key: cord-1018499-7zpziwky
authors: Yang, Fan; Zhao, Hai; Liu, Hongtao; Wu, Xiuying; Li, Yongnan
title: Manifestations and mechanisms of central nervous system damage caused by SARS-CoV-2
date: 2021-09-24
journal: Brain Res Bull
DOI: 10.1016/j.brainresbull.2021.09.015
sha: 97726aee827fd5ecfc602de625fdb4691411e4ff
doc_id: 1018499
cord_uid: 7zpziwky

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its threat to humans have drawn worldwide attention. The acute and long-term effects of SARS-CoV-2 on the nervous system pose major public health challenges. Patients with SARS-CoV-2 present diverse symptoms of the central nervous system. Exploring the mechanism of coronavirus damage to the nervous system is essential for reducing the long-term neurological complications of COVID-19. Despite rapid progress in characterizing SARS-CoV-2, the long-term effects of COVID-19 on the brain remain unclear. The possible mechanisms of SARS-CoV-2 injury to the central nervous system include: 1) direct injury of nerve cells, 2) activation of the immune system and inflammatory cytokines caused by systemic infection, 3) a high affinity of the SARS-CoV-2 spike glycoprotein for the angiotensin-converting enzyme ACE2, 4) cerebrovascular disease caused by hypoxia and coagulation dysfunction, and 5) a systemic inflammatory response that promotes cognitive impairment and neurodegenerative diseases. Although we do not fully understand the mechanism by which SARS-CoV-2 causes nerve injury, we hope to provide a framework by reviewing the clinical manifestations, complications, and possible mechanisms of neurological damage caused by SARS-CoV-2. With hope, this will facilitate the early identification, diagnosis, and treatment of possible neurological sequelae, which could contribute toward improving patient prognosis and preventing transmission.

The coronavirus disease 2019 (COVID-19) epidemic has become the centre of global attention. [1] Coronaviruses are a large family of viruses that can infect both humans and animals. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to the family of Coronaviridae and causes symptoms similar to those of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Since both coronaviruses act on the angiotensin-converting enzyme 2 (ACE2), the novel 2019 virus was named SARS-CoV-2. [2] SARS-CoV-2 causes COVID-19 disease, which manifests mainly as respiratory symptoms and pneumonia. Typical COVID-19 symptoms include fever, dry cough, and dyspnoea. Respiratory symptoms range from mild to severe, and the severity can progress from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the functions of the gastrointestinal tract, cardiovascular system, kidney, liver, and pancreas. Patients with severe disease are more likely to develop neurological symptoms, which range from headaches or dizziness to more serious convulsions and cerebrovascular disease (CVD). [3] Autopsy reports have documented cerebral oedema and neuronal degeneration in patients with severe disease. [4] In addition, acute seizures have been reported in two patients with severe COVID-19, which suggests that COVID-19 may cause central nervous system (CNS) damage. [5] Since the on-going COVID-19 outbreak poses a huge threat to global public health, there is a need for clinical understanding of the effect of SARS-CoV-2 on the CNS with respect to prevention, diagnosis, and treatment. This review analyses cases that had neurological symptoms at the onset or during the course of COVID-19 and explores the possible mechanisms underlying CNS involvement.

Coronaviruses are enveloped RNA viruses with a single-stranded positive-sense RNA genome and a spherical or oval shaped envelope of 100 nm diameter. Structural proteins encoded by the genome of human coronaviruses include the spike, membrane, envelope, and nucleocapsid proteins. The nucleocapsid protein is highly conserved across coronaviruses and increasingly expressed during the infection process; it is therefore is a key antigen for virus detection. [6] The spike protein is crucially involved in the neurovirulence of SARS-CoV-2, the coronavirus entry into the brain, and it plays a role in tropism and regulation. [7] Spike proteins cover the coronavirus envelope and can bind to ACE2 protein in the heart, lungs, kidneys, and gastrointestinal tract, which facilitates virus entry into the target cells. [8] Studies in mice found that the S1 subunit of the SARS-CoV-2 spike protein can cross the blood-brain barrier and bind to cells. [9] Among the seven known human coronaviruses, SARS-CoV-2, SARS-CoV, and the Middle East respiratory syndrome coronavirus each cause severe respiratory disease with high morbidity and mortality rates. There is 96% genomic similarity between SARS-CoV-2 and SARS-like bat coronaviruses. [8] Consequently, SARS-CoV-2 is believed to have originated from bats, with Malayan pangolins being the intermediate host. [10] SARS-CoV-2 and SARS-CoV-1 share close sequence identity. A systematic comparison among viruses revealed that the functional and pathogenic differences in SARS-CoV-2 could be attributed to amino acid substitutions. [8] SARS-CoV-2 is transmitted via respiratory droplets, the digestive tract, and aerosols. [2] It enters human cells by binding to the ACE2 protein, which is highly expressed in the airway epithelium, lung parenchyma, renal cells, and the cardiovascular and gastrointestinal systems; however, it has relatively low expression levels in the CNS. [11] Neural studies on ACE2 expression in the brain have revealed that ACE2 is expressed mainly in the cortex but also on neurons and glial cells. [12] [13] [14] Expression of ACE2 on glial cells and neurons in the brain may provide targets for the SARS-CoV-2 virus and lead to CNS infection. These findings indicate that ACE2 expression may be associated with the neurotropic potential of SARS-CoV-2. [14] [15] [16] The neuroinvasion of SARS-CoV-2 indicates that the virus can spread from the respiratory tract to the CNS, and damage the CNS by directly replicating or through the host's immune response. In addition, SARS-CoV-2 can enter the CNS by infecting the endothelial cells of the blood-brain barrier or binding with ACE2 expressed on the endothelial cells. Moreover, the cytokine storm caused by SARS-CoV-2 infection can degrade the blood-brain barrier, increase its permeability, and lead to viral entry into the CNS through infected immune cells. Therefore, the neuropathological correlates of SARS-CoV-2 infection include hypoxic/ischemic encephalopathy, acute cerebrovascular disease, encephalitis/meningitis, acute myelitis, demyelinating disorders, etc. These are caused by abnormal immune response and secondary inflammatory tissue damage [17] .

From June to August 2020, we systematically identified documents on the PubMed database regarding COVID-19 and related literature published until 31 July 2021. The following keywords were used in the search strategy to identify relevant topics: 'SARS-CoV-2' or 'COVID-19', and 'central nervous system', 'brain', 'neurology', 'neurotropism', 'neuroinvasion' 'neurovirulence', 'long-term neurological sequelae', or 'nerve injury'. The selected documents served as the final reference list.

The clinical manifestations of SARS-CoV-2 infections include fever, cough, pneumonia, and multiple organ dysfunction. A study on patients with COVID-19 in Wuhan, China reported that 36·4% (78/214 patients) presented CNS symptoms, including headaches, dizziness, and altered mental status. [18, 19] Moreover, some patients developed epilepsy, consciousness disorders, and CVD. [3] The clinical manifestations of nervous system damage caused by SARS-CoV-2 also include olfactory and gustatory disorders, toxic-metabolic encephalopathy, and encephalitis.

There is a relatively high incidence of headaches among patients with COVID-19. [20] A systematic review and analysis of 138 hospitalised patients with COVID-19 revealed 6·5-8·0% headache and 9·4% dizziness incidence rates. [21, 22] The pathological association between headaches and COVID-19 remains unclear. Neuroinflammation caused by cytokines released by nociceptors in the nervous system can cause headaches; therefore, the mechanism underlying headaches in COVID-19 patients may involve cytokines and chemokines released by macrophages. [23] A survey of patients with COVID-19 in Spain reported that 57·4% (483/841) of patients presented varying degrees of neurological symptoms, with headaches (14·1%, 119/841 patients) and dizziness (6·1%, 51/841 patients) being reported in the early stages of infection. [24] A retrospective cohort study on confirmed COVID-19 cases reported that patients with headache had a lower risk of mortality. Moreover, the presence of headache was an independent predictor for mortality risk among patients with COVID-19. [25] There is a need for further studies to clarify the mechanism underlying the manifestation of neurological symptoms in COVID-19 patients. Clinicians should monitor neurological symptoms closely for prompt prevention of complications.

Olfactory and gustatory disorders are common clinical manifestations of COVID-19, with some studies suggesting a possible correlation between olfactory disorders and COVID-19 severity. [26] A study on 72 patients with COVID-19 reported that they presented varying degrees of olfactory and gustatory disorders. [27] While children with COVID-19 often present mild respiratory symptoms, there are reports of children presenting with olfactory and gustatory disorders. [28] A European survey on 72 patients with COVID-19 revealed that 74% (53 cases), 69% (50 cases), and 68% (49 cases) of the patients exhibited hyposmia, hypogeusia, or both symptoms, respectively. A recent autopsy report of two patients with severe COVID-19 revealed leukocyte infiltration and focal mucosal atrophy in the olfactory epithelium. [29] The pathophysiological mechanism underlying the SARS-CoV-2 effects on the olfactory system remains unclear; however, it may be related to ACE2 expression on the sustentacular and basal cells, which increases their virus susceptibility. [30] 

An analysis of 214 patients in Wuhan, China found that 78 (36·4%) cases presented with neurological manifestations. The most common symptoms were headache (16·8%, 36 cases) and dizziness (13·1%, 28 cases); patients with disorders of consciousness accounted for 16 (7·5%) cases. Severely ill patients were more prone to acute CVD, disorders of consciousness, and skeletal muscle injury. [3] Disorders of consciousness in patients with COVID-19 may be associated with direct neuronal infection and subsequent damage of the brain parenchyma. Additionally, toxic encephalopathy, epilepsy, or demyelinating disease could cause impaired consciousness.

Patients with encephalopathy present mainly with delirium, lethargy, and impaired attention. A 53-year-old woman who was admitted due to cough, fever, and altered mental status was found to have acute haemorrhagic necrotising encephalopathy; magnetic resonance imaging showed haemorrhagic lesions. [31] Another study reported that among 82 confirmed cases of COVID-19 with neurological complications, 19 cases (23%) developed encephalitis or encephalopathy. [32] A recent study describing three patients with COVID-19 who developed encephalitis or encephalopathy reported that their cerebrospinal fluid analysis showed elevated anti-S1 IgM levels; the levels of the interleukins IL-6, IL-8, and IL-10 were significantly increased, but the virus was not detected in the cerebrospinal fluid. [33] In another confirmed COVID-19 case, a 59-year-old woman with aplastic anaemia developed disorders of consciousness and epileptic seizures 10 days after presenting with fever, cough, and headache. Computed tomography revealed diffuse brainstem swelling and other lesions indicative of severe encephalopathy; the patient died on the eighth day of admission. [34] In another case of aplastic anaemia, the patient developed acute necrotising encephalopathy after SARS-CoV-2 infection with brainstem swelling and haemorrhagic lesions. [34] A prospective, multicentre, observational study in New York found that 606 (13.5%) of 4491 patients infected with SARS-CoV-2 developed neurological diseases, including toxic-metabolic encephalopathy (6.8%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). [35] Encephalitis

The first reported case of meningitis/encephalitis associated with SARS-CoV-2 was of a 24-year-old patient admitted due to convulsions with unconsciousness and seizures. A 60-year-old patient infected with SARS-CoV-2 presented only mild breathing abnormalities but developed encephalitis. Cerebrospinal fluid analysis revealed elevated IL-8 and tumour necrosis factor (TNF)-α levels, while electroencephalography exhibited generalised θ-wave slowing. [36] A study on 29 patients with COVID-19 who required ventilator support in the intensive care unit (ICU) reported that six cases (20·6%) showed CNS involvement. Among them, magnetic resonance imaging revealed meningo-encephalitic lesions in three cases. Cerebrospinal fluid analysis did not detect pleocytosis, and virological testing was negative. [37] Acute disseminated encephalomyelitis, a relatively rare immune-mediated CNS disease, has also been reported after SARS-CoV-2 infection. [38] Acute CVD Between 23 March and 7 April 2020, five patients in New York aged < 50 years were diagnosed with COVID-19 and presented with new-onset symptoms of large-vessel ischaemic stroke; the average U.S. National Institutes of Health Stroke Scale score was 17 points (range: 0-42 points). [39] A retrospective study on the COVID-19 epidemic in Wuhan, China reported that older patients with risk factors were more likely to develop CVD; 5% of hospitalised patients with COVID-19 developed acute ischaemic stroke, with the youngest patient being 55 years old. [40] A recent retrospective neuroimaging cohort study reported that patients with COVID-19 showed manifestations of vascular involvement in both the central and peripheral nervous systems. [41] Patients with COVID-19 have increased plasminogen levels; plasminogen-related hyperfibrinolysis can increase D-dimer levels in severely ill patients and is often complicated by coagulopathy and vascular endothelial cell dysfunction. [42, 43] Critically ill patients with COVID-19 are more susceptible to acute cerebrovascular events, which may be associated with severe thrombocytopenia and elevated D-dimer levels. [44] Possible mechanisms underlying nerve damage induced by SARS-CoV-2

A recent report documented a 40-year-old woman with type 2 diabetes and obesity who was admitted to the hospital due to fever, syncope, and encephalitis. Cerebrospinal fluid analysis using a reverse transcription-polymerase chain reaction was positive for SARS-CoV-2. [45] Consequently, this was considered a case of SARS-CoV-2 encephalitis. Since the SARS-CoV-2 infection was confined entirely to the CNS, and there was no involvement of other organ systems, it was speculated to have been caused by direct viral infection of the CNS. There is also a recent report of SARS-CoV-2 being detectable in the brains of humans and mice, suggesting that SARS-CoV-2 has a neuroinvasive capacity and can infect neurons directly. [46] However, there are reports of virus being undetectable in the cerebrospinal fluid of patients infected with SARS-CoV-2, which might be related to systemic disease severity and viral neurotropism. [47] [48] [49] The presence of SARS-CoV-2 in the cerebrospinal fluid remains a controversial topic that requires further investigation. [50] Retrograde neuronal pathways By infecting peripheral neurons, viruses can gain access to the CNS through axonal transport mechanisms. [51, 52] Viruses can infect sensory or motor nerve endings and achieve retro-or anterograde neuronal transport. [53] The nasal respiratory tract is the main route for SARS-CoV-2 transmission. In a summary report on 72,314 cases, the Chinese Centre for Disease Control and Prevention showed that 62% of 44,672 confirmed cases of COVID-19 had positive viral nucleic acid tests of throat swab samples. [54] The olfactory nerve is composed of olfactory sensory neurons, which have dendrites that project into the nasal cavity; moreover, axons extend to the olfactory bulb via the cribriform plate. Although the olfactory bulb can effectively control viral entry into the CNS, [55] coronaviruses can enter the brain through the olfactory mucosa and olfactory tract during the early infection stages. [56, 57] Research has shown that olfactory bulb ablation can limit CNS invasion by coronaviruses. [58, 59] This suggests that the olfactory nerve and olfactory bulb provide CNS entry for many viruses. [60] A recent study found that the SARS-CoV-2 virus was detected in the olfactory neurons of COVID-19 patients. [61] These results indicate that coronaviruses can gain access to the CNS via retrograde neuronal transmission.

Viruses can enter the CNS and other sites by infecting leukocytes or the endothelial cells of the blood-brain barrier. [56, 62, 63] The blood-brain barrier is composed of vascular endothelial cells, astrocytes, pericytes, and the extracellular matrix. Since all vascular endothelial cells can express ACE2, SARS-CoV-2 can enter the CNS by binding to this membrane-bound enzyme on the capillary endothelial cells of the blood-brain barrier. [64] Additionally, viruses can cross the bloodbrain barrier by infecting peripheral leukocytes that enter the CNS through blood circulation. Systemic inflammatory cytokines, chemokines, and other soluble mediators induced by SARS-CoV-2 may also damage the blood-brain barrier, which increases its permeability and, thus, allows entry of viruses and infected immune cells into the CNS. [65] 

The antiviral immune response is crucial for pathogen elimination from the body. However, the cytokine storm resulting from excessive and abnormal host immune response can cause systemic inflammatory response syndrome. Increased inflammatory cytokine levels can also cause cognitive decline. [66] SARS-CoV-2 infection of epithelial cells, dendritic cells, and macrophages of the respiratory tract induces secretion of antiviral factors (interferons), pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and chemokines. [23] Another study reported that compared with mildly ill patients, severely ill patients showed significantly elevated levels of serum granulocyte colony-stimulatory factor (GCSF), IP-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and TNF-α. These studies indicate a positive correlation between cytokine storms and disease severity. [18] There is increasing evidence that patients with severe COVID-19 may experience such a cytokine storm. [67, 68] Compared to non-ICU patients, critically ill ICU patients were found to have higher plasma levels of IL-2, IL-7, IL-10, GCSF, IP-10, MCP-1, MIP-1α, and TNF-α; this suggests that the presence of cytokine storms is related to disease severity. [18] Viral replication may cause epithelial and endothelial cell apoptosis, as well as vascular leakage, and therefore trigger the release of pro-inflammatory cytokines and chemokines. [69] Critically ill patients often present increased IL-6 and IL-8 levels, as well as decreased lymphocyte counts, especially for CD4-and CD8-positive cells, which can predict disease characteristics and progression. The impairment of immune cytotoxic functions is dependent on IL-6 [70] ; additionally, IL-6 may serve as a biomarker for early detection of COVID-19 progression. [71] [72] [73] [74] The activation of immune cells and the increase of inflammatory factors may cause chronic inflammation of the brain and CNS complications. Moreover, tocilizumab (an IL-6 receptor blocker) can control the COVID-19-induced cytokine storm to a certain extent. [75] Immune cell activation can cause chronic inflammation and nerve damage in the brain. In summary, these results show that SARS-CoV-2 can trigger cytokine storms and neuroinflammatory responses by activating mast cells, neurons, glial cells, and endothelial cells. [76] 

Pulmonary inflammation in patients with SARS-CoV-2 can impair gas exchange, which leads to hypoxia in the CNS followed by cerebral vasodilation and interstitial oedema. Patients with COVID-19 may develop venous or arterial thromboembolism resulting from inflammation and hypoxia; this can cause complications that include ischaemic stroke, myocardial infarction, and pulmonary embolism. [77, 78] Patients with COVID-19 may develop coagulopathies caused by cytokine storms or sepsis, which can cause stroke. [79] Sepsis-induced coagulopathy is a precursor to disseminated intravascular coagulation, which can result in prolonged prothrombin time, elevated D-dimer levels, and thrombocytopenia with subsequent endothelial dysfunction and microthrombosis. [80] A retrospective cohort study on 466 patients with COVID-19 reported that critically ill patients had significantly increased occurrences of thrombocytopenia, prothrombin time, and levels of D-dimer and fibrin degradation products. [81] Most fatal cases of severely ill COVID-19 patients involved intracranial haemorrhage or pulmonary embolism, [82] which is consistent with COVID-19-induced coagulopathy. [83] Recent animal studies also suggest that severe SARS-CoV-2-infected mice developed thrombosis and vascular inflammation. [84] ACE2 ACE2 is an important element of the renin-angiotensin-aldosterone system. It is widely expressed in the human lung parenchyma, airway epithelium, kidneys, small intestine, and vascular endothelial cells; thus, it can be found throughout the body and CNS. [52, 85] ACE2 counters the effects of ACE1 and angiotensin-II, and therefore exerts cardiovascular protective effects. The spike protein of SARS-CoV-2 has a high affinity for ACE2, which makes ACE2 a key target for vaccine and antibody development. [86] The strong affinity of SARS-CoV-2 to the human ACE2 protein has resulted in its high pathogenicity. [87] Previous studies have detected ACE2 activity in the human cerebrospinal fluid; a recent immunocytochemistry study using mixed neurons derived from human pluripotent stem cells reported found high ACE2 expression in neuronal cell bodies and lesser expression in axons and dendrites. [88] Although this study did not use human brain tissue, it provides evidence of neuronal expression of ACE2 that makes neurons a possible target for SARS-CoV-2. [88] Infection of a mouse model expressing human ACE2 protein with SARS-CoV-2 showed high viral loads in the lungs, trachea, and brain. [89] SARS-CoV-2 binding to ACE2 may abnormally increase blood pressure and consequently increase the risk of cerebral haemorrhage. Moreover, SARS-CoV-2 can access the CNS by binding to ACE2 protein on vascular endothelial cells of the blood-brain barrier. [14, 56] Since ACE inhibitors result in increased ACE2 expression, future studies could explore whether patients with hypertension and diabetes who use ACE inhibitors are more susceptible to SARS-CoV-2 infection. [90] Long-term sequelae of nervous system and possible mechanisms Although various countries are actively developing antiviral drugs and vaccines, the long-term nervous system sequelae caused by SARS-CoV-2 is attracting more and more attention. [91] [92] [93] In the follow-up of 797 patients, 509 patients had sequelae within 6 months after discharge; neurological sequelae accounted for 20.8%. [94] From January 17 to August 4, 2020, a prospective, multicentre cohort study of 73197 hospitalized COVID-19 patients in the UK found that 4.3% (3115 patients) had neurological complications. [95] Studies have shown that the direct or indirect injury of neurons by SARS-COV-2 can cause mental disorders and cognitive impairment of nervous system. [96] [97] [98] The magnetic resonance imaging of 51 patients with COVID-19 taken 3 months after discharge was analysed [99] and, compared with the healthy control group, severe patients appeared to have indirect damage to the brain related to inflammatory factors (e.g., C-reactive protein, procalcitonin, and IL-6), especially in the thickness of the cerebral cortex; decreased cerebral blood flow and white matter microstructure changes are more serious, causing changes in brain volume, blood flow and white matter tracts, which may be one of the reasons for the long-term sequelae of the nervous system. In an investigation of 29 cognitively impaired COVID-19 patients, performed 3-4 months after discharge, it was found that language learning and executive functions were the most affected. Such patients should be systematically screened and targeted treatment. [100] The problem of cognitive impairment still requires further research. [101] Six months after acute infection, COVID-19 survivors are mainly troubled by fatigue or muscle weakness, sleep difficulties, and anxiety or depression; these are the main targets of long-term rehabilitation intervention. [102] In addition, studies have shown that about 30% of patients diagnosed with COVID-19 report persistent olfactory dysfunction. [103] A follow-up survey conducted on 55 COVID-19 subjects who experienced a loss of smell between the end of February and the beginning of March 2020 found that 91% of the patients recovered their sense of smell after eight months, 53% of which were fully recovered. [104] COVID-19 infection has a greater effect on patients with pre-existing neurological diseases; patients with Alzheimer's disease and dementia have a relatively higher risk of severe COVID-19 infection and neuropsychiatric disorders. [105] ACE2 is widely expressed in cerebral vascular endothelial cells. The high affinity of SARS-CoV-2 spike glycoprotein for ACE2 can damage the integrity of the blood-brain barrier to varying degrees. [106] In addition, cytokine storms, hypoxia, and coagulopathy can all reduce the integrity of the blood-brain barrier; any one or a combination of these could become the potential basis for long-term sequelae of the nervous system. [107, 108] Systemic inflammation can cause cognitive decline and neurodegenerative diseases, [109] which may result in neurodegeneration in patients with COVID-19 in the next few years. [110, 111] COVID-19 patients are likely to have activation of the NLRP3 inflammasome, [108] which can directly induce or aggravate the neurodegenerative process that leads to Alzheimer's disease. [112] In addition, NLRP3-driven and IL-1β-mediated regulation of phosphokinases and phosphatases play a role in the pathological formation of neurofibrillary tangles, which may induce or aggravate neurodegeneration in patients with COVID-19. [113] Studies have revealed that the ACE2 protein in the brain of Alzheimer's disease patients is up-regulated, and there is a moderately positive correlation between the increased expression of ACE2 protein and oxidative stress. [114] This could be one possible factor related to the long-term nervous system sequelae caused by the SARS-CoV-2 virus.

The effects of SARS-CoV-2 on the CNS may cause acute and long-term changes of the nervous system or aggravate existing neurological diseases or symptoms. Long COVID refers to diseases in people that have recovered from COVID-19 infection but are still affected by the persistence of infection, or that the duration of symptoms is much longer than expected. Long-term COVID can affect several systems, including the respiratory system, cardiovascular system, and nervous system. Patients experience symptoms that include fatigue, dyspnoea, cardiac abnormalities, cognitive impairment, sleep disorders, post-traumatic stress disorder, muscle pain, concentration problems, and headaches. [115] SARS-CoV-2 neuropathology-related factors include the SARS-CoV-2 spike protein binding with ACE2 on host cells; SARS-CoV-2 can interrupt the ACE/ACE2 balance and activate the renin angiotensin aldosterone system activation, leading to disease progression in patients with hypertension, diabetes, and cardiovascular disease. SARS-CoV-2 can enter the CNS through the blood-brain barrier through the blood-derived pathway, and systemic inflammatory response will further increase the permeability of the bloodbrain barrier; this promotes the invasion of infected immune cells into the CNS. Immune responses and inflammatory mediators can also neuropathologically cause brain injury. Because of COVID-related hypoxia, the increase of inflammatory factors and coagulation dysfunction caused by SARS-CoV-2 will increase the incidence of cerebrovascular disease; therefore, reducing hypoxia and protecting the brain from cytokines are important therapeutic goals. Because SARS-CoV-2 can activate the immune system and increase systemic inflammatory factors, immunomodulatory interventions may be needed in COVID-19 patients in the future to reduce the acute and long-term nervous system complications related to SARS-CoV-2 infection.

In future research, determining how to reduce the nervous system invasion and neurotoxicity of SARS-CoV-2 through drugs is a problem that needs to be solved. This long-term work requires personal efforts, government intervention, and full cooperation among countries to minimize the infection rate. In the future, people will have to monitor the effects of COVID-19 on the human nervous system for a long time to make detailed assessments, diagnoses, and treatment plans. Future studies need to clarify the effects of SARS-CoV-2 on human cognitive function and neurodegenerative diseases. Clarification of the mechanism of SARS-CoV-2 on the brain needs to be combined with the study of delayed neuropsychiatric sequelae; this will require a large amount of worldwide clinical epidemiological data. Clinical and basic research also needs to be promoted; in particular, nonspecific neurological complications caused by hypoxic encephalopathy need to be distinguished from neurological manifestations that are directly or indirectly caused by viruses. [116] For patients with COVID pneumonia with a neurological symptom as the first symptom, timely diagnosis and identification are of great importance in preventing sequelae in the nervous system. Further research should focus on elucidating the pathophysiology and risk factors for COVID-19-related neurological complications to improve its prognosis, as well as reduce its social, medical, and economic burdens. SARS-CoV-2 can enter the CNS by infecting the endothelial cells of the blood-brain barrier or binding with ACE2 expressed on endothelial cells. In addition, the cytokine storm caused by SARS-CoV-2 can destroy the blood-brain barrier, increase its permeability, and enter the CNS through infected immune cells. In addition, SARS-CoV-2 can enter the CNS through blood circulation. The virus-induced increase in cytokine levels could cause coagulopathies, which result in cerebral thrombosis or bleeding disorders. This figure was created by an author using the website https://app.biorender.com. 

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Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice

Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins

A comprehensive investigation of the mRNA and protein level of ACE2, the putative receptor of SARS-CoV-2, in human tissues and blood cells

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Nervous system involvement after infection with COVID-19 and other coronaviruses

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Inflammatory olfactory neuropathy in two patients with COVID-19

Olfactory and Gustatory Dysfunction in Coronavirus Disease 19 (COVID-19)

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Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease

COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia

A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in

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Nervous System Involvement in COVID-19: Results from a Retrospective Consecutive Neuroimaging Cohort

Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility

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Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures

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Neuroinvasion of SARS-CoV-2 in human and mouse brain

Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid

Guillain-Barré Syndrome Associated with SARS-CoV

Miller Fisher syndrome and polyneuritis cranialis in COVID-19

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Viral diseases of the central nervous system

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Early evidence of pronounced brain involvement in fatal COVID-19 outcomes

Coagulopathy and Antiphospholipid Antibodies in Patients with

COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

SARS-CoV-2 Receptor and Regulator of the

Celebrating the 20th Anniversary of the Discovery of ACE2. 2020

Expression of ACE2 in Human Neurons Supports the Neuro-Invasive Potential of COVID-19 Virus

A Mouse Model of SARS-CoV-2 Infection and Pathogenesis

Neurologic complications of coronavirus infections

Cognitive impact of COVID-19: looking beyond the short term

Alzheimer's research & therapy 2020

Multiple Neuroinvasive Pathways in COVID-19

Neurological associations of COVID-19

Sequelae, persistent symptomatology and outcomes after COVID-19 hospitalization: the ANCOHVID multicentre 6-month follow-up study

Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study

Neuropsychiatric and Cognitive Sequelae of COVID-19

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study. The Lancet Respiratory medicine

The chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning

Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations

Cognitive impairments four months after COVID-19 hospital discharge: Pattern, severity and association with illness variables

Central Nervous System Manifestations of COVID-19: A Critical Review and Proposed Research Agenda

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Randomized clinical trial "olfactory dysfunction after COVID-19: olfactory rehabilitation therapy vs. intervention treatment with Palmitoylethanolamide and Luteolin

Anosmia in the first coronavirus disease 2019 outbreak in Europe: functional recovery after eight months

The effects of the COVID-19 pandemic on people with dementia

Lifting the mask on neurological manifestations of COVID-19

Medical science monitor : international medical journal of experimental and clinical

Immediate and long-term consequences of COVID-19 infections for the development of neurological disease

Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients

Long-term cognitive impairment and functional disability among survivors of severe sepsis

Long-term cerebral consequences of sepsis

NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice

NLRP3 inflammasome activation drives tau pathology

Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer's Disease

Long covid-mechanisms, risk factors, and management

Neurological associations of COVID-19

Figure Legends Figure 1. Mechanism underlying SARS-CoV-2 damage to the CNS: the olfactory nerve pathway

The olfactory sensory neurons extend axons to the olfactory bulb and pass the virus through the axonal transport mechanism to the CNS. B) SARS-CoV-2 can also spread to neuronal cell bodies through trans-synaptic transfer via exocytosis and endocytosis between synapses. This shows that SARS-CoV-2 can enter the CNS through the retrograde neuronal pathway