**3. SARS-CoV-2: neurotropic or not?**

The CNS is an immune privileged system of the body, owing to the highly protective brain-cerebrospinal fluid barrier, blood-brain barrier as well as surveillance by innate immune sentinels [44, 45]. Viral adaptations can allow multiple entry routes, either via the peripheral nerves or through the hematogenous routes. This can lead to neural and endothelial destruction causing CNS dysfunctions [46]. A variety of

#### *Neurotropic SARS-CoV-2: Causalities and Realities DOI: http://dx.doi.org/10.5772/intechopen.108573*

neuropathological viruses are the respiratory viruses belonging to the categories of the influenza virus (IV), the coronaviruses (CoV), human metapneumovirus (hMPV), and human respiratory syncytial virus (hRSV) [47–49]. They are known to enter the CNS through various routes and mechanisms and invade the system leading to long-term neurological sequalae in the patients [49]. Such viral infections, under severe conditions, usually lead to neurological impairments such as encephalitis, seizures, epilepsy, and other encephalopathies [50–52]. In subsequent section of the chapter, we review the neuroinvasive nature of CoVs and how studying them over the years has helped us understand the SARS CoV-2-mediated complications better. We will also highlight the ongoing debate about the neurotropic nature of the SARS-CoV-2 in the upcoming subsections.

#### **3.1 Neuro-invasive capabilities of coronaviruses**

The three kinds of epidemic-causing CoVs, the SARS CoV-1, Middle East Respiratory Syndrome (MERS) CoV, and the currently prevailing SARS CoV-2, have all been demonstrated to exhibit neurological invasive capabilities [53, 54]. Viral encephalitis, i.e., lesions in the brain parenchyma including neuronal damage caused due to virus, has been confirmed in COVID-19 patients [55]. Genomic sequencing of viral particles in the CSF of the patient verified the case of encephalitis [56]. In fact, encephalitis, polyneuropathy, and aortic ischemic stroke were also commonly observed in severe cases of SARS-CoV epidemic that occurred in 2003 [53]. SARS CoV-2 shares 79.5% genetic similarity with SARS-CoV virus, and hence, finding out the mechanisms of neurological impairments by CoV-2 might be more tractable [57]. Acute viral infection causing hypoxia, systemic toxemia, and other metabolic disorders can result in toxic encephalopathy. It is mainly characterized by cerebral edema and symptoms include headache, delirium, dysphoria, and in extreme cases, lead to loss of consciousness, coma, and paralysis [58]. COVID-19 patients often suffer from hypoxia, viremia, and even headache and disturbed consciousness, which can potentially lead to acute toxic encephalopathy. In extreme cases of COVID-19, enhanced cytokine storm, increased levels of D-dimer, and reduced platelet count can even allow viral-induced cerebrovascular events to occur [59]. Multiple reports of confirmed viral infection in the brain have been narrated since the beginning of the pandemic outbreak. MRI scan of a young COVID-19 female patient with mild symptoms and normal chest CT showed significant cortical hyperintensity in the right gyrus rectus and subtle hyperintensity in the OBs suggestive of viral invasion in these brain regions [60]. In autopsies assessment of brains of six patients who suffered from COVID-19, brainstem neural damage, meningitis, and pan-encephalitis were reported [61, 62]. HCoV-OC43, HCoV-229E, and SARS-CoV-1 are the human-infecting CoVs, which are capable of infecting the neurons directly, apart from causing CNS damage due to immunological and inflammatory responses [63, 64]. HCoV-OC43 has been associated with multiple sclerosis (MS) with its RNA detected in the CSF of 12 of 22 patients suffering with MS [65]. MERS-CoV, although, enters via a dipeptidyl peptidase receptor and has affected only ~2500 individuals since 2012, it also has been shown to generate neurological impairments such as seizures, headaches, and perceiving confusion [66]. Cases of Guillain-Barrè syndrome (GBS), axonal neuropathy, and Bickerstaff brainstem encephalitis have been reported under MERS-CoV infection [67]. This virus, however, was never detected in the human CSF. In case of COVID-19 as well, electromyography and other assessments had confirmed occurrence of GBS and axonal neuropathy in infected patients as well [68–70].
