key: cord-0735100-prxzcp1x
authors: De Felice, Fernanda G.; Tovar-Moll, Fernanda; Moll, Jorge; Munoz, Douglas P.; Ferreira, Sergio T.
title: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System
date: 2020-04-21
journal: Trends Neurosci
DOI: 10.1016/j.tins.2020.04.004
sha: 3d24d0257d58a1726bc5d956096da4d49369839a
doc_id: 735100
cord_uid: prxzcp1x

Emerging evidence indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can cause neurological complications. We provide a brief overview of these recent observations and discuss some of their possible implications. In particular, given the global dimension of the current pandemic, we highlight the need to consider the possible long-term impact of COVID-19, potentially including neurological and neurodegenerative disorders.

cough, loss of smell and taste, sore throat, leg pain, headache, diarrhea, and fatigue. Although most patients infected with SARS-CoV-2 are asymptomatic or develop mild to moderate symptoms, a subset of patients develop pneumonia and severe dyspnea, and require intensive care. Because acute respiratory syndrome is the hallmark feature of severe COVID-19, most initial studies on COVID-19 have focused on its impact on the respiratory system. However, accumulating evidence suggests that SARS-CoV-2 also infects other organs and can affect various body systems. As many scientists have already noted, these emerging findings call for investigations into the short-and long-term consequences of COVID-19 beyond the respiratory system. In the next sections we briefly discuss recent observations suggesting an association between SARS-CoV-2 infection and neurological complications. We place these findings in the context of previous studies demonstrating that various viruses, including CoVs, can have effects on the central nervous system (CNS). Lastly, we highlight the possibility that SARS-CoV-2 infection could promote or enhance susceptibility to other forms of CNS insults that may lead to neurological syndromes. Given scope limitations, we offer only a sample of the substantial literature on the CNS impact of viral infection, with the purpose of underscoring some of the sequelae and mechanisms that may be involved in the context of COVID-19, and that require further investigation.

Cerebrovascular diseases are among the comorbidities of patients with confirmed COVID-19 who develop severe respiratory complications [1] . For example, one study reported hypoxic/ischemic encephalopathy in~20% of 113 deceased patients with COVID-19 [2] . A recent study evaluated 214 patients diagnosed with COVID-19 from China and found that 36% had neurological manifestations, 46 including acute cerebrovascular disease and impaired consciousness [3] ; a case 48 of acute hemorrhagic necrotizing enceph-49 alopathy has also been reported [4] . . Of note, early preclinical 101 studies showed that intranasal/intraocular 102 inoculation in non-human primates [12] 103 led to detection of CoV RNA or antigen 104 in the brain, and post-mortem analyses 105 indicated the presence of brain pathology, 106 including inflammation and white matter 107 edema. Future studies may reveal whether 108 the intranasal route of infection is con-109 nected to anosmia (loss of sense of smell) 110 that is described as a frequent and early 111 symptom of COVID-19 [13].

112 Studies on CNS invasion by neurotropic 113 viruses, and on the underlying mecha-114 nisms leading to neuroinflammation and 115 neurological symptoms, have made signif-116 icant strides in recent years (e.g., [14, 15] ). 117 These studies may provide guidance on 118 key areas of investigation to clarify whether 119 and how SARS-CoV-2 affects the CNS. 120 Notably, brain inflammation has been 121 shown to underlie, at least in part, CNS 122 damage associated with infection by 123 West Nile, Zika, and herpes simplex 124 viruses, conditions in which long-lasting 125 inflammatory processes develop within 126 the CNS. In addition, the intense systemic 127 inflammatory response linked to viral in-128 fection can lead to blood-brain barrier 129 (BBB) breakdown. This in turn can allow 130 peripheral cytokines to gain access to 131 the CNS, where they may trigger or 132 exacerbate neuroinflammation leading 133 to encephalitis [15] .

134 Possible Long-Term CNS 135 Consequences of SARS-CoV-2 136 Infection 137 Human neurodegenerative diseases often 138 involve a gradual process that evolves, in 139 some cases, over several decades. Large 140 numbers of young adults worldwide are 141 now infected, or will be infected in the 142 near future, by SARS-CoV-2. For some, the severity of the disease will require hospitalization, opening up the possibility of detailed medical examination which could be leveraged for longitudinal studies, as discussed later. Literature on previously studied viruses raises the possibility that SARS-CoV-2 may affect the CNS. The inflammatory response elicited in acute or chronic infection may trigger or accelerate early and subclinical mechanisms that underlie the earliest stages of neurodegenerative disorders. Moreover, because findings in neurodegenerative diseases and other viral infections suggest that systemic inflammatory mediators may access the CNS and trigger damage via impaired BBB function, systemic inflammation triggered by SARS-CoV-2 infection may further contribute to neuroinflammatory processes and increase susceptibility to neurological syndromes. CNS infections may thus promote the development of neurodegenerative disease in individuals already at risk. There is an urgent need for longitudinal studies to determine whether the COVID-19 pandemic will lead to enhanced incidence of neurodegenerative disorders in infected individuals (Box 1).

To conclude, emerging evidence suggests that SARS-CoV-2 is associated with neurological alterations in COVID-19 patients It will be crucial to conduct detailed cognitive testing on COVID-19 patients to detect possible cognitive b1:12 impairments, as well as longitudinal studies that include brain imaging, neurological, and neuropsychological b1:13 evaluation to examine multiple cognitive domains. 

Are specific groups of COVID-19 patients more prone to developing neurological alterations?

Is SARS-CoV-2 present in post-mortem brain tissue or in the CSF of COVID-19 patients? Is there preferential targeting of CNS structures in patients who develop neurological alterations?

Is anosmia indicative of SARS-CoV-2 infection in the CNS. or does it reflect an impact on the peripheral nervous system (e.g., olfactory nerve)? Can SARS-CoV-2 be found in the olfactory or optic nerves as potential conduits for invasion of the CNS?

Considering potential neurological consequences, what strategies (clinical, imaging, biomarkers) should be adopted in the long-term neurological follow up of COVID-19 patients? 

Alzheimer's Society Canada and the

D.F), the National 211 Institute for Translational Neuroscience (INNT/Brazil)

Científico e Tecnológico (CNPq) and Fundação de

2020) with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI Features

Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV)

Human coronaviruses and 220 other respiratory viruses: Underestimated opportunistic 221 pathogens of the central nervous system?

Entry of coronavirus into primate 240

Isolated sudden onset anosmia 243 in COVID-19 Infection. A novel syndrome? Rhinology

Mechanisms of pathogen invasion