May 29, 2020 Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019A Review Adeel S. Zubair, MD1; Lindsay S. McAlpine, MD1; Tova Gardin, MD, MPP1; Shelli Farhadian, MD, PhD2,3; Deena E. Kuruvilla, MD4; Serena Spudich, MD3 Article Information JAMA Neurol. Published online May 29, 2020. doi:10.1001/jamaneurol.2020.2065 1; SARS-CoV-2 causes a clinical syndrome, coronavirus disease 2019 (COVID-19), and its pulmonary manifestations have been well described. There is growing evidence of neurological complications and disease in patients with COVID-19. Two similar human coronaviruses (CoV), Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV-1), have also been associated with neurological disease in rare cases. This raises the questions of whether SARS-CoV-2 is neurotropic and whether it contributes to postinfectious neurologic complications. A handful of case reports have described neurological complications in patients with COVID-19.1-4 However, it remains unknown to what extent SARS-CoV-2 damages the central nervous system (CNS) or if neurological symptoms are attributable to secondary mechanisms. 5 These viruses infect humans and numerous animal species, generally causing upper or lower respiratory tract, gastrointestinal, neurological, or hepatic disease.6,7 Currently, there are 7 CoV that can infect humans, including human coronavirus (HCoV)–229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, MERS-CoV, SARS-CoV-1, and SARS-CoV-2.8 Betacoronaviruses SARS-CoV-2, SARS-CoV-1, and MERS-CoV are associated with severe disease in humans.1,3,8 Although HCoV are typically associated with respiratory tract disease, 3 HCoV have been shown to infect neurons: HCoV-229E, HCoV-OC43, and SARS-CoV-1. 9 Oligodendrocytes, astrocytes, microglia, and neurons are susceptible to acute infection with HCoV-OC43, and all except microglia support persistent infection.10 In murine models, HCoV-OC43 can invade the CNS intranasally, which is followed by a rapid spread throughout the CNS. Neuronal damage appears to be caused by direct, virus-mediated, and not immune-mediated injury.11 The CNS damage causes a range of neurological disorders in mice, including encephalitis and transient flaccid paralysis.12 13,14 In 1 study,15 HCoV-OC43 RNA was also detected in the cerebrospinal fluid (CSF) in 10 of 20 living patients with MS. Although the mechanism of potential demyelination during HCoV-OC43 infection is unknown, this may be because of an adaptive immune response against HCoV-OC43 antigens that cross-react with myelin antigens. Indeed, peripheral T-cell clones in patients with MS have been shown to cross-react to both HCoV-OC43 and myelin antigens.16 In addition to demyelinating disease, there have also been pediatric case reports of children with severe immunosuppression developing encephalitis associated with HCoV-OC43 infection, with brain biopsies having positive results for HCoV-OC43 RNA on metagenomic sequencing.17,18 19 A group from Taiwan reported 3 cases of axonal-variant Guillain-Barré syndrome (GBS) and 5 cases of ischemic stroke.20,21 One report22 described a patient with SARS presenting with a seizure with a positive CSF polymerase chain reaction result for SARS-CoV-1, although contamination of the CSF sample was possible. In addition, SARS-CoV-1 has been reliably detected in brain tissue specimens of autopsy donors with SARS, specifically in the cytoplasm of neurons in the cortex and hypothalamus, sometimes associated with neuronal edema and nuclear degeneration.23,24 Examination of autopsy tissue from a patient with encephalitis revealed neuronal necrosis, glial cell hyperplasia, and infiltration of monocytes and T cells.25 Additionally, virions were visualized in neurons on electron microscopy, and SARS-CoV-1 RNA was isolated from the specimen.25 In murine models, SARS-CoV-1 enters the CNS via the olfactory bulb and exhibits rapid transsynaptic spread. The infection causes significant neuronal damage and death without significant inflammatory infiltration.2 26 Unlike SARS-CoV-1 and SARS-CoV-2, MERS-CoV binds to the dipeptidyl peptidase 4 receptor on cells to gain entry. Dipeptidyl peptidase 4 is widely expressed throughout the body on epithelia, vascular endothelia, and the brain.27,28 There have been several clinical case reports that suggest MERS-CoV can lead to neurological complications in humans. In a study29 of 70 patients, 6 (9%) developed seizures, 9 (13%) reported headache, and 18 (26%) experienced confusion. A case series30 highlighted 3 severe cases of neurological disease in MERS-CoV, including suspected acute disseminating encephalomyelitis, encephalitis, and widespread ischemic infarcts. Another case series4 highlighted neuromuscular disease in MERS-CoV, including 3 cases of GBS and a case of Bickerstaff encephalitis. However, although murine models develop CNS infection after intranasal inoculation with MERS-CoV, this virus has never been detected in the CNS of humans.28
