**8. Nervous system involvement and COVID-19 infection**

With dreadful presentation of SARS-CoV-2 infection with acute respiratory failure requiring ventilatory support, it also has been implicated in activation of prothrombotic pathways leading to cerebrovascular stroke and Central nervous system (CNS) affection in form of parenchymal and vascular inflammatory responses leading to various neurological manifestations [46–55]. The commonly found (80%) early symptom of anosmia and dysgeusia despite absence of nasal congestion and discharge, suggests the involvement of olfactory bulb and tract [47]. The virus may invade CNS through olfactory epithelium and neuro-mucosal interface [48]. There can be neurological dysfunction due to metabolic derangements due to organ failure and hypoxemia in the form of encephalopathy. In one multicenter study conducted in 69 ICUs across 14 countries, it was found that 55% patients with COVID-19 admitted in ICU had delirium [49]. The authors also found high prevalence of acute brain dysfunction in these patients [49]. Also, encephalopathy can be the primary symptom especially in elderly patients [50].

The direct injury to cerebral blood vessels due to invasion of virus into endothelial cells has also been reported in few autopsy findings, with similar findings in other organs – lungs, kidneys, heart and liver [51]. These findings are evidence suggesting direct invasion of nervous system. Patients with COVID-19 infection are at increased risk of cerebrovascular events. Cerebral venous sinus thrombosis, ischemic stroke, subarachnoid hemorrhage and intraparenchymal hemorrhage have been reported, among them ischemic stroke being the most common [52]. Besides the presence of traditional risk factors for vascular thrombosis, COVID-19infection per se is associated with a hypercoagulable state which is reflected by elevated levels of D-dimer [53].

Isolated cases of meningoencephalitis, acute hemorrhagic necrotizing encephalopathy, acute disseminated encephalomyelitis (ADEM) and GBS have also been reported. In one case report of meningoencephalitis in 24-year-old male who presented with seizures and altered mental status, virus was isolated from CSF [54]. There are increasing number of patients with hemorrhagic encephalomyelitis, with MRI features of hemorrhagic lesions in medial temporal lobes, bilateral thalami and sub insular regions [55].
