Neurological manifestations of SARS-CoV-2: complexity, mechanism and associated disorders

The human body contains three different types of capillary networks. These three types of capillaries are sinusoidal, fenestrated, and continuous. The endothelial cell-based lining of the body consists of continuous capillaries. Since these cells line up one after the other, they are called continuous. The large openings between the cells allow fast substance exchange in continuous, fenestrated capillaries [25]. Kidneys, small intestine, and endocrine glands comprise these types of capillaries. The continuous capillaries are further of two types: continuous-fenestrated and continuous non-fenestrated. Only small molecules such as water, glucose, hormones, and gases can pass through the gaps in the lining of continuous non-fenestrated capillaries known as intracellular clefts [24]. These capillaries are in the nervous system, skin, and lungs. Sinusoidal capillaries, also known as discontinuous capillaries, have bigger holes and gaps. Sinusoidal capillaries are present in the bone marrow, lymph nodes, endocrine glands, liver and spleen. The discontinuous capillaries are the most absorbent, while the continuous ones are the least permeable. Fenestrated capillaries have pores in their endothelial cells to facilitate more movement than continuous capillaries. Since the capillaries that BBB uses are unique, they are comprised of continuous, non-fenestrated capillaries with strong connections between their endothelial cells, which prevents paracellular trafficking [27]. The basic structure of the BBB is depicted in Fig. 2. These cells can precisely control the flow of infections and undesirable substances between the blood and the brain due to the absence of gaps between the endothelial cells in these capillaries, and they also lack pinocytic vacuoles. These endothelial cells also have adherent junctions and tight junctions. Only molecules with specific mass and lipophilicity can pass through the CNS's endothelial cells because of their high levels of selectiveness. The BBB is further supported structurally by the tight and adherent junctions that hold endothelial cells tightly together at the interface. The primary purpose of these tight junctions is to stop ions, large macromolecules and other soluble compounds from passing through them via paracellular diffusional channels [28]. Occludin, claudins, and other proteins that traverse the intercellular cleft make up tight junctions. These proteins are connected to crucial scaffolding proteins and other regulatory proteins, including Zona Occludens (ZO)-1, 2, 3, and Cingulin. Among all the isoforms of claudins reported to date, in vivo research has shown that claudin-5 and claudin-3 are necessary for proper BBB function [28]. The basal lamina is the second line of defence, which comprises collagen, heparin sulphate, proteoglycans and laminin. Besides this, the basal lamina houses pericytes and macrophages responsible for forming tight junctions and reducing vascular permeability. The glial cells or the astrocytic end feet are the third lines of defence along with angiotensin and glial cells derived neurotrophic factors, which maintain the ionic balance, and aid in the repair mechanism of the BBB [19, 21].

Some sections of the BBB do not possess these three layers, although they constitute most of the BBB zones. The prominent ones are the hypothalamus, Pineal gland, and area postrema, because these regions have sensory receptors, which are the hormonal regulatory regions of the brain [29]. Even after the tri-layer protection acts as a roadblock for substances entering the brain, some pathogens can still penetrate through this barrier [31]. An infection with a neurotropic virus also affects the BBB's functional homeostasis, because it changes the BBB's permeability and causes anti-inflammatory and pro-inflammatory innate immune reactions (Table 1). Numerous neurotropic viruses, such as the HIV of the Retroviridae family, the West Nile virus, the Zika virus, the Japanese encephalitis virus, the Venezuelan equine encephalitis virus of the family Togaviridae, tick-borne encephalitis virus (Flaviviridae family), and others, can enter the BBB via a haematogenous pathway and infiltrate the CNS. Viral entry into the BBB occurs via three distinct pathways: the trans-cellular pathway, the paracellular pathway, and a Trojan Horse mechanism utilising the diapedesis of infected cells [30, 31]. Researchers have found that SARS-CoV-2 can infect the respiratory system and the CNS. Following an autopsy, a recent analysis of COVID-19 patients revealed the isolation of SARS-CoV-2 from cortical neurons [32]. In addition to other organs, post-mortem tissue from the brain also contained SARS-CoV-2 RNA [32]. The data from human brain organoids has also confirmed that SARS-CoV-2 can invade neurons. The possible transport mechanisms by which any substance can move across the BBB are depicted in Fig. 3. Although the diseases penetrate the BBB, this strong line of defence does not allow neurological drugs to move across the BBB. Paracellular transport is usually impossible across the BBB due to tight junctions and the inactivating enzymes released by endothelial cells. These endothelial cells allow active and passive diffusion across the BBB through transmembrane proteins, usually claudins, which are the pore-forming structures within them [33]. Besides these hydrophobic molecules, lipophilic molecules and molecules with a weight of fewer than 500 Daltons can cross the BBB for transport to the brain through the CSF [34]. Neutral amino acids and glucose transporters transport amino acids and glucose, respectively. Monocarboxylates, glutathione, nucleosides, hexoses, amines etc., are transported with the help of facilitated diffusion, which includes transport through a transporter which induces conformational changes in the proteins present in the membrane [35]. This efflux and nutrient transportation is called vesicle-mediated transport regulation across the BBB.

The third method of transport includes transcytosis; it is a mechanism to facilitate transcellular transport by enclosing the molecule to be transported in a vesicle. This vesicle penetrates through the apical membrane and transfers the material to be transported; this process is called endocytosis. The vesicle is moved across the cell (intracellular vesicle trafficking) and ejected by the basolateral plasma membrane. This process is termed exocytosis. Specific receptors are responsible for mediating transcytosis across the BBB. Some of these include albumin receptors, transferrin receptors and insulin receptors. This transcytosis mechanism operates in two ways: through adsorptive transcytosis, which functions as described previously, and the other with the help of carriers or transporters. Researchers have identified three kinds of vesicles in endothelial cells: macro-pinocytotic vesicles, clathrin-coated pits and Caveolae [36‐39].

These transport mechanisms do not provide a way to transport some pivotal drugs for treating brain-related diseases. To overcome the problem of drug transport, scientists have come across other ways. The first way is transporting the drug via cerebrospinal fluid (CSF), which makes up the lining of the ventricles of the brain and subarachnoid spaces of the spine and the skull. The choroid plexus regulates drug transport via CSF, constituting the blood–CSF barrier [42, 43]. The drugs are intrathecally injected, equivalent to a slow intravenous injection. Following this, passive diffusion through the BBB occurs, which is a slow process [44]. The second method involves the use of vasoactive compounds. These compounds have the property of dilating or contracting the blood capillaries, aiding the movement of drugs. However, these are distinctive from the vasopressors and inotropes as they raise blood pressure and cardiac output. Four commonly used FDA-approved vasoactive drugs are phenyl epinephrine, norepinephrine, epinephrine, and vasopressin. The third method relies on the pharmacology of drug action in which highly lipid-soluble drugs are used to make their passage facile through the BBB via transporter proteins. These drugs include phenytoin, carbamazepine, oxprenolol, and timolol [40, 41, 45]. The fourth strategy involves interfering with endogenous transport mechanisms and blocking the efflux transporter, which pumps medicines back into the bloodstream [46]. Several other approaches have been tested for transporting drugs across the BBB. The contemporary is the nanoparticle approach in which Molecular Envelope Technology (MET) engineering is used [47]. Nanoparticles exhibit specific characteristics, such as non-toxicity, biocompatibility, small size, extended blood circulation, controlled drug release and targeted efficiency, making them suitable for drug transport across the BBB. Drug-delivery nanovesicles are designed for this purpose [48]. There have been recent experiments regarding using a polyacid (lactide–co-glycolic) for synthesising nanoparticles employed to transport drugs to treat Alzheimer’s disease. Besides this, polyethene imine and L-glutathione have been used to increase cyto-compatibility [49]. Some studies have focused on using human serum albumin-based nanoparticles and nanoparticles made up of poly ethyl cyanoacrylate to treat inflammation in brain tissue. Along with these polymeric nanoparticles, dendrimers have been used for transport across the BBB. These are unique nano polymeric molecules formed by the consecutive layering of a branching group over the other. The core molecule and the branched molecular layers are the same. There are functional groups present on the outer layer. Polyamidoaminedendrimers are being extensively used [50]. The other category of nanoparticles is micelles, amphiphilic molecules with particle sizes of 5–50 nm. They self-orient themselves with the hydrophobic portion called the tail forming the centre and the hydrophilic portion called the head directing outwards. These are usually deployed for the transport of poorly water-soluble substances. Inorganic nanoparticles such as gold nanoparticles, silica nanoparticles and carbon nanotubes are also used, but these typically lack the property of biodegradation and are hence used for bio-imaging purposes [51]. Levodopa and peptides specific to β-amyloid have been used as functional groups on gold nanoparticles in treating Alzheimer's and Parkinson's disease. Another study involved injecting mice with insulin-coated gold nanoparticles, which caused a build-up of insulin in the mice's brain, according to the results of micro-computed tomography. Carbon tubes can be multi or single-walled and consist of nano-scaled diameter graphite tubes. These possess characteristic features of functionalisation with different chemical compounds resulting in conformational, chemical, and physical changes. Drugs such as piracetam, pentoxifylline and pyridoxine have been delivered using silica nanoparticles [49]. In addition, newer discoveries about cyclic peptide nanocarriers and liposomes can be used to cross the BBB [52]. These developments highlight the need to re-evaluate some notions about drug delivery to the brain and also provide exciting possibilities for novel drug delivery techniques through various transport mechanisms.

Besides drugs, these transport mechanisms can also be apprehended to be involved in the transportation of SARS-CoV-2. Our comprehension of this relationship has improved due to numerous neurological studies showing that SARS-CoV-2 changes the BBB's functionality. Patients with minor COVID-19 infection have reported symptoms, such as dysgeusia, anosmia, and headache [30]. In addition,symptoms for patients with severe COVID-19 include delirium, disseminated encephalomyelitis, psychosis, catatonia, mania, Guillain–Barre syndrome, and seizures. Following 6-month COVID-19 infection, recent research examining the association between anxiety, sadness, and exhaustion has demonstrated that those who have long-term COVID experience serious neurological consequences [53]. This neurological evidence explains how COVID-19 could affect the nervous system via the BBB, among other mechanisms. It justifies the possibility that SARS-CoV-2 could enter the BBB through one of the above-mentioned pathways or other channels [29].

There has been little evidence for neurotropism in COVID-19, but the traced neurotropic properties of SARS-CoV-2 could be inferred from the neurovirulence of SARS-CoV. There is evidence that glial cells and neurons express ACE2. Axons and dendrites typically exhibit less robust ACE2 expression than the cell body of neurons. In addition, autopsy studies from SARS patients showed that SARS-CoV almost exclusively resides in neurons [73]. The neuro-invasive ability of SARS-CoV-2 must be considered a potential contributing factor for the severe respiratory symptoms in acute COVID-19 cases. In addition to symptoms connected to cranial nerves, such as hyposmia, neuroglia, hypogeusia, and hyposmia, examples of neurological symptoms seen in COVID-19 individuals include headache, vertigo, impaired consciousness, etc. Neuronal necrosis and glial cell hyperplasia were reported after a pathological investigation of the brain tissue [74]. In addition, SARS genome sequences in the neuronal cytoplasm of infected patient autopsies have been studied using light microscopy (LM), real-time polymerase chain reaction (RT-PCR) and electron microscopy (EM). All eight verified SARS autopsies revealed SARS virus particles in the neurons, and six confirmed cases of scattered red neurodegeneration and edema were documented [36]. The findings revealed that in mice engineered for human ACE2, the brain was the primary target organ for SARS-CoV [74]. Since SARS-CoV-2 has a similar sequence and mode of infection as SARS-CoV, the findings in the case of SARS-CoV are speculated to be related to SARS-CoV-2 [75].

Anti-spike or anti-nucleocapsid antibodies are used to identify cells positive to viral proteins in the medulla oblongata. SARS-CoV-2 nucleoprotein and RNA occurrence have also been reported from certain cranial nerves that emerged from the lower brainstem [14]. Evidence that SARS-CoV-2 can directly enter and get access to the brain comes from the virus' discovery in cerebrospinal fluid and brain epithelial cells. Exploring how SARS-CoV-2 penetrates the brain has been the subject of extensive research. It has been found that there are three mechanisms through which the virus can gain access to the brain [75]. The most prominent route is via the ACE2 receptors. The ACE2 gene has 18 exons and just one catalytic domain on chromosome Xp22. ACE2 balances ACE activity by catalysing the conversion of angiotensin II (Ang-II) to angiotensin 1–7 (Ang 1–7). ACE2 mainly breaks down angiotensin II into compounds that neutralize its harmful effects, including inflammation and the death of cells. Angiotensin is a hormone that leads to water and salt (sodium) intake and constricts (narrows) blood vessels to assist in regulating blood pressure. Angiotensin possesses four distinct forms, which are identified as Ang-I to Ang-IV. Angiotensin I is hydrolysed by ACE2 to produce Angiotensin 1–9, and Angiotensin II (the primary and active form of the hormone) is hydrolysed to produce Angiotensin 1–7. Antagonism exists between the Ang-II and Ang 1–7 peptides. The Ang II–AT1R axis is pro-inflammatory, profibrotic, and prothrombotic, whereas Ang II–AT2R and Ang 1–7-Masaxes are anti-fibrotic, anti-inflammatory, antithrombotic, and have vasodilatory effects. The C-terminal segment of ACE2 is a counterpart of the renal protein, collectrin that controls the movement of amino acid carriers to the cell surface, giving ACE2 various physiological roles. Due to the numerous physiological functions that ACE2 performs, SARS-CoV-2 uses it as a receptor. Both SARS-CoV andSARS-CoV-2 in complex with ACE2 have been structurally characterized. The main spike glycoprotein of SARS-CoV-2 interacts with the N-terminal of the ACE2 receptor and contains 380 amino acid substitutions that are distinct from SARS-CoV, which corresponds to variations in five of the six essential amino acids in the receptor-binding motif in between viral protein and the N-terminal region of the human ACE2. Forty-one viral spike proteins are well-recognized as significant targets for developing treatments and vaccines, because they are essential markers of host tropism. In addition, both S-protein and ACE2 contain host cell proteolytic enzymes crucial for SARS-CoV-2 entry and cell infection. To attach the S-protein and to facilitate cell entrance after receptor engagement, SARS-CoV-2 has evolved to use a variety of host proteases, notably trypsin, cathepsin L, factor X, cathepsin B, furin, elastase, and TMPRSS2. Spike protein can be activated by the host serine protease TMPRSS2 and the cysteine proteases Cathepsin B/L, opening up SARS-CoV-2 to two different entry paths for the pathogen [54, 55]. SARS-CoV-2 enters cells due to the spike protein's interaction with the extracellular domains of transmembrane ACE2 proteins and the subsequent down-regulation of surface ACE2 receptors [75].

The second route which aids SARS-CoV-2 entry into the brain is by olfactory means, as the primary route of its entry is through the nose via inhalation. The major symptoms of COVID-19 infection specified by the WHO include cough, fever, and loss of smell and taste, the prominent among these being respiratory infections. This depicts the association of SARS-CoV-2 with the respiratory tract, and the nasal passage serves as the entrance for the respiratory tract. According to studies done on transgenic mice, SARS-CoV and MERS-CoV may enter the nose and go to the brain via the olfactory nerves before fast spreading to the thalamus and brainstem [64]. Interestingly, MERS-CoV was found in the brains and not in the lungs of experimentally infected animals with low inoculum doses of the virus. This shows that the infection in the CNS predominantly caused the significant mortality rate observed in the afflicted animals. One of the main areas of the brain that MERS-CoV affects is the brainstem [76]. According to research, the novel coronavirus may attack peripheral nerve terminals before entering the CNS via a synapse-connected pathway. Researchers' studies show clathrin-coated transmission of HEV across neurons through these routes [77]. Similarly, reports of avian bronchitis virus trans-synaptic transmission have been made. In addition to bronchitis or pneumonia, intranasal avian influenza virus inoculation in mice has also resulted in brain infection. The two diseased areas of the brainstem: nucleus ambiguus and nucleus of the solitary tract, were revealed to contain viral antigens [78]. The nucleus of the solitary tract receives sensory information and respiratory tract information. In contrast, efferent fibres from the nucleus ambiguus and the nucleus of the solitary tract perfuse nasal passages, smooth muscle glands and the circulatory system, providing information about them. This explains the connection between the circulatory system and infection by the avian influenza virus.

The third possible entry route for SARS-CoV-2 is via cytokine storms. Cytokine storm happens due to excessive secretion of cytokines by the immune system. These chemicals can stimulate the functioning of other immune cells while promoting inflammation. Immunotherapy, autoimmune diseases, and infections such as COVID-19 can all result in cytokine storms. Pro-inflammatory chemicals are known to cause neuro-inflammation after viral infection. Studies are still underway to determine the link between cytokine storms and SARS-CoV-2 brain penetration [75].

Although the respiratory system is the primary site of inflammation caused due to SARS-CoV-2 infection, inflammatory response affecting extra-pulmonary tissues has also been noted in many cases globally. With a clinical phenotype that appears to be influenced by epidemiological characteristics, such as age, sex, or ethnicity, the signs and symptoms linked to this overactive immune response are highly varied and can mirror various autoimmune or inflammatory disorders. The intensity of the manifestations also varies greatly, from benign, self-limiting features to systemic disorders that might be fatal [79]. Acute respiratory distress syndrome (ARDS), a clinical syndrome characterised by acute lung inflammation and increased-permeability pulmonary oedema as a result of damage to the alveolar capillary barrier, can occur in some COVID-19 patients and result in a severe, acute virus-induced lung injury [80, 81]. Pro-inflammatory cytokine concentrations that are high, shock incidence that is enhanced, and unfavourable clinical outcomes are the hallmarks of the hyperinflammatory phenotype of ARDS. 'Cytokine storm' has become synonymous with the pathophysiology of COVID-19-induced ARDS, even though its processes are still being clarified. The terms "cytokine storm" and "cytokine release syndrome" (CRS) are widely used interchangeably to refer to immune-related dysregulation caused by the release of enormous amounts of cytokines that cause systemic inflammation, multi-organ failure, and high death rates [82]. Fever, tachycardia, tachypnoea, and hypotension are the major symptoms distinguishing CRS from systemic inflammatory response syndrome, one of the most common serious adverse effects of chimeric antigen receptor T (CAR-T) cell therapy [83]. A major modulator of the acute inflammatory response in ARDS and CRS, the pro-inflammatory cytokine IL-6 also appears to play a role in severe COVID-19 and contributes to increased C-reactive protein levels, hypercoagulation, and hyperferritinemia. However, compared to patients with CRS, ARDS, sepsis, or even influenza, patients with COVID-19 have significantly lower serum IL-6 concentrations [81].

ACE2 functions as a functional SARS-CoV-2 receptor, which causes ACE2 to be downregulated and Ang II to be expressed more prominently. The multiorgan dysfunction seen in COVID-19 patients may be explained by the fact that ACE2 is primarily expressed by vascular endothelial cells of the lung, as well as in extrapulmonary tissue, the heart, neurological system, gut, kidneys, blood vessels, and muscles on cell surfaces. Pneumonia, ARDS, sepsis, coagulopathy, a high rate of thrombosis, and organ damage are all part of the complicated clinical picture of COVID-19 patients with severe consequences. These conditions are brought on by diverse effects of highly expressed Ang II on vasculopathy, coagulopathy, and inflammation [84].

SARS-CoV-2 infection of the lungs damages the endothelium lining of the blood vessels and increases capillary permeability, allowing the virus to spread from the lungs to the pulmonary microcirculation. SARS-CoV-2 may enter the CNS after crossing the BBB by directly interacting with ACE2 receptors or by changing the tight junction proteins produced by endothelial cells lining the BBB. Proinflammatory cytokines (IL-1, IL-1, TNF-, IL-6, IL-12, etc.), thrombin, fibrinogen, and plasmin concentrations rose after SARS-CoV-2 infection and caused hypoxia that breaks down the BBB may allow SARS-CoV-2 to pass through paracellularly and enter the CNS [85]. By acting  via  a "Trojan horse mechanism" (decoy), infected leukocytes or endothelial cells can carry viruses over the blood–brain barrier (BBB) and into the brain. Viruses can also cross the blood–CSF barrier through choroid plexus epithelial cells. In wild-type mice, the S1 subunit of the spike protein is transported to the brain parenchyma through a vesicle-dependent process known as adsorptive transcytosis, even though viral RNA or particles have not consistently been demonstrated to exist in a patient's CSF or brain tissues. It is noteworthy that persons with COVID-19 neurological symptoms typically have anti-SARS-CoV-2 antibodies in their CSF. The BBB and/or blood–CSF barrier leaking are probable explanations for this [86].

Brain infections are less frequent than other organs and depend on unusual circumstances that enable the virus to cross the blood–brain barrier. Systemic viruses do not typically infect the brain. Those who do so might profit from infrequent occurrences such as the blood–brain barrier breaking down or an infection of immune cells that resemble Trojan horses and can cross the blood–brain barrier but release viruses. The entrance point and route may significantly impact the final symptoms produced. Neurological issues can be brought on by viruses in a variety of ways, such as apoptosis by vesicular stomatitis virus (VSV), disruption of brain cells by cytomegalovirus or additional harm brought on by the release of glutamate, DNA, and other factors that contribute to more brain damage [11]. Evidence state that viruses enter the brain via the bloodstream or, in the case of rabies, by advancing over peripheral nerves. Viruses such as rabies do not cause the death of neurons; instead, they hijack cellular transcriptional processes to activate viral instead of neuronal genes, causing the loss of neuronal function while maintaining a regular appearance on standard pathological inspection [11]. In 1918, during the influenza pandemic, caused by the H1N1 virus with avian origin genes, research revealed that those infected experienced encephalitis, lethargy, sleep abnormalities, movement disorders, and mental illnesses [87]. In addition, it has been discovered that the common herpes infection brought on by the Herpes Simplex Virus (HSV) is linked to inflammation in the brain and Alzheimer's disease (AD). HSV infection is linked to Alzheimer's due to brain inflammation, and COVID-19 can cause neurological symptoms in 36.4% of cases.

Because of the widespread expression of ACE2 across the brain, the virus is believed to attack the CNS. In essence, the BBB could be destroyed by SARS-interaction CoV-2's with ACE2 in the capillary endothelium, allowing the virus to reach the CNS [75]. Furthermore, there is compelling evidence that mRNA from closely related SARS viruses, such as SARS-CoV, which interacts with ACE2, is present in the brains of infected patients. Given the similarities between SARS-CoV and SARS-CoV-2, it is likely that the presence of ACE2 in brain tissues facilitates the migration of SARS-CoV-2 into the CNS and hence, causes neuro infection [69].

SARS-CoV-2 enters the brain via the olfactory nerves through the nasal canal and may infect neurons that control respiration. This information stems from a previous study that found approximately 89 per cent of SARS-CoV-2 patients needing intensive care could not breathe independently. They had neurological symptoms, such as nausea, headache, and vomiting. Almost half of the patients were ill briefly and died from respiratory failure. Although it has not been proven that neurons that control respiration are likely to be infected [104].

T-cells and antibodies are the two most crucial components of the immune system's defence against viruses. The presence of SARS-CoV-2-specific cells was observed in patients recovered from COVID-19, suggesting they may have prophylactic antiviral impact. However, some research suggests that severe COVID-19 may be brought on by an overactive immunological reaction [105]. ARDS leads to the entire lung being inflamed and developing a significant barrier of fluid that leaks into the interstitial space. In addition, these capillaries begin to leak fluid into the alveolar space, filling with proteinaceous liquid. This substance keeps oxygen from entering the bloodstream, resulting in hypoxic blood that makes breathing difficult for the patient. Viral invasion can set off a cascade of immunological reactions that can result in a cytokine storm and, death from ARDS. The cytokine storm has been found to have a significant role in the pathophysiology of SARS and MERS in clinical and animal studies [32]. In clinical investigations, critical patients had higher levels of pro-inflammatory molecules in plasma than mild to moderate patients, implying that the cytokine storm is also linked to the severity of COVID-19 [106].

Brain dysfunction, such as delirium or coma found in patients with severe COVID-19, is caused by physiological anomalies of the disease, which range from high temperature to low oxygen levels to organ failures. Delirium is a well-known symptom and an indication of serious disease in older adults. Delirium is a severe insanity that can cause a changed state of consciousness, disorientation, inattention, and other symptoms of confusion and disruptions in cognition. It is common in elderly humans and is linked to adverse outcomes, such as prolonged hospitalisations and even death [107].

COVID-19 can cause blood clots or bleeding in the brain, resulting in a stroke. It can destroy the protecting cells that form the BBB, allowing hazardous substances such as viruses to pass through. The condition can wreak havoc on a person's lungs to the point, where their brain runs out of oxygen [106]. According to a group of neurologists from The National Hospital for Neurology and Neurosurgery (NHNN), London and The University College of London (UCL), clinical findings of COVID-19 patients who later suffered a stroke indicate coronavirus may create clots within blood vessels (arteries) in the brain. The results recommend D-dimer testing at an earlier stage, which may lower the number of people who have more strokes or blood clots elsewhere in the body.

A stroke happens when the body's flow of blood flow to the brain is interrupted. Ischemic stroke, also known as brain or cerebral ischemia, is the most common type of stroke and occurs due to a blockage in the arteries surrounding the brain. The obstruction causes the brain to get less blood and oxygen, which damages or kills brain cells and may become irreparable if blood flow is not quickly restored. ACE2 hydrolyzes Ang-II into angiotensin-(1–7), and the ACE2/angiotensin-(1–7)/MAS counteracts the unfavourable effects of the RAS while also having anti-inflammatory actions, in addition to serving as the receptor for SARS-CoV and SARS-CoV-2. SARS-CoV-2 infection has been shown to downregulate ACE2 expression in cells and cause severe organ damage, disrupting the physiological equilibrium between ACE/ACE2 and Ang-II/angiotensin-(1–7) [93]. In conjunction with this, without angiotensin-17, inflammation may increase Von Willebrand's factor (VWF), which further couples with factor VIII, sometimes referred to as an anti-haemophilic factor and is a crucial blood-clotting protein ultimately causing arterial thrombosis. The most common type of ischemic stroke seen in patients with COVID-19 is Embolic stroke. It happens when the blood clots break off from one area of the blood vessel and block an artery or tiny capillaries, causing a high inflammatory response leading to hyper-coagulation. Elevated D-dimer levels have been observed, indicating prominent blood clots in neurological patients [114]. The age group most commonly affected by ischemic stroke are the young and middle-aged patients (30–45 years). Strokes are one of the major cardiovascular disorders that affect the brain and results in inefficient blood supply to the brain [115]. Strokes can be categorized as haemorrhage or Ischemic. The proper causation of strokes remains unclear for different cases but specific infections (bacterial or viral) lead to the formation of strokes. Different medical records showed a clear relation between stroke cases and COVID-19 infection, which increased the risk of ischemic and cryptogenic stroke in general [116]. In the case of children, the relation was infrequent, and there was no evidence between these two conditions [117]. However, to drive any conclusion regarding the relation between strokes and SARS-CoV-2, testing must be increased, followed by data analysis and further interpretation. Another unusual finding was that these patients had no significant risk factors, such as high cholesterol levels, diabetes, or high blood pressure problems [118].

The COVID-19 epidemic has had a profound impact on stroke care globally. During this time, the Society of Vascular and Interventional Neurology supplied advice on treating stroke. Stroke risk has gone up due to COVID-19, and healthcare delivery has been made more difficult. Hospitals have prioritised operations such as thrombectomy to assess and treat stroke patients to solve these issues quickly. The need to raise public knowledge about stroke has been emphasised. Patients with COVID-19 have been isolated from others to stop the spread of the disease. Stroke care quality has been maintained through multidisciplinary teamwork and procedural optimisation. With the help of these experiences, future pandemic scenarios can be prevented, and stroke care can be provided effectively worldwide [119, 120].

Cerebral Venous Sinus Thrombosis (CVST) is a condition leading to the formation of blood clots/thrombus due to blockage of a vein in the brain (Fig. 6). This causes the blood flow to cease and build up pressure, causing severe headaches and may also damage the surrounding tissues. This may result in various stoke symptoms, such as confusion, loss of movement and consciousness, blurred vision, seizures, and coma. Many researchers concluded that this disease is based upon multi-factorial symptoms and results due to pro-thrombotic risk factors in synergy with clinical conditions, such as infections [121].

A recent study reveals that thrombotic events and severe thrombocytopenia have been linked to immunisation against SARS-CoV-2. With both ischemic and hemorrhagic consequences, this syndrome, known as VITT (vaccine-induced immune thrombotic thrombocytopenia), has been linked to a high risk of catastrophic outcomes. It is still necessary to determine the best course of action. Two patients with VITT-associated CSVT were treated with high-dose intravenous immunoglobulins (IVIGs), corticosteroids, and argatroban in the hyperacute phase, followed by dabigatran, with outstanding results, according to the study [19].

Guillain Barre’s Syndrome, or GBS, is when a myelinated neuron is damaged and loses its ability to transmit the nerve impulse properly. During viral or bacterial infection, the human body produces an immune response that corresponding to activity against viral or bacterial cells [123]. In some cases, the immune system acts against its neural system, damaging a neuron’s myelin sheath. This affects the neuron’s functioning and proper transmission of nerve impulses [124]. Demyelination of neurons and improper signal transmission is depicted in Fig. 7.

Since the pandemic, reports have confirmed increased GBS cases following COVID-19. The International GBS Outcome Study (or IGOS), a global cohort of GBS patients, was used by researchers to study patients from January 30 through May 30 2020. During this time, the study included 49 GBS patients from different countries. This cohort analysis reported that COVID-19 infection was present in 22% of the GBS patients. All of these patients were above 50, and the majority (65%) had a demyelination form of GBS and facial palsy. 73% of the COVID-19-infected Guillain–Barré patients had elevated inflammatory markers at hospital admission [124].

A demyelinating illness of the nerve cells, multiple sclerosis (MS) is a long-lasting condition, where the immune system destroys the myelin sheath that insulates [125]. The virus's disruption of immune responses increased the risk of MS and was reported in numerous people post-COVID-19 infection [126]. The causal agent of MS in humans is not well-known, but there are many theories. Some suggest Vitamin D deficiency or inadequate consumption of Vitamin D could lead to MS [127]. At the same time theories state that the effect of viruses on the neural system contributes to this condition, for instance, in the case of Epstein Barr Virus (EBV) infection [128]. Elevated levels of antibodies against EBV antigens before the onset of MS are good indicators of the relation of EBV with MS [69, 103].

Multiple factors contribute to the pathophysiology of MS, and compelling data indicate a probable viral trigger-like EBV. The olfactory bulb is the direct entry point for SARS-CoV-2 into the CNS, where it can lead to neuronal injury and prevent oligodendrocytes (OLs) differentiation and remyelination. Microglial cell death, which results in poor clearance of myelin debris, and the release of neurotoxic soluble substances from activated astrocytes are two processes that contribute to these pathologic reactions. There are two ways that SARS-CoV-2 infection could aggravate MS. First, as a direct result of a pro-inflammatory reaction, it may cause MS relapses in affected patients. Second, it may permanently change the cellular and structural makeup of the CNS in infected individuals, raising their long-term risk of developing MS. Limited retrospective studies have been done until now to investigate the aggravation of MS symptoms after SARS-CoV-2 infection, and those that have been found have yielded conflicting results. To demonstrate a rise in the disease's incidence or its rate of recurrence during COVID-19, extensive epidemiological research would be required [27].

Meningitis is a viral infection which results in the inflammation of the meninges of the brain and spinal cord [129]. Some clinical signs and symptoms of meningitis include fever, vomiting, and headaches. Meninges are the membranous layers that protect the brain and spinal cord. Usually, bacterial or viral infections take place before meningitis. Traces of SARS-CoV-2 have been found in the CSF, which led to the development of meningitis and encephalitis in a patient [13]. Inflammation resulting from meningitis is shown in Fig. 8. In some cases, RBCs have been reported in CSF, pointing to a BBB breach, which can happen in SARS-CoV-2 infection and has been associated with cytokine storm disorder. Furthermore, the observation that individuals with severe SARS-CoV-2 infection respond to IL-6 receptor blockers supports the theory that COVID-19 patients with cytokine storm syndrome incur severe symptoms and brain damage [130]. Along with CT (Computed Tomography) scans, brain MRI scans must be done for detailed imaging to diagnose inflammation in the brain.

Encephalitis is similar to meningitis. Meningitis leads to inflammation of the meninges, while in the case of encephalitis, the entire brain is inflamed [106, 107, 131]. However, solid conclusions cannot be derived from data generated in low diagnostic studies and testing levels.

Incidences of encephalitis in patients admitted to ICUs for respiratory distress, and cases of SARS-CoV-2 infections that mainly target the CNS have been reported [132]. The SARS-CoV-2 infection was linked to every occurrence of encephalitis in this prospective multicentre research which included data from 13 neurological facilities in Italy. The cerebrospinal fluid (CSF) analyses, common electroencephalograms, and brain MRI were all performed on each of the 25 individuals. The findings show that SARS-CoV-2 infection is related to a range of encephalitis types, including limbic encephalitis, tuberculosis-related meningo-encephalitis, acute necrotizing encephalitis (ANE)/acute demyelinating encephalomyelitis (ADEM) with varying clinical presentations, therapeutic responses, and prognoses. The incidence of encephalitis cases was determined to be 50 per 100,000 as per the study's findings [133].

Compared to the S protein of SARS-CoV, the S protein of SARS-CoV-2 exhibits a greater affinity for ACE2. The peptidase ACE2 is found on the surfaces of immune cells, neurons, vascular endothelium, smooth muscle, and alveolar and gastrointestinal epithelial cells. This suggests that SARS-CoV-2 may target vascular endothelial cells mainly via the ACE2 receptor, leading to endothelial cell dysfunction and endothelial barrier breakdown. When the endothelium is damaged, exposed sub-intimal collagen can activate and assemble platelets, leading to thrombosis and cerebral ischemia [135]. ACE2 plays a role in the neural regulation of numerous physiological processes, including stress response, neurogenesis, metabolism, and cardiovascular activity, due to its extensive distribution in the brain. It has been observed that SARS-CoV-2 spreads through the neurons to other parts of the mouse model's brain after entering the olfactory bulb. Numerous COVID-19 patients have reported olfactory and gustatory dysfunctions, pointing to the olfactory bulb's role in SARS-CoV-2 infection.

COVID-19 patients often display elevated D-dimer levels, indicating a hypercoagulable state with active coagulation and fibrinolysis systems [135, 136]. Inflammatory factors, elevated plasma levels of tissue factors, and platelet aggregation may be stimulated by greater sympathetic activity and more extensive micro-endothelial damage, which alter capillary blood flow and cause blood coagulation [109, 110]. This heightened procoagulant state poses a significant risk of blood clot formation, potentially leading to cerebrovascular complications, such as ischemic strokes. The presence of thrombotic events, including deep vein thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism (VTE), highlights the potential for blood clots to form and travel to various parts of the body, including the brain. Severe inflammation, diffuse intravascular coagulation (DIC), immobilization, and hypoxia associated with lung injury in COVID-19 patients further contribute to the increased risk of thrombotic events [137]. Thus, healthcare professionals must closely monitor and manage cerebrovascular implications in COVID-19 patients, especially those with pre-existing cardiovascular conditions, to optimize patient outcomes and prevent potential adverse effects on cerebrovascular health.

In the context of COVID-19, the elevated D-dimer levels and hypercoagulable state pose significant cerebrovascular implications, particularly when considering the impact of changes in oxygen concentration on the brain. Hypoxia, caused by alterations in oxygen levels, can lead to pathophysiological changes that directly affect the brain. The potential harm to vital organs, including the brain, is a serious concern if hypoxia is not promptly addressed. In the brain, hypoxia can raise cerebral capillary pressure and intracranial blood flow, leading to tissue fluid generation. In addition, hypoxia causes membrane lipid peroxidation and the release of endogenous inhibitors. Anaerobic glycolysis produces elevated levels of oxygen free radicals, lactic acid, and lipid peroxides, which compromise the antioxidant system and lead to blood–brain barrier (BBB) dysfunction [138]. When combined with the procoagulant state indicated by elevated D-dimer levels, the risk of cerebrovascular complications, such as ischemic strokes, becomes even more pronounced.

Acute infection, as seen in COVID-19, can activate self-protective defenses in the human body, leading to potential stress responses. This can result in the release of hyperglycemic hormones, exacerbating insulin resistance and causing elevated blood glucose levels [139]. Hyperglycemia, in turn, may contribute to increased oxidative stress by promoting the overproduction of reactive oxygen species (ROS) in the mitochondrial electron transport chain. These ROS can further activate various events associated with the progression of atherosclerosis, including pathways, such as the protein kinase C pathway and the generation of advanced glycation end-products [139].

According to research findings, stress has been identified as an independent cause of stroke, indicating its potential impact on cerebrovascular health. However, the precise link between cardiovascular diseases and acute psychological stress remains uncertain. Previous studies have demonstrated that under conditions of pathophysiologic stress, the production and release of plasminogen activator inhibitor type-1 (PAI-1) increase. PAI-1 is a serine protease inhibitor that specifically interacts with tissue plasminogen activator (t-PA). This interaction leads to the rapid inactivation of t-PA, and PAI-1 may play a significant role as a key mediator in stress-induced hypercoagulability and thrombosis [140].

Furthermore, SARS-CoV-2 has been found to infect the pancreas via the ACE2 receptor, which is more abundantly expressed in this organ. Consequently, this viral infection can lead to pancreatic damage and impaired insulin production, resulting in the emergence of hyperglycemia, even in individuals without pre-existing Diabetes Mellitus (DM). In addition, individuals with pre-existing DM may experience worsened symptoms if SARS-CoV-2-induced damage affects their pancreas. Peripheral insulin resistance is also induced by the inflammatory response and cytokine storm triggered by COVID-19, characterized by significant increases in the levels of inflammatory markers, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) [141]. Various disorders and complications associated with COVID-19 are described in Table 2.