Archives of Academic Emergency Medicine. 2021; 9(1): e34 https://doi.org/10.22037/aaem.v9i1.1210 OR I G I N A L RE S E A RC H Neurological Manifestations and their Correlated Factors in COVID-19 Patients; a Cross-Sectional Study Farzad Ashrafi1, Davood Ommi1, Alireza Zali1, Sina Khani2, Amirali Soheili2, Mehran Arab-Ahmadi3, Behdad Behnam4, Shabnam Nohesara5∗, Farbod Semnani6, Alireza Fatemi7, Mehri Salari1, Reza Jalili khoshnood1, Mohammad Vahidi2, Niloofar Ayoobi-Yazdi3, Saeed Hosseini Toudeshki8, Elham Sobhrakhshankhah4 1. Functional Neurosurgery Research Center, Shohadaye Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Advanced Diagnostic and Interventional Radiology Research Center, Tehran University of Medical Sciences, Tehran, Iran. 4. Department of Internal Medicine, Iran University of Medical Sciences, Tehran, Iran. 5. Mental Health Research Center, Iran University of Medical Sciences, Tehran, Iran. 6. Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. 7. Department of Infectious Diseases, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 8. Department of Radiation Oncology, Iran University of Medical Sciences, Tehran, Iran. Received: February 2021; Accepted: February 2021; Published online: 27 April 2021 Abstract: Introduction: COVID-19 might present with other seemingly unrelated manifestations; for instance, neuro- logical symptoms. This study aimed to evaluate the neurologic manifestations and their correlated factors in COVID-19 patients. Methods: This retrospective observational study was conducted from March 17, 2020 to June 20, 2020 in a tertiary hospital in Iran. The study population consisted of adult patients with a positive result for COVID-19 real-time reverse transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal swabs. Both written and electronic data regarding baseline characteristic, laboratory findings, and neurological mani- festations were evaluated and reported. Results: 727 COVID-19 patients with the mean age of 49.94 ± 17.49 years were studied (56.9% male). At least one neurological symptom was observed in 403 (55.4%) cases. Headache (29.0%), and smell (22.3%) and taste (22.0%) impairment were the most prevalent neurological symptoms, while seizure (1.1%) and stroke (2.3%) were the least common ones. Patients with neurological manifestations were significantly older (p = 0.04), had greater body mass index (BMI) (p = 0.02), longer first symptom to admission duration (p < 0.001) and were more frequently opium users (p = 0.03) compared to COVID-19 patients without neurological symptoms. O2 saturation was significantly lower in patients with neurological manifestations (p = 0.04). In addition, medians of neutrophil count (p = 0.006), neutrophil-lymphocyte ratio (NLR) (p = 0.02) and c-reactive protein (CRP) (p = 0.001) were significantly higher and the median of lymphocyte count (p = 0.03) was significantly lower in patients with neurological manifestations. Conclusion: The prevalence of neurological manifestations in the studied cases was high (55.4%). This prevalence was significantly higher in older age, grated BMI, longer lasting disease, and opium usage. Keywords: COVID-19; Neurologic Manifestations; Blood cell count; Risk Factors Cite this article as: Ashrafi F, Ommi D, Zali A, Khani S, Soheili A, Arab-Ahmadi M, Behnam B, Nohesara S, Semnani F, Fatemi A, Salari M, Jalili khoshnood R, Vahidi M, Ayoobi-Yazdi N. Neurological Manifestations and their Correlated Factors in COVID-19 Patients; a Cross-Sectional Study. Arch Acad Emerg Med. 2021; 9(1): e34. ∗Corresponding Author: Mental Health Research Center, First Floor, Tehran Psychiatry Institute, Shahid Mansouri Alley, Niayesh Avenue, Sattarkhan Street, Tehran, Iran. Tel: +989122899816, Fax: +98.2122701022, Email: shno- hesara@gmail.com, ORCID: https://orcid.org/0000-0003-4944-7033. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem F. Ashrafi and et al. 2 1. Introduction Several studies showed clinical characteristics of the “coro- navirus disease 2019 (COVID-19)” disease. In a systematic review by Leiwen Fu et al., fever (83.3%) cough (60.3%) and fatigue (38.0%) were the most common clinical symptoms (1). Respiratory tract infections and pneumonia have been commonly observed in infected patients. However, in some occasions, they show neurological alterations and signs in- cluding seizure, status epilepticus, impairment of conscious- ness, and encephalopathies (2). Besides, a study reported that some patients without typical symptoms of COVID-19 including fever, cough, anorexia, and diarrhea presented neurological manifestations as the initial symptoms such as dizziness, headache, impaired consciousness, acute cere- brovascular disease, ataxia, and seizure (3). These neu- rological symptoms were also seen in SARS-CoV infection, which caused polyneuropathy, encephalitis, and ischemic stroke and in MERS-CoV infection, which caused distur- bance of consciousness, paralysis, ischemic stroke, Guillain- Barre syndrome, and seizure (4). Although there is no una- nimity regarding the underlying mechanisms, it is proba- bly due to exaggerated cytokine responses and/or the sub- sequent hypercoagulopathy in vessels, which cause anos- mia, stroke, paralysis, cranial nerve deficits, encephalopa- thy, delirium, meningitis, and seizure (5). Due to lack of comprehensive and sufficient evidence concerning COVID- 19 and its neurological manifestations, hereby, we report the characteristic neurological manifestations of SARS-CoV-2 in- fection in patients with a laboratory-confirmed diagnosis of COVID-19 and investigate the association between neurolog- ical symptoms and baseline characteristics as well as labora- tory findings. 2. Methods 2.1. Study design and setting This retrospective observational study was conducted in Shohadaye Tajrish Hospital, a tertiary academic hospital lo- cated in Tehran, Iran. This hospital is among the major designated centers for COVID-19 patients during the pan- demic. From March, 17, 2020 to June 20, 2020 all suspected individuals aged >18 years presenting with typical COVID- 19 symptoms were tested for COVID-19 using a throat swab. Then, throat swab samples were put into 150 µL viral protec- tive solution for further molecular examinations. Based on the WHO interim guidance (6), a confirmed case of COVID- 19 is defined as a person with a positive result for RT-PCR test for SARS-CoV-2. The current study was performed ac- cording to the principles of the Declaration of Helsinki. An ethical approval was obtained from ethics committee of Shahid Beheshti University of Medical Sciences (Ethics code: IR.SBMU.RETECH.1399.115). 2.2. Participants This study included all patients aged 18 years and above ad- mitted to the hospital with typical COVID-19 symptoms and a positive throat swab COVID-19 test in evaluations. Con- venience sampling method was used. Patients with previous neurocognitive disorders such as Alzheimer’s disease and pa- tients who were unconscious at the time of admission were excluded from the study. 2.3. Data gathering Demographic data (age, sex, body mass index (BMI)), his- tory of comorbid diseases (diabetes mellitus, hypertension, chronic kidney disease, cardio and cerebrovascular disease, cancer), clinical symptoms (fever, dyspnea, cough, gastroin- testinal discomforts, sore throat), laboratory findings, and neurological manifestations were gathered for all patients us- ing hospital’s both electronic and written records. If there was missing data, data clarification was performed via phone call or consulting with related physicians. Neurological man- ifestations were categorized into three classes: I. Symptoms related to skeletal muscular injury; II. Central nervous sys- tem (CNS) manifestations including headache, drowsiness, convulsion, ataxia, impaired consciousness, and acute cere- brovascular disease; III. Peripheral nervous system (PNS) fea- tures such as nerve root pains and cranial nerve symptoms such as anosmia, ageusia, visual discomforts, and photopho- bia. Critical cases were defined as those admitted to intensive care unit (ICU) with acute respiratory distress syndrome (ARDS) criteria consisting of severe dyspnea, respiratory rate ≥30/minute, blood oxygen saturation ≤80%, PaO2/FiO2 ra- tio and unstable vital signs (7). Trained medical students were responsible for data gathering. 2.4. Statistical analysis Data were presented as mean ± standard deviation (SD) for normally distributed, median (Q1 – Q3) for skewed vari- ables, and frequency (percent) for categorical data. Nor- mality assumption was checked using Kolmogorov-Simonov test. Mean and median differences were tested using in- dependent T-test and Mann-Whitney U test, respectively. The distribution of categorical data was assessed using chi- square test (with exact p-value). P<0.05 was considered as significance level and all statistical analyses were performed using IBM SPSS Statistics 23. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2021; 9(1): e34 Figure 1: The frequency of neurological manifestations in patients with COVID-19. 3. Results 727 COVID-19 patients with the mean age of 49.94 ± 17.49 years (22 - 91) were enrolled (56.9% male). At least one neu- rologic symptom was observed in 403 (55.4%) cases. Fig- ure 1 displays the prevalence of neurological manifestations in the studied participants. Headache (29.0%), and smell (22.3%) and taste impairment (22.0%) were the most preva- lent neurologic symptoms, while seizure (1.1%) and stroke (2.3%) were the least common ones. Table 1 compares the baseline characteristics and labora- tory findings of studied cases between cases with and with- out neurological manifestations. Patients with neurological manifestations were significantly older (p = 0.04), had greater BMI (p = 0.02), longer first symptom to admission duration (p < 0.001) and were more frequently opium users (p = 0.03) compared to COVID-19 patients without neurological symp- tom. O2 saturation was significantly lower in patients with neurological manifestations (p = 0.04). In addition, medians of neutrophil count (p = 0.006), neutrophil-lymphocyte ratio (NLR) (p = 0.02) and c-reactive protein (CRP) (p = 0.001) were significantly higher and the median of lymphocyte count (p = 0.03) was significantly lower in patients with neurological manifestations. 85 (11.7%) cases were critically ill and ad- mitted to ICU. Table 2 compares the prevalence of neuro- logic manifestations between stable and critically ill patients. The prevalence of neurologic manifestations was not signif- icantly different between stable and critically ill patients ex- cept for headache and dizziness, which were higher in sta- ble patients (30.2% vs 20.0%, p=0.049 and 20.6% vs 9.4%, p= 0.014, respectively). 4. Discussion Herein, neurological symptoms of 727 hospitalized patients with COVID-19 were evaluated. Overall, 403 (55.4%) pa- tients had at least one of the reported neurological symp- toms. Among all neurological symptoms, headache (29.0%) and smell impairment (22.3%) were the most prevalent ones. Neutrophil count, NLR, and CRP were significantly higher in patients with neurological manifestations. Moreover, the prevalence of neurologic manifestations was not signif- icantly different between stable and critically ill patients ex- cept for headache and dizziness, which were more prevalent in stable patients. According to the literature, among gastrointestinal distur- bances in COVID-19, anorexia is the most prevalent one (8), which is parallel to our findings. Anorexia is probably due to the release of inflammatory cytokines along with the ad- verse effects of various drugs consumed by these patients. Headache is also a prominent feature in COVID-19 patients, which has been described among the most prevalent neu- rological symptoms by many studies (3, 9-11). It may oc- cur due to systemic inflammation or virus invasion to brain blood vessels. About a quarter of patients reported smell and taste impairment without significant difference between crit- ical and stable groups. We found that patients with neurolog- ical symptoms were significantly older (p = 0.005), had higher BMI (p = 0.02), longer hospitalization (p = 0.002), and longer first symptom to admission duration (p < 0.001) compared to COVID-19 patients without neurological symptoms. In a study in China, it was shown that obese patients were at greater risk of developing severe COVID-19 infection com- pared to normal-weight patients and this is of great impor- tance, because it may indeed lead to increased hospitaliza- tion and worse clinical outcomes (12). The prevalence of neurologic manifestations was not significantly different be- tween stable and critically ill patients except for headache and dizziness, which were more prevalent in stable patients. This may be related to the fact that critically ill patients are commonly bedridden and headache and dizziness are com- monly triggered by walking. Up to now, several studies have been performed to identify and characterize COVID-19 pathophysiologic mechanisms leading to its neurological manifestations. A study by M. Fo- tuhi et al. categorized neurological symptoms into a con- ceptual framework of their own so-called “NeuroCovid Stag- ing”, which included 3 stages. In the proposed NeuroCovid Stage I infection with SARS-CoV2 is limited to nasal and gustatory epithelial cells and the cytokine storm is limited. Then, in the NeuroCovid Stage II, there is a vigorous cy- tokine storm resulting in a hypercoagulable state, which is also responsible for blood clot formation and higher prob- ability of strokes in these patients. Finally, during the Neu- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem F. Ashrafi and et al. 4 Table 1: Comparing the baseline characteristics and laboratory findings of COVID-19 patients between cases with and without neurological manifestations Variables Neurological manifestation P No (n = 324) Yes (n = 403) Age (years) Mean ± SD 48.50 ± 17.31 51.10 ± 17.57 0.04 Sex Female 138 (42.6) 175 (43.4) 0.82 Male 186 (57.4) 228 (56.6) BMI (kg/m2) Mean ± SD 25.71 ± 4.52 26.54 ± 4.26 0.02 Habit Smoke (yes) 42 (13.0) 39 (9.7) 0.16 Ex-Smoke (yes) 20 (6.2) 38 (9.4) 0.11 Alcohol (yes) 8 (2.5) 6 (1.5) 0.34 Opium (yes) 2 (0.6) 11 (2.7) 0.03 Hospitalization (day) 1 (0 – 4) 1 (0 – 4) 0.22 First Symptom to Admission (day) 2 (1 – 4) 4 (2 – 8) <0.001 Vital signs Heart Rate (/minute) 87.92 ± 13.71 88.56 ± 14.48 0.15 RR (/minute) 18.02 ± 3.53 18.72 ± 7.12 0.09 Temperature (Celsius) 37.32 ± 0.77 37.30 ± 0.79 0.70 O2 saturation (%) 94 (91 – 96) 93 (90 – 96) 0.04 SBP (mmHg) 116.68 ± 13.00 118.51 ± 14.35 0.08 DBP (mmHg) 74.27 ± 9.26 74.61 ± 9.33 0.64 Laboratory findings WBC (/µL) 6.2 (4.4 – 8.5) 5.8 (4.6 – 8.1) 0.96 Hemoglobin (g/dL) 13 (11.8 – 14) 13 (11.8 – 14.3) 0.55 Platelet (/µL) 179 (139 – 214) 166 (131– 223) 0.54 Neutrophil (/µL) 7.0 (6.0 – 8.0) 7.5 (6.5 – 8.3) 0.006 Lymphocyte (/ µL) 2.5 (1.5 – 3.3) 2.1 (1.5 – 3.0) 0.03 NLR 2.8 (1.9 – 5.3) 3.5 (2.2 – 5.7) 0.02 PLR 1.3 (0.9 – 1.7) 1.3 (0.9 – 1.9) 0.12 Cr (mg/dL) 1.0 (0.9 – 1.3) 1.1 (1.0 – 1.4) 0.06 BUN (mg/dL) 13 (11– 17.8) 14 (11 – 18) 0.31 CRP (mg/dL) 15.0 (7.4– 34.0) 25.0 (11 – 45.3) 0.001 CPK (IU/L) 110 (60.3 – 162.8) 118 (61 – 256) 0.13 LDH (U/L) 495 (373 – 599) 495 (399 – 629) 0.55 Data are presented as mean ± standard deviation, median (Q1 – Q3), or frequency (%). BMI: body mass index; RR: respiratory rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; WBC: white blood cells; NLR: neutrophil-to-lymphocyte ratio; PLR: platelet-to-lymphocyte ratio; Cr: creatinine; BUN: blood urea nitrogen; CRP: c-reactive protein; CPK: creatine phosphokinase; LDH: lactate dehydrogenase. roCovid Stage III, virus-induced cytokine storm damages the blood brain barrier resulting in the penetration of inflamma- tory factors and consequent severe complications including delirium, encephalopathy, and seizure (5). In a recent review by Ellul et al., it was stated that acute ischemic stroke might occur due to a destabilized carotid plaque or as a result of atrial fibrillation. Viral replication in the cerebral blood ves- sels could be a possible reason for such manifestations (13). It seems that COVID-19 is also related with chronic neuro- logic complications, particularly a greater risk of stroke, even in youths. In a case-series by Ashrafi et al. all six COVID-19 patients presenting with stroke were younger than 55 and did not have any major risk factors for stroke (14). Moreover, COVID-19 patients are more prone to anxiety, which is even more prevalent among patients with preexist- ing comorbidities such as Parkinson. Further studies should be performed to evaluate the correlation between neurolog- ical comorbidities and anxiety during the COVID-19 pan- demic (15). This might be the result of SARS-CoV-2 directly attacking the CNS as the virus was also found in the CSF fluid. Cytokine storm may also be responsible for these neurological symp- toms particularly by resulting in a hypercoagulable state. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2021; 9(1): e34 Table 2: Comparison of neurological manifestations of COVID-19 patients between critically ill patients and others Variables Critically ill P No (n = 642) Yes (n = 85) Neck pain 25 (3.9) 4 (4.7) 0.77 Headache 194 (30.2) 17 (20.0) 0.05 Impaired consciousness 72 (11.2) 13 (15.3) 0.27 Dizziness 132 (20.6) 8 (9.4) 0.014 Ataxia 48 (7.5) 2 (2.4) 0.08 Seizure 6 (0.9) 2 (2.4) 0.24 Smell impairment 147 (22.9) 15 (17.6) 0.27 Taste impairment 143 (22.3) 17 (20.0) 0.63 Sleep disturbances 124 (19.3) 15 (17.6) 0.82 Neuralgia 21 (3.3) 4 (4.7) 0.52 Stroke 13 (2.0) 4 (4.7) 0.13 Total* 362 (56.4) 41 (48.2) 0.16 *At least one of the measured neurological symptoms was observed. Data are presented as frequency (%). 5. Limitations Some of the neurological features such as encephali- tis, encephalopathy, acute disseminated encephalomyelitis (ADEM) and myelitis might not be diagnosed at the time of hospitalization as they will manifest later. However, in cases with impaired consciousness, infection with SARS-CoV-2 is not the only trigger and other possible causes like drugs, tox- ins and metabolic derangement should also be considered. Furthermore, admission to the intensive care unit is an im- portant risk factor, as critical states like sepsis may result in neurological manifestations such as encephalopathy. 6. Conclusion According to our findings, more than half of COVID-19 pa- tients had at least one of the studied neurological symptoms. This prevalence was significantly higher in older age, grated BMI, longer lasting disease, and opium usage. 7. Declarations 7.1. Conflict of interest The authors declare that they have no competing interests. 7.2. Acknowledgments None. 7.3. Funding and support Not applicable. 7.4. Authors’ contributions F.A.: Conceptualization & Study Design, Reviewing and Edit- ing, Supervision D.O.: Conceptualization & Study Design, Writing – Original manuscript A.Z.: Conceptualization & Study Design, Methodology, Su- pervision S.K.: Literature search, Writing – Original manuscript, Re- viewing and Editing A.S.: Literature search, Writing – Original manuscript, Re- viewing and Editing M.A.: Writing – Original manuscript, Reviewing and Editing, Supervision B.B.: Methodology, Writing – Original manuscript S.N.: Conceptualization & Study Design, Methodology F.S.: Methodology, Literature search, Reviewing and Editing A.F.: Data Curation & Interpretation, Methodology M.S.: Methodology, Reviewing and Editing, Supervision R.J.K.: Conceptualization & Study Design, Literature search M.V.: Literature search, Writing – Original manuscript N.A.Y.: Writing – Original manuscript, Reviewing and Editing S.H.T.: Conceptualization & Study Design, Data Curation & Interpretation E.S.: Methodology, Reviewing and Editing References 1. Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta- analysis. J Infect. 2020;80(6):656-65. 2. Bohmwald K, Galvez NMS, Rios M, Kalergis AM. Neu- rologic Alterations Due to Respiratory Virus Infections. Front Cell Neurosci. 2018;12:386. 3. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neuro- logic Manifestations of Hospitalized Patients With Coro- navirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020. 4. Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem F. Ashrafi and et al. 6 19 and other coronaviruses. Brain Behav Immun. 2020. 5. Fotuhi M, Mian A, Meysami S, Raji CA. Neurobiology of COVID-19. J Alzheimers Dis. 2020. 6. organization Wh. Clinical management of severe acute respiratory infection when Novel coronavirus (nCoV ) in- fection is suspected: interim guidance. 2020. 7. Organization WH, Organization WH. Report of the who- china joint mission on coronavirus disease 2019 (covid- 19). Geneva; 2020. 8. Tian Y, Rong L, Nian W, He Y. Review article: gastroin- testinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;51(9):843- 51. 9. Ahmad I, Rathore FA. Neurological manifestations and complications of COVID-19: A literature review. J Clin Neurosci. 2020;77:8-12. 10. Whittaker A, Anson M, Harky A. Neurological Manifesta- tions of COVID-19: A systematic review and current up- date. Acta Neurol Scand. 2020;142(1):14-22. 11. Correia AO, Feitosa PWG, de Sousa Moreira JL, Nogueira SÁR, Fonseca RB, Nobre MEP. Neurological manifesta- tions of COVID-19 and other coronaviruses: a systematic review. Neurology, Psychiatry and Brain Research. 2020. 12. Cai Q, Chen F, Wang T, Luo F, Liu X, Wu Q, et al. Obesity and COVID-19 Severity in a Designated Hospital in Shen- zhen, China. Diabetes Care. 2020;43(7):1392-8. 13. Cai Q, Chen F, Wang T, Luo F, Liu X, Wu Q, et al. Obesity and COVID-19 Severity in a Designated Hospital in Shen- zhen, China. Diabetes Care. 2020;43(7):1392-8. 14. Ashrafi F, Zali A, Ommi D, Salari M, Fatemi A, Arab- Ahmadi M, et al. COVID-19-related strokes in adults be- low 55 years of age: a case series. Neurological Sciences. 2020:1-5. 15. Salari M, Zali A, Ashrafi F, Etemadifar M, Sharma S, Ha- jizadeh N, et al. Incidence of Anxiety in Parkinson’s Dis- ease During the Coronavirus Disease (COVID-19) Pan- demic. Mov Disord. 2020;35(7):1095-6. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References