Updates on What ACS Reported: Emerging Evidences of COVID-19 with Nervous System Involvement.

With the ongoing pandemic of coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), our knowledge of the pathogenesis of COVID-19 is still in its infancy. Almost every aspect of the pathogen remains largely unknown, ranging from mechanisms involved in infection transmission, interplay with the human immune system, and covert mechanisms of end-organ damage. COVID-19 has manifested itself worldwide with a syndromic appearance that is dominated by respiratory dysregulations. While clinicians are focused on correcting respiratory homeostasis, echoing the original SARS, SARS-CoV-2 is also invading other end-organs, which may not exhibit overt clinical features. Nervous system involvement was not initially considered to play a significant role in patients with COVID-19. However, since this viewpoint was initially published, multiple studies have been released regarding the possible neurovirulence of SARS-CoV-2. In our previous viewpoint, we implored our colleagues to recognize the covert tactics of SARS-CoV-2 and emphasized that symptoms like anosmia, dysgeusia, ataxia, and altered mental status could be early signs of the neurotropic potential of this virus. The past few weeks, after the viewpoint surfaced, it was noticed that it has enabled clinicians and healthcare professionals to compute the neurovirulence associated with SARS-CoV-2 in COVID-19 patients, as evidenced by very recently reported studies.

Features that Raise Suspicion of Neurological Involvement with COVID-19

COVID-19 has now become a global pandemic. Common presenting symptoms reported by patients with COVID-19 are high-grade fever, cough, dyspnea, and chest pain.[1] Difficulty breathing and fever are obvious and troubling symptoms for any patient. Comparatively, the loss of smell and taste in patients with COVID-19 may seem insignificant. The published reports[1,2] that first emerged from hospitals in Wuhan, China described several clinical features in patients severely affected by COVID-19. Neurologic symptoms such as acute cerebrovascular diseases, impaired consciousness, and skeletal muscle injury[2] implore us to consider the central nervous system (CNS) as a target of SARS-CoV-2. The loss of smell and taste could be a manifestation of the involvement of the nervous system and does occur in a diverse list of other viral infections. Reports of anosmia and taste-related changes should be taken as an indication of SARS-CoV-2 infection and a heralding sign for COVID-19. In the weeks after the above paper was published in ACS Chemical Neuroscience,[3] the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) released a statement noting that anosmia and dysgeusia are “significant symptoms” associated with COVID-19.[4]

Serious Neurological Manifestations in COVID-19

Though symptoms like anosmia and hypogeusia can be of significance in altering COVID-19 occurrence in this outbreak, SARS-CoV-2 is proving to be more sinister. The first reported case of COVID-19-associated acute necrotizing hemorrhagic encephalopathy was reported in a female with a 3 day history of cough, fever, and altered mental status. This patient was diagnosed with COVID-19 by RTq-PCR performed on a specimen of the nasopharyngeal swab for SARS-CoV-2. Brain MRI demonstrated hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions that were consistent with acute necrotizing hemorrhagic encephalopathy.[5] Cases of Guillain−Barré Syndrome have also been reported in patients with COVID-19. Regardless of how SARS-CoV-2 gains entry into the CNS, recently published data has reinforced our rationale of SARS-CoV-2 targeting endothelial ACE2 receptors, including documentation of vasculitis in patients with COVID-19[3,8] and findings observed in the brain MRI of an affected patient.[5] Although SARS-CoV-2 was isolated from the specimen of a nasopharyngeal swab, isolation of SARS-CoV-2 from the cerebrospinal fluid (CSF) would be more convincing for neurotropism when coupled with the MRI changes described above.[5] The latter study details that although CSF was obtained, a CSF analysis for SARS-CoV-2 was not possible because of a traumatic lumbar puncture.[5] A parallel study reported on a 56-year-old patient diagnosed with COVID-19 in Beijing Ditan Hospital. The patient was diagnosed with COVID-19-associated encephalitis, and the patient’s gene sequencing confirmed the presence of SARS-CoV-2 in the CSF.[6] These two cases add to the existing data on potential neurovirulence of SARS-CoV-2 and serve to better prepare healthcare professionals in identifying, diagnosing, and treating patients presenting with neurologic deficits in COVID-19.

Pathways of SARS-CoV-2 that lead to COVID-19 Encephalopathy

We had previously debated and proposed possible pathways adopted by SARS-CoV-2 to gain entry into the CNS,[3] and these pathways can be argued and further investigated to elucidate the exact route(s) that SARS-CoV-2 adopts to access to the nervous system. Hematogenous, transcribrial, and neuronal retrograde dissemination pathways have been proposed for SARS-CoV-2 to reach the CNS.[2,3,6] The exact pathway to the nervous system could be any one of these routes or a combination. Future studies, as well as autopsy and pathology reports, are expected to provide necessary data in the coming weeks. Discussing potential transmission pathways, as well as other unknown issues related to the pathogenesis of COVID-19, will better prepare the scientific community to fight against this pandemic. Treatments and therapies that minimize SARS-CoV-2 from taking these routes in early or late-stage COVID-19 may prove to be lifesaving by minimizing neurological damage. Systemic dysregulation caused by SARS-CoV-2 in COVID-19 can result in respiratory failure[3] and invasion of the brainstem respiratory regulatory centers by SARS-CoV-2 via neuronal retrograde dissemination;[2,6] hematogenous and other possible routes should be taken into consideration in patients with COVID-19. The significance of understanding the underlying SARS-CoV-2 pathways to the nervous system is the explanation it can provide and the remedy it can determine for the occurrences of acute respiratory failures by possible neuronal damage,[2,3,6] necessitating the use of ventilators in patients with COVID-19.

Conclusion and Future Directions

There are several aspects of COVID-19 that we are trying to understand. As each day passes in the ongoing pandemic, researchers are amassing more data on SARS-CoV-2. The pathogenesis of nervous system involvement, mechanism of alveolar damage, role of vascular endothelial injury, and end-organ damage in COVID-19 are becoming clearer. A comprehensive investigation of the unique features of COVID-19 and its causative agent SARS-CoV-2 will help in the fight against this deadly pathogen. So, what is the translational value of searching for the answers of curious symptoms like loss of smell and taste in COVID-19? The AAO-HNS established the COVID-19 “Anosmia” reporting tool for clinicians on March 26, 2020.[4] This tool allows clinicians and healthcare providers worldwide to submit related data to confidentially report on anosmia and dysgeusia related to COVID-19. Another related yet priceless indication of the efforts was observed recently when patients suffering from anosmia and dysgeusia, from the COVID-19 affected areas worldwide, called the healthcare professionals and scientists, seeking reassurances, explanations, and advice.[7]