COVID-19 and the nervous system

Journal of NeuroVirology (2020) 26:143–148 https://doi.org/10.1007/s13365-020-00840-5 REVIEW COVID-19 and the nervous system Joseph R. Berger 1,2 Received: 31 March 2020 / Revised: 31 March 2020 / Accepted: 2 April 2020 / Published online: 23 May 2020 # Journal of NeuroVirology, Inc. 2020 Abstract A pandemic due to novel coronavirus arose in mid-December 2019 in Wuhan, China, and in 3 months’ time swept the world. The disease has been referred to as COVID-19, and the causative agent has been labelled SARS-CoV-2 due to its genetic similarities to the virus (SARS-CoV-1) responsible for the severe acute respiratory syndrome (SARS) epidemic nearly 20 years earlier. The spike proteins of both viruses dictate tissue tropism using the angiotensin-converting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue and endothelial cells among the tissues of many other organs. Neurological complications have been observed with COVID-19. Myalgia and headache are relatively common, but serious neurological disease appears to be rare. No part of the neuraxis is spared. The neurological disorders occurring with COVID-19 may have many pathophysiological underpinnings. Some appear to be the consequence of direct viral invasion of the nervous system tissue, others arise as a postviral autoimmune process, and still others are the result of metabolic and systemic complications due to the associated critical illness. This review addresses the preliminary observations regarding the neurological disorders reported with COVID-19 to date and describes some of the disorders that are anticipated from prior experience with similar coronaviruses. Keywords COVID-19 . Coronavirus . SARS-CoV-2 . Neurological complications . Meningitis . Stroke . Encephalitis . Myositis Background In mid-December 2019, patients with an unusual pneumonia were recognized in Wuhan, China. On December 31, 2019, this new infection was reported to the World Health Organization 31, 2019 (CNN 2020). By January 7, 2020, genetic analysis of viral isolates from affected patients indicated that the etiologic agent was a novel coronavirus distinct from those causing severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). By January 16, 2020, it is recognized in Japan in a Japanese man who had travelled to Wuhan (CNN 2020). From the time of its appearance in December 2019, this novel coronavirus spread a lightening-like speed through the world’s population. As of March 29, 2020, the illness referred to as coronavirus disease * Joseph R. Berger 1 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 2 Department of Neurology, Perelman School of Medicine, Perelman Center for Advanced Medicine, Room 765 South Tower, Philadelphia, PA 19104, USA 2019 (COVID-19) has been recognized in 172 of the world’s 192 countries (Organization WH 2020). The total number of confirmed cases was 634,835, and the number of deaths attributed to the disease was 29,957 (Organization WH 2020) and rapidly rising. The coronavirus:SARS-CoV-2 Coronaviruses, the family of viruses to which the virus causing COVID-19 belongs, were first identified in humans in 1965 from a child with an upper respiratory infection (McIntosh 1985). Serologic surveys have indicated a worldwide distribution, and depending on the season, they are responsible for 1 to 35% of upper respiratory infections (McIntosh 1985). Community-acquired coronavirus was chiefly associated with a mild upper respiratory infection. However, the severe acute respiratory syndrome (SARS) in 2002–2003 which affected more than 8000 persons worldwide with a nearly 10% mortality (CDC 2020) and the middle east respiratory syndrome (MERS) epidemic that started in 2012 affected nearly 2500 persons with a nearly 35% mortality (Organization, W.H 2020) were caused by coronaviruses. 144 Coronaviruses are enveloped viruses measuring 100– 150 nm in diameter with a positive-sense single-stranded RNA genome (McIntosh 1985). The nucleocapsid demonstrates a helical symmetry. By electron microscopy, coronaviruses display spike peptomer projections measuring 20 nm in length that are responsible for the virus’ tropism. It is the “crown-like” appearance of these projections that gave rise to the name coronavirus. Coronaviruses have four main structural proteins: spike (S)-protein, membrane (M), envelope (E), and nucleocapsid (N)-proteins that are all encoded with in the 3′ end of the virus (Fehr and Perlman 2015). The spike protein is a trimeric fusion protein that mediates attachment to the host receptor. The membrane protein is the most abundant structural protein in the virion. The envelope protein facilitates assembly and release of the virus, and the ion channel activity in SARS-CoV envelope protein is required for pathogenesis. The N-protein constitutes the only protein present in the nucleocapsid. It is composed of 2 domains that bind RNA (Fehr and Perlman 2015). The hemagglutinin-esterase protein is present in a subset of β-coronaviruses and binds sialic acids on surface glycoproteins and contains acetylesterase activity (Li 2016). The attachment of the virus to the host cell is initiated by the S-protein and its receptor. This interaction is the primary determinant for tissue tropism (Fehr and Perlman 2015). Different coronaviruses have an affinity for different receptors. As stated, SARS-CoV-2 interacts with the ACE-2 receptor (Fehr and Perlman 2015). Coronaviruses are classified into four genera: alpha, beta, gamma, and delta. Coronaviruses in the beta genus include SARS, MERS, and the new coronavirus, referred to as SARS-Cov-2. There are now at least six human coronaviruses including SARS-CoV-1, SARSCoV-2, MERS-CoV, HcoV-OC43, HCoV-229E, HCoVNL-63, and HCoV-HKU1 (Arabi et al. 2015). SARSCoV-2 was named for its close genetic relationship to the SARS virus. The “spike proteins” of both SARS (Imai et al. 2010) and SARS-CoV-2 (Lu et al. 2020) use the angiotensin-converting enzyme receptor type 2 (ACE-2) to bind to cells. The ACE-2 receptor is widely distributed in the body present in the lungs, oral and nasal mucosa, bone marrow and spleen, skin, heart, arteries, kidneys, adipose tissue, reproductive system, and brain (Hamming et al. 2004). ACE 2 receptor is also expressed in the central nervous system predominantly in thalamic nuclei, cerebellum, and inferior olivary nuclei (Allen et al. 2009). The location of these receptors in the brain may be of relevance with respect to coronavirus encephalitis. The SARS-CoV-2 genome is 29,903 bases long, and estimates of viral evolution suggest that it arose no earlier than the end of October J. Neurovirol. (2020) 26:143–148 2019. A 96% homology with bat coronavirus indicates that it originated as a bat virus with an intermediate host in another animal (Chan et al. 2020). Two different strains of SARS-CoV-2 have been identified: an S-strai (...truncated)