Introduction

Coronavirus disease 2019 (COVID-19), a consequence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, emerged in Wuhan, China, in December 2019 and spread globally with a massive impact on the health system, community relations, and economics [1]. According to the World Health Organization (WHO), there are 25,327,098 confirmed cases of COVID-19 and 848,255 confirmed deaths in 216 countries, areas, and territories until September 1, 2020. The SARS-CoV-2 is most closely related to the beta-coronaviruses (beta-CoVs) genus, which mainly infects the human respiratory system. Human beta-CoVs include the Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV), and SARS-CoV-2. They contain a single-stranded (positive-sense) RNA genome surrounded by a membrane envelope and use their spike (S) proteins to infect the host cells [2, 3]. The S protein in SARS-CoV-2 predominantly exploits human protein receptors, named angiotensin-converting enzyme 2 (ACE2), in the cell surface to invade the human cells. Considering the genomic analysis, SARS-CoV-2 has high homological sequence similarity with SARS-CoV; however, the tendency of SARS-CoV-2 to ACE2 is 10- to 20-fold higher compared to SARS-CoV [4, 5]. SARS-CoV-2 primarily invades the lungs and creates COVID-19, which is a complex multi-system disease that affects several human organs, including the respiratory, cardiovascular, gastrointestinal, and hematopoietic, as well as immune and nervous systems [6,7,8,9,10]. In a considerable portion of infected patients, COVID-19 presents a moderate illness. On the other hand, respiratory failure and pneumonia, as well as multi-organ dysfunction and septic shocks, characterize patients with severe disease [10,11,12,13]. According to clinical observation, in addition to common respiratory symptoms, neurological manifestations have been reported particularly among COVID-19-hospitalized patients with severe or critical illnesses [14,15,16,17]. Concordant with other CoVs, neurological complications associated with SARS-CoV-2 have been reported. These complications generally are related to both central and peripheral nervous systems (CNS and PNS, respectively) with no distinguished underlying mechanism [16, 17]. Indeed, due to the specific immunity, including a multilayer blood-brain barrier (BBB), and effective immune responses, the nervous system is highly protected from the invasion of pathogenic agents [18, 19]. While the nervous system invasion is not a selective advantage for viruses, it has been demonstrated that some zoonotic RNA viruses, including CoVs, introduce adverse effects on the nervous system [18, 20, 21]. Neurological complications of COVID-19 may include either a rare direct infection of nerve ends or through the secondary or systemic effects of immune system malfunction and vascular system dysregulation [17, 18]. Several studies have described COVs, particularly SARS-CoV-2, as neurotropic viruses with neuroinvasive capabilities that directly invade the CNS through neuronal retrograde routes and result in neurological pathologies such as encephalomyelitis [14, 22,23,24,25,26]. Detection of SARS-CoV-2 and other CoVs, particularly SARS-CoV in the cerebrospinal fluid (CSF) of infected patients, provides additional support to the potential neuroinvasive contribution of SARS-CoV-2 [25,26,27,28,29,30,31].

One of the most widely accepted neurological complications of SARS-CoV-2 is related to immune system malfunction. Dysregulation of adaptive and innate immune system responses has been extensively reported in CoV-related infections including SARS-CoV, MERS-CoV, and severe cases of SARS-CoV-2 [11, 13, 21, 32, 33]. Accumulating evidence indicates that overreacting of the innate immune system results in the uncontrolled release of cytokines and chemokines in patients with severe COVID-19. As a result, it leads to vascular system dysfunction and consequent BBB disruption, which may provide a path for inflammatory mediators, immune cells, and virus particles to access the CNS [34,35,36,37,38,39,40]. Moreover, it is proposed that the overproduction of inflammatory cytokines in SARS-CoV-2 infection may lead to inflammatory damage in the brain tissue. So, it may present non-specific complications, including headache, dizziness, taste, and smell dysfunctions, or impaired consciousness [21, 37, 41]. This aberrant immune response may lead to complicated chronic CNS features including long- and short-term effects, depending on different factors related to disease severity [42]. Furthermore, acute cerebrovascular disease (CVD) is commonly reported in middle-aged and elderly patients with severe or critical COVID-19 disease. Consequently, it can increase the risk of other neurological complications, including coagulation and ischemic strokes, among COVID-19 patients, which may be associated with the inflammatory response and disease severity [1, 15, 16, 41,42,43,44,45,46,47,48].

Neurological manifestations, in line with evidence about SARS-CoV and MERS-CoV cerebral involvement, support the association of COVID-19 with the nervous system manifestations during the pandemic [21]. The presence of neurological complications in COVID-19 cases may increase the likelihood of misdiagnosis among patients with neurological symptoms [15, 32]. Moreover, it is proposed that the recurrence possibility of SARS-CoV-2 may be related to virus latency in the CNS [49]. These reported neurological complications highlight the importance of understanding the correlation of the SARS-CoV-2 infection with neurological damages and its association with disease severity and mortality. This review study is aimed to describe the clinical neurological complications following SARS-CoV-2 infection and the possible routes of nervous system involvement associated with COVID-19.

SARS-CoV-2 Structure and ACE2 Tissue Distribution

Coronaviruses genetically are classified into four genera, including alpha, beta, gamma, and delta. They have a diverse genome size of 26 to 32 kb and contain a changeable number of open reading frames (ORFs). The SARS-CoV-2 genome (29,903 bp) encodes 27 proteins through 14 ORFs. ORFa/b and ORF1a are located at the 5′-terminal of the genome to generate 15 non-structural proteins (nsps). Structural and accessory proteins are furthermore encoded by remaining ORFs. The structural proteins include the membrane (M), the envelope (E), nucleocapsid (N), and S surface glycoprotein. The accessory genes distributed within the structural genes encode 8 proteins namely, 3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14 [50, 51].

CoV protein, which belongs to the typical class I viral fusion proteins, requires protease cleavage for activation. It contains two subunits S1 and S2 that contribute to attachment and membrane fusion, respectively [52]. Like SARS-CoV, SARS-CoV-2 exploits the receptor-binding domain (RBD), the most variable part of the CoVs genomes [53] in the S protein, to attach to the ACE2 receptor on the host cells. Nevertheless, the affinity rate of SARS-CoV-2 to ACE2 is higher than that of SARS-CoV [2, 5]. It has been proposed that two consecutive steps, including cleavage at “S1 and S2 junction” and “S2 cleavage site,” promote activation of S protein in SARS-CoV and MERS-CoV [54, 55]. Similar to SARS-CoV, SARS-CoV-2 S protein undergoes cleavage processing on S1-S2 junction via transmembrane serine protease 2 (TMPRSS2) and cathepsin L host proteases [56]. A functional polybasic (furin) cleavage site is located at the S1-S2 boundary of the SARS-CoV-2 S protein. Although the functional consequence of this cleavage is unknown, it may increase the infectivity of SARS-CoV-2 [57].

ACE2 is a single-peptide component of the renin-angiotensin system (RAS) and plays a pivotal role in vascular, renal, and myocardial physiology [58]. Information from databases including Protein Atlas (https://www.proteinatlas.org) and UniProt (https://www.uniprot.org), as well as published studies, has indicated that ACE2 receptor is abundantly expressed in the epithelia of the lung and small intestine [59, 60]. ACE2 receptor is also expressed in vascular endothelium and arterial smooth muscle cells of different human organs like the stomach, colon, skin, liver, kidney, and brain [59]. Furthermore, the expression of ACE2 has been detected in CNS areas including the striatum, cortex, medulla, hypothalamus, and brainstem [21, 31, 49]. Interestingly, it has been reported that both neurons and glial cells express the ACE2 receptor in the brain [29, 61].

Clinical Manifestations

COVID-19 primarily targets the human respiratory tract and thus results in a critical clinical care condition in some patients [8, 9]. The incubation period of COVID-19 varies between 3 and 14 days, leading to various ranges of clinical symptoms. However, the clinical manifestations have been remained to be elucidated completely [6, 15]. The median day at which symptoms trigger is 14, which is reduced in patients who are 70 years of age or older. The median age of death is 75, with a higher rate of infection in men [62, 63]. The spectrum of clinical presentations is complicated among COVID-19 patients and contains asymptomatic and mild cases; however, for a few, the illness can progress to severe respiratory failure, multi-organ dysfunction, and death [6, 7, 11]. In clinical evaluation, fever, cough, dyspnea, myalgia, and fatigue are the most common symptoms following the SARS-CoV-2 infection. Further uncommon symptoms, including headache, sputum production, hemoptysis, and diarrhea, have been reported as well [8, 10, 11].

To better clarify the severity of the disease, COVID-19 patients are classified into mild, severe, and critical cases [9, 10, 12]. Following fever and pneumonia, acute respiratory distress syndrome (ARDS) manifests in up to 20% of COVID-19 patients, which are considered severe cases. Progressive respiratory failure and multiple organ dysfunction besides septic shock are considerable conditions in critical cases [11, 64, 65]. Regarding laboratory findings, leucopenia and lymphopenia are the fundamental characteristics of COVID-19 infections. Most patients show elevated levels of lactate dehydrogenase (LDH), creatinine kinase (CK), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) [8, 11].

The new coronavirus is highly contagious, and older people with underlying diseases are at higher risk of severe manifestation and mortality. The most prevalent underlying comorbidities are diabetes, hypertension, cardiovascular, and CVD [10, 63, 66, 67]. In some patients, the disease progresses to pneumonia, ARDS, and death due to extreme elevation in inflammatory cytokines, including interleukin-2 (IL2), IL7, IL10, granulocyte colony-stimulating factor (GCSF), interferon-inducible protein 10 (IP10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1 A (MIP1A), and tumor necrosis factor-alpha (TNFα), especially in critical cases [11, 35].

Chest computed tomography (CT) findings showed bilateral ground-glass opacity manifestation in the middle and outer zone of the lung in severe patients [9, 68, 69]. Other CT features have reported symptoms related to lung injury such as crazy paving pattern, airway changes, and reversed halo sign [70]. Furthermore, septic shock, alongside multi-organ failure, occurs in a considerable number of patients with critical condition and high fatality risk [9, 69, 70]. Indeed, systemic inflammatory response syndrome (SIRS) may result in multiple organ dysfunction syndrome (MODS), which is observed in patients with severe infection [71]. Accordingly, cardiovascular complications have been reported in a significant proportion of patients with COVID-19 [67]. Moreover, serious liver damage related to the increased level of LDH, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) has been observed. Elsewhere, increased blood urea nitrogen and creatinine levels indicated acute kidney injury presented in a significant proportion of patients with COVID-19 [15, 71].

Neurological manifestations have been reported from COVID-19 patients as a critical aspect of the disease [14, 16, 72,73,74,75,76,77]. These manifestations include specific neurological symptoms due to the direct effects of the virus on the nervous system and non-specific neurological complications that are just systemic features of the SARS-CoV-2 infection [24, 41, 73, 78, 79]. Skeletal muscle damage in association with increased CK levels and neurological manifestations are common among patients with severe infection. Neurological symptoms indicating CNS, PNS, and skeletal muscle involvements have been reported in a considerable portion of severe cases [15, 16]. Acute CVD, including ischemic stroke, intracerebral hemorrhage, and deep cerebral venous thrombosis, was reported in 0.5–5.9% of COVID-19 patients [80, 81]. Moreover, ischemic stroke is the most prevalent acute CVD and its risk of development is higher among severe or critical COVID-19 patients ranging from 0.8 to 9.8% [16, 80, 81]. There are multiple reports of Guillain-Barre syndrome (GBS), an acute disease of the peripheral nerves induced by inappropriate immune system response in patients with confirmed COVID-19 disease [82,83,84,85,86,87,88]. However, the aberrant function of peripheral nerve ends is evident because of the observed taste, smell, vision impairment, and nerve pain. Likewise, other neurological symptoms, including dizziness, headache, impaired consciousness, acute CVD, ataxia, and seizure, indicate the central nervous system involvement in the severe COVID-19 [16, 45, 84]. Although the reports of the nervous system manifestations are increasing, our knowledge about this aspect of COVID-19 disease is still limited. Therefore, it is crucial to perform an extensive autopsy and biopsy investigations to accurately explain COVID-19 accurate clinical symptoms.

Nervous System Involvement in CoVs Infection

As observed in numerous other zoonotic viruses [18], and regarding the neurological manifestations of COVID-19 [12,13,14,15,16, 73,74,75,76,77,78, 89, 90], nervous system is likely involved in SARS-CoV-2 infection (Fig. 1). These neurological manifestations have been demonstrated in other CoV infections such as SARS-CoV and MERS-CoV, which have provided strong evidence for CoV neuroinvasive capacity [21, 91]. SARS-CoV respiratory infection was determined to represent many neurological abnormalities, including encephalitis, aortic ischemic stroke, and polyneuropathy [91]. Interestingly, several reports have documented CSF samples that were positive for SARS-CoV RNA. Also, they have evidenced monocyte and lymphocyte infiltrations in the brain, ischemic changes of neurons, and demyelinating abnormalities [92]. Autopsy studies have reliably detected SARS-CoV in brain tissue specimens of patients manifesting with neuronal edema and meningeal vasodilation [22, 30, 93, 94]. The cerebrovascular complication and neuropathological manifestations, including ischemic stroke and GBS, respectively, have been reported in patients affected with SARS-CoV, as well [91, 95].

Fig. 1
figure 1

Nervous system involvements in COVID-19 disease. CoVs can attack the nervous system through neuronal retrograde routes. PNS may provide an accessible route for SARS-CoV-2 to gain access to the nervous system and neurological symptoms may manifest due to a direct SARS-CoV-2 attack on the myelin or axon of PNS neuron (a). The activation of the immune system following the SARS-CoV-2 infection can be detrimental to the nervous system. The overexpression of pro-inflammatory cytokines and chemokines called cytokine storm may have negative effects on peripheral nerve roots and the BBB integrity (b). Hematogenous pathways may provide another route for SARS-CoV-2 toward CNS. Impaired BBB provides a path for inflammatory cytokines and immune cells to access the CNS. In the hematogenous pathways, the endothelial cells of BBB act as a bed for SARS-CoV-2 accession to CNS (c)

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Several clinical studies have confirmed the presence of neurological complications in humans upon MERS-CoV infection along with other respiratory symptoms [96]. MERS-CoV is a potentially neuroinvasive virus according to clinical reports of neurological symptoms, including loss of consciousness, ischemic strokes, seizure attacks, paralysis, and other neuropathological manifestations [97,98,99,100]. MERS-CoV infection is accompanied by severe neurological diseases like encephalitis and neuromuscular disease such as GBS. Nevertheless, there is no report on MERS-CoV detection in the CNS of humans [96,97,98]. Likewise, the symptoms of CoVs infection in kids with encephalitis, the presence of CoVs nucleic acid in the human brain, and the ability of CoVs to infect CNS cell cultures have demonstrated the neurotropic properties of CoVs. Furthermore, the induced encephalitis in newborn mice has illustrated the neuroinvasive potential of CoVs [101].

The newly emerged CoV (i.e., SARS-CoV-2) involves neurological manifestations, especially in severely affected individuals [16, 17, 102, 103]. SARS-CoV-2 neurological manifestations are reported to include symptoms related to the CNS (e.g., impaired consciousness, acute CVD, corticospinal tract signs, ataxia, and seizure), PNS (e.g., taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscle damages [104,105,106]. Headache, myalgia, fatigue, confusion, anorexia, dizziness, malaise, and dyspnea are the most frequently reported neurological symptoms, which approximately affects one-third of patients with COVID-19 [72, 78]. Skeletal muscle damage in association with increased CK levels and neurological manifestations are common among patients with severe COVID-19 infection [15, 16]. Another most common reported neurological complication is smell and taste impairments. This problem shows the varying geographical frequency with high incidence in the studies from Europe and a lower frequency in the studies from Asian countries [16, 107]. It has been demonstrated that neurological complications commonly affect patients with severe COVID-19 infection, suggesting that neurological manifestations may be related to disease severity [73].

Neurological symptoms, including CNS, PNS, and skeletal muscle involvements, have been reported in a considerable portion of COVID-19 severe cases [15, 16]. Meningoencephalitis and encephalopathy are reported in multiple studies as other neurological presentations of COVID-19. Besides, CFS analyses have demonstrated elevated levels of inflammatory cytokines related to acute encephalopathy [25, 36, 77, 108, 109]. While the incidence of encephalitis has been reported to be lower than 1% in two retrospective studies of COVID-19 [110, 111], the CSF RT-PCR test has shown the presence of SARS-CoV-2 RNA in the CSF of four COVID-19 patients [78]. The typical neurological manifestations associated with encephalitis include irritability, confusion, and reduced consciousness, and may represent seizures, headache, and neck stiffness [46, 112, 113]. Few retrospective studies have demonstrated that seizures are common in SARS-CoV-2 infection with a frequency ranging from 0.5 to 1.4% [16, 111, 114,115,116]. All types of seizures, including febrile, focal, and generalized tonic-clonic seizures [114, 117,118,119,120], as well as status epilepticus myoclonic, status epilepticus, and non-convulsive status epilepticus [121,122,123] have been reported among the symptoms of COVID-19.

Acute CVD, including ischemic stroke, intracerebral hemorrhage, and thrombotic vascular events, has been reported in middle-aged and elderly cases of COVID-19 [1, 16, 43, 44, 110]. Cerebrovascular events related to COVID-19 are likely to share similar risk factors for stroke, e.g., older age, hypertension, hyperlipidemia, diabetes mellitus, smoking, and prior strokes [80, 124,125,126]. However, accumulating reports have been reported about the large vessel strokes among COVID-19 patients without significant vascular risk factors, suggesting additional etiologies specific to SARS-CoV-2 [14, 72, 127,128,129,130]. Acute CVD involves the brain parenchyma or subarachnoid space in COVID-19 patients. Furthermore, hypercoagulable states (increased prothrombin time and elevated levels of a fibrin degradation product called D-dimer) have been reported in some COVID-19-related strokes [14, 124].

Another neurological disease reported in COVID-19 is GBS and its variants. GBS is an acute disease that affects peripheral nerves. This health problem is characterized by rapidly progressive symmetrical limb weakness and sensory symptoms in SARS-CoV-2 infection. GBS is associated with inappropriate immune system response and all the variants of GBS like acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN) have been reported in COVID-19 patients [82,83,84, 131,132,133,134,135]. Other variants like Miller Fisher syndrome and facial diplegic variants have been also described [113, 136, 137]. Furthermore, GBS with no respiratory symptoms of COVID-19 has been reported in some individuals affected with SARS-CoV-2 [41, 78, 138]. Demyelinating disorders, including acute disseminated encephalomyelitis (ADEM), exacerbation of multiple sclerosis (MS) plaque, and the clinically isolated syndrome, have been reported in COVID-19 patients, as well [78, 139]. ADEM (a multifocal demyelination syndrome) and myelitis (defined as inflammation of the spinal cord) have been considered post-infectious diseases reported in COVID-19 patients [120, 140, 141].

Although the neurological symptoms have been reported in a considerable number of COVID-19 patients, the underlying molecular mechanisms of the nervous system involvement has not been well understood yet [15, 21]. In this regard, understanding the SARS-CoV-2 correlation with the reported neurological complication in COVID-19 patients is critical from this diagnostic and therapeutic outlook. The following section will dedicate the possible routes of nervous system involvement.

Direct Infection of the Nervous System (the Neuronal Retrograde Routes)

The inherent and specific characteristic of the nervous system immunity preserves the CNS from the invasion of pathogenic agents [19]. Due to the devastating and lethal nature of CNS infection, the capacity to invade the nervous system is a rather poor evolutionary feature [20]. However, some zoonotic RNA viruses like West Nile virus (WNV) and Nipah virus (NiV) have the potential to infect fully differentiated neurons [18]. In the case of the COVID-19 pandemic with the increasing trends in reporting of neurological manifestations, it is plausible that SARS-CoV-2 has the potential to infect the nervous system [15, 16, 21, 49]. The evidence of cerebral involvement in other CoVs (SARS-CoV and MERS-CoV) and the presence of SARS-CoV-2 genomic RNA in the CSF of COVID-19 patients [25, 27, 30, 78] have reinforced the assumption of CNS infection with the SARS-CoV-2 [31, 142]. Moreover, it has been suggested that the abnormal function of the cardiorespiratory center in the brain stem due to the neuroinvasive potential of SARS-CoV-2 might be the cause of respiratory failure in COVID-19 patients [4]. However, a recent report claims that respiratory failure in patients with COVID-19 is different from that caused by brain dysfunction [101]. This suggests that SARS-CoV-2 introduction to the brain is possible; nevertheless, it is a rare phenomenon due to non-specific symptoms observed in COVID-19 patients [101]. Overall, like other CoVs, there is no adequate evidence to prove CNS access by SARS-CoV-2, although it is proposed that described routes for other pathogens may provide a path to the brain for SARS-CoV-2 [4, 21, 31, 101].

Neuronal retrograde routes are one of the essential pathways for the respiratory neurotropic virus entry to the CNS (Fig. 1a) [42]. Indeed, the PNS provides accessible routes for this virus to gain access to the nervous system [18, 21]. Regarding this point, the transition of SARS-CoV-2 to the brain through the olfactory nerve is plausible. The evidence of alteration in the sense of smell (anosmia) supports this theory [4, 15, 21, 31]. However, bioinformatics analysis on bulk and single-cell RNA-Seq datasets for SARS-CoV2 receptor expression at the olfactory system showed that two critical genes for SARS-CoV-2 invasion (i.e., ACE2 and TMPRSS2) did not express at olfactory neurons. This study also showed that SARS-CoV-2-related proteins are expressed at non-neuronal olfactory system cells, probably leading to anosmia following COVID-19 contamination [143]. Nevertheless, other PNS components such as neuromuscular junctions might participate in the neurological complication of COVID-19. Increased levels of CK and myalgia or fatigue, which is observed among a significant portion of hospitalized COVID-19 patients, support the assumption that SARS-CoV-2 may aggress the myelin or axon of muscular neurons (Fig. 1a) [143, 144]. Another scenario in the nerve ends involvement is proposed since GBS has been reported in several cases associated with COVID-19 [82, 87, 132, 134, 144,145,146]. Although respiratory tract or gastrointestinal infection has been reported in two-thirds of GBS patients before the neuropathy manifestation, a pattern of the parainfectious profile was reported in GBS associated with COVID-19. GBS mechanism, which mimics autoimmune diseases, is commonly related to campylobacteriosis and viral infections such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and Zika virus [82, 84, 133]. While the underlying mechanism of the GBS manifestation in COVID-19 patients has not been elucidated, the immune system attack through inflammatory cytokine or antibodies against specific gangliosides is proposed in this regard [84]. Further investigation of the association of GBS with the COVID-19 infection can reveal neurological complications of the disease [38, 147]

Immune Response Dysfunction

Immune responses caused by a viral infection can damage the nervous system. Therefore, comprehensive knowledge about the brain reaction against viral infections is critical to combat neurological viral conditions. The activation of the immune system following the SARS-CoV2 infection (Fig. 1b) can be detrimental to the nervous system [19, 21]. It has been suggested that both viral and host factors participate in CoV pathogenicity. However, it is the uncontrolled immune response that leads to immune pathogenesis of the CoVs, including pulmonary tissue damage and reduced lung capacity. Therefore, the innate immune response can play a protective or destructive role in CoVs infection [148]. Elevated levels of neutrophils, monocytes, and macrophages have been observed in severe SARS-CoV and MERS-CoV infections [147].

As expected, such an increase in the number of leukocytes and neutrophils has been observed in patients with severe COVID-19. Moreover, lymphopenia and pneumonia, the most prevalent characteristics observed in patients with severe COVID-19 infection, are related to innate immune system dysfunction [138, 147]. Therefore, the aberrant immune system function, which is observed among severe cases of COVID-19, might be caused by a decline in the number of T lymphocytes, especially CD4+ T-cells. Furthermore, the elevated levels of neutrophil-to-lymphocyte ratio (NLR), which is a reliable marker of systemic inflammation and infection, indicated the serious immunologic condition in patients with severe COVID-19. Moreover, consistent with SARS-CoV and MERS-CoV infections, the overactive inflammatory response in patients with severe COVID-19 is plausible, regarding the elevated serum levels of the pro-inflammatory cytokine and chemokines (TNF-α, IL-1, IL-6, IL-7, IL-8, IL-9, IP10, GCSF, MCP1, and MIP1A) at their blood samples. Since the immune system dysregulation causes aberrant inflammation in COVID-19 patients, the correlation of these conditions with neurological manifestation is plausible [62, 138].

Inflammation, the immune system reaction to tissue damage, may have negative effects on the recovery process from an injury. So, many protective efforts have been triggered to overcome this detrimental condition [149]. All types of CNS cells, including neurons, macroglia, and microglia, participate in neuroinflammation responses [150]. Because of the paradoxical effects of cytokines in cells, cytokine functions are critical to determining the protective or destructive function of the immune system in the case of any pathogen exposure. Indeed, it is the ultimate turnover of cytokines that determines the invasion of leukocytes towered the brain parenchyma [151]. However, infection-related biomarkers such as procalcitonin, ESR, serum ferritin, CRP, and inflammatory cytokines (i.e., TNF-α, IL-2R, IL-6, IL-8, and IL10) are increased in blood samples of individuals with severe COVID-19 compared to the patients in the mild group [13, 138]. These findings suggest that lymphopenia and cytokine may play a key role in the neurological pathogenesis of novel SARS-CoV-2.

Infiltration of infected leukocytes through the “Trojan horse” mechanism is an efficient approach for some viruses to access the nervous system [18, 32]. The so-called Trojan horse mechanism, which refers to the crossing of infected leukocytes from the blood-brain barrier (BBB), is the main mechanism used by some lentiviruses like simian immunodeficiency virus (SIV) and HIV to transfer across CNS vascular barriers [152]. Previous studies have shown the ability of beta-CoVs to infect monocytes, macrophages, and dendritic cells. The SARS-CoVs can infect primary human monocytes [153], whereas MERS-CoV infects both monocytes and T cells [154]. Thus, dendritic cells could be infected by SARS-CoV-2 [64]. However, the low amounts of ACE2 receptors expressing on the cell surface of monocytes and macrophages suggest that other mechanisms might involve in communications between SARS-CoV-2 and the host innate immune response [147].

Accumulating evidence has indicated that overreacting of the innate immune system and inflammatory responses in patients with severe COVID-19 correlate with respiratory failure, ARDS, and adverse clinical outcomes [34]. This condition, which has been considered a cytokine storm syndrome, contributes to vascular permeability, leakage, and consequently devastating effects on pathological symptoms [32, 34, 64]. Cytokine storms cause BBB disruption, which protects the CNS by controlling the spread of circulating molecules, immune cells, or virus particles into the CNS. Indeed, impaired BBB provides a path for inflammatory mediators and immune cells to access the brain parenchyma (Fig. 1c). This offensive entry may occur following the CoV infection, and thereby, the brain inflammation is likely to exacerbate COVID-19-related neurological manifestations [18, 21, 32].

Hematogenous Pathways

It seems that the impairment of general hemostasis due to the pulmonary damage and MODS leads to the critical condition in COVID-19 patients [21, 155, 156]. Previous studies demonstrate that human CoVs have the potential to disseminate other regions of the human body [45]. The existence of SARS-CoV and MERS-CoV particles in the circulating blood cells, lymphoid tissue, and epithelial cells of different human tissues suggest the broad range of tissue tropism for CoVs [157]. SARS-CoV-2 has shown a multi-organ impact with significant effects on the vascular system and homeostasis maintenance [155, 158,159,160]. Although the hematogenous pathway is proposed as a possible route for neurotropic viruses toward the CNS, the vascular system derangements in COVID-19 patients are complicated and still unknown [90, 160, 161]. Intriguingly, human CoVs can pass through the epithelium cells and spread throughout the blood circulation pathways, thereby reaching the other regions, including CNS [42]. In the hematogenous pathways, the endothelial cells of BBB or blood-cerebrospinal fluid barrier provide a route for the accession of viruses to the CNS (Fig. 1c) [90]. The evidence of direct infection of endothelial cells by SARS-CoV-2 [161] and the presence of viral-like particles in brain capillary endothelium of COVID-19 patients [90] support the concept that the vascular system acts as a bed for SARS-CoV-2 to accesses the nervous system. Furthermore, an in vitro study has shown that SARS-CoV-2 can directly invade the engineered human blood vessel organoids; however, the evidence to support the CNS infection by CoVs particularly SARS-CoV-2 via hematogenous pathways is rare [21, 162].

Boosting inflammatory responses and the development of cytokine storm, observed in severe COVID-19 patients, contributes to vascular permeability and promotes the dysfunction of the endothelial cells [7, 155]. Accordingly, the immune system malfunction, aberrant inflammatory responses, and endothelial dysfunction participate in the induction of a prothrombotic state [156, 157]. Thrombosis, a physiological response termed immunothrombosis that involves blood coagulation and platelet aggregation, is a key effector of the innate immune response that delimitates pathogen spreading through the vascular system [163]. While the immunothrombosis state is inherently beneficial via the local control of the infection, endothelial dysfunction accompanied by the hyper-inflammation response due to SARS-CoV-2 infection might lead to a state of COVID-induced coagulopathy [155, 156, 161]. Disseminated intravascular coagulation and its related parameters like thrombocytopenia and D-dimer have been frequently reported in COVID-19 patients [155, 159, 164]. A study on 183 confirmed COVID-19 patients revealed that the levels of D-dimer are significantly higher in deceased COVID-19 patients (71.4%) compared to survivors (0.6%) [165]. Previously, in the case of SARS-CoV infection, the artery cerebral thrombosis was reported in critically ill patients with underlying conditions [166]. Likewise, the incidence of large vessel stroke has been reported among COVID-19 patients in association with the elevation of inflammatory markers and D-dimer levels [16, 18, 80, 166]. While acute ischemic stroke commonly occurs in older people [45], there are rare reports of intracerebral hemorrhage among COVID-19 patients [16, 45,46,47,48].

Despite the observed high levels of D-dimer markers and coagulation system dysfunction in COVID-19 patients, it seems likely to be associated with nervous system impairment [5]. It has not been understood that hemorrhagic events occur due to the SARS-CoV-2 infection or whether it is a coincidental situation [48]. However, the ACE2 receptor occupation on vascular endothelial cells with SARS-CoV-2 may cause aberrantly increased blood pressure and elevate the risk of intracranial hemorrhage [15, 20, 21]. Besides, it is of note that severe hypoxia development due to lung injury and respiratory failure might cause CVD-like ischemic stroke [21, 164]. Indeed, the progress of ARDS in severe COVID-19 patients leads to profound systemic hypoxemia, which may correlate with observed congestion and edema in the brain tissue [16, 89]. Furthermore, the induction of hypoxemia by lung injury and ARDS may facilitate SARS-CoV-2 access to the brain. Nevertheless, there are no adequate data to indicate that SARS-CoV-2 directly invades the CNS. So, research on the neuroinvasive potential of SARS-CoV-2 requires further consideration [89].

COVID-19 and Possible Long-Term Neurological Consequences

The accumulating information about nervous system involvement and evidence of cognitive impairment among COVID-19 patients provide an alarming document about the possible further delayed-onset neurological complications. This condition may include unpredictable outcomes, either via aggravating a pre-existing neurological disorder or causing a neurodegenerative disease in COVID-19 survivors [11, 167,168,169]. Although it is too early to conclude about the possible risk of developing long-term neurological consequences of COVID-19 infection, it is plausible that chronic neuroinflammation associated with SARS-CoV-2 may cause neurodegenerative diseases in the future. Moreover, the SARS-CoV-2 neuroinvasive nature may result in subsequent neurodegenerative disorders like multiple sclerosis (MS), Huntington, Parkinson’s (PD), and Alzheimer’s diseases (AD) [41, 79]. The significant risk of developing subsequent neurological complications in COVID-19 survivors is consistent with previous evidence that indicated other human CoVs latency in the nervous system and induced oxidative tissue injury and CNS chronic complications [42, 169, 170]. In other words, the potential neuroinvasive feature of SARS-CoV-2, as well as chronic neuroinflammation and cytokine storm associated with COVID-19 severity, spotlight the possible increased risk of neurodegeneration characteristic of this disease [171, 172]. The reports on CoVs in the CNS of patients with PD, AD, and MS raise the question of whether and how COVID-19 infection may be related to this neurodegenerative disease [173].

COVID-19 is accompanied by the impaired immune response and sustained rise of inflammatory cytokines, which can promote cognitive decline and neurodegenerative disorders [169, 174]. Available data recommend that chronic neuroinflammation associated with high levels of cytokines may implicate pathogenesis and different clinical features of neurodegenerative disorders. For instance, the COVID-19-associated cytokine storm may synergize with amyloid-stimulated type I interferon (IFN) response and exacerbate the cognitive decline in patients with AD. It has been reported that profound systemic hypoxemia complicates the presentation of dementia in AD patients that mostly manifest COVID-19 with diarrhea or drowsiness [175, 176]. These diverse clinical profiles may correspond to distinct pathogenesis and age-related concepts that influence patients with pre-existing neurological conditions [177]. Since elderly individuals are at a higher risk for developing both neurodegenerative and COVID-19 diseases, SARS-CoV2 infection may cause de novo neurodegenerative consequences like PD by accelerating aging in the brain tissue. Also, COVID-19 may complicate the clinical course of pre-existing PD, thereby resulting in worsening of its symptoms [172, 176,177,178,179]. Although the long-term effects of SARS-CoV-2 on the brain are not well characterized, the expression of ACE2 receptor in the CNS suggests that SARS-CoV-2 may infiltrate the brain regions to develop neurodegenerative disorders in the future [31, 49, 180]. The capacity of SARS-CoV-2 to reach the brain and the immunological complexity of COVID-19 can theoretically explain the likelihood of developing long-term neurodegenerative diseases. However, it is challenging to clarify the expected neurodegeneration sequelae in COVID-19 patients relying only on the conducted investigations [96, 169, 177, 178, 181]. In line with evidence from other coronavirus families that indicate their association with MS and other neurological diseases, COVID-19 complications in patients with neurodegenerative disease indicate the urgent attention that should be taken in the context of COVID-19 neurological studies [170, 181]. Overall, studies on critical outcomes and clinical presentations of COVID-19 in patients with pre-existing neurological conditions can provide valuable data to predict risk factors developing long-term brain damage and subsequent neurodegenerative diseases.

Conclusion

COVID-19 is a complex multi-system infectious disease that involves a set of currently unknown complications. The spectrum of clinical manifestations of SARS-CoV-2 is continuously broadened. Therefore, further studies are needed to evaluate whether these multi-organ failures are reflective of direct tissue viral invasion or due to the secondary or systemic effects of the virus. Neurological symptoms and complications observed in COVID-19 patients, especially in severe cases, suggest the impact of SARS-CoV-2 on the nervous system. Although neurological manifestations can be devastating clinical complications of COVID-19, the underlying precise molecular mechanism of neuroinvasion and interaction of SARS-CoV-2 with the nervous system is poorly defined. The neurological pathogenesis of COVID-19 seems to be a complex process. In this regard, hematogenous and neuronal retrograde routes may play an essential role in CNS involvement. While there are limited reports about the direct propagation and presence of SARS-CoV-2 in the human brain tissue, it has been proposed that immune system impairment, subsequent cytokine storm, and vascular system dysfunction might facilitate SARS-CoV-2 entry to the brain. In this respect, the potential of the SARS-CoV-2 invasion to the peripheral nerves might be correlated with the neurological complication of COVID-19. However, it is currently believed that SARS-CoV-2 in concert with host immune responses may participate in the neurological complication of COVID-19 disease. Hence, experimental studies focusing to unravel the precise molecular mechanisms by which CNS or PNS is affected by COVID19 are urgently needed. These studies with shedding light on the underlying molecular mechanisms of neurological complication of COVID-19, will potentially lead to develop more efficient preventive and treatment strategies for these neurological manifestations.