The other case of COVID-19 reported with neurological manifestations was a retrospective, observational case series in Wuhan, China (Mao et al. ). The case evidenced the involvement of the nervous system with the characteristic neurological manifestations of SARS-CoV-2. In the case series, 78 out of 214 patients were diagnosed with COVID-19, where neurological symptoms were observed in 36.4% of patients and common in 45.5% of patients with severe infection. In addition, the main neurological outcomes of the patients were categorized under three categories such as (1) manifestations of the central nervous system with dizziness, ataxia, headache, and seizure, (2) manifestations of the peripheral nervous system with smell, taste, and vision impairment, and (3) manifestations of injury of skeletal muscle. In addition to this case series, cases of Guillain-Barre Syndrome (GBS) have also been reported for COVID-19 patients. A case study of a 71-year-old male patient with severe paresthesia at limb extremities as well as distal weakness with rapidly developing tetraparesis was evidenced (Alberti et al. ). While undergoing neurological examination, the patient exhibited normal consciousness, no cranial nerve deficit, and normal plantar response. Brain computed tomography (CT) was normal, while the chest CT demonstrated multiple bilateral ground-glass opacities as well as pneumonia. SARS-CoV-2 was positive in the nasopharyngeal swab, while in the case of CSF, it was negative. Overall, all these possible findings were predicted as acute polyradiculoneuritis with prominent demyelination. In this context, the diagnosis was made according to GBS in association with COVID-19. Therefore, all these evidence-based case reports bringing the view that more autopsies of the patients, as well as isolation of SARS-CoV-2 from the glial cells, CSF, and neuronal tissue, may clarify the neurological outcomes and its impact on COVID-19 in the ongoing pandemic outbreak.
Initially, the viral infected microglia, macrophages, and astrocytes may activate glial cells and induce local pro-inflammatory cytokines (Li et al. ). These activated immune cells and T-cells eventually induce other immune cells, leading to neuronal damage, apoptosis, and demyelination (Alberti et al. ; Li et al. ). The term 'cytokine storm' is a condition characterized by a potent activation of the immune system leading to overproduction of many active components, viz., interferons (IFN), chemokines, interleukins (IL), and tumor necrosis factor-alpha (TNF-alpha). The release of large amounts of pro-inflammatory cytokines, viz., IFN-alpha, IFN-gamma, IL-1beta, IL-6, IL-12, IL-18, IL-33, TNF-alpha, TGF-beta, and several chemokines, viz., CXCL-8, 10, CCL-2, 3, and 5 at a time causes an aberrant systemic inflammatory response that attacks the body, which subsequently causes ARDS and multiple organ failure (Meduri et al. ; Jose et al. ). These hyperactive immune responses are also referred to as cytokine release syndrome or macrophage activation syndrome. According to previous reports, neurological insults like ANE involve an intense intracranial cytokine storm resulting in BBB disruption (Rossi). Growing pieces of evidence involving brain-CT scans and MRI reports have projected a sign of cytokine storm syndrome in a subgroup of COVID-19 patients (Mehta et al. ; Wong et al. ). This cytokine storm in ANE was reported to be initiated mainly by the helper T-cells, which secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce IL-6 producing macrophages (Mehta et al. ; Toljan). It was also noticed that the activation of coagulation pathways occurs simultaneously during the overproduction of pro-inflammatory cytokines worsening the negative effect of immunological response in COVID-19 patients (Tang et al. ). During the cytokine storm, the coagulation pathway is also impaired (Jose and Manuel). Thrombin promotes clot formation by activating platelets, and the process is regulated by a negative feedback mechanism. It is the key element augmenting the inflammation (Jose and Manuel). McGonagle and colleagues further described macrophage activation syndrome (secondary hemophagocytic lymphohistiocytosis) that entailed systemic hyper-inflammation in COVID-19 patients (McGonagle et al. ). Adding to the queue, Quin et al. reported an alteration in lymphocytes in a cohort of 452 COVID-19 patients (Quin et al. ). Very recently, Alberti et al. reported GBS related to COVID-19 infection, explaining acute dysimmune neuropathy involving the peripheral nervous system before the onset of pneumonia (Alberti et al. ). Also, Frontera and co-workers reported hospitalized COVID-19 patients having brain inflammation encephalitis with seizures caused due to hyper-reaction of the sympathetic nervous system. Some of them also lose consciousness, and others have strokes and lack a sense of smell (Dahm et al. ). Moreover, SARS-CoV-2 infection and a subsequent immunological debilitation might hamper the brain stem reflex that causes oxygen starvation leading to more worsening conditions (Dahm et al. ). All these evidences indicate a synergistic role of immunological elements that need to be deciphered to construct a fruitful treatment methodology against COVID-19.
Considering the cytokine storm in SARS-CoV-2 related pathophysiology, many researchers, clinicians, and medical practitioners have recommended anti-inflammatory drugs, steroids, selective inhibitory blockade, and Janus kinase (JAK) inhibition for possible therapeutics (Mehta et al. ; Richardson et al. ). Significantly, having experience from previous pandemics,, viz., SARS and MERS corticosteroids have not been routinely prescribed in COVID-19 related lung infection (Russell et al. ). However, immunosuppression may emerge beneficial in hyper-inflammation. Cavagna et al. reported the effect of immunosuppressant drug calcineurin-inhibitor on the COVID patients who were suffering from systemic rheumatic disorders or went on organ transplantation (Cavagna et al. ). Nevertheless, they did not exclude a direct antiviral activity of calcineurin-inhibitor but observe a positive outcome of this immunosuppressant drug on COVID patients who were already prescribed this drug following an organ transplant or rheumatic disorders. The prevention of massive alveolar macrophage activation and subsequent release of pro-inflammatory cytokines due to long-term immunosuppression might appear as the reason behind this positive outcome. Recently a randomized controlled trial of IL-6 receptor blockade, viz., tocilizumab has also been approved in COVID patients with increased IL-6 level in China (Mehta et al. ). On the contrary, Remy and colleagues reported that despite having an elevated level of IL-6, approximately 25% of COVID patients did not show an increase in other typical pro-inflammatory markers (Remy et al. ). Several studies showed more concern about the lymphopenia associated with COVID-19 than the episodic cytokine storm (Huang et al. ; Wang et al. ). Primary lymphocyte cells, including CD4+ and CD8+ T-cells, NK cells, are lost in SARS-CoV-2 infection (Zheng et al. ). These findings collectively support the hypothesis of the suppressed condition of adaptive and innate immunity in COVID-19 patients, which is contrary to the theory of hyper-inflammation. To find a solution to this debate, Remy et al. proposed a functional diagnosis of COVID-19 patient's immune status via enzyme-linked immunosorbent spot (ELISpot) assay (Remy et al. ).
The immunological state of a COVID patient is also crucial for the psychological well-being of individuals. With increasing age, immunosenescence causes dysregulation of the immune system and maintains a low-grade chronic inflammatory condition, a predisposing factor to SARS-CoV-2 severity (Grolli et al. ). The incidence of cytokine storm can eventually amplify this predisposing factor (Grolli et al. ). Moreover, the decisive factors of the severe inflammatory condition include the hypothalamus-pituitary-adrenal (HPA) axis (Waszkiewicz). The HPA axis functions in a negative feedback mechanism and holds homeostasis between the beneficial and harmful effects of pro-inflammatory cytokines. Following activation of the HPA axis, the hypothalamic hormone stimulates the release of adrenocorticotrophic hormone from the pituitary, which subsequently stimulates the adrenal glands to release corticosteroids (Chen et al. ). In a normal situation, the corticosteroid triggers negative feedback after reaching the brain and balances the stimulation of the pituitary and adrenal gland, and releases the corticosteroid itself (Chen et al. ). However, during the hyper-inflammation of COVID-19, the prolonged activation of the HPA axis by increased pro-inflammatory cytokines leads to the excessive release of corticosteroids (Steenblock et al. ). This excess amount of corticosteroids not only contributes to immune dysfunction but also influence to maintain an elevated viral load (Deek; Waszkiewicz).
On the other hand, hypoxia associated with COVID-19 is a significant risk factor for venous thromboembolism (Algahtani et al. ). Also, prolonged hypoxia following SARS-CoV-2 infection may worsen the immunothrombosis initiated by the virus (Thachil). Some hospitalized COVID patients suffer from acute hypoxia, which may indirectly cause further nervous system injury (Guo et al. ). Jaunmuktane et al. demonstrated that SARS-CoV-2 related neurological complications resulted from the thromboembolism or thrombus formation within the brain (Jaunmuktane et al. ). Also, the immune response to the virus leading to damage in the brain's blood vessel wall has been shown clearly by Jaunmuktane et al.. Moreover, a few autopsy reports confirmed the neuropathological manifestations due to hypoxia and subsequent thromboembolism in COVID patients' brains (Kantonen et al. ).
Altogether, these findings have proven interplay between several factors, including HPA axis, hypoxia, and immunological responses leading to a severe neuropathological condition in COVID patients.