Neurological manifestations or NeuroCOVID are part of the COVID-19 clinical picture, but questions remain regarding the frequency and severity of CNS symptoms, the mechanism of action underlying neurological symptoms, and the relationship of symptoms with the course and severity of COVID-19. Further clinical, epidemiological, and basic science research is urgently needed in order to understand and address neurological sequalae of COVID-19. We identified three key priority areas for NeuroCOVID:
First, are patients with COVID-19 in other countries experiencing neurologic symptoms and do these symptoms affect the severity and course of the illness, specifically are they associated with increased respiratory failure or death? Documentation of neuropsychiatric co-morbidities and drug treatment regimens are essential to aid ongoing discussions of drug-drug interactions and pharmacodynamic effects. Vaccine research discoveries need to be implemented while keeping in mind possible adverse events as shown by our experiences with the swine flu.[14]
Second, what is the mechanism of action causing the neurological symptoms seen in patients with COVID-19? It is possible that SARS-CoV-2 causes neurological sequelae via inflammation, as elevated inflammatory biomarkers in patients with COVID-19 have been noted. Pro-inflammatory cytokine release is known to cause severe pulmonary damage in COVID19 , termed “cytokine storm”, and likely affects the CNS as well. Indirect CNS damage, through cytokine storm, can cause high mortality rates, encephalopathy, and posterior reversible encephalopathy (PRES). In acute infections, cytokine release can also result in strokes, a number of which have been reported in SARS post infection. [17] MR imaging might provide further information to elucidate the role of brainstem respiratory centres in COVID-19 patients.
Third, is SARS-CoV-2 a neurotropic virus? While we know that other coronaviruses demonstrate neurotropism, it is unknown how much of this knowledge is relevant for SARS-CoV-2. Li et al. postulate that SARS-CoV-2 neuroinvasion via the olfactory nerves is partially responsible for respiratory failure.[5,[1]] Is hyposmia or anosmia part of a prodrome of symptoms in COVID-19? Further research is needed in this area to further understand why steroids may be counterproductive in management of COVID-19. [18] This signifies the importance of carrying out research into therapeutic options systematically with shared protocols and critical comparison of results.
Many patients present dysgeusia, dysphagia, dysarthria (personal observation AP) indicating a possible vagal involvement which could also indicate the possibility for diaphragmatic paresis and tachycardia thus potential bulbar infections. We know that SARS-CoV-1 enters cells through the ACE2 receptor mainly in renal, cardiovascular and gastrointestinal systems. [19-22] In mice, infected hippocampal cells were isolated in the CNS several days post infection indicating that SARS-CoV-1 has the capability to spread to the CNS after clearance by the lungs.[23] In humans, SARS-CoV-1 has been found in the CSF [24] and in neurons on autopsy.[25,26] Another coronavirus (swine hemagglutinating encephalomyelitis virus) travels via peripheral nerves to the brainstem via trigeminal and vagal sensory nuclei. [27-29] HCoV OC43 (a coronavirus responsible for the common cold) infects human microglia leading to persistent infection and has been found in the CSF and brain tissue of patients.[30-32] In mice it travels to the CNS from the olfactory bulbs and, importantly, is blocked by destroying olfactory sensory neurons[33]. This potential mechanism becomes crucially important clinically when considering that wearing masks could likely be the most effective prevention against viral entry into the CNS.
Finally, prospective cohort studies are needed to understand the long-term impacts of COVID-19 on neurological functions. It is currently unknown if people who have recovered from severe COVID-19 suffer any lasting neurological sequalae. It is certainly true and well known that several patients discharged from ICU, thus also several COVID 19 patients, suffer of chronic illness myopathy or neuropathy or both which might worsen the clinical outcomes. Concomitant risk factors or determinants (e.g. demographic factors, comorbidities, or available biomarkers) that may predispose a person with COVID-19 to neurological manifestations should be identified.
We are aware that this review has limitations including that it was limited to articles published in English and that there is a tremendous growth in the volume of published literature on COVID-19, so that findings and recommendations are constantly evolving as new evidence arises and thus other relevant information and data could be lacking. Answers to all the above questions, however, require close coordination and open-data sharing between hospitals, academic institutions and fast establishment of harmonised research priorities and research consortia to face the neuroCOVID19 complications.