**Abstract**

The respiratory system is the most common target of COVID-19, however, various experimental studies and case reports have shown its affinity for neural tissues. In this chapter, we described pathogenesis and propagation of SARS-CoV-2 virus in the nervous system, potential routes of the SARS-CoV-2 invasion in the brain, as well as indirect effects of COVID-19 on multiorgan disorders. We have also presented all of the reported neurological manifestations in COVID-19 with an explanation of possible underlying pathways. Among patients who tested positive on SARS-CoV-2, various neurological irregularities have been described, affecting both the central and peripheral nervous systems. In general, neurological complications in COVID-19 patients occur within 1 and 14 days, in most cases on average on the 5th day of the incubation period. We have demonstrated all of the reported neurological findings, whereas the most commonly reported were headache, dizziness, myalgia, hypogeusia, hyposmia, and impaired consciousness. More serious neurological conditions in COVID-19 included meningitis, encephalitis, and ischemic or hemorrhagic stroke.

**Keywords:** SARS-CoV-2, neurologic manifestations, pathogenesis, COVID-19, coronavirus

### **1. Introduction**

The infection of coronavirus (SARS-CoV-2) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the World Health Organization (WHO) on March 11, 2020 [1]. Regarding its structure and infection mechanism, SARS-CoV-2 is mostly similar to familiar coronaviruses such as the SARS-CoV-1 and Middle East respiratory syndrome (MERS) [2, 3]. Identified in Wuhan, China, it has abruptly spread all over the world with more than 164.513.450 reported cases to date [4]. The respiratory system is the most common target of infection however, various experimental studies and case reports have shown an affinity for neural tissues. Considering observational studies, SARS-CoV-2 patients were registered with complaints of headache, nausea, vomiting, dizziness, myalgia, hypogeusia, hyposmia, and impaired consciousness, all symptoms that indicate involvement of the nervous system [5]. Even though, the exact mechanism which SARS-CoV-2 penetrates the central nervous system has not yet been determined, prior experimental models have

shown that other coronaviruses can compromise the nervous system and respiratory drive by directly targeting neurons located in cardiorespiratory centers [6], due to the preliminary observation of cases concerning the COVID-19 pandemic, suggesting a higher affinity of SARS-CoV-2 virus for CNS targets.

The aim of this chapter is to present all of the reported neurological manifestations in COVID-19 with the explanation of possible underlying pathways.

#### **2. COVID-19 and nervous system**

In the previous months, reports of meningitis, encephalitis, myelitis, or peripheral nerve affection in regard to COVID-19 infection were presented, implying that SARS-CoV-2 can directly infect the nervous system.

#### **2.1 Pathogenesis**

The SARS-CoV-2 spike protein (S) can bind to the host cellular angiotensinconverting enzyme 2 (ACE-2) receptor because of its high binding affinity, which is of importance to cell tropism [7]. Preparing and processing of the S protein by the transmembrane protease serine 2 (TMPRSS2) have been demonstrated to be crucial for the synthesis of viral and host cellular membranes, furthermore entrance of SARS-CoV-2 [8]. The increased expression of the ACE-2 receptor has been found on neurons and glial cells of several brain structures including the cerebral cortex, the striatum, the posterior hypothalamic area, the substantia nigra, and brain stem. ACE-2 is strongly expressed in the ventrolateral medulla and the nucleus of tractus solitarius, both areas involved in the regulation of the respiratory cycle [9].

Arguably, several mechanisms could be taken into account as possible viral access routes, such as axonal transport and trans-synaptic transfer, and hematogenous or potentially lymphatic system routes. The infiltration of the CNS through the transcribial system describes an infection of the olfactory epithelium continuing transmission through the cribriform plate to the subarachnoid space. On the other side, the axonal and trans-synaptic transport would combine numerous peripheral nerve terminals which leads to contamination by spreading onward neurons (olfactory bulb, the trigeminal nerve, the vagus nerve, etc.) [10].

Another way of CNS infiltration could be through the circulatory system or on the other hand, the lymphatic system routes. Transfer over the brain endothelium could be accomplished through abluminal virus release into the CNS parenchyma, by direct infection of brain microvascular endothelial cells (BMEC), or via endocytosis, through virally affected leukocytes or disrupted tight junctions on BMEC-s [11].

However, direct contamination of cells is not the only way of virus transmission. Indirect neurotoxicity may be caused by immune system disorders, coagulation disorders, cardiovascular comorbidities, disorders of glucose and lipid metabolism, hypoxic encephalopathy, and/or gastrointestinal disorders.

Other than ACE-2, SARS-CoV-2 may utilize extracellular matrix metalloproteinase inducer also known as basigin (BSG; CD147) and transmembrane glycoprotein neuropilin-1 (NRP1) as receptors. Some enzymes that catalyze proteolysis such as TMPRSS11A/B, cathepsin B and L, and furin (FURIN), have been presented to promote viral cell entry and replication [12].

#### **2.2 Propagation of SARS-CoV-2 virus in the nervous system**

Dissemination of SARS-CoV-2, in which the virus has an effect on peripheral neurons via active transport, synaptic terminals, and retrograde transport to the

#### *Neurological Involvement in COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.99309*

neuronal body of the cell, has been hypothesized [13]. Studies have been conducted, explaining the mechanism of trans-synaptic transfer involving the hemagglutinating encephalomyelitis virus strain 67 N (HEV-67 N), which represents the first SARS-CoV-2 strain that was found to infect the porcine cerebrum [14]. Data from human single nuclei RNA-seq databases suggest that vascular endothelial cells may express ACE-2 in the human cerebrum at low levels, however non-canonical SARS-CoV-2 receptors (e.g., BSG/CD147) are displayed in several different brain cell types, making them exposed to the virus [15].

## **2.3 Potential routes of SARS-CoV-2 invasion in brain**

Provided by other viruses of the family Coronaviridae, certain possible routes of entry for SARS-CoV-2 have been established [16].

#### *2.3.1 Olfactory route*

The olfactory nerve (CN I) is the first and shortest cranial nerve. It is a special visceral afferent nerve, which transmits information relating to smell. The sense of smell is distinguished by olfactory receptors situated within the nasal epithelium. Their axons amass into small bundles of olfactory nerves, which infiltrate small foramina in the cribriform plate of the ethmoid bone and enter the cranial cavity. The absence of the sense of smell is defined as anosmia. A temporary loss of smell can be caused by infection or by local disorders, in contrast, a permanent loss of smell may be caused by head injury or tumors. Infection of the olfactory system is consistent with the observation that loss of smell is a frequent neurological manifestation in COVID-19. Some evidence, demonstrate increased MRI signal in the olfactory cortex during the acute phase of SARS-CoV-2 infection [17]. As represented in the case of other coronaviruses, the virus could be disguised in nerve terminals by endocytic mechanisms, transported retrogradely, and spread transsynaptically to other regions of the cerebrum [18]. As described before, ACE-2 and TMPRSS2 have been identified in the nasal mucosa, epithelial cells (sustentacular cells), but not olfactory neurons [19]. However, there are some evidences of neuronal involvement.

## *2.3.2 Blood: brain route*

The blood–brain barrier (BBB) acts as an additional boundary between circulating blood and the extracellular space of the brain. The barrier is highly selective, protecting the brain from toxins, pathogens and even circulating neurotransmitters (e.g. glutamate) that can be potentially damaging to neurons. The BBB is a typical route of entry of blood-borne viruses into the brain. In SARS-CoV-2 infection, dissemination of the virus into the blood has been reported, even though frequencies are extensively ranging (1–41%) [16]. Immunoreactivity of ACE-2 was described in brain vessels of a patient with multiple ischemic infarcts. However, the cellular localization was not resolved. Other receptors, such as NRP1 and BSG, could be another possibility of infection due to their more widely expression in the cerebral vasculature [20]. Nonetheless, SARS-CoV-2 associated cytokines – interleukins (IL-6, IL-1b, IL-17) and tumor necrosis factor (TNF) can potentially damage the BBB, which is another way of virus invasion [21]. In several autopsy studies, a lack of florid cerebrovascular inflammation has been described [22]. Comorbidities, as have oftentimes been seen in COVID-19, such as cardiovascular risk factor or pre-existing neurological diseases, in combinations with activation of cytokines, increase the permeability of BBB [21].

#### *2.3.3 Infiltration of infected immune cells*

Infected immune cells (monocytes, neutrophils, and T cells) can cause brain infestation through the vasculature, the meninges, and choroid plexus [16]. In a study conducted by Chen et al., 2020, SARS-CoV-2 nucleocapsid protein (NP) immunoreactivity was observed in CD68+ cells in lymphoid organs, while singlecell RNA seq data showed viral RNA in macrophages of COVID-19 patients [23]. However, data about virus proliferation in macrophages are limited due to the unknown mechanisms of virus propagation (phagocytic uptake of virus-infected cells or extracellular virions) [24].
