Neurologic Complications in Adult and Pediatric Patients with SARS-CoV-2 Infection

: SARS-CoV-2 has an impact on the nervous system as a result of pathological cellular and molecular events at the level of vascular and neural tissue. Severe neurologic manifestations including stroke, ataxia, seizure, and depressed level of consciousness are prevalent in patients with SARS-CoV-2 infection. Although the mechanism is still unclear, SARS-CoV-2 has been associated with the pathogenesis of intravascular coagulation and angiotensin-converting enzyme-I, both exacerbating systemic inﬂammation and contributing to hypercoagulation or blood–brain barrier leakage, resulting in ischemic or hemorrhagic stroke. On the other hand, the SARS-CoV-2 spike protein in neural tissue and within the cerebrospinal ﬂuid may induce neural dysfunction, resulting in neuroinﬂammation, which is exacerbated by peripheral and neural hypercytokinemia that can lead to neuronal damage and subsequent neuroinﬂammation. A deeper understanding of the fundamental biological mechanisms of neurologic manifestations in SARS-CoV-2 infection can pave the way to identifying a single biomarker or network of biomarkers to help target neuroprotective therapy in patients at risk for developing neurological complications.


Introduction
While society is still grappling with the acute effects of the COVID-19 pandemic, the long-term sequelae from the illness remain largely unknown. Aside from the predominant respiratory manifestations that have been hallmarks of serious disease, severe acute respiratory syndrome coronaviruses (SARS-CoV-1 and SARS-CoV-2) have been implicated in a range of severe neurologic complications, including acute ischemic or hemorrhagic stroke [1][2][3][4][5][6], encephalopathy [7][8][9][10][11], encephalitis [12,13], epilepsy/seizures [14,15], acute transverse myelitis [16][17][18], and Guillain-Barre syndrome (GBS) [19,20]. While non-lifethreatening complications such as myalgia and ageusia affect 22% and 20% of patients, respectively, more severe complications such as encephalopathy and acute cerebrovascular disease are estimated to be seen in 2.5% to 10% of patients. Case reports from the United Kingdom of 143 patients with neurological symptoms revealed that 32% developed altered mental statuses, and almost 50% required intensive level care [21]. In the pediatric population, a multicenter study of children hospitalized with either acute COVID-19 or multi-system inflammatory syndrome in children (MIS-C) documented 22% of pediatric cases with neurological involvement, including 12% who developed life threatening neurologic complications [22]. The purpose of this critical review is to summarize current mechanistic theories of neurologic complications in both adult and pediatric patients with SARS-CoV-2 infection. A deeper understanding of the mechanisms behind these manifestations can lead to targeted therapeutic interventions and improved patient outcomes.

Neural Tissue
There is increased urgency to investigate the cause(s) of neurologic complications in patients infected with SARS-CoV-2. Approximately one in seven hospitalized adults who are SARS-CoV-2 positive develop neurologic complications secondary to infection. Severe manifestations include toxic/metabolic encephalopathy, seizure, stroke, and hypoxic/ischemic injury [23]. Long-term neurologic sequela in COVID-19 survivors include an increased burden of nervous system disorders, neurocognitive dysfunction, and psychiatric issues [24]. As the medical literature grows, identifiable trends may shed light on the underlying mechanisms, treatment modalities, and outcomes.
Understanding the pathophysiology of neurologic involvement in pediatric populations may aid our understanding of the neuroinflammatory changes seen in the context of SARS-CoV-2 infection. Multisystem inflammatory syndrome in children (MIS-C), a postinfection hyperinflammatory response, with associated neurologic complications portends serious outcomes in children and adolescents. Complications include diffuse CNS involvement (CNS infection, acute disseminated encephalomyelitis, severe encephalopathy, and acute fulminant cerebral edema) and vessel and peripheral nerve disorders (Guillain-Barre syndrome and variants) [25]. In a study of 1695 hospitalized pediatric patients admitted with either acute COVID-19 pneumonia or MIS-C, although the majority (88%) of children developed transient neurologic complications (such as headache and seizure) that resolved by the time of discharge, 12% of hospitalized patients developed life-threatening neurologic complications [26]. Not surprisingly, children who developed more severe neurologic manifestations had a higher neutrophil-to-lymphocyte ratios and D-Dimer level, indicating increased inflammation and coagulopathy [22]. Significant elevation of inflammatory markers including erythrocyte sedimentation rate (ESR), C-reactive protein, D-dimer, and fibrinogen are seen in patients with MIS-C [26]. The long-term neurologic and psychiatric implications of this inflammation are still largely unknown and determining the underlying mechanism of neurologic sequela in children infected with SARS-Cov-2 is imperative for identifying neuroprotective therapies.
Due to widespread reports of anosmia and ageusia in adult COVID-19 patients [27,28], it was initially hypothesized that SARS-CoV-2 may cross the blood-brain barrier. Initial studies reported the presence of the COVID-19 spike protein (S1) within olfactory nerves as well as viral mRNA samples within the cerebrospinal fluid, suggesting that the virus may be able to enter the central nervous system and induce neural dysfunction with resulting neuroinflammation [29]. However, new available information regarding SARS-CoV-2 s ability to invade the central nervous system has undermined this theory. Newer evidence suggests that it is the host's immune response to SARS-CoV-2 infection that is responsible for the neurologic complications secondary to viral infection. Immune cells mitigate viral infectivity by initiating an inflammatory response through the release of pro-inflammatory cytokines (most notably, IL-1, IL-6, IL-8, MCP-1, and tumor necrosis factor [TNF]) [30]. Hypercytokinemia, also known as a cytokine storm, occurs during a systemic inflammatory response resulting in signaling dysregulation and increased oxidative stress that can lead to neuronal damage and subsequent neuroinflammation [31].

Blood Vessels
There have been a number of hypotheses seeking to establish a link between SARS-CoV-2 and stroke. The predominant theory suggests coagulopathy and inflammation related to endothelial dysfunction develop in small to medium-size vessels [32]. SARS-CoV-2 has been associated with sepsis-induced coagulopathy leading to life-threatening disseminated intravascular coagulation (DIC). Multiple studies show virally infected pa-tients have a lower prothrombin activity, elevated D-dimer, and thrombocytopenia leading to microvascular thrombosis, endothelial dysfunction, and end-organ failure [32]. Additionally, patients with COVID-19 who tested positive for antiphospholipid (ApL) antibodies and anti-β2-glycoprotein antibodies had a higher incidence of cerebral infarction [33,34]. Another theorized mechanism of the development of stroke in SARS-CoV-2 is viral interaction with the angiotensin II receptor. The virus has been shown to deplete angiotensinconverting enzyme-II (ACE-II) via receptor-mediated endocytosis, in turn inducing an increase in systemic angiotensin II [35] and possibly exacerbating systemic inflammation. This inflammation may lead to an increase in tissue factor (TF), contributing to hypercoagulation or blood-brain barrier leakage and resulting in ischemic or hemorrhagic stroke, as depicted in Figure 1 [36]. Furthermore, recombinant ACE-II therapy has been found to prevent acute stroke in the setting of a COVID-19 infection in addition to routine anticoagulation with tissue plasminogen activator (tPA), low molecular weight heparin (LMWH), and/or full-dose heparin [35].

Blood Vessels
There have been a number of hypotheses seeking to establish a link between SARS-CoV-2 and stroke. The predominant theory suggests coagulopathy and inflammation related to endothelial dysfunction develop in small to medium-size vessels [32]. SARS-CoV-2 has been associated with sepsis-induced coagulopathy leading to life-threatening disseminated intravascular coagulation (DIC). Multiple studies show virally infected patients have a lower prothrombin activity, elevated D-dimer, and thrombocytopenia leading to microvascular thrombosis, endothelial dysfunction, and end-organ failure [32]. Additionally, patients with COVID-19 who tested positive for antiphospholipid (ApL) antibodies and anti-β2-glycoprotein antibodies had a higher incidence of cerebral infarction [33,34]. Another theorized mechanism of the development of stroke in SARS-CoV-2 is viral interaction with the angiotensin II receptor. The virus has been shown to deplete angiotensin-converting enzyme-II (ACE-II) via receptor-mediated endocytosis, in turn inducing an increase in systemic angiotensin II [35] and possibly exacerbating systemic inflammation. This inflammation may lead to an increase in tissue factor (TF), contributing to hypercoagulation or blood-brain barrier leakage and resulting in ischemic or hemorrhagic stroke, as depicted in Figure 1 [36]. Furthermore, recombinant ACE-II therapy has been found to prevent acute stroke in the setting of a COVID-19 infection in addition to routine anticoagulation with tissue plasminogen activator (tPA), low molecular weight heparin (LMWH), and/or full-dose heparin [35].

Conclusions
Due to the prevalence of neurologic complications, there is an urgent need to assess the underlying mechanisms of CNS involvement in SARS-CoV-2 infection. To optimize treatment modalities, it is essential to investigate the underlying pathways of neuroinflammation. If the virus itself is responsible, utilizing an antiviral agent may help prevent severe neurologic outcomes. On the contrary, if it is due to the host's immune response

Conclusions
Due to the prevalence of neurologic complications, there is an urgent need to assess the underlying mechanisms of CNS involvement in SARS-CoV-2 infection. To optimize treatment modalities, it is essential to investigate the underlying pathways of neuroinflammation. If the virus itself is responsible, utilizing an antiviral agent may help prevent severe neurologic outcomes. On the contrary, if it is due to the host's immune response and hypercytokinemia, then optimal treatment would consist of a more targeted immunosuppressive therapy. Although the long-term sequela of neurologic complications and neuroinflammation in patients with SARS-CoV-2 infection are still unknown, it will likely pose a significant obstacle to neurologic recovery and future studies will be required to optimize outcomes.
The hypothesis of the neuropathogenesis related with COVID-19 infection is as follows: Vascular and neuro cytokine storm, neurotropism of the virus, and activation of neuroin-flammatory cells mediate stroke and epileptiform abnormalities, resulting in cognitive deficit and seizures.