Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports

Abstract

Coronavirus disease 2019 (COVID-19) is a highly infectious pandemic caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It frequently presents with unremitting fever, hypoxemic respiratory failure, and systemic complications (e.g., gastrointestinal, renal, cardiac, and hepatic involvement), encephalopathy, and thrombotic events. The respiratory symptoms are similar to those accompanying other genetically related beta-coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East Respiratory Syndrome CoV (MERS-CoV). Hypoxemic respiratory symptoms can rapidly progress to Acute Respiratory Distress Syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis, leading to multi-organ system dysfunction syndrome. Severe cases are typically associated with aberrant and excessive inflammatory responses. These include significant systemic upregulation of cytokines, chemokines, and pro-inflammatory mediators, associated with increased acute-phase proteins (APPs) production such as hyperferritinemia and elevated C-reactive protein (CRP), as well as lymphocytopenia. The neurological complications of SARS-CoV-2 infection are high among those with severe and critical illnesses. This review highlights the central nervous system (CNS) complications associated with COVID-19 attributed to primary CNS involvement due to rare direct neuroinvasion and more commonly secondary CNS sequelae due to exuberant systemic innate-mediated hyper-inflammation. It also provides a theoretical integration of clinical and experimental data to elucidate the pathogenesis of these disorders. Specifically, how systemic hyper-inflammation provoked by maladaptive innate immunity may impair neurovascular endothelial function, disrupt BBB, activate CNS innate immune signaling pathways, and induce parainfectious autoimmunity, potentially contributing to the CNS complications associated with SARS-CoV-2 infection. Direct viral infection of the brain parenchyma causing encephalitis, possibly with concurrent neurovascular endotheliitis and CNS renin angiotensin system (RAS) dysregulation, is also reviewed.

Behavioral Changes Without Respiratory Symptoms as a Presenting Sign of COVID-19 Encephalitis

“…A total of 13 cases of COVID-19 meningoencephalitis have been reported in the literature [5]. The postulated mechanisms are direct invasion of the central nervous system and secondary immune-mediated inflammatory response to the virus [4]. Some of the presenting signs are altered mental status, fever, seizures, and neck stiffness.…”

“…The projected prevalence of central nervous system involvement due to COVID-19 is a total of 1805-9671 cases [3]. Some of the neurologic manifestations reported include stroke, acute necrotizing encephalopathy, seizures, acute disseminated encephalomyelitis, and meningoencephalitis [4].…”

Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists

“…Ischaemic stroke associated with COVID-19 disease occurs in patients of all ages, with more severe strokes, worse functional outcomes and higher mortality rates than are seen in a comparable group of non-COVID-19 patients [148][149][150][151][152]. Thus far, it appears that the major causes for these ischaemic strokes are derived from the hyperinflammatory state and resulting coagulopathy observed in COVID-19 patients, which lead to thromboembolism [153], neurovascular endothelial dysfunction, BBB breakdown, and consequent generalised activation of the CNS innate immune system [149]. Cardiomyopathy, and consequent intracardiac formation of thrombi, which may travel to the brain, is another potential cause of ischaemic stroke in COVID-19 [153].…”

Acute Seizures Occurring in Association With SARS-CoV-2

“…The upregulation of proinflammatory cytokines may also play a role in para-infectious immune-mediated neurological complications, such as demyelinating disease, acute necrotizing encephalopathy, or Guillain-Barre syndrome in COVID-19 (31)(32)(33)(34)(35)(36). Endothelial dysfunction and disruption of the integrity of the blood-brain barrier may result in cerebral antigen exposure and increased susceptibility to abnormal adaptive immunity.…”

“…Research continues in support of drugs targeting cytokines via the IL-6 receptor, such as tocilizumab, and IL-1 receptor, such as anakinra (36). Endothelial dysfunction may contribute to vascular events such as stroke (35). Viral cellular invasion via ACE2 expressed on the surface of glia, endothelial cells, myocardium, and arterial smooth muscle may predispose patients to thromboinflammation (42).…”