Saber Soltani , Alireza Tabibzadeh , Armin Zakeri , Amir Mohammad Zakeri , Tayebeh Latifi , Mahdi Shabani , Amir Pouremamali , Yousef Erfani , Iraj Pakzad , Pooneh Malekifar , Reza Valizadeh , Milad Zandi ORCID logo and Reza Pakzad ORCID logo

COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis

De Gruyter | Published online: January 13, 2021

Abstract

The ongoing pandemic of Coronavirus disease 2019 (COVID-19) has infected more than 27 million confirmed cases and 8,90,000 deaths all around the world. Verity of viral infections can infect the nervous system; these viral infections can present a wide range of manifestation. The aim of the current study was to systematically review the COVID-19 associated central nervous system manifestations, mental and neurological symptoms. For that we conducted a comprehensive systematic literature review of four online databases, including Web of Science, PubMed, Scopus and Embase. All relevant articles that reported psychiatric/psychological symptoms or disorders in COVID-19 without considering time and language restrictions were assessed. All the study procedures were performed based on the PRISMA criteria. Due to the screening, 14 studies were included. The current study result indicated that, the pooled prevalence of CNS or mental associated disorders with 95% CI was 50.68% (6.68–93.88). The most prevalence symptoms were hyposmia/anosmia/olfactory dysfunction (number of study: 10) with 36.20% (14.99–60.51). Only one study reported numbness/paresthesia and dysphonia. Pooled prevalence of numbness/paresthesia and dysphonia was 5.83% (2.17–12.25) and 2.39% (10.75–14.22). The pooled prevalence of depression and anxiety was 3.52% (2.62–4.54) and 13.92% (9.44–19.08). Our findings demonstrate that COVID-19 has a certain relation with neurological symptoms. The hypsomia, anosmia or olfactory dysfunction was most frequent symptom. Other symptoms were headache or dizziness, dysgeusia or ageusia, dysphonia and fatigue. Depression, anxiety, and confusion were less frequent symptoms.

Introduction

The ongoing pandemic of Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) (Soltani 2020), has infected more than 27 million confirmed cases and 8,90,000 deaths all around the world (World Health Organization 2020). The COVID-19 mean incubation period consider as 2–5 days (Wiersinga et al. 2020). The COVID-19 associated symptoms and death timeline ranged from 6 to 41 days, with a median of 14 days (Wang et al. 2020). The age and the patient’s immune system are critical factors in COVID-19 outcome (Wang et al. 2020). The most common presented symptoms in COVID-19 patients are fever, cough and fatigue; whereas other symptoms include sputum production, headache, hemoptysis, diarrhea, dyspnea, and lymphopenia were reported (Carlos et al. 2020; Huang et al. 2020; Ren et al. 2020).

Verity of viral infections can infect the nervous system; these viral infections can present a wide range of manifestation including severe encephalitis, toxic encephalopathy and severe acute demyelinating lesions developing after viral infections (Michalicova et al. 2017; Wright et al. 2008). Some viruses are neurotropic or infect immune cells of central nervous system (CNS) microglia or astrocytes (Al-Obaidi et al. 2018; Soung and Klein 2018). SARS-CoV-2 is highly homologous with SARS-CoV (Grifoni et al. 2020). Recent emergent coronaviruses, SARS-CoV and MERS-CoV can infect CNS in patients and animal models (Li et al. 2020). The possibility of SARS-CoV-2 infection in the CNS and conducting neurological damage is not negligible. Also, both SARS-CoV-2 and SARS-CoV invades human cells by angiotensin-converting enzyme-2 (ACE-2) (Hoffmann et al. 2020), an essential component of the renin-angiotensin system in the brain (Abiodun and Ola 2020). Neurological symptoms were reported in COVID-19 patients. These manifestations could be presented as headache, disturbed consciousness and paresthesia. A study of 214 COVID-19 patients introduced that the incidence of neurological damage caused by SARS-CoV-2 estimated as 36.4% (Mao et al. 2020). Previous studies in the field of the COVID-19 neurological manifestations are focused on the case reports of neurological manifestations (Ellul et al. 2020; Tsivgoulis et al. 2020). The aim of the current study was to comprehensively update previous studies in the field of the COVID-19 neurological manifestations. Also, due to the ongoing COVID-19 pandemic, the aim of the current review and meta-analysis was to systematically review the COVID-19 associated central nervous system manifestations and neurological symptoms.

Methods

Search strategy and screening

All the study procedures were conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Liberati et al. 2009). We conducted a comprehensive systematic literature review of four online databases, including Web of Science, PubMed, Scopus and Embase. All relevant articles that reported psychiatry/psychology symptoms/disorders in COVID-19 without considering time and language restrictions were retrieved. Social Science Research Network and MedRxiv searched to obtain unpublished or preprints. Google scholar was used for grey literature access. Search was conducted by using following keywords, “COVID-19”, “Coronavirus”, “Neurologic”, “Central nervous system”, “SARS-CoV-2”, “Psychiatry”, and “Psychology”. The PICO in this study was as follows:

Population: child and adult with Covid-19

Intervention: none

Comparison: none

Outcome:Psychiatry/Psychologydisorders/syndromes/signs/symptoms

The details of the search strategy are presented in Table 1.

Table 1:

Search strategy based on PICO for MEDLINE.

1. COVID-19 [text word] OR COVID-19 [Mesh term]
2. Coronavirus [text word] OR Coronavirus [Mesh term]
3. SARS-CoV-2 infection [text word] OR SARS-CoV-2 infection [Mesh term]
4. 1 OR 2 OR 3
5. Syndromes [text word] OR Syndromes [Mesh term]
6. Disorders [text word] OR Disorders [Mesh term]
7. characteristic [text word] OR characteristic [Mesh term]
8. Symptoms [text word] OR Symptoms [Mesh term]
9. Sign [text word] OR Sign [Mesh term]
10. 5 OR 6 OR 7 OR 8 OR 9
11. Psychiatry [text word] OR Psychiatry [Mesh term]
12. Psychology [text word] OR Psychology [Mesh term]
13. 11 OR 12
14. 4 AND 10 AND 13

    MeSH, Medical Subject Headings.

The conducted search result imported in EndNote Version. X9 (Thomson Reuters) and after duplicate removal the screening was performed. The screening in three steps was performed by title and abstract and full text. All included studies met the inclusion criteria. The screening was performed by two independent authors (RP & SS) and the third expert author (IP) strategy was used for conflicts. Blinding and task separation were applied in the study selection procedure. The inter-rater agreement was 92%. All of the studies on the field of the COVID-19 associated central nervous system manifestations and neurological symptoms were included. The exclusion criteria for current study were case report and case series studies conducted in less than five patients as sample size.

Data extraction

In the current study, any psychiatric disorders/psychology in COVID-19 patient were reviewed in addition other information’s such as name of the author, the publication year, the country, study design, sample size and participants age was extracted. Also other general symptoms include mental disorder, confusion, depression, dementia, anxiety, fatigue/weakness, sleep disorder/drowsiness, delirium, cerebrovascular disease, nervous system disorders, headache, dizziness, dysphonia, hyposmia/anosmia/olfactory dysfunction, dysgeusia/ageusia, auditory dysfunction and numbness/paresthesia were extracted.

Quality assessment

The Newcastle-Ottawa Scale (NOS) scale (Wells et al. 1999) was used for assessing the quality of included studies. The scaling of included studies was performed as previous research (Hashemi et al. 2020). This scale has three sections: 1-selection (4 items, maximum score: 4 points), 2-Confounder (1 item, maximum score: 1 points), and 3-Exposure (2 items, maximum score: 2 points). The studies were evaluated by two raters (RP & SS) independently, and a total score was calculated for each study. The studies were then assigned to one of the following categories accordingly: very good studies: 6–7 scores; good studies: 4–5 scores; satisfactory studies: 2–3 scores; unsatisfactory studies: 0–1 score.

Statistical analysis

The Stata version 14 was used for statistical analysis. Heterogeneity was assessed by Cochran’s Q test of heterogeneity and the I2 index was used to quantify heterogeneity. In accordance with Higgins classification, I2 values more than 0.7 were considered as high heterogeneity. The “metaprop” used for pooled prevalence calculation by using the random-effects model (Hallajzadeh et al. 2018; Hashemi et al. 2018; Hashemi et al. 2019; Hashemi et al. 2020; Pakzad et al. 2018). The exact method was used for standard error calculation. The meta-regression analysis was used to examine the effect of age, gender, sample size, and publication date as factors affecting heterogeneity among studies. The “metabias” command was used to check the publication bias, and if there was any publication bias, the prevalence rate was adjusted with the “metatrim” command using trim-and-fill method (Hallajzadeh et al. 2018; Hashemi et al. 2018; Hashemi et al. 2019; Hashemi et al. 2020; Pakzad et al. 2018). In all analysis a significance level of 0.05 was considered.

Results

Search results and study population

A total of 1995 studies were retrieved from different databases and 681 studies obtain after remove duplicate papers. Due to the screening, 14 studies were included (the detail are illustrated in Figure 1).

Figure 1: Follow diagram of systematic review and meta-analysis.

Figure 1:

Follow diagram of systematic review and meta-analysis.

The patient’s population in all 14 included studies was 3148 COVID-19 patients. The age was ranged from 19 to 95 years. The study setting assessment indicates 9 (64%) of the studies are Case series and 3 (21%) cross-sectional. The geographical location of the conducted studies indicated, 3 (21%) from China, 3 (21%) Italy and 2 (14.2%) USA. Other data is summarized in Table 2.

Table 2:

Characteristic of included studies of COVID-19 associated central nervous system manifestations and neurological symptoms.

Author Country Year Study Design Age (Range) SS Dementia as comorbidity Confusion Depression Anxiety Fatigue/Weakness Sleep disorder/Drowsiness Delirium
Aggarwal et al. 2020 USA 2020 CA 67 (38–95) 16 8
Bhat et al. 2020 USA 2020 CA 54.5 ± 11.5 8
Chen et al. 2020 China 2020 CA 55.5 ± 13.1 99 9
Chen et al. 2020 China 2020 CA 47.5 145 59
Hung et al. 2020 China 2020 CS 32–62 127
Speth et al. 2020 Switzerland 2020 CS 46.8 ± 15.9 103
Bianchetti et al. 2020 Italy 2020 CA 70.7 ± 12.9 627 82 55
Liguori et al. 2020 Italy 2020 CS 55 ± 14.65 103 23 39 34 33 51
Mao et al. 2020 China 2020 CA 52.7 ± 15.5 214
Lovell et al. 2020 UK 2020 CA 82 (72–89) 101 31 2 9 36 24
Tostmann et al. 2020 Netherlands 2020 CO - 90
Lechien et al. 2020 Europe 2020 CS 39.17 ± 12.09 1420 36
Heidari et al. 2020 Iran 2020 CA 37.4 23 4
Gelardi et al. 2020 Italy 2020 CA 49.7 (19–70) 72 29
CVD Headache/Dizziness Dysphonia Hyposmia/Anosmia/OD Dysgeusia/Ageusia Auditory dysfunction Numbness/Paresthesia
2 4 3 3
1 1
40 8
29 2
2 6 5
63 67
40 40 48 2 6
6 36 11 12
64 37
13 998 176 997 770
19
16 34 34

    CVD, Cerebrovascular disease; OD, Olfactory dysfunction; SS, Sample size; CA, Case series; CS, Cross-sectional; CO, Cohort.

Clinical presentations

By the assessment of 14 included studies, the CNS or mental associated disorders in all population study were listed in Table 1. Figure 2 and Table 3 are shown pool prevalence of symptoms/psychiatric disorders/psychology.

Figure 2: Pooled prevalence estimate (PPE) of psychiatry/psychology disorders/symptoms in patients with COVID-19 based on the random effects model. The diamond mark illustrates the pooled prevalence estimate and length of diamond indicates 95% confidence interval. (CVD, Cerebrovascular disease; NSD, Nervous system disorders; OD, Olfactory dysfunction).

Figure 2:

Pooled prevalence estimate (PPE) of psychiatry/psychology disorders/symptoms in patients with COVID-19 based on the random effects model. The diamond mark illustrates the pooled prevalence estimate and length of diamond indicates 95% confidence interval. (CVD, Cerebrovascular disease; NSD, Nervous system disorders; OD, Olfactory dysfunction).

Table 3:

Pooled prevalence estimate and 95% confidence interval of psychiatry/psychology disorders/symptoms in patients with COVID-19.

Symptom Heterogeneity Number of studies PPE% 95% CI
Mental disorder I2 = 98.21%; Tau2 = 0.72; p < 0.001 3 50.68 (6.85–93.88)
Confusion I2 = 0%; Tau2 < 0.001; p:0.346 2 15.27 (10.57–20.62)
Depression I2 = 91.7%; Tau2 = 0.057; p:0.001 2 3.52 (2.62–4.54)
Anxiety I2 = 79.7%; Tau2 = 0.038; p:0.026 2 13.92 (9.44–19.08)
Fatigue/weakness I2 = 88.90; Tau2 = 0.11; p < 0.001 6 29.80 (17.13–44.18)
Sleep disorder/drowsiness I2 = 0.01%; Tau2 < 0.001; p:0.321 2 42.57 (35.83–49.46)
Delirium I2 = 49.1%; Tau2 = 0.006; p:0.161 2 10.34 (8.21–12.69)
CVD/ NSD I2 = 98.38%; Tau2 = 0.320; p < 0.001 5 12.19 (0.59–33.35)
Headache/dizziness I2 = 98.89%; Tau2 = 0.52; p < 0.001 9 28.77 (9.93–52.39)
Dysphonia I2 = 0% ; Tau2 = -; p = - 1 12.39 (10.75–14.22)
Hyposmia/anosmia/OD I2 = 98.71%; Tau2 = 0.57; p < 0.001 10 36.20 (14.99–60.51)
Dysgeusia/ageusia I2 = 97.84%; Tau2 = 0.32; p < 0.001 7 35.20 (15.84–57.32)
Auditory dysfunction I2 = 0.01%; Tau2 < 0.001; p:0.965 2 1.59 (0.28–3.68)
Numbness/paresthesia I2 = 0%; Tau2 = -; p = - 1 5.83 (2.17–12.25)

    CVD, Cerebrovascular disease; NSD, Nervous system disorders; OD, Olfactory dysfunction; CI, Confidence interval; PPE, Pooled prevalence estimate.

According to this, the pooled prevalence of CNS or mental associated disorders with 95% CI was 50.68% (6.68–93.88). The most prevalence symptoms were hyposmia/anosmia/olfactory dysfunction (number of study: 10) with 36.20% (14.99–60.51). Only one study reported numbness/paresthesia and dysphonia. Pooled prevalence of numbness/paresthesia and dysphonia was 5.83% (2.17–12.25) and 2.39% (10.75–14.22); respectively. The pooled prevalence of depression and anxiety was 3.52% (2.62–4.54) and 13.92% (9.44–19.08). The pooled prevalence of the other disorders has been shown in Figure 2 and Table 3.

Heterogeneity and meta-regression

The Table 3 presents the results of the heterogeneity. According to Cochran’s Q test of heterogeneity, there was significant heterogeneity among studies for all outcomes except confusion, sleep disorder/drowsiness, delirium, dysphonia (because there was only 1 study for this sub group), auditory dysfunction and numbness/paresthesia (because there was only 1 study for this sub group) and Auditory dysfunction. The I2 index for most outcomes (including mental disorder, depression, anxiety, fatigue/weakness, CVD/NSD, headache/dizziness, hyposmia/anosmia/OD and dysgeusia/ageusia) was up to 80%. According to meta-regression results, the age had the significant effect on hyposmia/anosmia/OD prevalence; so that by increasing age, prevalence of hyposmia/anosmia/OD (coefficient: −2.81; p: 0.025) decreased significantly (Figure 3). For other outcomes the age has no effect on heterogeneity.

Figure 3: The association among prevalence of headache/dizziness (A) and hyposmia/anosmia/olfactory dysfunction (B) with age by means of meta-regression. Size of circles indicates the precision of each study. There is significant association with respect to prevalence of headache/dizziness and hyposmia/anosmia/olfactory dysfunction with age. The prevalence has been significantly decreased with increases of age in this survey.

Figure 3:

The association among prevalence of headache/dizziness (A) and hyposmia/anosmia/olfactory dysfunction (B) with age by means of meta-regression. Size of circles indicates the precision of each study. There is significant association with respect to prevalence of headache/dizziness and hyposmia/anosmia/olfactory dysfunction with age. The prevalence has been significantly decreased with increases of age in this survey.

Publication bias

Based on the results of Egger’s test, there is no significant publication bias in our meta-analysis.

Discussion

The aim of the current review and meta-analysis was to systematically review the COVID-19 associated central nervous system manifestations and neurological symptoms. Due to the screening and inclusion criteria 14 studies with 3148 sample size were assessed. Neurological symptoms in COVID-19 patients were reported from USA, China, Switzerland, Italy, UK, Netherland, Europe and Iran (Table 2). The current study result indicated that, the pooled prevalence of CNS or mental associated disorders with 95% CI was 50.68% (6.68–93.88). The most prevalence symptoms were hyposmia/anosmia/olfactory dysfunction with 36.20% (14.99–60.51), numbness/paresthesia 5.83% (2.17–12.25), dysphonia 2.39% (10.75–14.22), depression 3.52% (2.62–4.54) and anxiety 13.92% (9.44–19.08). Dysphonia and numbness or paresthesia was only seen in Europe and Italy in 39.17 ± 12.09 and 55 ± 14.65 ages (Range) respectively (Lechien et al. 2020; Liguori et al. 2020).

Neurological disease have reported in some respiratory viruses such as RSV (Bohmwald et al. 2018; Halfhide et al. 2011), influenza A and B (Xu et al. 1998) and enterovirus D68 (Imamura et al. 2014). The viruses can be detected in blood and they may use circulatory system to reach the CNS (Desforges et al. 2020). Respiratory syncytial virus (RSV) is a cause of lower respiratory tract infection in infects and children. The virus classified in the Orthopneumovirus genus (Walker et al. 2019). There are evidences due to the RSV neuroinvasive properties (Antonucci et al. 2010; Bohmwald et al. 2018; Nair et al. 2010). The RSV neurological manifestations could be including convulsions, febrile seizures and different types of encephalopathy and ataxia (Picone et al. 2019; Wallace and Zealley 1970). Also, human metapneumovirus (hMPV) is a respiratory pathogen and sporadically can induce seizures, encephalitis and encephalopathies (associated with epileptic symptoms) (Fernández et al. 2012; Wallace and Zealley 1970). Most influenza virus infections are limited to the upper respiratory tract but also its complications can involve the CNS (Kuiken and Taubenberger 2008; Popescu et al. 2017). Several studies have demonstrate that influenza A can be associated with encephalitis, Reye’s syndrome, febrile seizure, Guillain–Barré syndrome, acute necrotizing encephalopathy and probably acute disseminated encephalomyelitis (Jang et al. 2009; Sivadon-Tardy et al. 2009; Zeng et al. 2013). The influenza a virus can also increasing the risk of Parkinson’s disease developing (Jang et al. 2009; World Health Organization 2020). Recent investigations on suggested that, the influenza virus could induce experimental autoimmune encephalomyelitis (EAE), which reminds that recurrence of multiple sclerosis (MS) have been associated with viral infections (including influenza A) (Chen et al. 2017; Edwards et al. 1998). Various respiratory viruses have neurotropic features and can affect the nervous system, result in neuropathological outcomes, in the high-risk groups (Yachou et al. 2020). The MERS-CoV and the SARS-CoV can cause CNS symptoms such as neuroinvasive capabilities, Also the neurological manifestations have been seen in the SARS-CoV-2 infected patients (Yachou et al. 2020). HCoV-OC43 also is a coronavirus that can invade the CNS (Zubair et al. 2020). Seizures and encephalitis are common symptoms in the reviewed viruses except HCoV-OC43. Encephalitis, confusion, fatigue, headache, ataxia, dizziness, anosmia and Guillain–Barré syndrome are mental symptoms of COVID-19 that are common symptoms in above viruses.

One of the frequent complications of COVID-19 patient with neurologic disorders was cerebrovascular problems among which acute ischemic cerebrovascular accident was the most frequent. A rare neurologic complication caused by cytokine storm and damage to the blood-brain barrier is acute necrotizing encephalopathy (ANE), It is more common associated with influenza but SARS-CoV-2 has also been associated with this condition (Reshef et al. 2014; Rossi 2008). Guillain-Barré Syndrome (GBS) is another complication of SARS-CoV-2 that reported in 5 cases in Italy and 2 cases from Wuhan, China (Toscano et al. 2020; Zhao et al. 2020). Hemophagocytic lymphohistiocytosis (HLH) is the next complication which often observes in hematologic malignancy, immunosuppression, or critical infections but has also been described in patients with SARS-CoV-2 (Al-Samkari and Berliner 2018).

Many drugs used for COVID-19 patients treating such as antivirals (e.g., remdesivir, ribavirin, lopinavir/ritonavir, favipiravir), biologic agents (tocilizumab) and antimalarials (hydroxychloroquine, chloroquine). Remdesivir is a nucleotide-analog inhibitor of RNA polymerases and neurologic effects and medication interactions of it is unknown (Wang et al. 2020). Ribavirin is RNA and DNA virus replication inhibitor and interferon alpha have neuropathic and neuropsychiatric sequelae (Fried and Russo 2003; Sleijfer et al. 2005). Chloroquine and hydroxychloroquine are endosomal/organelle pH modifications which correlate with neuropsychiatric side effects, ataxia and seizures. Methylprednisolone have an inflammation reduction mechanism and correlates with delirium (Bridwell et al. 2020). Ribavirine also used for SARS-CoV in patients with seizure, anosmia, myalgia and GTC (Hung et al. 2003; Hwang 2006; Lau et al. 2004). Intravenous immunoglobulin (IVIg), methylpred nisolone, ribavarin, convalescent serum and low molecular weight heparin (LMWH) use for loss of consciousness treating in SARS-CoV patients (Umapathi et al. 2004). Tazocine use in MERS-CoV patient for headache, dizziness, and intracerebral hemorrhage treating (Algahtani et al. 2016). Ribavirine and methylprednisolone also usage in therapy of intracerebral hemorrhage in MERS-CoV patients (Al-Hameed 2017). Interferon α2a, Ribavirin, and Lopinavir/Ritonavir use in Guillain–Barré syndrome, acute sensory neuropathy, headache, Confusion and seizure treating of MERS-CoV (Kim et al. 2017).

Our results indicated that COVID-19 could represent neurological and mental manifestations. The current study result shows that, headache and dizziness are the most prevalence neurological symptoms in adults in Netherlands and Europe (Lechien et al. 2020; Tostmann et al. 2020). By the assessment of all included studies, the Hypsomia, Anosmia or olfactory dysfunction was most frequent symptom. Other symptoms were headache or dizziness, dysgeusia or ageusia, dysphonia, fatigue, cerebrovascular disease, delirium and sleep disorder or drwosiness. Also, other less frequent symptoms were includes depression, anxiety, and confusion, auditory dysfunction and numbness or paresthesia. The headache as one of the most common neurologic symptoms in COVID-19 was reported earlier. Also, it’s reported that headache can be found in the early stages of the disease (Pinzon et al. 2020). In another studies headache was the most prevalence after myalgia (Nepal et al. 2020; Wang et al. 2020). Neurologic symptoms in SARS-CoV and MERS-CoV are included anxiety, depressed mood, insomnia and exacerbation of a panic disorder. According to studies delirium is common in SARS and MERS (Rogers et al. 2020). All of the mentioned highlights the importance of further investigations for the assessment of neurologic, CNS and mental symptoms in COVID-19 patients.

Our study had some strong points. We do an extensive search in different data-base to achieve of a large number of articles. Also this was the first study that used a meta-regression analysis to identify the determinants of heterogeneity that is novelty of our study. However, our study had some weakness. The major limitation of the current study was the limited number in primary studies in this particular field. Also most of the studies that included in this review came from low to moderate quality studies because have low sample size and case series design.

Conclusion

Our findings demonstrate that COVID-19 has a certain relation with neurological symptoms. the hypsomia, anosmia or olfactory dysfunction was most frequent symptom. Other symptoms were headache or dizziness, dysgeusia or ageusia, dysphonia, fatigue, cerebrovascular disease, delirium, and sleep disorder or drowsiness. Oder less frequent symptoms were includes depression, anxiety, and confusion, auditory dysfunction and numbness or paresthesia. Moreover, knowledge about mental disorders in COVID-19 patients in different ages and region is a step forwards to better knowledge for the COVID-19 disease progression and treating patients.

Funding source: Tehran University of Medical Sciences

Award Identifier / Grant number: 50001

    Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

    Research funding: The authors are grateful to the Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran. (Grant no: 50001).

    Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Received: 2020-09-23
Accepted: 2020-10-23
Published Online: 2021-01-13
Published in Print: 2021-04-27

© 2020 Walter de Gruyter GmbH, Berlin/Boston