Neurological and Neuropsychological Changes Associated with SARS-CoV-2 Infection: New Observations, New Mechanisms
Abstract
SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.
Introduction
An outbreak of a novel coronavirus (CoV) disease was first identified in Wuhan City, Hubei Province in China on December 29, 2019 (Chen and others 2020b; Zhao and others 2020). The disease, later called COVID-19, is caused by the SARS-CoV-2 virus (Zhou and others 2020b). This virus belongs to the Betacoronavirus genus of the Coronaviridae family of viruses (Coronaviridae Study Group of the International Committee on Taxonomy of Viruses 2020; Weiss and Navas-Martin 2005), which are enveloped viruses with a non-segmented single-strand, positive-sense 26–32 kilobase RNA genome (Zhou and others 2020b). The virus was annotated SARS-CoV-2 due to sharing high sequence similarities with the previously identified coronaviruses, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1) (79.5%), and bat-CoV (RaTG13) (96.2%) (Lu and others 2020; Zhou and others 2020b). In addition, a recent study showed that SARS-CoV-2 also shares up to 91.02% genome homology with coronavirus isolated from dead Malayan pangolins (Zhang and others 2020c).
SARS-CoV-2 is easily transmissible, and person-to-person transmission occurs via direct contact or through droplets spread by coughing or sneezing (Rothan and Byrareddy 2020; Zhao and others 2020). Many of the human pathogenic coronaviruses (i.e., HCoV-NL63, -229E, -OC43, and -HKU1) are associated with mild, acute respiratory infections. In the past 20 years, two viral strains of this family have led to epidemics in different regions of the world. The SARS-CoV-1 outbreak began in 2002, originating in Foshan, China spreading to 33 different countries before subsiding after almost 8 months (European Centre for Disease Prevention and Control 2016). A decade later, in 2012, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in Saudi Arabia, resulting in 2521 laboratory-confirmed cases worldwide and a total of 919 deaths (European Centre for Disease Prevention and Control 2020b). In humans, the MERS-CoV incubation period ranges from 2 to 14 days, similar to SARS-CoV-1 (European Centre for Disease Prevention and Control 2016), but the interhuman transmission is limited. Compared with the previous two outbreaks, COVID-19 has spread more widely and rapidly due to several reasons, including sustained human-to-human transmission and increased globalization.
A key factor that contributed to SARS-CoV-2’s widespread is that infected individuals do not always present signs and symptoms as rapidly as with patients infected with SARS-CoV-1 or MERS-CoV. Hence, many cases remain asymptomatic while the disease is being spread (Rothe and others 2020). This adds an extra layer of complexity in controlling the outbreak. The onset of COVID-19 symptoms generally occurs 5 to 6 days after infection. Patients usually present with fever, cough, fatigue, and shortness of breath, all of which develop slowly over a period of 2 weeks (World Health Organization 2020b). During this time, the virus replicates in the upper and lower respiratory tract and forms multiple lesions (Chan and others 2020; Vellingiri and others 2020). In more severe forms of the disease, patients can experience severe pneumonia and acute respiratory distress syndrome (ARDS) which necessitate life-support (Chan and others 2020).
SARS-CoV-2, similar to other related coronaviruses, uses its membrane-bound spike proteins, known as S glycoproteins, to attach to and enter host cells (Fehr and Perlman 2015; Lee and Hsueh 2020). The S glycoprotein, as shown in Figure 1, comprises two functional subunits: the S1 subunit, which binds to the host cell receptor, and the S2 subunit, which catalyzes the fusion of viral and cellular membranes. The receptor-binding domain (RBD) of S1 directly binds to the peptidase domain of the human angiotensin-converting enzyme 2 (ACE2) (Coutard and others 2020; Letko and others 2020; Lu and others 2015). For proper entry into the cell, after S1 binds to the host ACE2, the S protein is further cleaved by host proteases at a second cleavage site found within the membrane-embedded S2 subunit (Bosch and others 2003; Coutard and others 2020; Lu and others 2015) as illustrated in Figure 2. This cleavage reveals other S2 domains comprising the fusion peptide (FP) and internal fusion peptide (IFP) and allows the virus to fuse with the cell membrane and facilitate its entry (Walls and others 2017).
Interestingly, a recent study showed that the host ACE2-RBD binding affinity during initial viral attachment determines the host susceptibility to SARS-CoV-2. Thus, the higher transmissibility of SARS-CoV-2 over SARS-CoV-1 is partly attributed to the former’s higher ACE2 binding affinity (European Centre for Disease Prevention and Control 2020a). Due to its wide-ranging expression, ACE2 provides SARS-CoV-2 with an entryway to infect different human tissues.
Many viruses, including CoVs, have tropism for the nervous tissue and can cause severe neurological damage (Michalicova and others 2017). SARS-CoV-2 is not an exception as it has demonstrated neurotropic properties and an ability to cause neurological diseases. A recent report confirmed SARS-CoV-2 presence in the cerebrospinal fluid (CSF) of patients (Moriguchi and others 2020). However, the neuropathogenic mechanisms of SARS-CoV-2 are not fully deciphered. This necessitates an evaluation of the possible contributions of neurological tissue damage to the morbidity and mortality caused by COVID-19. Here, we present an overview of pathways used in SARS-CoV-2 infection and propose possible mechanisms of damage to the nervous system. However, to be able to do so, it is crucial to understand the receptor through which the virus enters target cells.
Virus Entryway: Angiotensin-Converting Enzyme 2
ACE is a key player in blood pressure regulation. Classically, the renin-angiotensin-aldosterone system (RAAS) orchestrates the coordination between the brain, heart, blood vessels, and kidneys to regulate blood pressure (Nehme and others 2019). Fluctuations in renal-associated processes such as tubular sodium content, renal perfusion pressure, and renal sympathetic nerve flow trigger the release of renin by renal juxtaglomerular cells into the blood. Renin then proceeds to cleave circulating liver-derived angiotensinogen into angiotensin-I (Ang-I). The membrane protein angiotensin-converting enzyme 1 (ACE1) subsequently cleaves Ang-I into Ang-II, which acts as the principal agonist at the angiotensin 1 receptor (AT1) (Almeida and others 2020). The kidneys respond to Ang-II by increasing sodium reabsorption, water retention, and potassium excretion. This is accompanied by arteriolar vasoconstriction and an increased release of anti-diuretic hormone (ADH, also known as vasopressin) from the posterior lobe of the pituitary gland to stimulate further water retention via the kidney (Nehme and others 2019). Despite its well-established role in blood pressure regulation, it has become increasingly apparent that the activity of the ACE1/Ang-II/AT1 pathway contributes to other important physiological processes. Several studies have demonstrated that this system is widely distributed in various organs where it is associated with pro-inflammatory, fibrotic, proliferative, and oxidative functions (Almeida and others 2020; Paul and others 2006).
The identification of ACE2, a homolog of ACE1, highlighted that RAAS contains an additional “arm,” which functions to counterbalance the effects of the ACE1/Ang-II/AT1 axis (Donoghue and others 2000). ACE2 cleaves the nonapeptide Ang-II (Ag1-9) into the heptapeptide Ag1-7, which exerts subsequent effects through other receptors. Ag1-7 mitigates the range of effects elicited by Ang-II (Tikellis and Thomas 2012). Besides its abundance in vascular endothelial cells, it is also detected in the heart, kidneys, testes, and brain, to name a few (Hamming and others 2004). For instance, the anti-inflammatory, anti-oxidative, anti-fibrotic, and anti-proliferative effects of ACE2 are well established in various organs and tissues (Grobe and others 2007; Simões e Silva and others 2013; Tikellis and Thomas 2012). In the heart, ACE2 inhibits cardiac hypertrophy and delays atherosclerotic lesion progression. Expectedly, ACE2 expression (or activity) is reduced in several diseases, including cardiovascular, renal, and pulmonary diseases. Indeed, many pathological states have increased involvement of the ACE1/Ang-II/AT1 arm and are associated with reduced ACE2 expression or absence of ACE2 activity (Tikellis and Thomas 2012).
Pulmonary ACE2, expressed on alveolar epithelial cells, has been identified as the preferential mode of entry for the SARS-CoV-1 and SARS-CoV-2 viruses. Once the virus has entered the bloodstream, it gains a far-reaching capacity due to the profuse ACE2 expression in the vessels (Wang and others 2020a). However, this is only speculative considering that only RNAemia has been reported with no evidence of viremia. While ACE2 provides protective anti-inflammatory and anti-fibrotic functions, its vast distribution in organs renders them susceptible to viral entry and damage, and it extensively increases the host tissue viral uptake (Chen and others 2020b). Conversely, since patients with comorbidities have reduced ACE2 expression, they also show diminished ACE2 ability to exert immune-modulatory activity through the RAAS axis (Rodrigues Prestes and others 2017). ACE2 behavior was also observed in models of diseases like atherosclerosis, cerebral ischemia, obesity, and so on by decreasing cytokine production and interfering with fibrotic signaling pathways (Rodrigues Prestes and others 2017). This can exacerbate inflammatory symptoms in SARS-CoV-2 infected patients. The binding of SARS-CoV-2 to ACE2 also lessens its availability to cleave Ang-II, extending its vasoconstrictive and pro-inflammatory roles (Zhang and others 2020b).
On another note, angiotensin converting enzymes also play a role in the kallikrein kinin system (KKS), which is at interplay with RAAS and could be involved in COVID-19 manifestations. The KKS comprises kallikreins, a group of serine proteases that cleave kininogens to produce kinins (Carvalho and others 2020). On cleavage, two molecules are produced: bradykinin (BK), a high molecular weight break-down product (BDP), and kallidin (also known as lysyl-BK) a low molecular weight BDP. These two proteins activate the bradykinin B2 receptors expressed ubiquitously in the body resulting in increased vascular permeability, vasodilation, and activation of nociceptors. Additionally, they activate the bradykinin B1 receptors which are highly expressed in inflammatory conditions (Hall 1992).
ACE1 cleaves and inactivates kinins by removing the carboxyl terminal of BK to generate BK(1-7). Additionally, carboxypeptidases (M and N) can remove the arginine from the C-terminal of BK to give desArg9-BK (DABK) that has a role in inflammation through bradykinin B1 receptors (Carvalho and others 2020). Furthermore, ACE2 down-regulation can initiate a cascade of events that implicates Ang-II and BK in SARS-CoV-2 pathogenesis. When SARS-CoV-2 enters host cells, it induces TNF-α converting enzyme (TACE), which depends on the shedding of the ectodomain of ACE2. SARS-CoV2/ACE2 binding results in ACE2 internalization; this down-regulation of ACE2 leads to an imbalance in RAAS that favors Ang-II binding to and activation of to the AT1 receptor. AT1 receptor activation is hypothesized to mediate the severe respiratory symptoms during COVID-19 infection by shifting the balance toward a pro-inflammatory condition that is exacerbated by the hypertension-inducing effects of AT1 (Carvalho and others 2020). Interestingly, the cysteine proteases present in the virus itself could participate in the production of BK and DABK from kininogens (Solowiej and others 2008). Transmembrane serine protease 2 (TMPRSS2), implicated in SARS-CoV-2 entry, cleaves kininogens and initiates the production of BK. All these factors increase the availability of BK to bind B2 receptors and initiate nitric oxide (NO) and prostaglandins synthesis. Thus, a cumulative inflammatory state emerges from a positive feedback loop mediated by enhanced generation of inflammatory cytokines, BK and DABK on one hand and, on the other hand, by the up-regulation of B1 receptors, which increase endothelial cell permeability and leukocyte migration. The interplay between all these different molecules and receptors are illustrated in Figure 3.
Clinical Manifestations: Respiratory and Emerging Neurological Symptoms
Respiratory Manifestations
The manifestations of COVID-19 have been classified according to the degree of respiratory symptoms severity (Feng and others 2020). Mild types display normal radiological findings while moderate cases are characterized by dry cough, fever, and pneumonia. Dry cough is prevalent in 57% to 82% of patients with only the minority reporting sputum production (Chen and others 2020a; Huang and others 2020; Zhou and others 2020a). Shortness of breath has also been reported in up to 50% of the cases, with a median onset between 5 and 8 days (Chen and others 2020a; Zhou and others 2020a).
Severe symptoms arise when patients develop respiratory distress (respiratory rate >30 per minute) and decreased oxygen saturation (<93%), presenting with tachypnea, tachycardia, and hypoxia (Feng and others 2020). Further severity extends to those with respiratory failure, requiring mechanical ventilation. This can be accompanied by other organ failures as well (Feng and others 2020). Disease progression is variable, with some reports suggesting that deterioration and the need for ventilation support occurs between days 9 and 12 from symptom onset (Feng and others 2020; Zhou and others 2020a). Failure to respond to appropriate oxygen supplementation may indicate that a patient is developing acute respiratory distress syndrome (ARDS), a complication seen in 15% to 33% of patients, forming the leading cause of death in these individuals (Chen and others 2020a). These extreme symptoms are more prevalent in the elderly, smokers, those who have undergone recent surgery, and those with underlying malignancies or chronic diseases like hypertension, cerebrovascular disease, and diabetes (Feng and others 2020).
Neurological Manifestations: An Overview
Since COVID-19 symptoms are not confined to the respiratory system, this review will focus on the evaluation of ACE2 expression and function in the CNS as this can explain the multifaceted roles ACE2 plays in neuronal inflammation, apoptosis, cerebral infarct volume, and oxidative stress. Several reports so far showed that SARS-CoV-2 could infect the CNS. In Beijing Ditan Hospital, the virus was detected in the CSF of a male patient who was later diagnosed with encephalitis (Xinhua News Agency 2020). A similar report provides the same evidenced encephalopathy development in a COVID-19 patient (Haseltine 2020). Also, Yamanashi University Hospital Laboratory Department presented the first case of SARS-CoV-2-associated meningitis/encephalitis in a 24-year-old male (Moriguchi and others 2020). Interestingly, in this case, unlike with other findings, SARS-CoV-2 was not detected in the patient’s nasopharyngeal swab but rather in the CSF (Moriguchi and others 2020). Another report revealed that one-third of SARS-CoV-2-infected patients in three COVID-19-specified hospitals in Wuhan, China, exhibited some sort of neurological manifestations ranging from dizziness and altered consciousness to acute cerebrovascular disease (Fitzgerald 2020). Also, a study of 214 people indicated that 37% of infected patients exhibited neurological symptoms (Stetka 26, 2020). Other reports even suggest that SARS-CoV-2 infection alters smell and taste or leads to their transient or prolonged loss (Stetka 2020; Yeager 2020). Delirium and agitation were also described among COVID-19 patients (Rogers and others 2020). Another study described a rare COVID-19-associated acute necrotizing hemorrhagic encephalopathy (Poyiadji and others 2020). As it shows, symptoms arising in the nervous system (NS) post- SARS-CoV-2 are diverse. The previously mentioned reports put a high focus on the prevalence of CNS symptoms and the importance of staying on the lookout for further manifestations. Table 1 adds to the previous literature and summarizes several reports that present rather unclassical NS manifestations due to the infection.
| Patient Number | Clinical Manifestations | Neurological Test Results | Other Test Results | Location and Reference |
|---|---|---|---|---|
| 64-year-old male patient | Cough and fever. Post hospital admission due to fall, paresthesia in hands and feet along with weakness in limbs started progressing. Areflexia and loss of vibration sense were also presented. | Elevated protein levels in CSF with normal cell count. Acute inflammatory demyelinating polyneuropathy presented on electromyography. |
Ground glass opacities on chest CT. | France (Camdessanche and others 2020) |
| 5 patients | Three patients presented with quadriparesis and one with paraparesis. One patient had facial diplegia, areflexia, limb paraesthesia, and ataxia. General symptoms included fever and cough. Anosmia and ageusia were also reported. | Axonal pattern in three patients was presented on nerve conduction study. This is along with demyelination in two of them. | CT scan of one of the patients showed ground glass opacities compatible with interstitial pneumonia. Another patient presented with interstitial pneumonia as well but without parenchymal opacities or alveolar damage. | Italy (Toscano and others 2020) |
| 417 patients | 357 out of 417 cases presented some sort of olfactory dysfunction with 342 reporting gustatory dysfunction. | N/A | N/A | Belgium, France, Italy, Spain, and Switzerland (Lechien and others 2020) |
| 61-year-old female patient | Severe fatigue accompanied with progressive lower and upper limbs weakness. This along with areflexia in lower limbs and decreased sensation distally. She developed fever and cough a week after her neurological symptoms. | Elevated proteins in CSF and acute inflammatory demyelinating polyneuropathy. | Blood tests revealed lymphopenia and thrombocytopenia. Ground glass opacities bilaterally were presented on chest CT. |
China (Zhao and others 2020) |
| 39-year-old male patient | Diplopia following fever and diarrhea. Abduction deficits in both eyes and fixation nystagmus consistent with bilateral abduction palsy. | Elevated proteins in CSF with normal cell account | Leucopenia | Spain (Gutiérrez-Ortiz and others 2020) |
| 71-year-old female patient | Cough and fever with right abducens palsy. | Enhancement of optic nerve sheaths and posterior tenon capsules were present on brain MRI | Chest x-ray showed bilateral opacities | USA (Dinkin and others 2020) |
| 50-year-old male patient | Cough, fever, malaise, headache, and anosmia. The patient later developed right internuclear opthalmoparesis with right fascicular oculomotor palsy. | Elevated proteins in CSF | Lymphopenia and elevated CRP. Serum analysis showed positivity for antiganglioside antibody GD1b-IgG | Spain (Gutiérrez-Ortiz and others 2020) |
CRP = C-reactive protein; CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging; N/A = not applicable.
To compare with other coronavirus infections, nearly 4% to 5% of all SARS-CoV-1 patients exhibited symptoms of CNS infection, including restlessness and convulsions, as reported in the early stages of the virus outbreak in Hong Kong, China. Some of these patients even had CNS lesions or marked brain damage, as shown in CAT scans reported in the Guangzhou Institute of Respiratory Diseases (Haseltine 2020). More specifically, in the MERS and SARS outbreaks, there were rare cases of acute disseminated encephalomyelitis as encephalitis, brainstem encephalitis, and even peripheral nervous system diseases like Guillain-Barre syndrome (Stetka 2020). These pathologies were attributed to either a direct infection to the brain or secondary effects mediated by activation of the immune system and likely involving altered immune response with markedly increased levels of inflammatory cytokines. Indeed, the cytokine profile detected in infected patients should be thoroughly evaluated because of the possibility of developing latent effects. This prospect will be discussed to assess how the immune system plays a role in the neurological manifestations observed in these patients. This venue is especially important in light of reports indicating that several patients exhibited encephalopathies while testing negative for the virus in their CSF, implying that cytokine-mediated inflammatory response may be a key player in COVID-19 associated neurological and behavioral systems (Helms and others 2020).
Neurological Manifestations: Encephalitis
The first reported encephalitis case was of a man in Japan who tested positive for SARS-CoV-2 RNA in his CSF (Moriguchi and others 2020). The patient presented with fever, headache, and generalized fatigue. His Glasgow Coma Scale (GCS) was 6, and he suffered neck stiffness. On MRI investigation, his right temporal lobe and hippocampus showed hyper-intense signal changes with minor hippocampal atrophy, which indicated right lateral ventriculitis and encephalitis. In one national UK registry involving 125 patients monitored over the course of 3 weeks, 13 presented encephalopathy, including seven with encephalitis (Varatharaj and others 2020). Another report by Poyiadji and colleagues presented a woman in her 50s with fever, cough, and altered mental state where MRI revealed acute necrotizing encephalitis in the bilateral thalami, medial temporal lobes, and sub-insular regions (Poyiadji and others 2020). Table 2 puts forth several publications showing encephalitis as a manifestation of SARS-CoV-2 infection.
| Number of Cases | Clinical Manifestations | SARS-CoV-2 RT-PCR Sample and Others | Neurological Test Results | Other Test Results | Location and Reference |
|---|---|---|---|---|---|
| 24-year-old male patient | Fatigue, headache, fever, sore throat, generalized seizures, reduced consciousness, and meningism | Negative: nasopharyngeal swab Positive: CSF |
Raised opening pressure of CSF (320 mm Hg) and cell count, no brain edema, hyperintensity in wall of right lateral ventricle on diffusion-weighted imaging, and hyperintensity in right medial temporal lobe and hippocampus on T2-weighted imaging. | Increased blood white cells (mostly neutrophils), decreased lymphocytes, increased CRP, small ground glass opacity in right upper zone and bilaterally in lower zones. | Japan (Moriguchi and others 2020) |
| 72-year-old male patient | Weakness, light headedness, hypoglycemic episodes, breathing difficulties, altered mental status, and seizures | N/A | Six left temporal seizures within 24 h, epileptogenic sharp waves in left temporal lobe. | Elevated brain natriuretic peptide (BNP), troponin, CRP, LDH. Decreased lymphocyte count. | USA (Sohal and Mossammat 2020) |
| 40-year-old male patient | Ataxia, diplopia, bilateral fascial weakness (rhombencephalitis), and progressive shortness of breath. | Nasopharyngeal swab | Increased signal lesion during MRI in right inferior cerebellar peduncle extending to small portion of the upper cord and swelling at affected tissues. | Lymphopenia, elevated CRP, abnormal raised liver function tests, and lower right zone consolidation during chest x-ray. | UK (Wong and others 2020) |
| Female patient | Cough, fever, altered mental status, acute necrotizing encephalopathy | Nasopharyngeal swab | Symmetric hypoattenuation in bilateral medial thalami in CT scan, hemorrhage displayed by hypo-intensity on susceptibility-weighted images and rim enhancement on postcontrast images. | N/A | USA (Poyiadji and others 2020) |
| 49 patients | 40 patients suffered agitation, 26 presented confusion, and 15 had dysexecutive syndrome. | Nasopharyngeal swab | CSF analysis in seven patients: Absence of pleocytosis, matched oligoclonal bands and one had elevated protein levels. MRI of 13 patients: Bilateral frontotemporal hypoperfusion, eight showed enhancement in leptomeningeal space, and two had acute ischemic stroke. EEG of eight patients: one displayed diffuse bifrontal slowing. |
N/A | France (Helms and others 2020) |
| 16 patients | Impaired consciousness. One patient presented with seizure with sudden onset of limb twitching. | Throat swab | N/A | Decreased lymphocyte and platelet count and increased blood urea nitrogen were prominent in patients with CNS disease as opposed to others without CNS disease. | China (Mao and others 2020b) |
| 74-year-old male patient | Fever and cough developed after two falls at home, along with confusion and agitation. Notably, patient had a history of Parkinson’s disease. |
Nasopharyngeal swab. Electron microscopy of brain tissue revealed viral particles in neural and endothelial cells. |
No acute changes were presented in the conducted CT head scans. | Thrombocytopenia and elevated ferritin, CRP, and D-dimer. Absence of changes in lung fields in chest radiology at first with development of bilateral changes on chest x-ray later. | USA (Paniz-Mondolfi and others 2020) |
CNS = central nervous system; CRP = C-reactive protein; CSF = cerebrospinal fluid; CT = computed tomography; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; N/A = not applicable.
The upcoming sections will discuss the virus-induced secondary inflammatory effects that have been suggested as a means for such complications. These include the release of cytokines inducing a cytokine storm which damages the tissue and disrupts the integrity of the BBB. This is the more likely mechanism considering that among all patients with neurological complications, only two had detectable SARS-CoV-2 RNA in their CSF, arguing against virus entry into brain tissue. It is important to explore this niche because studies have reported blood biomarkers that indicate neural inflammation and injury. For example, one postmortem brain dissection of a COVID-19 patient showed increased GFAP staining, which is indicative of astrocyte activation and thus inflammation (Dekosky and others 2020). Other reports have also shown the release of brain damage biomarkers post SARS-CoV-2 infection like GFAP, UCHL1, and S100B, adding weight to the problem. General debate on the link between SARS-CoV-2 and encephalitis entices that this complication is self-limiting. However, further investigation is needed to understand the mechanism. The later discussion on how the virus could directly infect the brain might also give insight into how encephalitis develops post-infection via direct invasion of the brain tissue.
Cytokine Profiling and the Role of Neuroinflammation in COVID-19-Associated Neurological Symptoms
Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukins (IL)-1β, IL-6, IL-10, and IL-8 are hallmarks of viral infection, which stimulates their expression via a pathway that involves the nuclear factor (NF)-kB, activator protein 1 (AP-1)- and activating factor-2 (ATF-2) (Mogensen and Paludan 2001). Previous findings supported this notion by revealing noticeably elevated IFN-γ, IL-1β, IL-6, and IL-12 levels in SARS patients for a minimum of 2 weeks after disease onset. Moreover, the chemokine profile showed a considerable elevation of IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th-1 chemokine IFN-γ-inducible protein-10 (IP-10) (Wong and others 2004). Interestingly, disease severity and unfavorable consequences in SARS have been linked to lymphocytopenia where a weak adaptive immune response arises from reduced CD4 and CD8 T lymphocyte levels (Wong and others 2003).
The fastest and most effective host response against viruses involves the production of type I-IFNs (IFN-α/β), indispensable components of the antiviral innate immune response. Secreted IFNs trigger cells in the infected micro-environment to express effective antiviral proteins (Haller and others 2006). IFN production, stimulated by the initial encounter with the virus, slows down or even halts viral replication, and institutes an adaptive immune response that takes advantage of this viral non-replicative period (Hertzog and others 2003). The generation of these interferons and other cytokines like IL-6 is mediated through several pattern recognition receptors which include toll-like receptors (TLRs) and nod-like receptors (NLRs). These are fundamental parts of the innate immunity and are expressed in many types of cells like monocytes, macrophages, and dendritic cells (O’Neill and Bowie 2007). Downstream of these TLR is Bruton’s tyrosine kinase (BTK) dependent recruitment of the NF-κB pathway, which, as aforementioned, leads to the production of cytokines and chemokines. Among these receptors, TLR3 recognizes single-stranded positive viral RNA (Cavassani and others 2008) and exerts its protective effects by increasing the release of interferons. TLR3 activation leads to monocyte infiltration, TNF expression, and hypercoagulation (Biswas and others 2015). TLR3 is expressed on endothelial cells and responds quickly to viral infection. Importantly, this has also been demonstrated in SARS-CoV-2 following virus detection in endothelial cells. TLR3 is also activated by hypoxic conditions. As such, hypoxemia caused by COVID-19-associated severe pulmonary impairment offers an additional pathway to activate TLR/TLR3 (Zhu and others 2020).
Despite being sensitive to IFNα/β, SARS-CoV-1, and other coronaviruses are highly pathogenic and have demonstrated mechanisms to counteract IFN production (Haller and others 2006). A correlation between the production of IFNs and the expression of IFN-stimulated genes (ISGs)—2-5AS, ISG20, and MxA—was found as their expression was up-regulated in SARS-CoV-1 and respiratory syncytial virus (RSV) infected cells in culture as opposed to influenza A virus (FluAV) and human parainfluenza virus type 2 (hPIV2) infected cells (Okabayashi and others 2006). SARS-CoV-1 was shown to inhibit interferon regulatory transcription factor-3 (IRF3), which is part of the cascade that leads to dsRNA-induced IFN production (Haller and others 2006).
Differences exist in cytokine induction profiles between neurotropic viruses and non-neurotropic viruses, and these differences are fundamental elements in the development of an inflammatory CNS disease. Although the brain lacks the lymphoid tissue component, two types of brain cells, astrocytes, and microglia play prominent roles in mediating immune responses within the CNS (Li and others 2004). In vitro cytokine mRNA profiling in astrocytes exposed to two strains of the Mouse Hepatitis Virus (MHV), a neurotropic MHV-A59 and a non-neurotropic MHV-2 revealed a substantial up-regulation of both pro-and anti-inflammatory cytokines. However, the mRNA levels of IL-12 p40, TNF-α, IL-15, IL-6, and IL-1β were considerably higher in cells exposed to MHV-A59 than in cells exposed to MHV-2 (Li and others 2004). Likewise, mRNAs of the same cytokines were higher in microglia exposed to the neurotropic MHV-A59 virus than in microglia exposed to the non-neurotropic MHV-2 virus (Li and others 2004). Similarly, this was observed in vivo where the same set of in vitro up-regulated pro-inflammatory cytokines’ mRNAs also peaked at the onset of acute infection in the brain and spinal cord in a mouse model of a chronic inflammatory demyelinating disorder that resembles the human multiple sclerosis pattern (Li and others 2004). This indicates a possible significant, albeit indirect, effects of inflammatory cytokines in the etiology of virus-associated CNS consequences.
In patients with CNS and respiratory tract coronavirus infections, too, cytokine expression profiling revealed discrete differences in the levels of distinct inflammatory cytokines. For example, coronavirus infections often trigger the granulocyte colony-stimulating factor (G-CSF), which causes local and systemic accumulation of inflammatory fluid (Gregory and others 2007). Although G-CSF serum levels were similar in patients with CNS or respiratory tract coronavirus infections, despite being increased compared to healthy controls, the serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were considerably higher in patients with CNS compared to respiratory infection. In addition, patients with CNS infection exhibited substantially higher levels of IL-6, IL-8, MCP-1, and GM-CSF in their CSF compared to serum (English and others 2016). Moreover, peripheral blood count comparisons revealed that lymphocyte and eosinophil counts were significantly lower in patients with CNS coronavirus infection than in patients with respiratory tract infection or healthy controls. Conversely, the neutrophil count was considerably higher in coronavirus patients with CNS infection than in patients with respiratory tract infection. Furthermore, monocyte count was significantly higher in patients with CNS infection compared to healthy controls (English and others 2016).
The evidence for SARS-CoV-1 associated cellular damage came into attention after the brain tissue analysis from a SARS patient who showed necrosis of neurons and extensive glial cell hyperplasia (Xu and others 2015). Histopathologic analysis and immunostaining revealed that the SARS-CoV-1 invasion of brain tissues stimulated monokine induction by IFN-γ (Mig) [also known as chemokine (C-X-C motif) ligand], a chemokine that stimulates chemotaxis, promotes differentiation and multiplication of leukocytes and causes tissue extravasation, as shown in Figure 4. Also, Mig production by glial cells signaled CD68+ monocytes/macrophages and CD3+ T lymphocytes to reach the sites of infection (Liu and others 2001). Further cytokine/chemokine profiling revealed high levels of IFN-γ-inducible protein 10 (IP-10) and Mig in the blood, but little or no changes in the levels of other cytokines/chemokines which were close to normal (Xu and others 2015).
Interestingly, IP-10 levels were low in the brain, indicating that Mig, rather than IP-10, was implicated in the identified SARS-CoV-1 induced brain immunopathology (Lazzeri and Romagnan 2005). The data confirm that CNS-immune system interactions are key players in SARS-CoV-1 induced nervous tissue damage. These findings are significant because they revealed the ability of SARS-CoV-1 to infect the CNS and cause additional damage mediated by latent and delayed cytokine/chemokine response that further aggravated the SARS-CoV-1 direct effects.
Inflammation and the BBB
The SARS-CoV-2 infection causes disseminated intravascular coagulation and blood clotting, disrupts endothelial cell integrity, and exacerbates BBB permeability. This causes micro lesions within the CNS, which provide an entry route for SARS-CoV-2. Consistent with viral brain infections, COVID-19-induced encephalitis can stem from systemic inflammation and disruption of the BBB and results in seizures and acute hemorrhagic necrotizing encephalopathy, a rare complication of viral infections. In addition, regulation of coagulation, clotting, and BBB permeability involves pro-inflammatory cytokines, such as IFN-γ, and inflammatory mediators such as arachidonic acid derivatives. Thus, anti-inflammatory agents should be evaluated as plausible therapies to abrogate encephalitis and improve neurological symptoms. Breakthrough results from Oxford University’s “RECOVERY” clinical trial established the efficacy of dexamethasone, an anti-inflammatory steroid, in reducing COVID-19-caused deaths (Ledford 2020). Evidently, there is also a need to assess whether non-steroidal anti-inflammatory drugs (NSAIDs) and anti-coagulation agents can relieve COVID-19 symptoms and improve neurological and overall patient outcomes and whether these effects involve improved BBB integrity since many inflammatory mediators promote coagulation. Exploring these venues may pave new effective ways for repurposing anti-rheumatic NSAIDs to deal with COVID-19 and thwart at least some of its short- and long-term effects.
Neurodegenerative Effects
The aforementioned findings, which characterize the immunological outcomes of SARS-CoV-2, necessitate looking at the possibility of their latent complications like neurodegenerative disorders, a group of diseases that share a set of hallmarks including neuronal cell destruction and protein aggregation (Zhou and others 2013). The link between them and viruses is not a novel concept; many studies investigated the relationships between these disorders and the influenza virus, Epstein-Barr virus (EBV), and so on. Epidemiological data also highlighted the relationship between post-encephalitic Parkinsonism and the 1918 pandemic (McCall and others 2008).
H5N1 influenza virus infection has been correlated with Parkinson’s disease (PD), and two mechanisms have been advanced to explain this relation (Jang and others 2009). The first one was through an indirect immune effect, characterized by increased levels of IL-18, IL-6, G-CSF, and monocyte chemoattractant protein-1 (MCP-1) (Jang and others 2009), a group of cytokines that have proven pathophysiological implications in PD as they prime susceptible neurons for degeneration (Deleidi and Isacson 2012). Similarly, increased levels of cytokines were reported in COVID-19, as mentioned previously, consolidating the need to investigate the link between SARS-CoV-2 and neurodegeneration. A second “hit and run” mechanism was proposed. Here, although H5N1 disappeared from the brain after 21 days of infection, it elicited lasting microglial activation and significant dopaminergic neuronal loss in the substantia nigra but elucidated (Jang and others 2009).
Destructive human coronavirus OC43 (HCoV-OC43) can cause neurodegeneration as it has shown to induce vacuolating degeneration in the gray matter of a mouse brain (Jacomy and Talbot 2003). The observed clear round vacuoles and neuronal death are hallmarks of several neurodegenerative disorders like Alzheimer’s disease (AD) and frontotemporal dementia (FTD, or Pick’s disease). These findings were yet again linked to the inflammatory response stimulated by HCoV-OC43 although the exact cytokine profile was not obtained. The same viral strain, in another report, was more prevalent in brain autopsies of patients with multiple sclerosis as opposed to other neurological diseases and healthy controls (Arbour and others 2000). Additionally, a study of MHV revealed the formation of spongiform lesions in several brain areas that were accompanied by vacuolization. These studies point at the potential for CoVs to provoke neurodegenerative (Kashiwazaki and others 2011).
A strong correlation exists between neurodegeneration and virus-induced immune reactions. Viral infections prime the immune system to carry out powerful effects, namely through chronic inflammation, which causes an enduring microglial activation and prolonged increase of inflammatory mediators (Zhou and others 2013). These effects lead to oxidative and nitrative stress, increasing the severity of the insult to brain tissue. In addition, activation of Toll-like receptor 4 dependent pathways has been implicated in innate immunity dysregulation that is observed in many neurodegenerative diseases (Zhou and others 2013). These are all key points that require investigation in SARS-CoV-2 infections. The etiology of neurodegeneration has been linked not only to inflammation but also to the formation of self-attacking antibodies.
Autoimmunity in Viral and Neurological Disorders
The concept of autoimmunity has been highly investigated in the areas of viral infections, brain injury, and neurodegenerative and psychiatric disorders. The immune system produces autoantibodies against self-antigens, whether specific or non-specific, which lead to a number of different diseases (Elkon and Casali 2008). Autoantibodies arise in a myriad of infections because of a process called molecular mimicry, whereby self-molecules share similar epitopes with pathogenic antigens (Oldstone 1998). The literature is replete with reports that examine the relationship between viral infections and autoantibodies, many of which explore molecular mimicry as a means for frequent cross-reactions between monoclonal antibodies against viral antigens and host proteins. Early research has shown that antiserum against a specific influenza virus strain reacted with a 37-kDa brain-specific protein enriched in the dentate gyrus and hypothalamus (Laing and others 1989). The cross-reactivity for two myelin antigens (myelin basic protein [MBP] and proteolipid protein [PLP]) has been reported for human sera against two serotypes of human coronaviruses (Boucher and others 2007). Also, inactivated SARS-CoV-1 vaccine was reported to cause cross-reactivity against human plasma α-1-acid glycoprotein (asialo-orosomucoid glycoprotein, ASOR) in vaccinated individuals (Wang and Lu 2004). The similarities in the carbohydrate moieties of ASOR and SARS-CoV-1 raised concerns about the role of autoimmunity in the virus pathogenicity due to the ubiquitous nature of ASOR, which makes 1% to 3% of total plasma protein (Colombo and others 2006). These findings were followed by the discovery that autoantibodies were formed against human epithelial cells after a month-long SARS-CoV-1 infection (Yang and others 2005). Such autoantibodies have previously been associated with a variety of diseases, mainly affecting blood vessels, including the brain’s vasculature (Yang and others 2005). Molecular mimicry was again exhibited in the cross-reactivity between SARS-CoV-1 S glycoprotein and the human host proteins, where the results implicated four viral pathogenic regions that might contribute to the antigenicity and formation of autoantibodies (Hwa and others 2008). One of these regions resulted in an antibody that cross-reacted with bradykinin.
These lines of evidence implicated autoantibodies in the latent effects of viral infections and put forth the need to investigate the roles they play in promoting delayed brain pathologies. Due to SARS-CoV-2 neuroinvasive potential and similarities to viruses previously proven to have auto-immunogenic effects, it is crucial to consider the possibility of forming cross-reactive immunoglobulins against brain-specific molecules as well as against epitopes found in other tissues. The theory of autoantibodies has been proposed foremost to explain the neurological effects of viruses like MERS-CoV because the virus could not be isolated from brain tissue even in the presence of neurological manifestations (Algahtani and others 2016). Therefore, the investigation of autoimmunity will aid in understanding disease progression, help in characterizing severity prediction markers and more efficient therapeutic strategies, and guide in the selection process of specific viral epitopes in immunization and vaccine production. Thus, the contribution of autoantibody-induced brain pathologies should be considered when looking at how viruses elicit cellular damage.
Infection Pathways in Central Nervous System
As indicated above, a plethora of neurological symptoms can result from direct or indirect consequences of SARS-CoV-2 infection, including a violent immune reaction (Stewart and others 1992; Wu and others 2020). Earlier throughout the pandemic, SARS-CoV-2 was detected in the CSF. Thus, its direct effects were still speculative and primarily based on comparing this novel coronavirus to SARS-CoV-1 and MERS-CoV. Recently, however, transmission electron microscopy revealed 80- to 110-nm viral particles with a SARS-CoV-2-like spike structure in postmortem frontal lobe tissue samples (Paniz-Mondolfi and others 2020). Additionally, the virus has been shown to replicate inside induced pluripotent stem cells (iPSCs)-derived human neural progenitor cells (hNPCs) and in neurospheres and brain organoids produced from these cells (Dekosky and others 2020; Zhang and others 2020a). Therefore, understanding the pathways through which SARS-CoV-2 can infect the nervous system should inform on more efficient ways to prevent and cure its CNS symptoms. In general, although viruses can invade the brain either through a hematogenous route or through the neurons, we will focus on ACE2 expression as a gateway for SARS-CoV-2 into the CNS (Algahtani and others 2016; Desforges and others 2014).
Neuronal Pathway
Neuronal invasion comprises entry into the neural cells where the virus interacts with dynein and kinesin motor proteins that facilitate its dissemination (Bohmwald and others 2018; Desforges and others 2014). This port of entry is established in primary infection sites. For instance, SARS-CoV-2 could cross into the brain through the nasal sinuses helped by its tropism for olfactory epithelium innervation (Eliezer and others 2020). Bilateral inflammation with sudden olfactory loss without nasal obstruction was observed in a COVID-19 patient suggesting viral entry through the olfactory neuroepithelia (Eliezer and others 2020). Viral infection was associated with hyposmia in 11 out of 214 patients, and this supports the olfactory bulb infection pathway (Mao and others 2020a). Previously, SARS-CoV-1 brain infection via the nose was demonstrated in mice transgenic for human ACE2 (Netland and others 2008) where olfactory innervations passing through the cribriform plate constituted the virus-used route to infect the brain without having to penetrate the BBB following hematogenous dissemination. The invasion starts in the olfactory bulb and spreads into other brain tissues. In the same study, SARS-CoV-1 viral particles started appearing in the olfactory bulb after 2 to 3 days of intranasal inoculation and propagated toward other regions that had first- or second-order connections with it (Netland and others 2008). HCoV-OC43 uses a similar infection pathway starting in the olfactory bulb and spreading to other brain regions (Dube and others 2018). Invasion through olfactory neurons provides for easy propagation of the virus that can reach distant brain areas like the brain stem. For instance, ultrastructural studies confirmed the presence of HEV 67N, another coronavirus from the same family, in medullary neurons following oronasal infection, demonstrating far-reaching trans-synaptic transport of the virus that depended on clathrin-coated exocytic/endocytic mechanisms (Li and others 2013). These findings emphasize the olfactory bulb’s importance as a potential entry route into the CNS. The viral spread to the brainstem may explain the broad spectrum of reported somatic symptoms because of the many vital medullary centers, including respiratory and cardiovascular control centers.
Hematogenous Dissemination
Another possible infectivity route comprises hematogenous dissemination. This proposed mechanism has been supported by previous evidence where viremia was observed in studies post intranasal inoculation with SARS-CoV-1 and HCoV-OC43 (Cheng and others 2020). Similar findings were observed with patients infected with SARS-CoV-1 and MERS-CoV (Chan and others 2015). Further support for this hypothesis comes from identifying SARS-CoV-2 viral particles in cytoplasmic vacuoles of neurons and in small vesicles of epithelial cells, suggesting that hematogenous dissemination could significantly contribute to the advancement of CNS symptoms (Paniz-Mondolfi and others 2020). Three different hypotheses can account for virus CNS entry from the blood. The first suggests that the virus crosses the BBB indirectly by hiding inside immune cells. Recently, it was proven that SARS-CoV-2 is capable of infecting T lymphocytes (Wang and others 2020b), which could then carry the virus into the brain parenchyma and cause CNS infection. However, this was only shown in vitro and thus might not mimic the natural infection in vivo. The second postulate looks at the possibility of the virus directly crossing the BBB. Combined with the fact that brain endothelia express ACE2 receptor, the slow movement of blood in microcirculation may offer a good enough opportunity for the virus to invade the brain facilitated by SARS-CoV-2-ACE2 interaction (Baig and others 2020). Besides, the previously presented increase in specific cytokines concomitant with CoV infections can expedite or contribute to virus entry (English and others 2016) as with IL-6 and MCP1, which increase BBB permeability (Pan and others 2011). Therefore, it is crucial to thoroughly investigate how capable the SARS-CoV-2 is at directly passing through the BBB. The third possibility suggests that the virus crosses into the brain through the brain’s circumventricular organs (CVOs), which are highly vascularized structures located around the third and fourth ventricles, comprising at least seven brain regions. They are characterized by their extensive and highly permeable capillaries, unlike those in the rest of the brain. Thus, CVO adjacent neurons are exposed to the general systemic extracellular fluid environment. Also, CVOs have been linked to certain parasitic and viral infections (Siso and others 2010). In addition, CVOs are capable of secreting substances directly into the circulation and sampling of the total contents of the systemic circulation. This renders them credible ports for SARS-CoV-2 entry because many of them express ACE2 (Kaur and Ling 2017). Specifically, it would be interesting to explore the area postrema of the dorsal caudal medulla (DCM) and the several hypothalamic CVOs considering that these brain regions have been previously shown to harbor high viral loads (English and others 2016; Li and others 2020b).
Stroke and Coagulation Events in SARS-CoV-2
SARS-CoV-2 infection increases stroke risk by 1.4-fold (Boehme and others 2018). COVID-19 patients exhibit circulatory complications, including disseminated pulmonary microthrombi, venous thromboembolism, and brain micro strokes (Divani and others 2020). Specifically, stroke has been reported by Mao and colleagues in 6 out of 214 patients infected with SARS-CoV-2(Mao and others 2020a). Around 5.7% of patients with severe COVID-19 exhibit acute cerebrovascular diseases, more commonly in the form of stroke. Several other reports have demonstrated the same complication comprising five cases of massive vessel stroke in under 50-year-old patients lacking any history of cerebrovascular accidents (Oxley and others 2020) and in 6 other individuals who suffered from a stroke or cerebrovascular complications (Al Saiegh and others 2020; Avula and others 2020). A summary of these reports is provided in Table 3.
| Authors | Study Design | Number of Cases | Cerebrovascular Complications |
|---|---|---|---|
| Mao et al. (Mao and others 2020b) | Retrospective study | 6 | 5 with ischemic stroke and 1 with hemorrhagic stroke |
| Oxley et al. (Oxley and others 2020) | Correspondence | 5 | Large vessel stroke |
| Avula et al. (Avula and others 2020) | Case series | 4 | Computed tomography proven stroke |
| Al Saiegh et al. (Al Saiegh and others 2020) | Case report | 2 | Subarachnoid hemorrhage and ischemic stroke with hemorrhagic conversion |
| Sharifi-Razavi et al. (Sharifi-Razavi and others 2020) | Case report | 1 | Massive intracerebral hemorrhage |
| Helms et al. (Helms and others 2020) | Retrospective study | 3 | Ischemic stroke |
| Morassi et al. (Morassi and others 2020) | Retrospective case series | 6 | 4 had ischemic stroke and 2 had hemorrhagic stroke |
| Li et al. (Li and others 2020a) | Retrospective observational study | 11 | 10 presented acute ischemic stroke and 1 had intracerebral hemorrhage |
Arterial smooth muscles, vascular endothelia, and myocardium express ACE2 rendering them (Hamming and others 2004) susceptible to direct injury or inflammatory damage mediated by SARS-CoV-2 entry, which predisposes patients to thrombogenesis and stroke (Valderrama and others 2020). During SARS-CoV-2 infection, endocytosis depletes ACE2 reducing its availability to convert Ang-II into Ang-(1-7); this increases ACE1-mediated Ang-II formation and causes hyperactivation of the classic RAAS axis and vasoconstriction of cerebral vessels leading to pro-fibrotic and pro-inflammatory consequences that harm brain parenchyma (Wright and Harding 2013).
COVID-19-induced coagulation has been demonstrated in several studies implicating a number of mechanisms. Coagulation abnormalities, endothelial injury, and microvascular thrombotic abnormalities have all been investigated in patients with SARS-CoV-2 revealing intense complement activation and terminal complement complex (C5b-9) deposition (Diao and others 2020). COVID-19-induced inflammation has been also correlated with coagulation, revealing activation of the thrombin regulatory mechanism. Activated thrombin cleaves fibrinogen into fibrin to further propel the coagulation cascade and the aggregation of platelets. Among the investigated thrombin regulators, antithrombin (AT), tissue factor pathways inhibitor (TFPI), and activated protein C (APC) have all been shown to be impaired in COVID-19 patients (Biswas and Khan 2020; Riewald and others 2003). This dysregulation in homeostasis favors a shift toward a more pro-coagulation and pro-inflammatory phenotype that disposes to the development of intravascular coagulation. Additionally, SARS-CoV-2 ability to induce a prothrombic state is correlated with elevated D-dimer levels that result from fibrin breakdown (Moore and others 2020). Indeed, according to one report, 25% of patients infected with SARS display venous thromboembolism with D-dimer levels exceeding 1.5 µg/ml (Cui and others 2020). Fibrin/fibrinogen degradation products are also increased in COVID-19 patients, especially in severe cases (Han and others 2020). This points at infection-induced alterations in coagulation pathways, promoting the risk of thrombosis.
SARS-CoV-2-associated hyperinflammatory state, mediated by increased inflammatory cytokines, such as IL-6, promotes blood hyper-viscosity and increases stroke risk (Valderrama and others 2020) (Fig. 5) . As monocytes and endothelial cells get activated during infection, released cytokines contribute to the development of disseminated intravascular coagulation (DIC), along with increased tissue factor expression and von Willebrand factor (VWF) secretion (Tang and others 2020). Besides, neutrophil activation leads to the release of myeloperoxidase (MPO), neutrophil elastase and chromatin (DNA and histones), which contribute to coagulation, DIC, and thrombosis (Fuchs and others 2010). Indeed, increased levels of citrullinated histone (CitH3) and MPO-DNA complexes have already been described in COVID-19 patients (Zuo and others 2020). Although the link between DIC and stroke remains speculative, its involvement in cerebrovascular complications post-SARS-CoV-2 infection remains a critical hypothesis to consider. Finally, vascular endothelial damage, intracerebral hemorrhage, micro thrombosis of small penetrating arteries, and dissection of larger arteries constitute additional stroke mechanisms in the context of SARS-CoV-2 infection (Valderrama and others 2020).
Psychological and Social Aspects of SARS-CoV-2
As with other pandemic-causing viruses, SARS-CoV-2 has not only manifested itself as a pathogen with extensive pathophysiological effects, but it has also played a role in affecting people’s psychological status. It is not a debate anymore that pandemics affect human mental health and cognition, especially that they are accompanied by anxiety, depression, and isolation (World Economic Forum 2020). Psychological distress is, at times, further worsened by symptoms of infection or adverse effects of treatments such as corticosteroids (Xiang and others 2020). Previous findings during the SARS outbreak reveal that survivors exhibited posttraumatic stress disorder (54.5%), depression (39%), pain disorder (36.4%), panic disorder (32.5%), and obsessive-compulsive disorder (15.6%) at 31 to 50 months post-infection (Lam and others 2009). Early results for survivors of the current pandemic reveal similar outcomes, particularly high rates of post-traumatic stress symptoms and depression (Vindegaard and Benros 2020).
Negative language, inflated facts, and fast inadequate information that the media offers often grow a great misunderstanding and increase the risk of fear and unjustified paranoia. In the era of scoops, news articles stress on morbidities and emergencies, which increases the pool of negative emotions. Besides, SARS-CoV-2 is a novel virus, and this provokes within human psychology the fear of the unknown (Schoch-Spana 2020). Additionally, research studies are being continuously under-translated into catchy nonscientific short articles, which take away a portion of the truth or even change it completely. Such misinformation subjects people to confusion and increases the risks that come with pandemics due to individualized approaches and decisions (World Economic Forum 2020).
This pandemic affects everyone, from children to elders. Children’s emotions and awareness are often underestimated. They are affected as much as adults due to the overwhelming experiences enforced by having to adapt to a whole new system of education, the fear of losing loved ones, and to heightened risks of violence or neglect within the domestic environment (World Health Organization 2020a). Also, the elderly population is at higher risk in this pandemic due to weakened immunity and underlying health conditions, which makes isolation the best method of prevention. However, this comes at an expense, considering frail health and declined cognitive abilities in the elderly population. The elderly are exposed to fear, neglect, anxiety, depression, and anger, which further compromise their mental and physical health (Schoch-Spana 2020). Besides, isolated elderly patients are put under strict obligations and can be shunned by society, which increases their feeling of guilt and fear of transmitting the infection even after full recovery. These factors fuel stress and anxiety and are likely to instigate emotional trauma (Schoch-Spana 2020). This is further aggravated by extreme physical pain imparted by infection-induced fever and breathing difficulty.
In addition, health workers are on top of the list of people susceptible to the psychological effects of this pandemic. The increasing numbers of virus infections oblige medical staff to serve longer shifts while witnessing increasing instances of human hardships that put them under extreme conditions of pressure, worsened by the shortage of personal protective equipment. Nurses may be subject to increased risks of developing posttraumatic syndrome, psychological distress, depression, and trauma exemplified by worries of the guilt of infecting their families and experiencing avoidance from people or attempts of violence.
The World Health Organization shares generalized and personalized guidance on how to manage and control the psychological aspect of this pandemic. The first major step is to address the conflict very clearly and boldly. This can be done by including healthy habits into the structure of the day, funding, and growing the networks of online consultancy and making it accessible to everyone (World Economic Forum 2020). Authorities can play a significant role in managing these aspects: the media and the government can do so through building a realistic understanding of the pandemic and a great sense of humanity, making information available to everyone, and adapting to the needs of the population. These are all major but not exclusive principles that should be founded to control all aspects of the current pandemic.
Conclusion
The presented evidence emphasizes the multifaceted damage that SARS-CoV-2 can cause, both at the molecular and psychological levels. Therefore, significant efforts are warranted to better understand the routes of infection employed by the virus. This step is a prerequisite for improving the prevention, management, and treatment of this debilitating virus. Moreover, SARS-CoV-2 neurotropism raises additional challenges and questions on how it invades the CNS and the roles of immunological and inflammatory factors in triggering its latent effects, including behavioral ones. Evidently, these efforts should be coupled with endeavors to abolish the pandemic’s effects at the macro-social and individual scales.
Acknowledgments
Special thanks go to Ms. Zaynab Shakour, MS; and Yara Yehya, MS, American University of Beirut, for their generous efforts in reviewing and editing the manuscript. We thank Dr. Samar Abdelhady, MD for her creative design and illustrations of the Covid-19 figures.
Author’s Note
Ali H. Eid is now affiliated with Department of Basic Medical Sciences, College of Medicine and Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work has been funded by a joint grant funded by the Flash Grant Call from the National Council for Scientific Research in Lebanon (CNRS-L) and the American University of Beirut (AUB) titled: “Neurological Complications Post-Coronavirus Disease (COVID-19): Assessment of Brain-Derived Autoantibodies as Diagnostic Markers of Neurological Outcomes, a Pilot Study (PI: Firas Kobeissy).
ORCID iDs
Muhammad Ali Haidar https://orcid.org/0000-0002-0236-1526
Ohanes Ashekyan https://orcid.org/0000-0002-1038-3506
Samar Abdelhady https://orcid.org/0000-0002-8206-6657
Maya Bizri https://orcid.org/0000-0003-0350-6157
Firas Kobeissy https://orcid.org/0000-0002-5008-6944
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