A new strain of human coronaviruses (hCoVs), Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has been identified to be responsible for the current outbreak of the coronavirus disease 2019 (COVID-19). Though major symptoms are primarily generated from the respiratory system, neurological symptoms are being reported in some of the confirmed cases, raising concerns of its potential for intracranial invasion and neurological manifestations, both in the acute phase and in the long-term. At present, it remains unclear the extent to which SARS-CoV-2 is present in the brain, and if so, its pathogenic role in the central nervous system (CNS). Evidence for neuroinvasion and neurovirulence of hCoVs has been recognised in animal and human studies. Given that SARS-CoV-2 belongs to the same family and shares characteristics in terms of receptor binding properties, it is worthwhile exploring its potential CNS manifestations. This review summarises previous findings from hCoVs in relation to the CNS, and compares these with the new strain, aiming to provide a better understanding of the effects of SARS-CoV-2 on the CNS.
Is SARS-CoV-2 likely to be present in the central nervous system?
At present, it remains unknown whether SARS-CoV-2 is present in the CNS, possibly due to limited access to brain tissue and CSF from patients infected with the virus. Autopsies are being increasingly carried out, however, initial biopsies have been taken only from lung, liver and heart for histopathology Given that several strains of hCoVs have been shown to be present in the brain, as well as CSF with neuroinvasion and neurovirulence shown in cell culture and animal models it is reasonable to consider that the SARS-CoV-2 may also be present in the CNS. This is further supported by the fact that some COVID-19 patients present with headache, nausea and vomiting, symptoms that potentially indicates neurological involvement The frequency of neurological manifestations including changes in consciousness and acute cerebrovascular disease increase in parallel with the severity of the disease.One study on nasal epithelium samples taken from a subset of COVID-19 patients exhibiting olfactory dysfunction has suggested that the disturbance of smell in these patients is more possibly due to SARS-CoV-2 infection of non-neuronal cells rather than olfactory neurons.More recently, the report of a cohort of 58 COVID-19 patients showed a correlation between acute respiratory distress syndrome (ARDS) and encephalopathy, mainly agitation, confusion and corticospinal tract signs.However, these findings need to be confirmed by studies on brain samples or CSF. The most efficient way to identify involvement of neurological systems remains to be determined. The presence of SARS-CoV-2 in CSF was confirmed by gene sequencing in a 56-year-old patient with COVID-19, which was the first direct evidence for the neuroinvasion of this novel coronavirus.Brain samples remain the gold standard of confirmation, however, access to such samples will almost certainly remain very limited and it is not a practical or ethical consideration in larger cohorts, especially in mild to moderate cases. Several pathways of invasion for hCoVs have been proposed, including via the olfactory nerve, neurotransmitter pathways, hematogenous route, Virchow-Robin space surrounding arterioles and venules, lymphatic systems and receptors, from which alternative parameters and types of samples may offer opportunity for proof of CNS involvement. More studies are needed to evaluate and compare these alternative pathways and parameters. In addition, the timing of sampling needs further investigation, as the change of viral load in the human body at different stages of COVID-19-related infection and recovery remains unclear.
Catching a viral infection with ensuing cytokine release and tissue lesions may lead to a variety of CNS-related manifestations (delirium, headache, vomiting, etc.), which are recognizable for many viruses including hCoVs, however, these non-specific clinical symptoms and signs may be constitutional and represent systemic involvement rather than direct CNS infection. Therefore, we should be cautious when reporting cases with neurological symptoms and/or signs that lack solid evidence for CNS infection (e.g. absence of viral detection in CSF samples or abnormalities supportive of infection on brain imaging). It is particularly challenging when evaluate the neurological deficits during the advanced stage of COVID-19-related disease. The clinical diagnosis and treatment strategy has to be made on the basis of a differential diagnosis which includes hypoxia, respiratory, metabolic acidosis, ARDS-related encephalopathy, the effect or withdrawal of medications, and viral infection of the CNS.
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