SARS-CoV2 and involvement of the nervous system: an update of the literature (July 2020)
Coronaviruses (CoV), which are large enveloped viruses, generally cause respiratory and enteric diseases in animals and humans. While most CoV cause mild respiratory disease in humans (such as for example the HCoV-229E and HCoVOC43 strains), the worldwide spread of two previously unrecognized CoV, the Severe Acute Respiratory Syndrome CoV (SARS‐CoV) and Middle East respiratory syndrome CoV (MERS‐CoV) had drawn attention to the lethal potential of human CoVs a few years ago.
Signs & symptoms of SARS CoV2 infection : some hints of a viral action in the Nervous System?
The emergence in December 2019 in China of another highly pathogenic CoV, SARS‐CoV‐2, has led to a pandemic (CoViD 19, Coronavirus Disease 2019) responsible for more than 571.000 deaths worldwide (July 13th, 2020). The most common symptoms of COVID-19 illness are fever, cough, dyspnea and fatigue. In the most severe cases, patients develop pneumonia, acute respiratory distress syndrome, acute cardiac problems, and multiorgan failure. If the major clinical signs of SARS-CoV2 infection are respiratory-related, some patients with COVID‐19 additionally show neurologic signs, such as headache, nausea, and vomiting. In a recent letter to the editor of the European Journal of Neurology, Prof Tassorelli and her team reported that “several patients in the latest stages of disease, when their lung parenchyma is devastated by the infection, may not manifest dyspnea (personal observations)… On the other hand, patients with severely affected lungs may be paucisymptomatic and recover fully from the infection (Tassorelli, Mojoli et al. 2020) ”. As suggested by these authors, the death of some patients may be explained –at least in part- by the multiple pathological mechanisms induced by the virus (including myocardial injury, kidney failure or shock for example). However, the discrepancy between the severity of the lung involvement and the respiratory function raises the question of the potential existence of additional mechanisms, including an action of the virus at the peripheral and central nervous system. Thus, it might be worth considering “that the respiratory failure may be driven by a dysfunction of the cardiorespiratory centers in the brainstem” (Tassorelli, Mojoli et al. 2020).
Many features of SARS-CoV2 and Human coronaviruses (HCoV) in general suggest that there might be indeed some overlooked involvement of the nervous system. This raises the possibility that strokes as well could be associated with SARS-CoV2 infection and encephalitis could be a potential complication (Nath 2020).
How coronaviruses gain entry into the CNS
Coronaviruses are neurotropic and potentially neurovirulent (Desforges, Le Coupanec et al. 2020). Like SARS-CoV, SARS‐CoV2 exploits the receptor angiotensin converting enzyme 2 (ACE2) to gain entry inside the cells. In humans, ACE2 is expressed in the capillary endothelium, as well as in the brain, offering some potential sites of interaction between the virus and its receptor (Baig, Khaleeq et al. 2020). An interesting hypothesis has emerged around the use of angiotensin-converting enzyme (ACE) inhibitors to treat diabetes, which leads to increased expression of ACE2, making the cells more vulnerable to infection with the virus. Clinical studies are underway to test this hypothesis. Yet, the presence of ACE2 is not sufficient to make host cells susceptible to infection.
Autopsies from SARS patients in 2002 have demonstrated the presence of SARS CoV particles in their brain (Li, Bai et al. 2020). While a case of Acute Hemorrhagic Necrotizing Encephalopathy was recently described (Poyiadji, Shahin et al. 2020), there is now a report of detection of the SARS Cov2 virus in the CSF of one patient (encephalitis.info/blog/coronavirus).
Experiments in mice revealed that the SARS CoV and MERS CoV given intranasally were able to enter the brain, probably via the olfactory nerves, heavily infecting the brainstem. Even though the exact route used by the virus is not definitely proven, it has been suggested that it might first invade the peripheral nerve terminals, and then gain access to the CNS via a trans-synaptic route (Li, Bai et al. 2020). Furthermore, some coronaviruses have been shown to spread via a trans-synaptic route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Could the anosmia observed in some CoVid 19 patients reflect the involvement of the olfactory bulbs? Could SARS Cov2 infect the nucleus of the solitary tract and nucleus ambiguous, potentially destroying medullary neurons and from there on, induce acute respiratory failure of patients with COVID‐19 (Li, Bai et al. 2020)?
Neurological implications and perspectives
Viruses infecting human CNS cells have been suggested to cause not only different types of encephalopathy, including encephalitis, but also long-term neurological diseases. Like other neuroinvasive human viruses, respiratory viruses may damage the CNS either directly (virus-induced neuropathology) or indirectly (virus-induced neuro-immunopathology) (Desforges, Le Coupanec et al. 2020). Much evidence implicates a cytokine storm in the case of SARS CoV2, a feature which might (at least partly?) underlie the reported effect of azithromycine on COViD 19 patients. Indeed, apart from being an antibiotic, azithromycine has also been shown to reduce TNF, a cytokine demonstrated to be highly raised in CoviD 19 patients (Zhang, Zhao et al. 2020).
Last but not least, viruses have been long suspected to play a role in human neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease but also in Multiple Sclerosis. The emergence of a novel virus suspected to potentially enter the nervous system undoubtedly paves the way for a wealth of interdisciplinary studies. Moreover, as already advocated by (Nath) in 2015 , this pandemic reminds us that there is a clear need for improved training programs in neuroinfectious diseases.