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Frontiers of Medicine

Front. Med.
Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain
Zhengqian Li1, Taotao Liu1, Ning Yang1, Dengyang Han1, Xinning Mi1, Yue Li1, Kaixi Liu1, Alain Vuylsteke2, Hongbing Xiang3(), Xiangyang Guo1()
1. Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China;
2. Department of Anaesthesia and Intensive Care, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK;
3. Department of Anesthesiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.

Keywords coronavirus disease 2019 (COVID-19)      SARS-CoV-2      neurological manifestations      neuroinvasion      brain     
Corresponding Authors: Hongbing Xiang,Xiangyang Guo   
Just Accepted Date: 04 April 2020   Online First Date: 07 May 2020   
 Cite this article:   
Zhengqian Li,Taotao Liu,Ning Yang, et al. Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain[J]. Front. Med., 07 May 2020. [Epub ahead of print] doi: 10.1007/s11684-020-0786-5.
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Zhengqian Li
Taotao Liu
Ning Yang
Dengyang Han
Xinning Mi
Yue Li
Kaixi Liu
Alain Vuylsteke
Hongbing Xiang
Xiangyang Guo
Fig.1  The main organs and potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. SARS-CoV-2 binds to angiotensin-converting enzyme type 2, which is widely distributed in the lungs, heart, liver, kidney, and intestine. SARS-CoV-2 induces the intrinsic immune response, a cytokine storm, acute respiratory distress syndrome, and damages peripheral tissues. It may simultaneously invade the brain through the vascular, peripheral nerve, lymphatics, and cerebrospinal fluid pathways. Consequently, the brain may be involved in the systemic response after being subjected to hypoxemia.
Fig.2  Potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain. Inhalation droplets and close contact transmission are the main person-to-person transmission routes of COVID-19. Once the virus enters a host cell, the innate immune response may trigger a cytokine storm, especially under profound hypoxemia conditions induced by ARDS in patients with severe COVID-19. (i) When SARS-CoV-2-carrying droplets contact the eye conjunctiva, they can enter the brain after infecting the trigeminal nerve (V), resulting in decreased vision. (ii) The virus may also infect the sensory neurons in the taste buds, ascend to the nucleus of the solitary tract (VII, IX, and X) or trigeminal nerve (V) and enter the CNS through neuronal retrograde transport. (iii) Once the virus-containing droplets land on the nasal mucosa, SARS-CoV-2 may enter the brain along the olfactory nerve. In addition, the abundant capillary blood vessels and lymphatics underlying the nasal mucosa provide opportunities for virus invasion. (iv) Viruses that enter the respiratory tract flow into the bloodstream through ACE2 receptors expressed in the epithelial cells of the respiratory tract. In addition to the vascular pathways, the virus spreads toward the CNS through the vagus nerve branch (X) that innervates the respiratory tract, resulting in dry cough, dyspnea, and exacerbating acute respiratory distress syndrome. (v) Similarly, poor hand hygiene gives the virus the opportunity to enter the gastrointestinal tract and then enter the brain through the vasculature, vagus nerve, and lymphoid pathways. These patients may experience loss of appetite, nausea, vomiting, and diarrhea. (vi) The virus that enters the circulation can invade the brain through the damaged BBB and leak into the interstitial fluid, and then enter the cerebral spinal fluid through the intracerebral lymphatic circulation. Viruses in the blood can also enter the fourth ventricle directly through a damaged blood cerebral spinal fluid barrier.
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