An early report of neurological manifestation, vascular lesions, and impaired consciousness was reported in Wuhan, China, in their hospitalized patients [6]. Coronaviruses have also been reported to develop neurological manifestations with febrile seizures, convulsions, changes in mental status, and encephalitis [7]. Coronaviruses enter the central nervous system through the olfactory bulb, causing demyelination and inflammation after nasal infection. This entrance gives the coronavirus a neuroinvasive and neurotropic capability which has already been proved in humans [8]. Some COVID-19 patients had been observed with the symptoms of headaches and confusion, more specifically neurological manifestations such as seizure and cerebrovascular problems [9]. Microvascular injury has also been seen in many COVID-19 patients in the olfactory bulb and brain stem cells. Respiratory failure has been revealed in the neuroinvasion of SARS-CoV-2 [8]. Healthy nutrition has become the top priority for COVID-19 patients, which can create lesser damage to the human body. Further, peripheral inflammation can cause long-term consequences in a recovered patient in the forms of neurodegenerative and neuropsychiatric diseases like dementia, psychosis, schizophrenia, and major depressive disorder possibly through a neuroinflammatory mechanism that is associated with an unhealthy diet [10].
In an interesting case, even though there was no direct sign of SARS-CoV-2, still damage was found as an inflammatory reaction probably caused by the coronavirus [11]. Hence, researchers inferred that somehow coronavirus is affecting the brain and damaging the neuronal cells. We hope that these results will help researchers and physicians understand the partial problems of COVID-19 patients so that we can come up with better neurological treatments. In a study of 214 people, it had been seen that 36.4% of patients were showing neurological manifestation. Older people with more severe infection to their respiratory status were more affected by the neurological manifestation which included acute cerebrovascular event, less severe disturbance of consciousness, and skeletal muscle injury [6].
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Neurological Association of angiotensin-converting enzyme 2 (ACE2) with COVID-19 evident by brain-related findings
ACE2 has been extensively identified as the SARS-CoV-2 receptor and regulator of the renin-angiotensin system including the central nervous system along with lungs, cardiovascular system, gut, kidney, and adipose tissue [12]. Therefore, it can be considered that due to the ubiquitous abundance of ACE-2, the central nervous system can also be infected by the virus [13]. Concerning the mechanism of action, the spike proteins spread over the outer surface of coronavirus are accountable for their binding to the ACE2 receptor followed by entry into the cells. In this context, surface units S1 and S2 assist in strengthening the bond to the ACE2 receptors. This is cooperated by serine protease TMPRSS2 for the priming S proteins [14] (Fig. 1). Besides, there is evidence of the presence of the ACE2 mRNA in the brain from interacting closely with the SARS virus including SARS-CoV-2 in the infected patient [15].
Furthermore, a relationship was drawn between the COVID-19 virus and the brain when the first case of meningitis was revealed in Wuhan, China. The specific SARS-CoV-2 was not detected in the nasopharyngeal swab specimen but the cerebrospinal fluid (CSF) was found to contain it. After that, physicians dealing with COVID-19 patients have been warned about those patients who already had CNS symptoms [16]. Also, in order to find out the relation of COVID-19 with the nervous system, a retrospective study had been done by neuroimaging 185 COVID-19 infected patients. Lesion within the parenchyma was the most common susceptible abnormality. They concluded that COVID-19 disease had a wide range of inflammatory and vascular effects on both the central nervous system and peripheral nervous system [17].
In another clinical study of 37 patients, one of them had a direct connection with COVID-19 revealed after detecting the RNA of SARS-CoV-2 in the CSF. Besides, 8 neurological patients produced signal abnormalities in the medial temporal lobe, non-confluent multifocal white matter, white matter micro hemorrhage, and hyperintense lesion, revealed after the brain magnetic resonance imaging (MRI) [18]. Additionally, there was a case study series of 27 critically ill patients, among which 11 were COVID-19 positive and went through brain MRI. It was found out that there were the effect of COVID-19 on diffuse leukoencephalopathy, juxtacortical and callosal microhemorrhages through brain imaging by T2 hyperintensity. Among the positive COVID-19 patients, four had diffuse leukoencephalopathy, one had microhaemmorrohage in juxtacortical and/or callosal and 6 had both [19].
The above-mentioned effects involve intra-axial abnormality with oval shape microvascular pathology with a greater impact on the corpus callosum and juxtacortical areas. Further, macro-hemorrhagic and ischaemic manifestation with signal abnormalities in the olfactory bulb, leukoencephalopathy, cytotoxin lesion of the corpus callosum, enhancement of parenchyma, and leptomeninges was determined [17]. In a reference center of Paris, Pitié-Salpêtrière Hospital, a large number of patients were observed to possess neurological manifestation. They found out that there is an abnormality in the basal ganglia on analysis of cerebrospinal fluid with the presence of SARS-CoV-2 RNA [18]. The researchers also emphasized the radiographic evidence of strokes in the patients of COVID-19 who were confirmed by RT-PCR. It suggests that radiographic imaging could be the potential tool to minimize mortality and morbidity [20].