Mechanisms of SARS-CoV-2-induced Encephalopathy and Encephalitis in COVID-19 Cases.

The SARS-CoV-2 virus caused an unprecedented pandemic around the globe, infecting 36.5 million people and causing the death of over 1 million in the United States of America alone. COVID-19 patients demonstrated respiratory symptoms, cardiovascular complications, and neurologic symptoms, which in most severe cases included encephalopathy and encephalitis. Hypoxia and the uncontrolled proliferation of cytokines are commonly recognized to cause encephalopathy, while the retrograde trans-synaptic spread of the virus is thought to cause encephalitis in SARS-CoV-2-induced pathogenesis. Although recent research revealed some mechanisms explaining the development of neurologic symptoms, it still remains unclear whether interactions between these mechanisms exist. This review focuses on the discussion and analysis of previously reported hypotheses of SARS-CoV-2-induced encephalopathy and encephalitis and looks into possible overlaps between the pathogenesis of both neurological outcomes of the disease. Promising therapeutic approaches to prevent and treat SARS-CoV-2-induced neurological complications are also covered. More studies are needed to further investigate the dominant mechanism of pathogenesis for developing more effective preventative measures in COVID-19 cases with the neurologic presentation.

COVID-19 and the brain.

Entering the third year into the pandemic, overwhelming evidence demonstrates that Coronavirus disease 2019 (COVID-19) infection is a systemic illness, often with involvement of the central nervous system. Multiple mechanisms may underlie the development of neurologic manifestations of illness, including hypoxia, systemic illness, hypercoagulability, endothelial dysfunction, general critical illness, inflammatory response, and neurotropism of the severe acute respiratory syndrome coronavirus 2 (SARS-Co-V2) virus. COVID-19 infection is associated with neurologic involvement in all stages; acute infection, subacute/post-infection, and growing evidence also suggests during a chronic phase, the post-acute sequalae of COVID-19 (PASC). With over 20,000 published articles on COVID and the brain at the time of writing, it is virtually impossible to present an unbiased comprehensive review of how SARS-Co-V2 impacts the nervous system. In this review, we will present an overview of common neurologic manifestations, in particular focusing on the cerebrovascular complications, and proposed pathophysiology.

CROI 2021: Neurologic Complications of HIV-1 Infection or Covid-19

The 2021 Conference on Retroviruses and Opportunistic Infections (CROI) featured a timely review of the neurologic complications of COVID-19 as well as new research findings on mechanisms by which SARS-CoV-2 may affect the brain. CROI included new and important findings about the neurologic complications of HIV-1, human polyomavirus 2 (also known as JC Virus), and cryptococcus. New long-term analyses of cognition in people with HIV-1 identified that cognitive decline over time is associated with multimorbidity, particularly diabetes, chronic lung disease, and vascular disease risk conditions. These conditions are associated with aging, and the question of whether people with HIV are at risk for premature aging was addressed by several reports. New findings from large analyses of resting state networks also provided valuable information on the structural and functional networks that are affected by HIV-1 infection and cognitive impairment. Several reports addressed changes after initiating or switching antiretroviral therapy (ART). Findings that will improve understanding of the biologic mechanisms of brain injury in people with HIV were also presented and included evidence that host (eg, myeloid activation, inflammation, and endothelial activation) and viral (eg, transcriptional activity and compartmentalization) factors adversely affect brain health. Other research focused on adjunctive therapies to treat HIV-1 and its complications in the central nervous system. This summary will review these and other findings in greater detail and identify key gaps and opportunities for researchers and clinicians.Copyright © 2021, IAS-USA. All rights reserved.

Neurologic Complications of Patients With COVID-19 Requiring Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.

In COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO), our primary objective was to determine the frequency of intracranial hemorrhage (ICH). Secondary objectives were to estimate the frequency of ischemic stroke, to explore association between higher anticoagulation targets and ICH, and to estimate the association between neurologic complications and in-hospital mortality. DATA SOURCES: We searched MEDLINE, Embase, PsycINFO, Cochrane, and MedRxiv databases from inception to March 15, 2022. STUDY SELECTION: We identified studies that described acute neurological complications in adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requiring ECMO. DATA EXTRACTION: Two authors independently performed study selection and data extraction. Studies with 95% or more of its patients on venovenous or venoarterial ECMO were pooled for meta-analysis, which was calculated using a random-effects model. DATA SYNTHESIS: Fifty-four studies (n = 3,347) were included in the systematic review. Venovenous ECMO was used in 97% of patients. Meta-analysis of ICH and ischemic stroke on venovenous ECMO included 18 and 11 studies, respectively. The frequency of ICH was 11% (95% CI, 8-15%), with intraparenchymal hemorrhage being the most common subtype (73%), while the frequency of ischemic strokes was 2% (95% CI, 1-3%). Higher anticoagulation targets were not associated with increased frequency of ICH (p = 0.06). In-hospital mortality was 37% (95% CI, 34-40%) and neurologic causes ranked as the third most common cause of death. The risk ratio of mortality in COVID-19 patients with neurologic complications on venovenous ECMO compared with patients without neurologic complications was 2.24 (95% CI, 1.46-3.46). There were insufficient studies for meta-analysis of COVID-19 patients on venoarterial ECMO. CONCLUSIONS: COVID-19 patients requiring venovenous ECMO have a high frequency of ICH, and the development of neurologic complications more than doubled the risk of death. Healthcare providers should be aware of these increased risks and maintain a high index of suspicion for ICH.

Are we sure that the neurological impact of COVID 19 in childhood has not been underestimated?

BACKGROUND: Presently, it is known that, even if less frequently than in adults, children can develop a severe new coronavirus disease 2019 (COVID-19). Children with the SARS-CoV-2 infection can have neurological signs and symptoms of disease more frequently than previously thought, revealing the involvement of the central nervous system, the peripheral nervous system, or both. Aim of this manuscript is to highlight the neurologic complications associated with SARS-CoV-2 among pediatric patients with COVID-19, suggesting when to monitor carefully neurologic development. MAIN FINDINGS: Children with a severe chronic underlying disease, infants and toddlers and those who develop the so-called multisystem inflammatory syndrome (MIS-C) are those with the highest incidence of neurological complications. Fortunately, in most of the cases, neurological manifestations, mainly represented by headache and anosmia, are mild and transient and do not significantly complicate the COVID-19 course. However, in some cases, very severe clinical problems associated with relevant alterations of neuroimaging, electroencephalography, nerve conduction studies and electromyography findings can develop. Generally, almost all the children with COVID-19 and neurological manifestations till now described have made a complete recovery, although in some cases this has occurred after several weeks of treatment. Moreover, COVID-19 infection during pregnancy has been found associated with an increased risk of obstetric complications that can lead to neurological acute and long-term manifestations in neonates. CONCLUSIONS: Based on data showing the neurologic impact of COVID-19 in pediatric age, we suggest monitoring neurological development a few months after healing in pediatric patients who have presented MIS-C, seizures or other neurological manifestations and in children of pregnant women with COVID-19 in order to detect overt and subtle deficits.

Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19.

Neurologic complications can be seen in mild to severe COVID-19 with a higher risk in patients with severe COVID-19. These can occur as a direct consequence of viral infection or consequences of treatments. The spectrum ranges from non-life-threatening, like headache, fatigue, malaise, anosmia, dysgeusia, to life-threatening complications, like stroke, encephalitis, coma, Guillain-Barre syndrome. A high index of suspicion can aid in early recognition and treatment. Outcomes depend on severity of underlying COVID-19, patient age, comorbidities, and severity of the complication. Postacute sequelae of COVID-19 range from fatigue, headache, dysosmia, brain fog, anxiety, depression to an overlap with postintensive care syndrome.

Pregnancy and neurologic complications of COVID-19: A scoping review.

While neurologic complications are frequently reported among patients with COVID-19 in the general population, they are unknown in pregnant women. This paper summarizes the case reports of pregnant women with confirmed SARS-CoV-2 infection plus a specified neurologic diagnosis. Until November 2021, 18 case reports were found. Both the central and peripheral nervous systems were equally affected: delirium (n = 1), posterior reversible encephalopathy syndrome (n = 4), cerebrovascular disease (n = 2), acute cerebral demyelinating disease (n = 1), acute necrotizing encephalopathy (n = 1), Guillain-Barré syndrome (n = 5), including one patient who also had vestibular neuritis, Bell's palsy (n = 3), and rhabdomyolysis (n = 1). The median maternal age was 32.5 (25-35) years, the median gestational age was 34 (30-36.5) weeks, and 38.9% presented previous medical conditions. Respiratory symptoms were reported in 76.5%, and 76.5% received immunotherapies to treat the COVID-19 or the neurologic complications. Half the women required admission to ICU and, more often, were those with central nervous system involvement (77.8% vs. 22.2%; Chi-square test, p = .018). For 64.7% of women, the most common method of delivery was surgical, although just one case was due to the neurologic complication. There were reports of one spontaneous abortion, two fetal deaths, and no maternal deaths. Only one case presented a poor neurologic outcome. It is possible that our findings are underestimated, considering that there are thousands of reports regarding neurologic complications in the general population with COVID-19.

Bihemispheric ischemic strokes in patients with COVID-19.

BACKGROUND: There is emerging evidence that COVID-19 can trigger thrombosis because of a hypercoagulable state, including large-vessel occlusion ischemic strokes. Bihemispheric ischemic stroke is uncommon and is thought to indicate an embolic source. Here, we examine the findings and outcomes of patients with bihemispheric stroke in the setting of COVID-19. METHODS: We performed a retrospective cohort study at a quaternary academic medical center between March 1, 2020, and April 30, 2020. We identified all patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who presented with simultaneous bihemispheric ischemic strokes. RESULTS: Of 637 COVID-19 admissions during the 2-month period, 13 had a diagnosis of acute ischemic stroke, including 5 who developed bihemispheric cerebral infarction. Three of those 5 (60%) were female, median age was 54 (range 41-67), and all five were being managed for severe COVID-19-related pneumonia complicated by acute kidney injury and liver failure before the diagnosis of cerebral infarction was established. Five presented with elevated ferritin, lactate dehydrogenase, and interleukin-6 (IL-6) levels, and four had lymphopenia and elevated D-dimer levels. All patients underwent neuroimaging with computed tomography for persistent depressed mentation, with or without a focal neurologic deficit, demonstrating multifocal ischemic strokes with bihemispheric involvement. Outcome was poor in all patients: two were discharged to a rehabilitation facility with moderate-to-severe disability and three (60%) patients died. CONCLUSIONS: Stroke is implicated in SARS-CoV-2 infection. Although causality cannot be established, we present the imaging and clinical findings of patients with COVID-19 and simultaneous bihemispheric ischemic strokes. Multifocal ischemic strokes with bihemispheric involvement should be considered in COVID-19 patients with severe infection and poor neurologic status and may be associated with poor outcomes.

Association of COVID-19 with Intracranial Hemorrhage during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: A 10-Year Retrospective Observational Study.

Extracorporeal membrane oxygenation (ECMO) is potentially lifesaving for patients with acute respiratory distress syndrome (ARDS) but may be accompanied by serious adverse events, including intracranial hemorrhage (ICRH). We hypothesized that ICRH occurs more frequently in patients with COVID-19 than in patients with ARDS of other etiologies. We performed a single-center retrospective analysis of adult patients treated with venovenous (vv-) ECMO for ARDS between January 2011 and April 2021. Patients were included if they had received a cranial computed tomography (cCT) scan during vv-ECMO support or within 72 h after ECMO removal. Cox regression analysis was used to identify factors associated with ICRH. During the study period, we identified 204 patients with vv-ECMO for ARDS, for whom a cCT scan was available. We observed ICRH in 35.4% (n = 17/48) of patients with COVID-19 and in 16.7% (n = 26/156) of patients with ARDS attributable to factors other than COVID-19. COVID-19 (HR: 2.945; 95%; CI: 1.079-8.038; p = 0.035) and carboxyhemoglobin (HR: 0.330; 95%; CI: 0.135-0.806; p = 0.015) were associated with ICRH during vv-ECMO. In patients receiving vv-ECMO, the incidence of ICRH is doubled in patients with COVID-19 compared to patients suffering from ARDS attributable to other causes. More studies on the association between COVID-19 and ICRH during vv-ECMO are urgently needed to identify risk patterns and targets for potential therapeutic interventions.

Narrative Review of Neurologic Complications in Adults on ECMO: Prevalence, Risks, Outcomes, and Prevention Strategies.

Extracorporeal membrane oxygenation (ECMO), a life-saving technique for patients with severe respiratory and cardiac diseases, is being increasingly utilized worldwide, particularly during the coronavirus disease 2019(COVID-19) pandemic, and there has been a sharp increase in the implementation of ECMO. However, due to the presence of various complications, the survival rate of patients undergoing ECMO remains low. Among the complications, the neurologic morbidity significantly associated with venoarterial and venovenous ECMO has received increasing attention. Generally, failure to recognize neurologic injury in time is reportedly associated with poor outcomes in patients on ECMO. Currently, multimodal monitoring is increasingly utilized in patients with devastating neurologic injuries and has been advocated as an important approach for early diagnosis. Here, we highlight the prevalence and outcomes, risk factors, current monitoring technologies, prevention, and treatment of neurologic complications in adult patients on ECMO. We believe that an improved understanding of neurologic complications presumably offers promising therapeutic solutions to prevent and treat neurologic morbidity.

Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.

OBJECTIVE: To describe clinical features, diagnostic findings, treatments, and outcomes in patients with new-onset postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders following SARS-CoV-2 infection (COVID-19). METHODS: We retrospectively reviewed medical records for patients who presented with persistent neurologic and cardiovascular complaints between April and December 2020 following COVID-19 infection. RESULTS: Twenty patients (70% female) were included in this study.Fifteen had POTS, 3 had neurocardiogenic syncope, and 2 had orthostatic hypotension. Six patients had abnormalities on cardiac or pulmonary testing, and 4 had elevated autoimmune or inflammatory markers. All patients were treated with non-pharmacologic therapies, and most required pharmacologic therapies. Six to 8 months after COVID-19, 17 (85%) patients had residual autonomic symptoms, with 12 (60%) unable to return to work. CONCLUSIONS: POTS can follow COVID-19 in previously healthy patients. Appropriate diagnostic investigations and therapies are necessary to identify and treat autonomic dysfunction after COVID-19.

Neurologic and Neuroscientific Evidence in Aged COVID-19 Patients.

The COVID-19 pandemic continues to prevail as a catastrophic wave infecting over 111 million people globally, claiming 2. 4 million lives to date. Aged individuals are particularly vulnerable to this disease due to their fraility, immune dysfunction, and higher rates of medical comorbidities, among other causes. Apart from the primary respiratory illness, this virus is known to cause multi-organ dysfunction including renal, cardiac, and neurologic injuries, particularly in the critically-ill cohorts. Elderly patients 65 years of age or older are known to have more severe systemic disease and higher rates of neurologic complications. Morbidity and mortality is very high in the elderly population with 6-930 times higher likelihood of death compared to younger cohorts, with the highest risk in elderly patients ≥85 years and especially those with medical comorbidities such as hypertension, diabetes, heart disease, and underlying respiratory illness. Commonly reported neurologic dysfunctions of COVID-19 include headache, fatigue, dizziness, and confusion. Elderly patients may manifest atypical presentations like fall or postural instability. Other important neurologic dysfunctions in the elderly include cerebrovascular diseases, cognitive impairment, and neuropsychiatric illnesses. Elderly patients with preexisting neurologic diseases are susceptibility to severe COVID-19 infection and higher rates of mortality. Treatment of neurologic dysfunction of COVID-19 is based on existing practice standards of specific neurologic condition in conjunction with systemic treatment of the viral illness. The physical, emotional, psychologic, and financial implications of COVID-19 pandemic have been severe. Long-term data are still needed to understand the lasting effects of this devastating pandemic.

Neurological Complications of COVID-19: Guillain-Barre Syndrome Following Pfizer COVID-19 Vaccine.

Since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in Wuhan, China, in December 2019, Coronavirus - 19 (COVID-19) has become a global pandemic with multiple neurological complications. In December 2020, two vaccines have been approved in the United States for the prevention of COVID-19. We report a case of Guillain-Barre Syndrome (GBS) after receiving the first dose of Pfizer - COVID-19 vaccine.

The Neurological Complexities and Prognosis of COVID-19.

Several neurological manifestations and complications linked to SARS-CoV-2 have been reported along with well-known respiratory pathology. The global active transmission of SARS-CoV-2 and its unexplained characteristics has led to a pandemic. Since its rapid emergence from Wuhan, China, in December 2019, several studies have reported the impacts of COVID-19 on the CNS and PNS and its implications. This comprehensive review article comprises case reports, case series, metaanalysis, cohort studies, retrospective studies, and narrative reviews focusing on COVID-19-associated CNS and PNS complexities. The authors searched for over 200 articles and used 52 publications related to the neurological complexities of COVID-19 affecting the CNS and PNS as part of the literature review process. The predominant CNS symptoms noted in COVID-19 patients were headaches and dizziness, and the most common PNS symptoms were alterations in smell and taste. Case reports on headache/dizziness, intracerebral hemorrhage, acute hemorrhagic necrotizing encephalopathy, meningitis/encephalitis, encephalopathy, cerebrovascular events, chemosensory dysfunction, Guillain-Barre syndrome, and acute transverse myelitis/acute necrotizing myelitis in PCR-confirmed SARS-CoV-2 subjects are also reported. New-onset neurological symptoms were also observed in children with PCR-confirmed SARS-CoV-2 that developed pediatric multisystem inflammatory syndrome (PIMS). This comprehensive review article will assist the clinicians and researchers to gain information about the neurological manifestations and complications associated with COVID-19 and develop planning to treat these symptoms in concerned patients of all ages. However, it is unclear whether SARS-CoV2-associated neurological effects are due to primary infections or secondary response to the possible mechanisms discussed in this review.