Neurological Components in Coronavirus Induced Disease: A Review of the Literature Related to SARS, MERS, and COVID-19

Universidad Nacional de San Agust́ın de Arequipa, Peru Center of Biomedical Technology, Laboratory of Cognitive and Computational Neuroscience, Madrid, Spain Department of Nuclear Medicine, National Institute of Neoplastic Diseases, Lima, Peru Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru Psychiatry Department, University of California, San Diego, CA, USA Neurology Department, Clinic Vallesur AUNA, Arequipa, Peru Universidad Católica de Santa Maŕıa, Arequipa, Peru


Introduction
Difficult days are being witnessed as the COVID-19 pandemic continues to evolve, generating uncertainty and stress throughout the world. e emergence of infectious diseases throughout the history has been the cause of suffering for many human groups, in addition to economic instability and disruption of daily life [1]. Considering that COVID-19 is the new pandemic of the 21st century [2,3], research has increased exponentially in recent months.
Coronaviruses were initially identified in animals, causing different diseases in the respiratory system, gastrointestinal system, and central nervous system (CNS) [4]. In the last 18 years, various studies and clinical reports concerning epidemics caused by coronavirus with a substantial impact on human health, especially in Asiatic and Middle East countries, have been reported. ese animal-tohuman transmission (zoonotic transmission) and then human-to-human transmission were initially described in Guangdong, China, with the outbreak of the severe respiratory syndrome named "SARS-CoV" [5], which infected 8098 individuals with a mortality rate of 9%, across 26 countries in the world [5]. e subsequent appearance, 10 years later, of the Middle East respiratory syndrome (MERS-CoV) in Saudi Arabia [6] raised a global alarm about the possible impact on the healthcare system. Similar to SARS-CoV, patients suffered from pneumonia, followed by severe acute respiratory syndrome and kidney failure [5,7].
Recently, a highly contagious pandemic has emerged, challenging the healthcare system of governments around the world.
is severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, China, at the start of December and started spreading rapidly around the world, generating COVID-19. e transmission rate of SARS-CoV-2 is higher than that of SARS-CoV [5], and this virus rapidly spread across China and 200 countries around the world, becoming the third epidemic caused by coronavirus in the 21st century [8]. SARS-CoV-2 causes severe respiratory illness similar to fatal coronavirus infections caused by SARS-CoV and MERS-CoV [9].
SARS-CoV-2 infection produces a wide range of clinical symptoms from mild/moderate fever, cough, shortness of breath, and fatigue to more severe pneumonia and cardiorespiratory failure [10,11]. Nonetheless, a group of patients present with nontypical symptoms like headache, conjunctivitis, diarrhea, vomiting, sputum, hemoptysis [11], anorexia [12], hyposmia/anosmia [13], and dysgeusia [14]. ese symptoms may reflect the different initial niches and progression of the viral infection. Nevertheless, it is still not clear if the virus was limited to the upper respiratory tract. Since the main targets of SARS-CoV-2 are the lungs, early epidemiological reports do not mention alterations in the CNS [13,15], and thus, its potential for opportunistic infection of the central nervous system has been underestimated [16].
Considering the previous description of neurological symptoms after the virus infection by coronaviruses (SARS-CoV and MERS-CoV) and the recent limited descriptions of clinical cases with SARS-CoV-2, this review aims to provide a summary and critical analysis of early findings on neurological symptoms and provide meaningful information for future research related to neurological disorders/syndromes by SARS-CoV-2, as well as support decision-making on strategies to handle this public health emergency.

Methods
An exhaustive search of different original articles and clinical, experimental, and review studies was performed in MEDLINE/PubMed, Scopus, and Web of Science, with the search words "coronavirus" or "SARS-CoV" or "MERS" or "COVID-19"or "SARS-CoV-2" and "neurological syndrome" or "central nervous system" or "brain" or "brain infection" or "neurological disorder" (see Appendix for word combinations). e studies were selected based on their relevance analyzing the possible neurological syndrome related to COVID-19. ese articles have been published in magazines or in preprints. We found 92 articles that were organized according to the search words. e references of these selected articles were also scanned for additional studies related to human coronaviruses and CNS infection. A flowchart of the search is shown in Figure 1.
As part of the selection, the following criteria were considered: extensive description of clinical cases, central nervous system infection, and neurological syndrome and studies conducted in animal models or human patients diagnosed with coronavirus. Additionally, a brief review of COVID-19 is performed, and we then explored its relationship with the CNS.
SARS-CoV first appeared in 2002, and it has caused more than 8000 cases of infection, leading to more than 750 deaths in China, Canada, Hong Kong, Vietnam, Singapore, Ireland, Germany, and EEUU [27,28]. On the other hand, the MERS-CoV outbreak occurred in Saudi Arabia and affected 27 countries, and 2,000 people were affected by the disease [29]. Currently, SARS-CoV-2 has spread to about 200 countries, and the WHO has reported more than 5,19,000 cases and 23,000 deaths. ese coronaviruses have the potential to cause more severe disease among vulnerable people, such as the elderly or people with chronic debilitating diseases. It is important to note, however, that in the case of SARS-CoV-2, transmission and COVID-19 have also been reported in pregnancy, newborns, infants [30], and young adults.

Comparison of Characteristics of COVID-19 with SARS and MERS.
Coronaviruses have the largest genome among the RNA viruses, with a nonsegmented 30 kb positive-singlestranded polyadenylated RNA possessing 4 or 5 genes encoding structural proteins (S, E, M, N, and HE) and several genes encoding nonstructural proteins [31]. e most prominent feature of coronaviruses is the club-shaped spike projections emanating from the surface of the virions. e spike proteins are believed to be a major determinant of the pathogenic phenotype [32], and these spikes are a defining feature of the virions and give them the appearance of a solar corona; four coronavirus genera (α, β, c, and δ) have been identified so far [18]. Coronaviruses attach to a specific cell surface receptor and then enter the cell by fusion at the plasma membrane or after endocytosis, producing high replication of their genomic RNA [18]. ese virions egress from exocytosis after vesicular transport to the cell membrane or cell membrane rupture. e human host may transmit the virions by direct transmission of respiratory secretions like nose drops and saliva. [17,26,33], but other transmission routes are also possible, such as contact with infected objects, aerosol transmission, human feces [26], and others probably not tears [34]; nonetheless, niche viral infection may be possible. Table 1 describes the main biological characteristics of the new SARS-CoV-2 coronavirus, the severe acute respiratory syndrome coronavirus (SARS-CoV), and the Middle East respiratory syndrome coronavirus (MERS-CoV).

Possible Mechanism of Nervous System Infection by
Coronaviruses. Different coronaviruses can outwit the immune response and infect extrarespiratory organs, including the CNS [16,48]. Its presence in the brain tissue demonstrates the neuroinvasive and opportunistic capacity of these pathogens [49,50]. Autopsy studies have demonstrated by in situ hybridization that coronaviruses can infect the brain, detecting viral particles [51,52].
Furthermore, experimental studies display that coronaviruses infect the mice brain transnasally, and it seems that the infection invades the peripheral nerve terminals and then gains access to the CNS by trans-synapse route or skips the synapse retrograde from infected tissues [16,53], generating behavioral and cognitive impairment [49].
In patients affected with SARS-CoV, the dissemination in the systemic circulation understandably allows it to pass into the cerebral circulation. One of the factors which may facilitate the interaction of the virus spike protein with the ACE2 receptor at the endothelial could be the slow blood movement within the microcirculation. Another proposed mechanism could be the movement of the virus via the cribriform plate close to the olfactory bulb, potentially allowing brain invasion [47]. Furthermore, the haematogenic or lymphatic route may be possible [54]. By these two mechanisms, coronaviruses possess neuroinvasive and neurotropic properties; initially, they can infect the endothelial cells of the blood-brain barrier (BBB), white blood cells, glial cells, or even neurons inducing neurodegeneration and death [55,56]. In that way, the coronaviruses contribute to an overactivation of the immune system, triggering or exacerbating the neurological symptoms [49]. ere is evidence that these viral infections are possible etiological agents of demyelinating disease [57] or encephalopathy [58][59][60], although they underlie other brain pathologies.
Neurologic manifestations associated with SARS coronavirus infections include axonopathic polyneuropathy, myopathy, and ischemic stroke [18]. Other studies report dysphoria, vomiting, and deliria [61] and in advance stages, seizures [62]. Brain infection by MERS-CoV has shown a variety of neurologic manifestations such as ataxia, motor   Host-pathogen interaction [15] Bat ⟶ camel ⟶ human Bat ⟶ civet cat ⟶ human Bat ⟶ snake or pangolin ⟶ human Transmission [42] Animal-human, human-human, zoonotic disease Incubation period [14] 2-10 days 2-14 days Organ affected [35,43] Unciliated bronchial epithelial cells and type II pneumocytes, epithelial cells in the kidney, small intestine, liver, prostate, and neurological system Lymphocytes, monocytes and lymphoid tissues, ciliated bronchial epithelial cells and type II pneumocytes, intestinal mucosa, epithelium of renal distal tubules, tissueresident macrophages, and neurons in the brain Lung alveolar epithelial cells and enterocytes of small intestine remarkably, the kidneys and liver Immunological response [44] Speed of spread [45] Low Moderate High Recruitment of immune cells [46] Dendritic cells, macrophages, and T cells Monocyte/macrophages, dendritic cells
deficits, and altered mental state from confusion to coma [63] or headache, nausea, and vomiting [54]. e rapid infection and replication of MERS-CoV in human dendritic cells, macrophages, and primary T cells aggravate the infection and production of proinflammatory cytokine/chemokine [64], worsening the response and inducing massive apoptosis [65].
Perhaps, the neuroinvasive potential by SARS-CoV-2 needs some more elucidation. Taking the previous work with human coronavirus and other zoonotic infections as reference, neuroinvasive propensity has been demonstrated as a common feature of coronaviruses [53,66], especially between SARS-CoV and SARS-CoV-2 [67]. Other studies show that the human brain cell lines are capable of or have been infected by coronaviruses [68], including astrocytoma, neuroblastoma, and oligodendrocytes cell lines [61].
Recently, the presence of the ACE2 receptor has been demonstrated on glial cells and neurons.
e COVID-19 virus uses a protein S1 that interacts with the ACE2 receptor and allows the binding of the virions to the target cell membrane [47]. Even the peak proteins of the three coronaviruses are similar, not identical, which explains the greater affinity of the COVID-19 peak protein with the human ACE2 receptor.

Neurological Syndrome by Coronaviruses. SARS-CoV
and MERS-CoV are zoonotic diseases that can infect both humans and animals. Both viruses have a very similar structure. Infection by these viruses in humans produce typical clinical characteristics such as fever, myalgia, cough, and dyspnea, which typically proceed to shortness of breath and pneumonia. Other clinical characteristics consider nontypical symptoms like diarrhea, anorexia, anosmia, and hyposmia. Furthermore, it seems that SARS, MERS, and COVID-19 have similar incubation periods [69].
Different studies point out that, before and after virus confirmation by reverse transcriptase polymerase chain reaction in the respiratory sample, neurologic symptoms would be present and may have been underdiagnosed previously. ese symptoms included dizziness, headache, vomiting, and confusion. It may also include weakness in the upper and lower limbs, altered reflexes, or ataxia. More severe symptoms may range from generalized tonic-clonic seizures, loss of consciousness, coma, and death. A review of different studies is shown in Table 2.
Given the progression of those symptoms, changes in the immune response were manifested [81], especially macrophage activation, increased lymphocytes, and expression of chemokine receptors on activated T cells. [58], which are usually analyzed in a blood sample or CFS, and also cytopathic effects are observed. Neuroimaging methods such as tomography and MRI showed inconclusive results, with some patients showing normal values and others displaying hypodensity and hyperintensity in different areas of the brain, including stroke [62].
In addition, the human respiratory epithelium is highly susceptible to SARS-CoV and MERS-CoV which may support productive viral replication, as shown in the first case. Most patients had three or more damaged organs or systems after exposure to SARS-CoV-2 [9], and it is possible to define, additionally, the first symptoms associated with the infection of the CNS.

Clinical Symptoms in Neurological COVID-19 Patients.
At present, there are some reports referring to the neurological symptoms of COVID-19 patients. ese studies indicate that neurological signs, such as headache, nausea, and vomiting, are the initial symptoms. Some other documents indicate a diminished sense of smell, diminished sensation of taste, or even anosmia ( Table 2). e reported neurologic signs are clinical symptoms similar to those informed in SARS-CoV and MERS-CoV. Considering that SARS-CoV and MERS-CoV have a similar structure and as several reports point out, comparable neurological symptoms are notable which indicates that the progression would be similar. Different coronaviruses are linked to CNS dysfunction, and they are reported as the probable cause of multiple sclerosis, encephalitis, and meningitis [82][83][84]. Hence, viruses could be another potential source of brain dysfunction even in the absence of a lung with low respiratory tract infection.
Well-defined mechanisms of transmission between the lower and upper respiratory tracts of the CNS remain unknown. From other studies on coronaviruses, however, we could suggest that transmission begins even in the upper or lower respiratory tract, forming different viral niches with the possibility of altering the respiratory epithelium, reaching the bloodstream or lymph and spreading to the CNS [49,85], and crossing the BBB and infecting the brain neurons such as glial cells or neurons, for example [84], the latter being more susceptible to infection by coronaviruses [46] (Figure 2). Another variant of infection would be by axonal transport, retrograde transmission from the respiratory organs, or even the enteric nervous system as do other coronaviruses [85][86][87][88][89].
Examination of the data suggests that coronavirus may reach the CNS and induce the disease in the short term, but it is not known whether it can persist in resident human CNS cells and may become a factor or cofactor in neuropathogenesis associated with a long-term neurological syndrome or sequel in vulnerable populations with other comorbidities, children [90] or elderly populations.

Discussion
e aim of this review was to elucidate the possible neurological component by coronavirus infections, specifically SARS-CoV, MERS-CoV, and SARS-CoV-2. Considering the recent descriptions of neurological symptoms after SARS-CoV-2 infection, we reviewed more than 90 papers in the last 20 years related to coronavirus brain infection and included different human, clinic, and experimental studies. We detail a neurologic syndrome related to COVID-19 and review the transmission mechanism and CNS pathology related to another virus with the similar structure (SARS/MERS).
Despite many other coronaviruses being discovered before SARS-CoV outbreak [91], different researches took Neurology Research International       place involving the mechanisms of infection, transmission, etc. e appearance of epidemics by novel viruses of the same family displays the coronavirus as a fast-evolving virus [7] and particularly important for the investigation of its extensive contagious properties, its spread in several countries, morbidity and mortality. Similar to other viruses, the SARS-CoV-2 virus spread rapidly through human-to-human transmission. Insufficient awareness of infection control in hospitals and international air travels facilitated the rapid global spread [71]. Today, more than 200 countries around the world have reported patients with COVID-19, and there have been more than 25 000 deaths. Although there are a high number of recovered patients, no follow-up studies on the nonrespiratory symptoms have been reported. In this paper, we focus on the symptoms and infections of the central nervous system caused by coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2). e incubation period of COVID-19 is from 2 to 14 days [8,14]. Different reports mention several symptoms, including fever, cough, and fatigue assumed as the most common symptoms [80]. In addition to these aforementioned signs, acute respiratory distress syndrome, shock, acute cardiac injury, and acute kidney injury are reported, with 20% to 30% of cases developing serious illness [78].
Previous studies demonstrated that coronaviruses contain neuroinvasive, neurotropic, and neurovirulent properties regardless of the pulmonary infection, as it has been shown in some cases. e presence of SARS-CoV and MERS-CoV viruses was usually confirmed by RT-PCR, immunohistochemistry, and in situ hybridization in postmortem studies [52]. Other clinical approaches may include CT, MRI, and cerebrospinal fluid (CSF) test, to check SARS-CoV-2 by reverse transcriptase polymerase chain reaction. Analysis of the data suggests that a significant percentage of patients infected with COVID-19 may have neurological complications that may last longer than the lung infection itself. Initial neurological symptoms are diverse and include deterioration of mental status, confusion or coma, dizziness, headache, nausea and vomiting, anosmia/hyposmia, dysgeusia/hypogeusia, and seizures.
Further studies are urged to be performed to distinguish between opportunistic and disease-associated viral presence in the human brain [25] and also to describe the key mediator mechanism in brain damage induced by SARS-CoV-2 infection.
ere have been some suggested mechanisms through which this virus affects the central nervous system, pointing to neuroinvasive characteristics similar to other human coronaviruses [31]. Because the exact mechanism is not thoroughly understood, autopsy studies are needed to further understand the mechanism [54]. It is possible that the neuroinvasive potential includes different routes such us hematogenous, lymphatic routes, olfactory tract [46], and optic nerve. erefore, the advent of neurological symptoms should be monitored and analyzed more intensively. Surveillance should be maintained promptly, identifying other nonrespiratory symptoms, along with the follow-up of recovered patients and asymptomatic COVID-19-positive individuals [83]. e incubation period may vary for the infection of the lungs and other tissues, depending on the viral niche accumulation. A confirmative test is always recommended in the respiratory tract and CSF if a patient presents neurologic symptoms. ose are important to exploit the knowledge of neuroinvasion and dissemination of other similar coronaviruses to increase the ability to control the viral infection, detection of symptoms, and research focus on the possible mechanisms of neuropathogenesis. e recent appearance and discovery of COVID-19, in addition to the ease of its transmission, has made SARS-COV-2 a virus with a great impact on the public health worldwide. e profiling of the condition and the understanding of the affected organs, in particular the central nervous system whose condition could have sequelae over time, are of vital importance. erefore, the establishment of an adequate profile of the disease will also favor the adoption of health measures.

Limitations.
is study has potential limitations. First, a few reported cases of neurological symptoms caused by COVID-19, observations of the process, and prognosis of the neurologic disease are needed. Second, this paper mainly uses the descriptive analysis to review and summarize the clinical cases.

Conclusion
Recent findings in COVID-19 are closely related to those reported in SARS and MERS. Specifically, here, we review those related with the neurologic syndromes. e structural homology and nucleotide identity are higher than 51% in MERS and 79% in SARS [25]. In both epidemics cases, reports regarding neurologic syndrome were investigated. To our concern, there have been no follow-up studies related to the CNS. Now, with the global pandemic, COVID-19, case reports suggest similar CNS infection by the SARS-CoV-2 opportunistic virus [92]. Coronaviruses are a rapidly evolving virus that can disrupt the human life, infect many organs such as the CNS, and probably leave different niches of infection that can generate a variety of clinical symptoms from typical cough, fever, and pneumonia infection to a more complex presentation that includes neurological syndromes. Consequently, further studies are necessary to elucidate if this neurological syndrome is reversible or if it may refer to possible disabilities or if it may even promote other brain pathologies that may include encephalitis, multiple sclerosis, or others.

D. Web of Science Search Words
Filters: English/2000/article, review, case report, and clinical trial.
Note: it does not allow putting Human as filter.

E. Types of Documents
Articles or reviews or case reports.

F. Research Area
Neurosciences, Neurology, and Psychiatry or Behavioral Sciences or Psychology.

Conflicts of Interest
e authors declare that there are no conflicts of interest.

Authors' Contributions
Zegarra-Valdivia conceptualized the study; Zegarra-Valdivia and Chino-Vilca were involved in the methodology; Zegarra-Valdivia, Chino-Vilca, and Tairo-Cerron were responsible for the writing and preparation of the original draft; Zegarra-Valdivia, Chino-Vilca, Tairo-Cerron, Munive, Lastarria-Perez, and Ames-Guerrero contributed in writing, review, and editing. All authors have read and agreed to the final submitted version of the manuscript for publications.