Uribarri A.
      • Becerra-Muñoz V.M.
      • Aguado M.G.
      • Huang J.
      • Rondano E.
      • Cerrato E.
      • Alfonso E.
      • Mejía A.F.C.
      • Marin F.
      • Roubin S.R.
      • Pepe M.
      • Feltes G.
      • Maté P.
      • Cortese B.
      • Buzón L.
      • Mendez J.J.
      • Estrada V.
      COVID-19 anosmia and gustatory symptoms as a prognosis factor: a subanalysis of the HOPE COVID-19 (health outcome predictive evaluation for COVID-19) registry.
      ]. In the aforementioned meta-analysis, patients with severe COVID-19 were less likely than those with mild disease to have decreased smell (OR 0.44, 95% CI 0.28–0.68) and taste (OR 0.62, 95% CI 0.42–0.91) [
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ].
      The incidence of headache in the aforementioned meta-analysis was 13% (95% CI 12%–15%, 202 studies) [
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ], lower than what we observed in our cohort (20.7%). Interestingly, a subgroup analysis has shown that the pooled prevalence of headache was higher from April to September 2020 (16%–22%) compared to January–March 2020 (8%–14%). In Brazil, the first COVID-19 case was at the end of February, and there were only a few cases included in this cohort in March, as it can be seen in a previous publication by our group [
      • Marcolino M.S.
      • Ziegelmann P.K.
      • Souza-Silva M.V.R.
      • Nascimento I.J.B.
      • Oliveira L.M.
      • Monteiro L.S.
      • Sales T.L.S.
      • Ruschel K.B.
      • Martins K.P.M.P.
      • Etges A.P.B.S.
      • Molina I.
      • Polanczyk C.A.
      Brazilian COVID-19 registry investigators. Clinical characteristics and outcomes of patients hospitalized with COVID-19 in Brazil: results from the Brazilian COVID-19 registry.
      ]. We hypothesize that this may explain the difference in incidence when compared to the point estimate.
      Acute encephalopathy was the most common clinically-defined neurological syndrome (9.7%) in our study, similar to the one reported in the aforementioned systematic review [
      • Andalib S.
      • Biller J.
      • Di Napoli M.
      • Moghimi N.
      • McCullough L.D.
      • Rubinos C.A.
      • O’Hana Nobleza C.
      • Azarpazhooh M.R.
      • Catanese L.
      • Elicer I.
      • Jafari M.
      • Liberati F.
      • Camejo C.
      • Torbey M.
      • Divani A.A.
      Peripheral nervous system manifestations associated with COVID-19.
      ]. This review showed that 1 in every 3 hospitalized older patients with COVID-19 had delirium compared to 5% of younger adults. In addition, acute encephalopathy has shown to be a risk factor for severe COVID-19 and mortality, up to one year of hospitalization [
      • Misra S.
      • Kolappa K.
      • Prasad M.
      • Radhakrishnan D.
      • Thakur K.T.
      • Solomon T.
      • Michael B.D.
      • Winkler A.S.
      • Beghi E.
      • Guekht A.
      • Pardo C.A.
      • Wood G.K.
      • Hsiang-Yi Chou S.
      • Fink E.L.
      • Schmutzhard E.
      • Kheradmand A.
      • Hoo F.K.
      • Kumar A.
      • Das A.
      • Srivastava A.K.
      • Agarwal A.
      • Dua T.
      • Prasad K.
      Frequency of neurologic manifestations in COVID-19: A systematic review and Meta-analysis.
      ,
      • Mahdizade Ari M.
      • Mohamadi M.H.
      • Shadab Mehr N.
      • Abbasimoghaddam S.
      • Shekartabar A.
      • Heidary M.
      • Khoshnood S.
      Neurological manifestations in patients with COVID-19: A systematic review and meta-analysis.
      ]. Actually, the World Health Organization has alerted clinicians about the importance of implementing measures to prevent acute encephalopathy or delirium, as well as its prompt identification and management [
      • World Health Organization
      Clinical management of COVID-19 patients: living guideline.
      ].
      The Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID), and the European Academy of Neurology (EAN) Neuro-COVID Registry (ENERGY) worked together producing a joint report from four cohorts [
      • Collantes M.E.V.
      • Espiritu A.I.
      • Sy M.C.C.
      • Anlacan V.M.M.
      • Jamora R.D.G.
      Neurological manifestations in COVID-19 infection: A systematic review and Meta-analysis.
      ] and observed a higher prevalence of neurological manifestations overall. The presence of clinically-defined syndromes, but not reported symptoms, were associated with worse outcomes, i.e. increased risk of in-hospital mortality, as observed in our study. It is worth noticing that despite meaningful results and aiming at a global representativeness of COVID-19 neurological impact, both GCS-NeuroCOVID and ENERGY cohorts clearly had a skewed composition of developed countries in North America and Europe [
      • Collantes M.E.V.
      • Espiritu A.I.
      • Sy M.C.C.
      • Anlacan V.M.M.
      • Jamora R.D.G.
      Neurological manifestations in COVID-19 infection: A systematic review and Meta-analysis.
      ]. Additionally, in some of those cohorts only patients with neurological manifestations were eligible. Therefore, the overall incidence of neurological manifestations was overestimated.
      The pooled prevalence of stroke in the aforementioned systematic review of neurological manifestations of COVID-19 was 2% (95% CI 1–2%, but with high heterogeneity, I2 = 86%), a number ten times higher than the one observed in our cohort (0.2%). This might be partially explained by the fact that our cohort probably included more severe cases of COVID-19 leading to a higher mortality rate. Another hypothesis that could explain this difference is that in our study we analyzed neurological manifestations at hospital presentation, meanwhile stroke may be presented during disease course. It is worth mentioning that the diagnosis of stroke can be overlooked in critically-ill patients, especially those requiring sedation for ventilation support [
      • World Health Organization
      Clinical management of COVID-19 patients: living guideline.
      ].
      The pathogenesis of neurological manifestations is still under investigation, and it seems to involve different mechanisms for distinct signs or symptoms [
      • Chou S.H.
      • Beghi E.
      • Helbok R.
      • Moro E.
      • Sampson J.
      • Altamirano V.
      • Mainali S.
      • Bassetti C.
      • Suarez J.I.
      • McNett M.
      • GCS-NeuroCOVID Consortium and ENERGY Consortium
      Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium.
      ,
      • Ellul M.A.
      • Benjamin L.
      • Singh B.
      • Lant S.
      • Michael B.D.
      • Easton A.
      • Kneen R.
      • Defres S.
      • Sejvar J.
      • Solomon T.
      Neurological associations of COVID-19.
      ]. Overall, while a direct role of CNS infection remains controversial, hypoxemia, hypovolemia, inflammatory and/or immune-mediated damage are very likely to play relevant roles. For example, patients with encephalopathy have increased serum levels of pro-inflammatory molecules, such as interleukins 6 and 8. Furthermore, critically ill patients with COVID-19 commonly develop delirium, which can be a prodromal symptom of hypoxia secondary to severe respiratory failure, microvascular disease, and/or inflammatory brain changes, with significantly higher microglial activation in the hippocampus [
      • Talavera B.
      • García-Azorín D.
      • Martínez-Pías E.
      • Trigo J.
      • Hernández-Pérez I.
      • Valle-Peñacoba G.
      • Simón-Campo P.
      • de Lera M.
      • Chavarría-Miranda A.
      • López-Sanz C.
      • Gutiérrez-Sánchez M.
      • Martínez-Velasco E.
      • Pedraza M.
      • Sierra Á.
      • Gómez-Vicente B.
      • Guerrero Á.
      • Arenillas J.F.
      Anosmia is associated with lower in-hospital mortality in COVID-19.
      ,
      • Boldrini M.
      • Canoll P.D.
      • Klein R.S.
      How COVID-19 affects the brain.
      ,
      • Orsucci D.
      • Ienco E.C.
      • Nocita G.
      • Napolitano A.
      • Vista M.
      Neurological features of COVID-19 and their treatment: a review.
      ,
      • Pantelis C.
      • Jayaram M.
      • Hannan A.J.
      • Wesselingh R.
      • Nithianantharajah J.
      • Wannan C.M.
      • Syeda W.T.
      • Choy K.C.
      • Zantomio D.
      • Christopoulos A.
      • Velakoulis D.
      • O’Brien T.J.
      Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19.
      ,
      • Helms J.
      • Kremer S.
      • Merdji H.
      • Schenck M.
      • Severac F.
      • Clere-Jehl R.
      • Studer A.
      • Radosavljevic M.
      • Kummerlen C.
      • Monnier A.
      • Boulay C.
      • Fafi-Kremer S.
      • Castelain V.
      • Ohana M.
      • Anheim M.
      • Schneider F.
      • Meziani F.
      Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients.
      ,
      • Wilcox M.E.
      • Shankar-Hari M.
      • McAuley D.F.
      Delirium in COVID-19: can we make the unknowns knowns?.
      ,
      • Poloni T.E.
      • Medici V.
      • Moretti M.
      • Visonà S.D.
      • Cirrincione A.
      • Carlos A.F.
      • Davin A.
      • Gagliardi S.
      • Pansarasa O.
      • Cereda C.
      • Tronconi L.
      • Guaita A.
      • Ceroni M.
      COVID-19-related neuropathology and microglial activation in elderly with and without dementia.
      ,
      • Lee M.H.
      • Perl D.P.
      • Nair G.
      • Li W.
      • Maric D.
      • Murray H.
      • Dodd S.J.
      • Koretsky A.P.
      • Watts J.A.
      • Cheung V.
      • Masliah E.
      • Horkayne-Szakaly I.
      • Jones R.
      • Stram M.N.
      • Moncur J.
      • Hefti M.
      • Folkerth R.D.
      • Nath A.
      Microvascular injury in the brains of patients with Covid-19.
      ]. In contrast, patients with headache (but no encephalopathy) did not display increased levels of inflammatory cytokines [
      • Espíndola O.M.
      • Gomes Y.C.P.
      • Brandão C.O.
      • Torres R.C.
      • Siqueira M.
      • Soares C.N.
      • Lima M.A.S.D.
      • Leite A.C.C.B.
      • Venturotti C.O.
      • Carvalho A.J.C.
      • Torezani G.
      • Araujo A.Q.C.
      • Silva M.T.T.
      Inflammatory cytokine patterns associated with neurological diseases in coronavirus disease 2019.
      ].
      In a recent meta-analysis assessing the impact of neurological manifestations on COVID-related mortality, involving 21 studies, the authors observed a higher mortality among patients with any neurological manifestations than the one observed for the ones with neurological manifestations in the current analysis (18.3% vs. 27% [95% CI 19%–35%]) [
      • Misra S.
      • Kolappa K.
      • Prasad M.
      • Radhakrishnan D.
      • Thakur K.T.
      • Solomon T.
      • Michael B.D.
      • Winkler A.S.
      • Beghi E.
      • Guekht A.
      • Pardo C.A.
      • Wood G.K.
      • Hsiang-Yi Chou S.
      • Fink E.L.
      • Schmutzhard E.
      • Kheradmand A.
      • Hoo F.K.
      • Kumar A.
      • Das A.
      • Srivastava A.K.
      • Agarwal A.
      • Dua T.
      • Prasad K.
      Frequency of neurologic manifestations in COVID-19: A systematic review and Meta-analysis.
      ]. Some of the studies included in the meta-analysis only assessed clinically-defined neurological syndromes, which could explain the higher mortality rate. In our study, when assessing patients with any neurological manifestations at hospital presentation when compared to matched controls, there were no significant differences in the assessed outcomes. For the comparison of patients with clinically defined neurological syndromes with matched controls, our findings were in line and expanded the results of the meta-analysis, with higher frequency of septic shock, ICU admission, and mortality, regardless of previous history of neurological diseases. This novel information may be useful to clinicians and healthcare managers, alerting to the need of careful neurological follow-up of these patients who may need more intensive clinical care and possibly should be prioritized for an ICU bed.
      Surprisingly, patients with reported neurological symptoms had a lower mortality than matched controls. A recent meta-analysis of 45 articles including 42,120 COVID-19 patients from 17 different countries has shown that severely ill COVID-19 patients have a lesser chance of experiencing anosmia than non-severely ill patients (odds ratio0.527 [95% CI 0.373–0.744; p < 0.001]) [
      • Boldrini M.
      • Canoll P.D.
      • Klein R.S.
      How COVID-19 affects the brain.
      ]. There is also evidence of an independent association between anosmia and lower mortality (OR: 0.180, 95% CI: 0.069–0.472) and ICU admission (OR: 0.438, 95% CI: 0.229–0.838, p = 0.013) [
      • Talavera B.
      • García-Azorín D.
      • Martínez-Pías E.
      • Trigo J.
      • Hernández-Pérez I.
      • Valle-Peñacoba G.
      • Simón-Campo P.
      • de Lera M.
      • Chavarría-Miranda A.
      • López-Sanz C.
      • Gutiérrez-Sánchez M.
      • Martínez-Velasco E.
      • Pedraza M.
      • Sierra Á.
      • Gómez-Vicente B.
      • Guerrero Á.
      • Arenillas J.F.
      Anosmia is associated with lower in-hospital mortality in COVID-19.
      ,
      • Purja S.
      • Shin H.
      • Lee J.Y.
      • Kim E.
      Is loss of smell an early predictor of COVID-19 severity: a systematic review and meta-analysis.
      ]. Previous publications have shown differences in inflammatory response in patients with anosmia, including significantly lower serum IL-6 and fibrinogen levels, as well as higher leukocyte and CD8-lymphocyte counts [
      • Sanli D.E.T.
      • Altundag A.
      • Kandemirli S.G.
      • Yildirim D.
      • Sanli A.N.
      • Saatci O.
      • Kirisoglu C.E.
      • Dikensoy O.
      • Murrja E.
      • Yesil A.
      • Bastan S.
      • Karsidag T.
      • Akinci I.O.
      • Ozkok S.
      • Yilmaz E.
      • Tuzuner F.
      • Kilercik M.
      • Ljama T.
      Relationship between disease severity and serum IL-6 levels in COVID-19 anosmia.
      ].
      This study has several strengths, including its sample size, careful characterization of neurological manifestations, control for multiple confounding variables, and representativeness of multiple Brazilian regions, ensuring the diversity of the population studied. Also, it is the first study that evaluates the prevalence of neurological manig = festations of COVID-19 in the Brazilian population, corroborating with findings from studies from different regions while also bringing the association between milder neurological symptoms (such as anosmia and ageusia) and better disease prognosis. However, the present study also has limitations that must be acknowledged. Even though the classification of neurological manifestation was based on the one used in ENERGY study, which included three large multicentric neurological cohorts [
      • Chou S.H.
      • Beghi E.
      • Helbok R.
      • Moro E.
      • Sampson J.
      • Altamirano V.
      • Mainali S.
      • Bassetti C.
      • Suarez J.I.
      • McNett M.
      • GCS-NeuroCOVID Consortium and ENERGY Consortium
      Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium.
      ] the categorization has methodological limitations. We opted to use the same classification to enable comparisons of the frequencies of the different categories in that study with our results. Additionally, we did not assess the impact of the neurological manifestations across ethnicities. Brazil is a highly miscigenic country, and there is evidence of worse prognosis among Pardo and Black populations [
      • Baqui P.
      • MPhil I.B.
      • Marra V.
      • Ercole A.
      • MVD Schaar
      Ethnic and regional variations in hospital mortality from COVID-19 in Brazil: a cross-sectional observational study. The lancet.
      ]. That is an important topic for future studies. Second, the study is subjected to the drawbacks inherent to data retrospectively obtained from medical record reviews. To minimize that, the research staff was extensively trained and the data was subject to periodic auditing to ensure data quality. Another limitation is the fact that we had to exclude patients who were admitted on mechanical ventilation (for being attended first by the emergency medical service, or being transferred from another institution without any information about reported neurological symptoms or clinically defined neurological syndromes before intubation), which unable full neurological exam and collection of clinical history. Additionally, the pragmatic design of the study implies that it was not possible to control for interexaminer reliability in neurological examination and diagnosis. The severity of reported neurological symptoms could not be determined, and relevant information (e.g. neuroimaging results) was not available in all sites, during admission. Furthermore, participant hospitals were not randomly selected, and they are not necessarily representative of the whole healthcare system in Brazil. Finally, SARS-CoV-2 is susceptible to genetic modifications, which result in the development of multiple variants [
      • Cascella M.
      • Rajnik M.
      • Aleem A.
      • Dulebohn S.C.
      • Di Napoli R.
      Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2022 May 4.
      ]. These may have different profiles regarding neurological symptoms, therefore our data can not be fully extrapolated to other waves.

      5. Conclusion

      Our findings in a large Brazilian cohort corroborate the emerging view that neurological manifestations represent a significant risk of morbidity in COVID-19 patients. More importantly, the development of clinically-defined neurological syndromes have prognostic implications.

      Funding

      This study was supported in part by Minas Gerais State Agency for Research and Development (Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG) [grant number APQ-00208-20], National Institute of Science and Technology for Health Technology Assessment (Instituto de Avaliação de Tecnologias em Saúde – IATS)/ National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq) [grant number 465518/2014–1], and CAPES Foundation (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) [grant number 88887.507149/2020–00].

      Role of the funder/sponsor

      The sponsors had no role in study design; data collection, management, analysis, and interpretation; writing the manuscript; and deciding to submit it for publication. MSM had full access to all the data in the study and had responsibility for the decision to submit for publication.

      Data sharing statement

      Since data was obtained through patients' records, data is available upon reasonable request.

      Transparency declaration

      The lead authors (MSM and ALT) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

      Contributorship statement

      Substantial contributions to the conception or design of the work: MSM, MCP, ALT.
      Substantial contributions to the acquisition, analysis, or interpretation of data for the work: MSM, MCP, LEFR, LFIA, FA, LK, ASMC, MCAN, HD, KPMPM, LBM, CTCAS, NRO, PKZ, MHGJ, MOSSL, RLOA, LSMM, TFO, MDS, BLF, CCRC, AOM, SMMG, SFA, GFN, DVS, KBR, TCO, AVS, LAN, MAF, VBS, CMR, JCA, ALBAS, ERFM, GPC, JDLB, DP, JMR, AFBB, PJLM, HRV, LCC, CRGM, GGV, ECP, JMC, MFG, ALTJ.
      Drafted the work: MSM, ALT, MCP, DNP, IGB, FA, LK, PDP.
      Revised the manuscript critically for important intellectual content: all authors.
      Final approval of the version to be published: all authors.
      Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ALT, MSM, MCP.

      Declaration of Competing Interest

      The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

      Acknowledgments

      We would like to thank the hospitals which are part of this collaboration, for supporting this Project. For this analysis, we thank the hospitals: Hospital Nossa Senhora da Conceição, Hospitais da Rede Mater Dei, Hospital Julia Kubitschek, Hospital Eduardo de Menezes, Hospital das Clínicas da UFMG, Hospital de Clínicas de Porto Alegre, Hospital Santo Antônio, Hospital Tacchini, Hospital Márcio Cunha, Hospital Metropolitano Doutor Célio de Castro, Hospital Metropolitano Odilon Behrens, Hospital Risoleta Tolentino Neves, Hospital Santa Rosália, Hospital São João de Deus, Hospital Semper, Hospital UNIMED, Hospital Mãe de Deus, Hospital Universitário Canoas, Hospital Universitário de Santa Maria, Hospital Moinhos de Vento, Instituto Mário Penna/ Hospital Luxemburgo, Hospital Nossa Senhora da Conceição, Hospital João XXIII, Hospital Regional Antônio Dias, Hospital Mãe de Deus, Hospital Regional do Oeste, Hospital das Clínicas da Faculdade de Medicina de Botucatu, Hospital das Clínicas da Universidade Federal de Pernambuco, Hospital Universitário Ciências Médicas, Hospital Bruno Born, Hospital SOS Cárdio, Hospital São Lucas da PUCRS.
      We also thank all the clinical staff at those hospitals, who cared for the patients, and all undergraduate students who helped with data collection.

      Appendix A. Supplementary data

      References

        • SeyedAlinaghi S.
        • Mirzapour P.
        • Dadras O.
        • Pashaei Z.
        • Karimi A.
        • MohsseniPour M.
        • Soleymanzadeh M.
        • Barzegary A.
        • Afsahi A.M.
        • Vahedi F.
        • Shamsabadi A.
        • Behnezhad F.
        • Saeidi S.
        • Mehraeen E.
        • Jahanfar Shayesteh
        Characterization of SARS-CoV-2 different variants and related morbidity and mortality: a systematic review.
        Eur. J. Med. Res. 2021; 26: 51https://doi.org/10.1186/s40001-021-00524-8
        • Shi C.
        • Wang L.
        • Ye J.
        • Gu Z.
        • Wang S.
        • Xia J.
        • Xie Y.
        • Li Q.
        • Xu R.
        • Lin N.
        Predictors of mortality in patients with coronavirus disease 2019: a systematic review and meta-analysis.
        BMC Infect. Dis. 2021; 21: 663https://doi.org/10.1186/s12879-021-06369-0
        • Marcolino M.S.
        • Pires M.C.
        • Ramos L.E.F.
        • Silva R.T.
        • Oliveira L.M.
        • Carvalho R.L.R.
        • et al.
        ABC2-SPH risk score for in-hospital mortality in COVID-19 patients: development, external validation and comparison with other available scores.
        Int. J. Infect. Dis. 2021; 110 (Epub 2021 Jul 24): 281-308https://doi.org/10.1016/j.ijid.2021.07.049
        • Muccioli L.
        • Zenesini C.
        • Taruffi L.
        • Licchetta L.
        • Mostacci B.
        • Di Vito L.
        • Pasini E.
        • Volpi L.
        • Riguzzi P.
        • Ferri L.
        • Baccari F.
        • Nonino F.
        • Michelucci R.
        • Tinuper P.
        • Vignatelli L.
        • Bisulli F.
        Risk of hospitalization and death for COVID-19 in persons with epilepsy over a 20-month period: the EpiLink Bologna cohort, Italy.
        Epilepsia. 2022; (Epub ahead of print)https://doi.org/10.1111/epi.17356
        • Cascini S.
        • Agabiti N.
        • Marino C.
        • Acampora A.
        • Balducci M.
        • Calandrini E.
        • Davoli M.
        • Bargagli A.M.
        Incidence and outcomes of SARS-CoV-2 infection in older adults living with dementia: A population-based cohort study.
        J. Alzheimers Dis. 2022; (Epub ahead of print)https://doi.org/10.3233/JAD-220369
        • Johansson A.
        • Mohamed M.S.
        • Moulin T.C.
        • Schiöth H.B.
        Neurological manifestations of COVID-19: A comprehensive literature review and discussion of mechanisms.
        J. Neuroimmunol. 2021 Sep 15; 358 (Epub 2021 Jul 10): 577658https://doi.org/10.1016/j.jneuroim.2021.577658
        • Collantes M.E.V.
        • Espiritu A.I.
        • Sy M.C.C.
        • Anlacan V.M.M.
        • Jamora R.D.G.
        Neurological manifestations in COVID-19 infection: A systematic review and Meta-analysis.
        Can J Neurol Sci. 2021; 48 (Epub 2020 Jul 15): 66-76https://doi.org/10.1017/cjn.2020.146
        • Andalib S.
        • Biller J.
        • Di Napoli M.
        • Moghimi N.
        • McCullough L.D.
        • Rubinos C.A.
        • O’Hana Nobleza C.
        • Azarpazhooh M.R.
        • Catanese L.
        • Elicer I.
        • Jafari M.
        • Liberati F.
        • Camejo C.
        • Torbey M.
        • Divani A.A.
        Peripheral nervous system manifestations associated with COVID-19.
        Curr Neurol Neurosci Rep. 2021; 21: 9https://doi.org/10.1007/s11910-021-01102-5
        • Chou S.H.
        • Beghi E.
        • Helbok R.
        • Moro E.
        • Sampson J.
        • Altamirano V.
        • Mainali S.
        • Bassetti C.
        • Suarez J.I.
        • McNett M.
        • GCS-NeuroCOVID Consortium and ENERGY Consortium
        Global incidence of neurological manifestations among patients hospitalized with COVID-19-A report for the GCS-NeuroCOVID consortium and the ENERGY consortium.
        JAMA Netw. Open. 2021; 4: e2112131https://doi.org/10.1001/jamanetworkopen.2021.12131
        • Misra S.
        • Kolappa K.
        • Prasad M.
        • Radhakrishnan D.
        • Thakur K.T.
        • Solomon T.
        • Michael B.D.
        • Winkler A.S.
        • Beghi E.
        • Guekht A.
        • Pardo C.A.
        • Wood G.K.
        • Hsiang-Yi Chou S.
        • Fink E.L.
        • Schmutzhard E.
        • Kheradmand A.
        • Hoo F.K.
        • Kumar A.
        • Das A.
        • Srivastava A.K.
        • Agarwal A.
        • Dua T.
        • Prasad K.
        Frequency of neurologic manifestations in COVID-19: A systematic review and Meta-analysis.
        Neurology. 2021; 97 (Epub 2021 Oct 11): e2269-e2281https://doi.org/10.1212/WNL.0000000000012930
        • García-Azorín D.
        • Trigo J.
        • Martínez-Pías E.
        • Hernández-Pérez I.
        • Valle-Peñacoba G.
        • Talavera B.
        • Simón-Campo P.
        • de Lera M.
        • Chavarría-Miranda A.
        • López-Sanz C.
        • Gutiérrez-Sánchez M.
        • Martínez-Velasco E.
        • Pedraza M.
        • Sierra Á.
        • Gómez-Vicente B.
        • Guerrero Á.
        • Arenillas J.F.
        Neurological symptoms in Covid-19 patients in the emergency department.
        Brain Behav. 2021 Apr; 11 (Epub 2021 Feb 22)e02058https://doi.org/10.1002/brb3.2058
        • Talavera B.
        • García-Azorín D.
        • Martínez-Pías E.
        • Trigo J.
        • Hernández-Pérez I.
        • Valle-Peñacoba G.
        • Simón-Campo P.
        • de Lera M.
        • Chavarría-Miranda A.
        • López-Sanz C.
        • Gutiérrez-Sánchez M.
        • Martínez-Velasco E.
        • Pedraza M.
        • Sierra Á.
        • Gómez-Vicente B.
        • Guerrero Á.
        • Arenillas J.F.
        Anosmia is associated with lower in-hospital mortality in COVID-19.
        J. Neurol. Sci. 2020; 15 (Epub 2020 Oct 1): 117163https://doi.org/10.1016/j.jns.2020.117163
        • Caronna E.
        • Ballvé A.
        • Llauradó A.
        • Gallardo V.J.
        • Ariton D.M.
        • Lallana S.
        • López Maza S.
        • Olivé Gadea M.
        • Quibus L.
        • Restrepo J.L.
        • Rodrigo-Gisbert M.
        • Vilaseca A.
        • Hernandez Gonzalez M.
        • Martinez Gallo M.
        • Alpuente A.
        • Torres-Ferrus M.
        • Pujol Borrell R.
        • Alvarez-Sabin J.
        • Pozo-Rosich P.
        Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution.
        Cephalalgia. 2020; 40: 1410-1421https://doi.org/10.1177/0333102420965157
        • Trigo J.
        • García-Azorín D.
        • Planchuelo-Gómez Á.
        • Martínez-Pías E.
        • Talavera B.
        • Hernández-Pérez I.
        • Valle-Peñacoba G.
        • Simón-Campo P.
        • de Lera M.
        • Chavarría-Miranda A.
        • López-Sanz C.
        • Gutiérrez-Sánchez M.
        • Martínez-Velasco E.
        • Pedraza M.
        • Sierra Á.
        • Gómez-Vicente B.
        • Arenillas J.F.
        • Guerrero Á.L.
        Factors associated with the presence of headache in hospitalized COVID-19 patients and impact on prognosis: a retrospective cohort study.
        J Headache Pain. 2020; 21: 94https://doi.org/10.1186/s10194-020-01165-8
        • Gonzalez-Martinez A.
        • Fanjul V.
        • Ramos C.
        • Serrano Ballesteros J.
        • Bustamante M.
        • Villa Martí A.
        • Álvarez C.
        • García Del Álamo Y.
        • Vivancos J.
        • Gago-Veiga A.B.
        Headache during SARS-CoV-2 infection as an early symptom associated with a more benign course of disease: a case-control study.
        Eur. J. Neurol. 2021; 28 (Epub 2021 Feb 2. PMID: 33417287): 3426-3436https://doi.org/10.1111/ene.14718
        • Ellul M.A.
        • Benjamin L.
        • Singh B.
        • Lant S.
        • Michael B.D.
        • Easton A.
        • Kneen R.
        • Defres S.
        • Sejvar J.
        • Solomon T.
        Neurological associations of COVID-19.
        Lancet Neurol. 2020; 19 (Epub 2020 Jul 2): 767-783https://doi.org/10.1016/S1474-4422(20)30221-0
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gøtzsche P.C.
        Vandenbroucke JP; STROBE initiative. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
        J. Clin. Epidemiol. 2008; 61: 344-349https://doi.org/10.1016/j.jclinepi.2007.11.008
        • Marcolino M.S.
        • Ziegelmann P.K.
        • Souza-Silva M.V.R.
        • Nascimento I.J.B.
        • Oliveira L.M.
        • Monteiro L.S.
        • Sales T.L.S.
        • Ruschel K.B.
        • Martins K.P.M.P.
        • Etges A.P.B.S.
        • Molina I.
        • Polanczyk C.A.
        Brazilian COVID-19 registry investigators. Clinical characteristics and outcomes of patients hospitalized with COVID-19 in Brazil: results from the Brazilian COVID-19 registry.
        Int. J. Infect. Dis. 2021; 107 (Epub 2021 Jan 12): 300-310https://doi.org/10.1016/j.ijid.2021.01.019
        • World Health Organization
        Diagnostic testing for SARS-CoV-2. Interim guidance. Online.
        (Available at:)
        • Harris P.A.
        • Taylor R.
        • Minor B.L.
        • Elliott V.
        • Fernandez M.
        • O’Neal L.
        • McLeod L.
        • Delacqua G.
        • Delacqua F.
        • Kirby J.
        • Duda S.N.
        • REDCap Consortium
        The REDCap consortium: building an international community of software platform partners.
        J. Biomed. Inform. 2019; 95 (Epub 2019 May 9)103208https://doi.org/10.1016/j.jbi.2019.103208
        • Marcolino M.S.
        • Alkmim M.B.M.
        • Assis T.G.P.
        • Palhares D.M.F.
        • da Silva G.A.
        • Cunha L.R.
        • Sousa L.
        • de Abreu M.P.
        • Figueira R.M.
        • Ribeiro A.L.
        A Rede de Teleassistência de Minas Gerais e suas contribuições para atingir os princípios de universalidade, equidade e integralidade do SUS – relato de experiência.
        in: RECIIS. Revista Eletrônica de Comunicação, Informação & Inovação em Saúde (Edição em Português. Online). 7. 2013: 1https://doi.org/10.3395/reciis.v7i2.480
        • AMB Matos
        • Dahy F.E.
        • JVL Moura
        • RMN Marcusso
        • ABF Gomes
        • FMM Carvalho
        • GBP Fernandes
        • Felix A.C.
        • Smid J.
        • Vidal J.E.
        • NAF Frota
        • Casseb J.
        • Easton A.
        • Solomon T.
        • Witkin S.S.
        • Malta Romano C.
        • ACP Oliveira
        • NeuroCovBR Study Group
        Subacute cognitive impairment in individuals with mild and moderate COVID-19: A case series.
        Front. Neurol. 2021; 4678924https://doi.org/10.3389/fneur.2021.678924
        • Espíndola O.M.
        • Gomes Y.C.P.
        • Brandão C.O.
        • Torres R.C.
        • Siqueira M.
        • Soares C.N.
        • Lima M.A.S.D.
        • Leite A.C.C.B.
        • Venturotti C.O.
        • Carvalho A.J.C.
        • Torezani G.
        • Araujo A.Q.C.
        • Silva M.T.T.
        Inflammatory cytokine patterns associated with neurological diseases in coronavirus disease 2019.
        Ann. Neurol. 2021; 89 (Epub 2021 Feb 24): 1041-1045https://doi.org/10.1002/ana.26041
        • World Health Organization
        Coronavirus Dashboard.
        (Online. Available at:) (accessed at 8/16/2021)
        • Aziz M.
        • Goyal H.
        • Haghbin H.
        • Lee-Smith W.M.
        • Gajendran M.
        • Perisetti A.
        The association of “loss of smell” to COVID-19: A systematic review and Meta-analysis.
        Am J Med Sci. 2021; 361 (Epub 2020 Nov 1): 216-225https://doi.org/10.1016/j.amjms.2020.09.017
        • Porta-Etessam J.
        • Núñez-Gil I.J.
        • González García N.
        • Fernandez-Perez C.
        • Viana-Llamas M.C.
        • Eid C.M.
        • Romero R.
        • Molina M.
        • Uribarri A.
        • Becerra-Muñoz V.M.
        • Aguado M.G.
        • Huang J.
        • Rondano E.
        • Cerrato E.
        • Alfonso E.
        • Mejía A.F.C.
        • Marin F.
        • Roubin S.R.
        • Pepe M.
        • Feltes G.
        • Maté P.
        • Cortese B.
        • Buzón L.
        • Mendez J.J.
        • Estrada V.
        COVID-19 anosmia and gustatory symptoms as a prognosis factor: a subanalysis of the HOPE COVID-19 (health outcome predictive evaluation for COVID-19) registry.
        Infection. 2021; 49 (Epub 2021 Mar 1): 677-684https://doi.org/10.1007/s15010-021-01587-9
        • Mahdizade Ari M.
        • Mohamadi M.H.
        • Shadab Mehr N.
        • Abbasimoghaddam S.
        • Shekartabar A.
        • Heidary M.
        • Khoshnood S.
        Neurological manifestations in patients with COVID-19: A systematic review and meta-analysis.
        J. Clin. Lab. Anal. 2022; 36 (Epub 2022 Apr 6)e24403https://doi.org/10.1002/jcla.24403
        • World Health Organization
        Clinical management of COVID-19 patients: living guideline.
        Online. 2020; 23
        • Boldrini M.
        • Canoll P.D.
        • Klein R.S.
        How COVID-19 affects the brain.
        JAMA Psychiatry. 2021; 78: 682-683https://doi.org/10.1001/jamapsychiatry.2021.0500
        • Orsucci D.
        • Ienco E.C.
        • Nocita G.
        • Napolitano A.
        • Vista M.
        Neurological features of COVID-19 and their treatment: a review.
        Drugs Context. 2020; 11https://doi.org/10.7573/dic.2020-5-1
        • Pantelis C.
        • Jayaram M.
        • Hannan A.J.
        • Wesselingh R.
        • Nithianantharajah J.
        • Wannan C.M.
        • Syeda W.T.
        • Choy K.C.
        • Zantomio D.
        • Christopoulos A.
        • Velakoulis D.
        • O’Brien T.J.
        Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19.
        Aust N Z J Psychiatry. 2021; 55 (Epub 2020 Oct 1): 750-762https://doi.org/10.1177/0004867420961472
        • Helms J.
        • Kremer S.
        • Merdji H.
        • Schenck M.
        • Severac F.
        • Clere-Jehl R.
        • Studer A.
        • Radosavljevic M.
        • Kummerlen C.
        • Monnier A.
        • Boulay C.
        • Fafi-Kremer S.
        • Castelain V.
        • Ohana M.
        • Anheim M.
        • Schneider F.
        • Meziani F.
        Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients.
        Crit. Care. 2020; 24: 491https://doi.org/10.1186/s13054-020-03200-1
        • Wilcox M.E.
        • Shankar-Hari M.
        • McAuley D.F.
        Delirium in COVID-19: can we make the unknowns knowns?.
        Intensive Care Med. 2021; 47 (Epub 2021 Jun 30): 1144-1147https://doi.org/10.1007/s00134-021-06467-2
        • Poloni T.E.
        • Medici V.
        • Moretti M.
        • Visonà S.D.
        • Cirrincione A.
        • Carlos A.F.
        • Davin A.
        • Gagliardi S.
        • Pansarasa O.
        • Cereda C.
        • Tronconi L.
        • Guaita A.
        • Ceroni M.
        COVID-19-related neuropathology and microglial activation in elderly with and without dementia.
        Brain Pathol. 2021; 31 (Epub 2021 Jun 18)e12997https://doi.org/10.1111/bpa.12997
        • Lee M.H.
        • Perl D.P.
        • Nair G.
        • Li W.
        • Maric D.
        • Murray H.
        • Dodd S.J.
        • Koretsky A.P.
        • Watts J.A.
        • Cheung V.
        • Masliah E.
        • Horkayne-Szakaly I.
        • Jones R.
        • Stram M.N.
        • Moncur J.
        • Hefti M.
        • Folkerth R.D.
        • Nath A.
        Microvascular injury in the brains of patients with Covid-19.
        N. Engl. J. Med. 2021; 384 (Epub 2020 Dec 30): 481-483https://doi.org/10.1056/NEJMc2033369
        • Purja S.
        • Shin H.
        • Lee J.Y.
        • Kim E.
        Is loss of smell an early predictor of COVID-19 severity: a systematic review and meta-analysis.
        Arch. Pharm. Res. 2021; 44 (Epub 2021 Jul 24): 725-740https://doi.org/10.1007/s12272-021-01344-4
        • Sanli D.E.T.
        • Altundag A.
        • Kandemirli S.G.
        • Yildirim D.
        • Sanli A.N.
        • Saatci O.
        • Kirisoglu C.E.
        • Dikensoy O.
        • Murrja E.
        • Yesil A.
        • Bastan S.
        • Karsidag T.
        • Akinci I.O.
        • Ozkok S.
        • Yilmaz E.
        • Tuzuner F.
        • Kilercik M.
        • Ljama T.
        Relationship between disease severity and serum IL-6 levels in COVID-19 anosmia.
        Am. J. Otolaryngol. 2021; 42 (Epub 2020 Oct 28): 102796https://doi.org/10.1016/j.amjoto.2020.102796
        • Baqui P.
        • MPhil I.B.
        • Marra V.
        • Ercole A.
        • MVD Schaar
        Ethnic and regional variations in hospital mortality from COVID-19 in Brazil: a cross-sectional observational study. The lancet.
        Glob. Health. 2020; 8: e1018-e1026https://doi.org/10.1016/S2214-109X(20)30285-0
        • Cascella M.
        • Rajnik M.
        • Aleem A.
        • Dulebohn S.C.
        • Di Napoli R.
        Features, Evaluation, and Treatment of Coronavirus (COVID-19). 2022 May 4.
        in: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL)2022