Abstract
Objective: Review and integrate the neurologic manifestations of the Coronavirus Disease 2019 (COVID-19) pandemic, to aid medical practitioners who are combating the newly derived infectious disease.
Methods: We reviewed the clinical research, consisting of mainly case series, on reported neurologic manifestations of COVID-19. We also reviewed basic studies to understand the mechanism of these neurologic symptoms and signs.
Results: We included 79 studies for qualitative synthesis and 63 studies for meta-analysis. The reported neurologic manifestations were olfactory/taste disorders (35.6%), myalgia (18.5%), headache (10.7%), acute cerebral vascular disease (8.1%), dizziness (7.9%), altered mental status (7.8%), seizure (1.5%), encephalitis, neuralgia, ataxia, Guillain-Barre syndrome, Miller Fisher syndrome, intracerebral hemorrhage, polyneuritis cranialis, and dystonic posture.
Conclusions: Neurologic manifestations in COVID-19 may alert physicians and medical practitioners to rule in high-risk patients. The increasing incidence of olfactory/taste disorders, myalgia, headache, and acute cerebral vascular disease renders a possibility that COVID-19 could attack the nervous system. The cytokine secretion and bloodstream circulation (viremia) are among the most possible routes into the nervous system.
Keywords: COVID-19, pandemic, neurologic, headache, taste, olfactory, ACE2, cytokine
Introduction
COVID-19 first occurred in late 2019 in Wuhan, China (1). As of May 01, 2020, the COVID-19 pandemic had infected 3,291,008 worldwide and caused 232,478 deaths (data from the World Health Organization). The most common clinical symptoms are cough, sputum production, fatigue, shortness of breath, and mainly respiratory tract symptoms. However, an increasing number of cases have presented with neurologic manifestations, such as olfactory and taste disorders (2), and the phenomenon requires further attention.
COVID-19 is a new RNA virus strain from the family Coronaviridae (including the Middle East respiratory syndrome CoV [MERS-CoV] and severe acute respiratory syndrome CoV [SARS-CoV]). Phylogenetic analysis of the complete viral genome revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (3). As such, it was previously termed SARS-CoV-2. In the review article published in 2018 (4), researchers found that the human coronavirus can enter the central nervous system through the olfactory bulb, causing demyelination and inflammation (cultured glial cells have been described to secrete cytokines including IL-6, IL-12p40, IL-15, TNF-a, CXCL9, and CXCL10 upon viral infection). The authors of a recent article (5) investigated the mechanism of COVID-19 nervous system involvement, and they stated that similar to SARS-CoV, the COVID-19 virus exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. The brain has been reported to express ACE2 receptors that have been detected over glial cells and neurons, which makes them a potential target of COVID-19. Recently, the research team in Harvard Medical School identified three main cells co-expressing ACE2 and TMPRSS2 (Type II transmembrane serine protease): lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells (6). And the other research team used single-cell RNA-Seq datasets to suggest possible mechanisms through which CoV-2 infection could lead to anosmia or other forms of olfactory dysfunction (7).
Methods
We searched the MEDLINE, CENTRAL, and EMBASE databases for eligible publications from December 2019 to April 30, 2020 written in English, using the following keywords: COVID-19, SARS-CoV-2, neuro, clinical, characteristics, manifestations. We also checked the reference lists of relevant studies to identify any missing publications. We reviewed the clinical researches, including case series and case reports, for neurologic manifestations of COVID-19 and organized them into tables. A confirmed case of COVID-19 (SARS-CoV-2) was defined and mostly diagnosed using the triple algorithm (epidemiological history, clinical symptoms, and laboratory or radiological findings) as a standard procedure proposed by the World Health Organization. We also reported data from the Taiwan Centers for Disease Control until May 01, 2020. Then we did the meta-analysis of all the case series to pool the data together and make it easier to understand. We used the software of Comprehensive Meta-Analysis Software (CMA), version 3, and chose the model of one group event rate, random effect, to draw the Forest Plot (Supplementary Figures 2–8).
Results
We used Preferred Reporting Items for Systematic reviews and Meta-Analyzes (PRISMA) guidelines for searching and listed our flowchart (Supplementary Figure 1). Then we made a list of the neurologic manifestations in the current COVID-19 pandemic (Table 1). We included 9 case series and 4 case reports of olfactory or taste disorders. We pooled the case series together and found around 35.6% of patients got these symptoms (Supplementary Figure 2). We included 43 studies of myalgia, about 18.5% of patients had this symptom (Supplementary Table 1 and Supplementary Figure 3). And 45 studies of headache, the percentage was 10.7% (Supplementary Table 2 and Supplementary Figure 4); 2 studies of acute cerebral vascular disease, the percentage was 8.1% (Supplementary Figure 5); 7 studies of dizziness, the percentage was 7.9% (Supplementary Figure 6); 4 case series and 2 case reports of altered mental status, the percentage was 7.8% (Supplementary Figure 7); and 2 studies of seizure, the percentage was 1.5% (Supplementary Figure 8). And still other case reports of encephalitis, neuralgia, ataxia, Guillain-Barre syndrome, Miller Fisher syndrome, intracerebral hemorrhage, polyneuritis cranialis, and dystonic posture.
Table 1.
List of the neurologic manifestations in the current COVID-19 pandemic.
| Neurologic manifestation |
Patient numbers (% in total participants) |
Total participants |
Age: mean [SD] or median [IQR] |
Published journal reference |
|---|---|---|---|---|
| With olfactory or/and taste disorders | 20 (33.9%) | 59 | 60 [50–74] | Clin Infect Dis (8) |
| 53 (12.4%) | 429 | 32 [4–88] | Taiwan CDC (9) | |
| 128 (75.7) | 169 | 43 [34–54] | Int Forum Allergy Rhinol (10) | |
| 25 (20%) | 126 | 43.5 [3–87] | Trav Med Infect Dis (11) | |
| 62 (19.4%) | 320 | No data | Laryngoscope (12) | |
| 31 (39.2%) | 79 | 61.6 [17.4] | Eur J Neurol (13) | |
| 130 (64.4%) | 202 | 56 [45–67] | JAMA (14) | |
| 1 | Case report | 80 | Eur J Case Rep Intern Med (15) | |
| 1 | Case report | 50 | Neurology (16) | |
| Olfactory disorder only | 3 (5.1%) | 59 | 60 [50–74] | Clin Infect Dis (8) |
| 11 (5.1%) | 214 | 52.7 [15.5] | JAMA Neurol (2) | |
| 357 (85.6%) | 417 | 36.9 [11.4] | EUR ARCH OTO-RHINO-L (17) | |
| 1 | Case report | 85 | Eur J Case Rep Intern Med (15) | |
| Taste disorder only | 5 (8.5%) | 59 | 60 [50–74] | Clin Infect Dis (8) |
| 12 (5.6%) | 214 | 52.7 [15.5] | JAMA Neurol (2) | |
| 342 (82%) | 417 | 36.9 [11.4] | EUR ARCH OTO-RHINO-L (17) | |
| 1 | Case report | 39 | Neurology (16) | |
| Dizziness | 1 (12.5%) | 8 | 48.1 [13–76] | Clin Infect Dis (18) |
| 13 (9.4%) | 138 | 56 [42–68] | JAMA (19) | |
| 37 (8.1%) | 452 | 58 [47–67] | Clin Infect Dis (20) | |
| 21 (8%) | 274 | 62 [44–70] | BMJ (21) | |
| 5 (7%) | 69 | 42 [35–62] | Clin Infect Dis (22) | |
| 1 (4.17%) | 24 | 32.5 [5–95] | Sci China Life Sci (23) | |
| 2 (2%) | 81 | 49.5 [11] | Lancet (24) | |
| Altered mental status | 9 (52.9%) | 17 | 86.5 [68.6–97.] | J Infect (25) |
| 9 (9%) | 99 | 55.5 [21–88] | Lancet (26) | |
| 1 (5.9%) | 17 | 75 [48–89] | J Med Virol (27) | |
| 3 (0.7%) | 452 | 58 [47–67] | Clin Infect Dis (20) | |
| 1 | Case report | No data | Radiology (28) | |
| 1 | Case report | 74 | J Med Virol (29) | |
| Seizure | 1 (4.8%) | 21 | 70 [43–92] | JAMA (30) |
| 1 (0.5%) | 214 | 52.7 [15.5] | JAMA Neurol (2) | |
| Acute cerebrovascular disease | 3 (23%) | 13 | 63 | N Engl J Med (31) |
| 6 (2.8) | 214 | 52.7 [15.5] | JAMA Neurol (2) | |
| 5 | No data | 40.4 [5.6] | N Engl J Med (32) | |
| Neuralgia | 5 (2.3%) | 214 | 52.7 [15.5] | JAMA Neurol (2) |
| Ataxia | 1 (0.5%) | 214 | 52.7 [15.5] | JAMA Neurol (2) |
| Guillain-Barre syndrome | 5 (0.4%) | 1,000–1,200 | No data | N Engl J Med (33) |
| 1 | Case report | 61 | Lancet Neurol (34) | |
| 1 | Case report | 65 | J Clin Neurosci (35) | |
| 1 | Case report | 71 | Neurol Neuroimmunol Neuroinflamm (36) |
|
| Encephalitis | 1 | Case report | 24 | Int J Infect Dis (37) |
| 1 | Case report | 56 | Travel Med Infect Dis (38) | |
| 1 | Case report | 74 | Cureus (39) | |
| 1 | Case report | No data | Brain Behav Immun (40) | |
| 1 | Case report | 41 | Brain Behav Immun (41) | |
| Intracerebral hemorrhage | 1 | Case report | 79 | New Microbes New Infect (42) |
| Miller Fisher Syndrome | 1 | Case report | 50 | Neurology (16) |
| Polyneuritis cranialis | 1 | Case report | 39 | Neurology (16) |
| Sustained upward gaze, dystonic bilateral leg extension and altered responsiveness | 1 | Case report | 6 week | Neurology (43) |
In addition, we reviewed some basic studies (4, 5, 44, 45) to determine the mechanism of these neurologic symptoms and signs. The cartoon figure summarized the possible mechanism (Figure 1).
Figure 1.
Neurological Manifestations of COVID-19 and the proposed mechanism. The COVID-19 virus may cause neurologic manifestations by cytokines secretion, general circulation (viremia), or direct invasion via the numerous ACE2 receptors in the olfactory epithelium. The olfactory disorder may cause by the olfactory epithelium damage. Fever was believed to be caused by the effect of cytokines or hypothalamus functional pertubation. The seizure may cause by cytokines storm, severely illed condition, or the brain parenchyma involvement, especially the mesial temporal lobe. Altered mental status may be a consequence of multiple organ failure, severe infection, or brainstem involvement. Headache is caused by meningeal irritation.
Discussion
The COVID-19 pandemic is currently progressing, and neurologists and medical practitioners worldwide will face additional challenges from the neurologic complications of the disease (46). An updated review focusing on the neurologic features may help clinicians early identify potential patients.
Interestingly, previous coronavirus infections, including MERS and SARS, did not have a large proportion of patients with olfactory and taste disorders (47). However, patients with COVID-19 frequently complain of abnormalities in smell and taste. In our analysis of data from Taiwan (9), we found that between January 21 and March 24, 2020, a total of 216 patients were confirmed to have COVID-19 infection, and 5 of them (2.3%) had olfactory or taste disorders. Between March 25 and May 01, 48 cases in 213 patients (22.5%) had olfactory or taste disorders. In the beginning, most COVID-19 patients had a contact history related to Wuhan. But after the government of China locked down many big cities, Taiwan's COVID-19 cases mostly originated from travelers from Europe, the Middle East, or the United States. Besides, according to 88 cases series (see Supplementary Tables 1, 2) in China (from December 2019 to April 25, 2020), only one study (2) conducted by neurologists in Wuhan reported olfactory or taste disorder.
On the other hand, an Italian researcher reported that 33.9% of COVID-19 patients in Italy experienced this problem (8). In the Middle East, researchers in Iran found a surge in the outbreak of olfactory dysfunction during the COVID-19 epidemic (based on an online checklist of 10,069 voluntary cases between March 12 and 17, 2020) (48). The different incidence of the olfactory and/or taste dysfunction by the timing and geographic distribution might reveal important information that the virus may carry the potential to alter its affinity to the central nervous system (49–51). However, the possibilities of a higher detection rate of olfactory dysfunction in patients diagnosed by certain sub-specialists, such as neurologists (2) or otolaryngologists, cannot be completely excluded. For example, the study conducted by otolaryngologists (17) found olfactory/taste disorders in more than 80% of the patients.
Fever is generally known as an elevation in body temperature caused by a cytokine-induced upward displacement of the set point of the hypothalamic thermoregulatory center. Small elevations in body temperature appear to enhance immune function and inhibit pathogen growth (52). In 2005, pathologists in Beijing performed autopsies of SARS patients and found signals of the SARS viral genome detected in numerous neurons in the hypothalamus (53). As a result, it is conceivable that fever may be caused mainly by the effect of cytokines or possible direct viral invasion to the hypothalamus.
Concerning seizure in viral infection, generally the paroxysmal spell may be a consequence of multiple complications of systemic disease, such as metabolic disturbances, hypoxia, etc. Considering the viral encephalitis, it frequently manifests with seizures in its acute phase (54). The most widely reported virus was HSV-1 (herpes simplex virus), which involves the highly epileptogenic mesial temporal lobe structures, including the hippocampus (54). In the two case reports (37, 39), both had mesial temporal lobe involvement (one by acute inflammation, one by previous ischemic stroke). Since the case number is limited, we can only speculate that seizures may be caused by the generalized poor condition, cytokine storm (55), or mesial temporal lobe involvement in severe COVID-19 patients.
Several countries are currently encountering a crisis of ventilator shortage. The respiratory failure of COVID-19 infected patients may be partly related to brainstem failure. The COVID-19 virus passes into the cell via the ACE2 receptor (5). ACE2 is expressed in the brain and is mainly found in the brainstem, specifically in the nuclei associated with cardio-respiratory control (56, 57). In the previous research on SARS-CoV-1 and MERS-COV, the brainstem was severely infected, which possibly contributes to the degradation and failure of respiratory centers (45). Besides, the ascending reticular activating system (ARAS), which is responsible for human consciousness, also originates from the brainstem (and then advances into the thalamus and cortex) (58). This may partly explain the altered mental status of COVID-19 patients. However, the maintenance of consciousness is complex. Considering many COVID-19 patients were severely ill with multi-organ failure, both the cytokine effect and systemic impact of organ dysfunction can also lead to the consciousness disturbance.
Both dizziness and headache are considered to be general non-specific symptoms. Etiologies attributed to infectious causes are important secondary causes of headache (59). It is known that cytokines induced by viral infection increase the permeability of vessels. This causes cerebral swelling and meningeal irritation. The meningeal irritation stimulates the trigeminal nerve terminals and triggers pain sensation (60).
Ischemic stroke also occurs in COVID-19 patients because the infection may cause D-dimer elevation, thrombocytopenia, and hypercoagulable state (61–66). Besides, the exaggerated systemic inflammation or a “cytokine storm” (55), cardioembolism from virus-related cardiac injury (67) could further increase the risk of stroke (68).
Most cases of Guillain-Barre syndrome appeared with a lag time from the primary infection of COVID-19 (33, 34); the pathogenesis is therefore likely to be postinfectious immune-mediated.
This review is obviously constrained by the current information and limited reports. And there was considerable heterogeneity in the data. In addition, the researches of the novel pandemic emerge fastly. We could only review the results up to April 30, 2020 in this regard. The cause of neurologic manifestation may be a cytokine storm, multiple organ failure, or direct viral infection. However, the detailed pathophysiology of causing COVID-19 nervous system involvement remains to be elucidated. We sincerely hope the review can help the first line clinicians identify the emerging neurologic manifestations when combating the viral pandemic.
Author Contributions
S-TT and M-KL did the literature search and drafted this manuscript. C-HT initiated this review and integrated the clinical and basic research. SS did the meta-analysis and made all the Forest Plot figures.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We thank Ms. Hsiu-Chen Lu for the help in graphing, the Enago (www.enago.tw) for the English language review, Dr. I-Chen Tsai, MD, Ph.D. for the PRISMA template.
Footnotes
Funding. The review was supported in part by grants from the Ministry of Science and Technology (MOST 105-2314-B-039-004-MY2, MOST 106-2410-H-008-054-, MOST 107-2314-B-039−017 -MY3, MOST 107-2221-E-008-072-MY2, and MOST 105-2410-H-039-003-) and China Medical University Hospital (DMR-108-206, DMR-109-069, DMR-109-229), Taiwan.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2020.00498/full#supplementary-material
Preferred Reporting Items for Systematic reviews and Meta-Analyzes (PRISMA), our searching strategy.
Forest plot for olfactory/taste disorder.
Forest plot for myalgia.
Forest plot for headache.
Forest plot for acute cerebral vascular disease.
Forest plot for dizziness.
Forest plot for altered mental status.
Forest plot for seizure.
Patients presented with myalgia.
Patients presented with headache (ordered by cases recruitment date).
References
- 1.Wang CJ, Ng CY, Brook RH. Response to COVID-19 in Taiwan: big data analytics, new technology, and proactive testing. JAMA. (2020) 323:1341–2. 10.1001/jama.2020.3151 [DOI] [PubMed] [Google Scholar]
- 2.Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. (2020) e201127. 10.1001/jamaneurol.2020.1127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wu F, Zhao S, Yu B, Chen Y-M, Wang W, Song Z-G, et al. A new coronavirus associated with human respiratory disease in China. Nature. (2020) 579:265–9. 10.1038/s41586-020-2008-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bohmwald K, Gálvez NMS, Ríos M, Kalergis AM. Neurologic Alterations Due to Respiratory Virus Infections. Front Cell Neurosci. (2018) 12:386. 10.3389/fncel.2018.00386 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. (2020) 11:995–8. 10.1021/acschemneuro.0c00122 [DOI] [PubMed] [Google Scholar]
- 6.Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. (2020). 10.2139/ssrn.3555145 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Brann DH, Tsukahara T, Weinreb C, Logan DW, Datta SR. Non-neural expression of SARS-CoV-2 entry genes in the olfactory epithelium suggests mechanisms underlying anosmia in COVID-19 patients. bioRxiv. (2020) 10.1101/2020.03.25.009084 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis. (2020) ciaa330. 10.1093/cid/ciaa330 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Taiwan Centers for Disease Control (Chinese Version Website) . Taipei. Available online at: https://data.cdc.gov.tw.
- 10.Yan CH, Faraji F, Prajapati DP, Ostrander BT, Deconde AS. Self-reported olfactory loss associates with outpatient clinical course in Covid-19. Int Forum Allergy Rhinol. (2020) 10.1002/alr.22592 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Popescu CP, Marin A, Melinte V, Gherlan GS, Banicioiu FC, Dogaru A, et al. COVID-19 in a tertiary hospital from Romania: epidemiology, preparedness and clinical challenges. Travel Med Infect Dis. (2020) 101662. 10.1016/j.tmaid.2020.101662 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and ageusia: common findings in COVID-19 patients. Laryngoscope. (2020) 10.1002/lary.28692 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Beltran-Corbellini A, Chico-Garcia JL, Martinez-Poles J, Rodriguez-Jorge F, Natera-Villalba E, Gomez-Corral J, et al. Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study. Eur J Neurol. (2020) 10.1111/ene.14273 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, et al. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. (2020) 10.1001/jama.2020.6771 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Villalba NL, Maouche Y, Ortiz MBA, Sosa ZC, Chahbazian JB, Syrovatkova A, et al. Anosmia and dysgeusia in the absence of other respiratory diseases: should COVID-19 infection be considered? Eur J Case Rep Intern Med 7:001641. 10.12890/2020_001641 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Gutierrez-Ortiz C, Mendez A, Rodrigo-Rey S, San Pedro-Murillo E, Bermejo-Guerrero L, Gordo-Manas R, et al. Miller Fisher Syndrome and polyneuritis cranialis in COVID-19. Neurology. (2020) 10.1212/WNL.0000000000009619 [DOI] [PubMed] [Google Scholar]
- 17.Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon SD, Rodriguez A, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. (2020) 1–11. 10.1007/s00405-020-05965-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Qian G, Yang N, Ma AHY, Wang L, Li G, Chen X, et al. A COVID-19 Transmission within a family cluster by presymptomatic infectors in China. Clin Infect Dis. (2020) ciaa316. 10.1093/cid/ciaa316 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. (2020) 323:1061–9. 10.1001/jama.2020.1585 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. (2020) ciaa248. 10.1093/cid/ciaa248 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. (2020) 368:m1091. 10.1136/bmj.m1091 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. (2020) ciaa272. 10.1093/cid/ciaa272 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Hu Z, Song C, Xu C, Jin G, Chen Y, Xu X, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci. (2020) 63:706–11. 10.1007/s11427-020-1661-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. (2020) 20:425–34. 10.1016/S1473-3099(20)30086-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Godaert L, Proye E, Demoustier-Tampere D, Coulibaly PS, Hequet F, Drame M. Clinical characteristics of older patients: The experience of a geriatric short-stay unit dedicated to patients with COVID-19 in France. J Infect. (2020) 10.1016/j.jinf.2020.04.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. (2020) 395:507–13. 10.1016/S0140-6736(20)30211-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Wang W, Tang J, Wei F. Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan, China. J Med Virol. (2020) 92:441–7. 10.1002/jmv.25689 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI Features. Radiology. (2020) 201187. 10.1148/radiol.2020201187 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, et al. Central nervous system involvement by Severe Acute Respiratory Syndrome Coronavirus−2 (SARS-CoV-2). J Med Virol. (2020) 10.1002/jmv.25915 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA. (2020) 323:1612–14. 10.1001/jama.2020.4326 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. (2020) NEJMc2008597. 10.1056/NEJMc2008597 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-vessel stroke as a presenting feature of covid-19 in the young. N Engl J Med. (2020) e60. 10.1056/NEJMc2009787 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni MG, et al. Guillain–Barré syndrome associated with SARS-CoV-2. N Engl J Med. (2020) NEJMc2009191. 10.1056/NEJMc2009191 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol. (2020) 19:383–4. 10.1016/S1474-4422(20)30109-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Sedaghat Z, Karimi N. Guillain Barre syndrome associated with COVID-19 infection: a case report. J Clin Neurosci. (2020) 10.1016/j.jocn.2020.04.062 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Alberti P, Beretta S, Piatti M, Karantzoulis A, Piatti ML, Santoro P, et al. Guillain-Barré syndrome related to COVID-19 infection. J Clin Neurosci. (2020) 7:e741. 10.1212/NXI.0000000000000741 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. (2020) 94:55–8. 10.1016/j.ijid.2020.03.062 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Zhou L, Zhang M, Wang J, Gao J. Sars-Cov-2: underestimated damage to nervous system. Travel Med Infect Dis. (2020) 101642. 10.1016/j.tmaid.2020.101642 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Filatov A, Sharma P, Hindi F, Espinosa PS. Neurological complications of Coronavirus Disease (COVID-19): encephalopathy. Cureus. (2020) 12:e7352. 10.7759/cureus.7352 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Ye M, Ren Y, Lv T. Encephalitis as a clinical manifestation of COVID-19. Brain Behav Immun. (2020) 10.1016/j.bbi.2020.04.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Duong L, Xu P, Liu A. Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2010. Brain Behav Immun. (2020) 10.1016/j.bbi.2020.04.024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental? New Microbes New Infect. (2020) 35:100669 10.1016/j.nmni.2020.100669 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Dugue R, Cay-Martinez KC, Thakur K, Garcia JA, Chauhan LV, Williams SH, et al. Neurologic manifestations in an infant with COVID-19. Neurology. (2020) 10.1212/WNL.0000000000009653 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. (2020) 10.1002/jmv.25728 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Steardo L, Steardo L, Jr, Zorec R, Verkhratsky A. Neuroinfection may potentially contribute to pathophysiology and clinical manifestations of COVID-19. Acta Physiol. (2020) 29:e13473 10.1111/apha.13473 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Bersano A, Pantoni L. On being a neurologist in Italy at the time of the COVID-19 outbreak. Neurology. (2020) 10.1212/WNL.0000000000009508 [DOI] [PubMed] [Google Scholar]
- 47.Hwang CS. Olfactory neuropathy in severe acute respiratory syndrome: report of A case. Acta Neurol Taiwan. (2006) 15:26–8. [PubMed] [Google Scholar]
- 48.Bagheri SHR, Asghari AM, Farhadi M, Shamshiri AR, Kabir A, Kamrava SK, et al. Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak. medRxiv. (2020) 10.1101/2020.03.23.20041889 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Delanghe JR, Speeckaert MM, De Buyzere ML. The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. Clin Chim Acta. (2020) 505:192–3. 10.1016/j.cca.2020.03.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Forster P, Forster L, Renfrew C, Forster M. Phylogenetic network analysis of SARS-CoV-2 genomes. Proc Natl Acad Sci USA. (2020) 117:9241–3. 10.1073/pnas.2004999117 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Rodriguez-Morales AJ, Rodriguez-Morales AG, Mendez CA, Hernandez-Botero S. Tracing new clinical manifestations in patients with covid-19 in chile and its potential relationship with the SARS-CoV-2 divergence. Curr Trop Med Rep. (2020) 18:1–4. 10.1007/s40475-020-00205-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Elizabeth AA, Dottie B, Carlton GB. Understanding the pathophysiology of fever. Nursing. (2008) 38:56cc51–2. 10.1097/01.NURSE.0000327497.08688.4718580670 [DOI] [Google Scholar]
- 53.Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. (2005) 202:415–24. 10.1084/jem.20050828 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Misra UK, Tan CT, Kalita J. Viral encephalitis and epilepsy. Epilepsia. (2008) 49(Suppl. 6):13–8. 10.1111/j.1528-1167.2008.01751.x [DOI] [PubMed] [Google Scholar]
- 55.Mehta P, Mcauley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395:1033–4. 10.1016/S0140-6736(20)30628-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Xia H, Lazartigues E. Angiotensin-converting enzyme 2: central regulator for cardiovascular function. Curr Hypertens Rep. (2010) 12:170–5. 10.1007/s11906-010-0105-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Gowrisankar YV, Clark MA. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures. J Neurochem. (2016) 138:74–85. 10.1111/jnc.13641 [DOI] [PubMed] [Google Scholar]
- 58.Yeo SS, Chang PH, Jang SH. The ascending reticular activating system from pontine reticular formation to the thalamus in the human brain. Front Hum Neurosci. (2020) 7:416. 10.3389/fnhum.2013.00416 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Prakash S, Patel N, Golwala P, Patell R. Post-infectious headache: a reactive headache? J Headache Pain. (2011) 12:467–73. 10.1007/s10194-011-0346-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Ogunlaja OI, Cowan R. Subarachnoid Hemorrhage and Headache. Curr Pain Headache Rep. (2019) 23:44. 10.1007/s11916-019-0785-x [DOI] [PubMed] [Google Scholar]
- 61.Aggarwal G, Lippi G, Michael Henry B. Cerebrovascular disease is associated with an increased disease severity in patients with Coronavirus Disease 2019 (COVID-19): A pooled analysis of published literature. Int J Stroke. (2020) 10.1177/1747493020921664 [DOI] [PubMed] [Google Scholar]
- 62.Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol. (2020) 10.1111/ijlh.13230 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. (2020) 127:104362. 10.1016/j.jcv.2020.104362 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Klok FA, Kruip MJHA, Van Der Meer NJM, Arbous MS, Gommers DAMPJ, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. (2020) 10.1016/j.thromres.2020.04.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. (2020) 10.1111/jth.14850 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. (2020) 10.1016/j.jacc.2020.04.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Akhmerov A, Marban E. COVID-19 and the heart. Circ Res. (2020) 126:1443–55. 10.1161/CIRCRESAHA.120.317055 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Markus HS, Brainin M. COVID-19 and stroke-A global World Stroke Organization perspective. Int J Stroke. (2020) 10.1177/1747493020923472 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Preferred Reporting Items for Systematic reviews and Meta-Analyzes (PRISMA), our searching strategy.
Forest plot for olfactory/taste disorder.
Forest plot for myalgia.
Forest plot for headache.
Forest plot for acute cerebral vascular disease.
Forest plot for dizziness.
Forest plot for altered mental status.
Forest plot for seizure.
Patients presented with myalgia.
Patients presented with headache (ordered by cases recruitment date).