The characteristics of SARS-CoV-2
SARS-CoV-2 was an enveloped positive single-stranded RNA virus, belonging to the genus B coronavirus [75-76].The genomic sequence of the infected patients with SARS-CoV-2 has 79.5% genetic similarity to SARS-CoV, about 50% homology to MERS-CoV [77-79], and 96% genetic similarity to bat coronavirus .SARS-CoV-2 contains four structural proteins (spines (S), envelope proteins (E), membrane proteins (M) and nucleocapsid proteins (N)) and 16 non-structural proteins (NSP1 −16).The entry of coronavirus into host cells is mediated by spiking glycoprotein (S protein), so spiking glycoprotein is the key for the entry and infection of coronavirus .Tang X. et al. found a total of 149 mutations in 103 SARS-CoV-2 genomic strains .The most easily altered sequence in the coronavirus genome is the receptor binding domain (RBD) of the S gene [82-83]. Up to now, 13 mutations have been found in Spike proteins.D614G mutation in Spike protein increases infectivity and transduction of a variety of human cell types. D614G mutation also reduces serum neutralization sensitivity of COVID-19 patients during recovery [85-86].
Evidence of neurological damage in COVID-19 patients
Firstly, according to our meta-analysis, the most common neurological manifestations of COVID-19 patients were altered mental status(39%) and encephalopathy (37%).Then, myalgia (31%), Headache (30%), smell impairment (28%), taste dysfunction (27%), acute ischemic stroke (23%), vision impairment (5%) and seizure (2%) were less common. Among them, smell impairment and taste dysfunction appeared earlier. This suggests that SARS-CoV-2 will affect functional areas such as temporal lobe, parietal lobe and occipital lobe, which will lead to clinical manifestations of the nervous system in patients.
Secondly, the etiological evidence are as follows：(1) Evidence related to cerebrospinal fluid: On March 8, 2020, Moriguchi et al. reported evidence of SARS-CoV-2 in cerebrospinal fluid for the first time in Japan .On June 20, 2020, Domingues et al. reported that the SARS CoV-2 virus genome was detected in cerebrospinal fluid and sequenced, and its sequence similarity with that of the world virus was 99.74-100%.(2) Autopsy evidence: Remmelink et al. conducted an autopsy study on August 12, 2020 on 17 adult patients with CoviD-19, and the results showed that SARS-CoV-2 RNA was found in 9 out of 11 brain samples .Other studies have also demonstrated that SARS-CoV-2 RNA or viral protein can be detected in the brain, olfactory bulb, trigeminal ganglion, medulla oblongata and cerebellum .At the same time, autopsy results of brain tissue of patients with CoviD-19 death showed edema, hemorrhage, infarction, atrophy, encephalitis, olfactory bulb asymmetry, glial cell proliferation, neuron loss or degeneration, etc. [91,107-109].(3) Experimental evidence: Zheng et al.  found that the primary target organ of SARS-CoV-2 was the lung in the early stage and the brain in the late stage by studying the K18-HCE2 mouse model.At 6 days after infection, immunostaining showed extensive staining in cerebral cortex, caudate nucleus/putamen, thalamus, hypothalamus, ventral striatum, olfactory bulb and other brain regions, as well as sublingual and postlingual nuclei.
Biomarkers reflecting nervous system damage in COVID-19 patients
A prospective study showed that total Tau, GFAP, and NFL protein levels in cerebrospinal fluid were elevated in 63%, 37%, and 16% of patients, respectively, and NFL protein was associated with disease severity, duration of intensive care and level of consciousness .Multiple studies on COVID-19 patients with ischemic stroke have shown that the neutrophil-lymphocyte ratio (NLR) is increased in 90% of the patients , CRP is increased in over 90% of the patients , and serum ferritin is also increased , in which serum ferritin can also predict the degree of nerve injury in patients with acute ischemic stroke .There was a significant correlation between the decrease of interleukin-6 level and the improvement of olfaction and taste function in COVID-19 patients .Elevated serum nerve filament light chain (SNFL) levels in critically ill patients with COVID-19 are closely associated with poor prognosis .
Examination methods reflecting nervous system damage in COVID-19 patients
In the early stages, acute thromboembolic infarction is the most common intracranial presentation. At present, the most common neurological imaging findings of acute infarction with a large number of blood clots, and intracranial hemorrhage (brain hemorrhage, subarachnoid hemorrhage, subdural hemorrhage or bleeding), the second including leukoencephalopathy, total lack of injury (basal ganglia, globus pallidus, hypothalamus, hippocampus and cortex), meningitis, and encephalitis, corpus callosum lesions, the olfactory bulb lesion, cranial nerve, spinal lesions and long-term changes in diffusion tensor imaging of the brain.Covid-19 is an independent risk factor for acute ischemic stroke, which is a valid indicator of poor prognosis.Meningitis and encephalitis are not very common [117-118].In one study, continuous EEG monitoring was performed in 11 of 16 patients with Covid-19, most of which showed non-specific encephalopathy.
Mechanisms of nervous system injury in COVID-19 patients
(1) ACE2：ACE2 has been proved to be a functional receptor of SARS-CoV-2, which binds to the ACE2 receptor through its Spike (S) protein C-terminal domain (CTD) .The expression profile of ACE2 is very extensive, and it is expressed in various regions of human brain, such as ventricle, motor cortex and posterior cingulate gyrus, middle temporal gyrus, substantia nigra, olfactory bulb, ventrolateral medulla oblongata, nucleus solitarius, vagus nerve, neurons, astrocytes, microglia and oligodendroglias, etc [120-121].Therefore, the nervous system is at risk of SARS-COV-2 infection.
(2) AXL and NRP1：It is worth noting that, in addition to ACE2, recent studies have shown that receptor tyrosine kinase AXL is a new phenotype receptor of choice for SARS-CoV-2, and AXL is widely expressed in almost all human organs, especially in human lung and bronchial epithelial tissues and cells, the expression of AXL is much higher than that of ACE2 .AXL is also found in cells in the brain, including radiating glia, astrocytes, and microglia .Another cellular mediator, neurociliary protein-1 (NRP1), also promotes the entry of SARS-CoV-2 into host cells, thereby increasing its infectivity.NRPs are involved in a variety of physiological processes, including neuronal development and axon control. Studies have observed high expression of NRP1 in olfactoric epithelial cells infected with SARS-CoV-2 [124-125].Therefore, AXL and NRP1 provide us with new research directions and intervention targets.
(3) Cross-neuronal hypothesis: Results from an animal experiment showed that SARS-CoV-2 may invade the brain retrograde along taste and trigeminal pathways in the early stage of infection .Some studies also found significant structural changes in olfactory nerve, olfactory bulb, olfactory cortex and other olfactory pathways in the MRI examination of CoviD-19 patients, suggesting that SARS-CoV-2 may enter the central nervous system through the olfactory bulb mediated cross-neuronal pathway [95-96].
(4) Hemogenous transmission and BBB transmission: viruses can infect the central nervous system by infecting BBB endothelial cells, acquiring access or infecting white blood cells .Perrin et al  found in an in vivo study that SARS-CoV-2 may also invade the central nervous system through the impaired blood-brain barrier.In addition, it has also been found that SARS-CoV can infect monocytes and macrophages and migrate through the blood-brain barrier.
(5) Hypoxia: Patients with COVID-19 are highly hypoxic, and persistent hypoxia can eventually lead to disorders in neurotransmitter metabolism, mitochondrial failure, and intracellular Ca2+ accumulation.The immediate consequence is irreversible nerve damage and even neuronal death, which increases the risk of stroke .
(6)Inflammatory response and hypercoagulability: The inflammatory response of severe pneumonia is not limited to lung tissue; when the systemic inflammatory response is activated, its amplification cascade impairs the function of distal organs .Intravascular coagulation secondary to systemic inflammation is the main cause of thrombosis, bleeding and stroke .
(7) Immune mechanism: After SARS-CoV-2 enters the human body through ACE2, the host triggers an immune response to the virus.When the virus invades the human brain, it will cause immune damage, causing brain damage and acute or chronic inflammation, thus forming a vicious cycle .
Prognosis of nervous system injury in COVID-19 patients
Nervous system damage is closely associated with the mortality of SARS-COV-2 infection, and whether the neurological symptoms are reversible is not yet clear.Patients with COVID-19 who require ICU admission for neurological problems or develop neurological dysfunction in the ICU have significantly increased mortality .In one animal study, 4 out of 14 infected mice developed significant respiratory distress and neurological symptoms 2 days after infection, and only the mice showing neurological symptoms died, suggesting that neurological involvement may be a cause of death .Some studies have confirmed that recovery from acute SARS-CoV-2 infection does not completely clear the virus, and has been found to have a higher potential risk for long-term residual neuropsychiatric and neurocognitive impairments, including depression, obsessive-compulsive disorder, psychosis, Parkinson's disease and Alzheimer's disease .An experimental animal study has also shown that coronavirus can persist in the central nervous system of its host .The study results of Helms et al. showed that 36% of severe COVID-19 survivors developed Dysfunction Syndrome , and some studies also reported that patients with severe Dysfunction after the acute phase had significant recovery after active neurological rehabilitation .In a prospective study, 68.33% of patients developed neurological symptoms during infection with SARS-CoV-2, and 50% recovered 3 months after infection but still had neurological symptoms .Imaging results of 60 patients after recovery of COVID-19 neurological symptoms suggest that the microstructure and functional brain integrity of the brain may be damaged during the rehabilitation phase, which may require long-term neurological and neuroimaging follow-up .
Advantages and disadvantages of this study
Our meta-analysis, involving 32,729 patients, detailed various common neurologic symptoms in COVID-19 patients and provided a comprehensive view of COVID-19 neurologic symptoms. The results were comprehensive.We started the discussion from the clinical manifestations, and analyzed the evidence, possible mechanism and prognosis of the nervous system injury caused by SARS-CoV-2.We also discussed the biomarkers and examination methods of nervous system injury caused by SARS-COV-2, providing some valuable suggestions for early identification, monitoring, screening, diagnosis and follow-up of nervous system injury and poor prognosis in patients with COVID-19 and potential targets for future clinical intervention strategies.
This study also has some limitations.Firstly, most of the included literatures were retrospective studies, which may cause some potential bias. Secondly, this study failed to provide an analysis of the correlation between various neurological manifestations and disease severity and mortality. The question of which neurological manifestations are the most insidious and which are the most difficult to recover from is currently unanswered, and more findings are needed in the future. Finally, the high degree of heterogeneity in our study may be due to differences in patient race selection, disease severity, comorbidities, only a few studies specifically assessed neurological symptoms, differences in the number of patients in different studies, or due to differences in publication bias and study methodology.