COVID-19-specific metabolic imprint yields insights into multiorgan system perturbations.

Corona disease 2019 (COVID-19) affects multiple organ systems. Recent studies have indicated perturbations in the circulating metabolome linked to COVID-19 severity. However, several questions pertain with respect to the metabolome in COVID-19. We performed an in-depth assessment of 1129 unique metabolites in 27 hospitalized COVID-19 patients and integrated results with large-scale proteomic and immunology data to capture multiorgan system perturbations. More than half of the detected metabolic alterations in COVID-19 were driven by patient-specific confounding factors ranging from comorbidities to xenobiotic substances. Systematically adjusting for this, a COVID-19-specific metabolic imprint was defined which, over time, underwent a switch in response to severe acute respiratory syndrome coronavirus-2 seroconversion. Integration of the COVID-19 metabolome with clinical, cellular, molecular, and immunological severity scales further revealed a network of metabolic trajectories aligned with multiple pathways for immune activation, and organ damage including neurological inflammation and damage. Altogether, this resource refines our understanding of the multiorgan system perturbations in severe COVID-19 patients.

The COVID-19 infection in children and its association with the immune system, prenatal stress, and neurological complications.

The Coronavirus disease 2019 (COVID-19)" caused by the "severe acute respiratory syndrome corona virus 2 (SARS-CoV-2)" has caused huge losses to the world due to the unavailability of effective treatment options. It is now a serious threat to humans as it causes severe respiratory disease, neurological complications, and other associated problems. Although COVID-19 generally causes mild and recoverable symptoms in children, it can cause serious severe symptoms and death causing complications. Most importantly, SARS-CoV-2 can cause neurological complications in children, such as shortness of breath, myalgia, stroke, and encephalopathy. These problems are highly linked with cytokine storm and proinflammatory responses, which can alter the physiology of the blood-brain barrier and allow the virus to enter the brain. Despite the direct infection caused by the virus entry into the brain, these neurological complications can result from indirect means such as severe immune responses. This review discusses viral transmission, transport to the brain, the associated prenatal stress, and neurological and/or immunological complications in children.

Long-term complications of COVID-19.

SARS-CoV-2 has rapidly spread across the globe and infected hundreds of millions of people worldwide. As our experience with this virus continues to grow, our understanding of both short-term and long-term complications of infection with SARS-CoV-2 continues to grow as well. Just as there is heterogeneity in the acute infectious phase, there is heterogeneity in the long-term complications seen following COVID-19 illness. The purpose of this review article is to present the current literature with regards to the epidemiology, pathophysiology, and proposed management algorithms for the various long-term sequelae that have been observed in each organ system following infection with SARS-CoV-2. We will also consider future directions, with regards to newer variants of the virus and their potential impact on the long-term complications observed.

MRI-negative myeloradiculoneuropathy following Covid-19 infection: An index case.

Covid-19 associated several neurological manifestation in the form of Post-infectious transverse myelitis(TM) and para-infectious TM has been reported. A 54 years old female patient presented to us with acute retention of urine and upper motor neuron type of bilateral lower limb weakness in shock stage, after 12 days of covid-19 infection. MRI (3T) brain and spine showed no abnormality and Nerve conduction study showed acquired motor axonal polyradiculoneuropathy in bilateral lower limbs. We herein present an index case of MRI-negative myeloradiculoneuropathy following covid-19 infection.

Infectious and immune-mediated central nervous system disease in 48 COVID-19 patients.

OBJECTIVES: To summarise and discuss current knowledge about SARS-CoV-2-associated infectious/immune-mediatedcentral nervous system (CNS)-disease. METHOD: Literature review. RESULTS: Altogether 28 articles were found, which reported 48 patients with SARS-CoV-2-associated infectious/immune-mediatedCNS-disease. Age ranged from 22 to 79y. There was male preponderance. There were 14 patients with infectious CNS-disease (meningitis (n = 1), encephalitis (n = 5), meningo-encephalitis (n = 5), myelitis (n = 3)), and 34 patients with parainfectious CNS-disease (encephalopathy (n = 18), autoimmune encephalitis (n = 11), acute, disseminated, encephalo-myelitis (n = 3), acute, haemorrhagic, necrotizing encephalopathy (n = 2)). The cerebrospinal fluid (CSF) was tested for SARS-CoV-2 in 40 patients and was positive for the virus in 4 patients with infectious CNS-disease but was negative for the virus in all patients with parainfectious CNS-disease. Immune-modulating treatment may be more effective than virostatics/antibiotics for SARS-CoV-2-associated infectious/parainfectious, non-vascular, non-hypoxic CNS-disease. In patients with autoimmune encephalitis plasmapheresis may be beneficial. Twenty-two patients recovered, 2 did not, and 6 patients died. CONCLUSIONS: SARS-CoV-2 can cause infectious/immune-mediatedCNS-disease. The CSF is positive for virus-RNA in only few patients with infectious CNS-disease but negative for virus-RNA in immune-mediatedCNS-disease, suggesting an immune-mediated pathophysiological mechanism. The outcome of SARS-CoV-2-associated infectious/immune-mediatedCNS-disease is favourable in the majority of cases but can be fatal in single cases.

Interactions of SARS-CoV-2 with the Blood-Brain Barrier.

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

SARS-CoV-2 Infection in the Central and Peripheral Nervous System-Associated Morbidities and Their Potential Mechanism.

The recent outbreak of SARS-CoV-2 infections that causes coronavirus-induced disease of 2019 (COVID-19) is the defining and unprecedented global health crisis of our time in both the scale and magnitude. Although the respiratory tract is the primary target of SARS-CoV-2, accumulating evidence suggests that the virus may also invade both the central nervous system (CNS) and the peripheral nervous system (PNS) leading to numerous neurological issues including some serious complications such as seizures, encephalitis, and loss of consciousness. Here, we present a comprehensive review of the currently known role of SARS-CoV-2 and identify all the neurological problems reported among the COVID-19 case reports throughout the world. The virus might gain entry into the CNS either through the trans-synaptic route via the olfactory neurons or through the damaged endothelium in the brain microvasculature using the ACE2 receptor potentiated by neuropilin-1 (NRP-1). The most critical of all symptoms appear to be the spontaneous loss of breathing in some COVID-19 patients. This might be indicative of a dysfunction within the cardiopulmonary regulatory centers in the brainstem. These pioneering studies, thus, lay a strong foundation for more in-depth basic and clinical research required to confirm the role of SARS-CoV-2 infection in neurodegeneration of critical brain regulatory centers.

Manifestaciones extrapulmonares de la infección por SARS-CoV-2.

The disease caused by a new coronavirus, which started in 2019, was named COVID-19 and declared a pandemic on March 11, 2020 by the World Health Organization. Although it is true that the first reports emphasized the respiratory manifestations of this disease as an initial clinical presentation, little by little cases with different initial manifestations began to appear, involving other systems. In cases where central nervous system involvement was identified, the most frequent findings were dizziness, headache, and alteration of alertness. Regarding the cardiovascular system, elevation of cardiac biomarkers and myocarditis are one of the most frequent findings. The main gastrointestinal symptoms described so far are: anorexia, nausea, vomiting, diarrhea, abdominal pain and/or discomfort. Venous thromboembolism is a frequent complication and a public health problem. Skin manifestations remain a field of investigation. Maculopapular rashes, reticular livedo, acral gangrene, among others, have been identified. Health personnel must be updated on new clinical findings and the forms of presentation of this partially known disease, which will make it possible to make more accurate and timely diagnoses, thus impacting the prognosis of these patients.

La enfermedad causada por un nuevo coronavirus, que inició en 2019, fue denominada COVID-19 y declarada pandemia el 11 de marzo de 2020 por la Organización Mundial de la Salud. Si bien es cierto que los primeros reportes enfatizaron las manifestaciones respiratorias de esta enfermedad como presentación clínica inicial, poco a poco empezaron a aparecer casos con manifestaciones iniciales distintas, involucrando otros sistemas. En los casos en los que se identificó afectación del sistema nervioso central, los hallazgos más frecuentes fueron mareo, cefalea y alteración del estado de alerta. Respecto al sistema cardiovascular, la elevación de biomarcadores cardiacos y la miocarditis son unos de los hallazgos más frecuentes. Los principales síntomas gastrointestinales descritos hasta el momento son anorexia, náuseas, vómitos, diarrea y dolor o disconfort abdominal. La tromboembolia venosa es una complicación frecuente y un problema de salud pública. Las manifestaciones cutáneas siguen siendo un campo de investigación. Se han identificado exantemas maculopapulares, livedo reticular y gangrena acral, entre otros. El personal sanitario debe estar actualizado sobre los nuevos hallazgos clínicos y las formas de presentación de esta enfermedad solo parcialmente conocida, lo que permitirá hacer diagnósticos más precisos y oportunos, y así impactar en el pronóstico de estos enfermos.

Neurological Manifestations of SARS-CoV-2: A Narrative Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic started as an outbreak in China and soon crossed borders to affect the populations in all countries of the world. During the initial course of the disease, COVID-19 was perceived as a pneumonia-like illness. However, recent findings of COVID-19 patients suggest that the virus has the potential to disseminate to different tissues and organs, and cause significant complications. SUMMARY: Neurological symptoms are of great significance as these usually present in and complicate critical cases. Many case reports and case series have documented the findings of neurological complications in COVID-19 patients. From the existing data, the most frequent symptoms in these patients were broadly classified into the central nervous system (CNS), peripheral nervous system, and skeletal muscular symptoms. CNS symptoms include meningitis, encephalitis, cerebrovascular complications, peripheral nervous system symptoms include anosmia, ageusia, and skeletal muscular symptoms include myalgias. It is postulated that the cause may be direct CNS injury through blood and neuronal pathways or indirectly because of an immune-mediated response, hypoxia caused by decreased oxygen saturation, or by the binding of subacute respiratory syndrome-coronavirus-2 to the host angiotensin-converting enzyme-2 receptors. Striking radiologic findings in COVID-19 patients with neurological symptoms have also emerged. CONCLUSIONS: As subacute respiratory syndrome-coronavirus-2 may potentially have lethal implications on the nervous system, it is important that neurologists are better informed about the spectrum of clinical manifestations, radiologic findings, and likely mechanisms of injury. Understanding the symptoms and radiologic imaging allows clinicians to consider brain imaging in any patient with suspected COVID-19 and neurological symptoms.

Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study.

BACKGROUND: The CNS manifestations of COVID-19 in children have primarily been described in case reports, which limit the ability to appreciate the full spectrum of the disease in paediatric patients. We aimed to identify enough cases that could be evaluated in aggregate to better understand the neuroimaging manifestations of COVID-19 in the paediatric population. METHODS: An international call for cases of children with encephalopathy related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and abnormal neuroimaging findings was made. Clinical history and associated plasma and cerebrospinal fluid data were requested. These data were reviewed by a central neuroradiology panel, a child neurologist, and a paediatric infectious diseases expert. The children were categorised on the basis of their time of probable exposure to SARS-CoV-2. In addition, cases were excluded when a direct link to SARS-CoV-2 infection could not be established or an established alternate diagnostic cause could be hypothesised. The accepted referral centre imaging data, from ten countries, were remotely reviewed by a central panel of five paediatric neuroradiologists and a consensus opinion obtained on the imaging findings. FINDINGS: 38 children with neurological disease related to SARS-CoV-2 infection were identified from France (n=13), the UK (n=8), the USA (n=5), Brazil (n=4), Argentina (n=4), India (n=2), Peru (n=1), and Saudi Arabia (n=1). Recurring patterns of disease were identified, with neuroimaging abnormalities ranging from mild to severe. The most common imaging patterns were postinfectious immune-mediated acute disseminated encephalomyelitis-like changes of the brain (16 patients), myelitis (eight patients), and neural enhancement (13 patients). Cranial nerve enhancement could occur in the absence of corresponding neurological symptoms. Splenial lesions (seven patients) and myositis (four patients) were predominantly observed in children with multisystem inflammatory syndrome. Cerebrovascular complications in children were less common than in adults. Significant pre-existing conditions were absent and most children had favourable outcomes. However, fatal atypical CNS co-infections developed in four previously healthy children infected with SARS-CoV-2. INTERPRETATION: Acute-phase and delayed-phase SARS-CoV-2-related CNS abnormalities are seen in children. Recurring patterns of disease and atypical neuroimaging manifestations can be found and should be recognised being as potentially due to SARS-CoV-2 infection as an underlying aetiological factor. Studies of paediatric specific cohorts are needed to better understand the effects of SARS-CoV-2 infection on the CNS at presentation and on long-term follow-up in children. FUNDING: American Society of Pediatric Neuroradiology, University of Manchester (Manchester, UK). VIDEO ABSTRACT.

Presentations and mechanisms of CNS disorders related to COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic. In addition to severe respiratory symptoms, there are a growing number of reports showing a wide range of CNS complications in patients with COVID-19. Here, we review the literature on these complications, ranging from nonspecific symptoms to necrotizing encephalopathies, encephalitis, myelitis, encephalomyelitis, endotheliitis, and stroke. We postulate that there are several different mechanisms involved in COVID-19-associated CNS dysfunction, particularly activation of inflammatory and thrombotic pathways and, in a few patients, a direct viral effect on the endothelium and the parenchyma. Last, critically ill patients frequently present with protracted cognitive dysfunction in the setting of septic encephalopathy likely due to multifactorial mechanisms. Further studies are needed to clarify the relative contribution of each of these mechanisms, but available data suggest that CNS complications in COVID-19 are rare and probably not directly caused by the virus.

Could Artesunate Have a Positive Effect on the Neurological Complications Related to Infection When It Is Used in the Treatment of COVID-19?

Artesunate is a safe noncytotoxic drug with low side effects which is used in the treatment of chloroquine-resistant malaria. In addition to being an antimalarial drug, artesunate also has immunomodulatory, anticarcinogenic, and antiviral activity. There are in vivo and in vitro studies reporting that artesunate may have a positive effect on the treatment of COVID-19. Artesunate may be effective based on its effect on the anti-inflammatory activity, chloroquine-like endocytosis inhibition mechanism, and nuclear factor kappa B (NF-κB) signal pathway. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause neurological complications in addition to targeting the respiratory system. In this study, we have discussed the possible neuroprotective action mechanisms of artesunate. We think that systemic and intranasal topical artesunate administration may have a positive effect on neurological complications resulting from COVID-19.

[Neuromuscular Manifestations and Pathogenesis of COVID-19].

A novel coronavirus infection, coronavirus disease 2019 (COVID-19), is frequently associated with neuromuscular symptoms. It is characterized by taste and smell disturbances, and nonspecific symptoms such as headache and dizziness. Neuromuscular complications such as cerebrovascular disease, encephalopathy, meningoencephalitis, peripheral neuropathy, and myositis/myopathy have been reported to date. In daily clinical practice, it is important to consider COVID-19 as a differential diagnosis, because these symptoms may be the first warning signs.

Current evidence of neurological features, diagnosis, and neuropathogenesis associated with COVID-19.

Recent reports indicate that besides respiratory and systemic symptoms among coronavirus disease (COVID-19) patients, the disease has a wide spectrum of neurological manifestations (encephalitis, meningitis, myelitis, acute disseminated encephalomyelitis, metabolic and acute hemorrhagic necrotizing encephalopathy, cerebrovascular diseases, Guillain-Barré syndrome, polyneuritis cranialis, dysautonomia, and myopathies). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread from the respiratory system to the central nervous system, using transneuronal and hematogenous mechanisms. Although not every COVID-19 patient will test positive for the virus in the cerebrospinal fluid exam, the appearance of neurological symptoms associated with SARS-CoV-2 infection reveals the importance of understanding the neurologic manifestations and capacity for neural invasion associated with the pathogen. These aspects are relevant for correct diagnosis and treatment, and for the potential development of vaccines. This review highlights the latest evidence of SARS-CoV-2 infection with a focus on neurological involvement and potential neuropathogenesis mechanisms.

Clinical and Neuroimaging Correlation in Patients with COVID-19.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) is increasingly being recognized for its multiorgan involvement, including various neurological manifestations. We examined the frequency of acute intracranial abnormalities seen on CT and/or MR imaging in patients with COVID-19 and investigated possible associations between these findings and clinical parameters, including length of hospital stay, requirement for intubation, and development of acute kidney injury. MATERIALS AND METHODS: This was a retrospective study performed at a large academic hospital in the United States. A total of 641 patients presented to our institution between March 3, 2020, and May 6, 2020, for treatment of coronavirus disease 2019, of whom, 150 underwent CT and/or MR imaging of the brain. CT and/or MR imaging examinations were evaluated for the presence of hemorrhage, infarction, and leukoencephalopathy. The frequency of these findings was correlated with clinical variables, including body mass index, length of hospital stay, requirement for intubation, and development of acute kidney injury as documented in the electronic medical record. RESULTS: Of the 150 patients, 26 (17%) had abnormal CT and/or MR imaging findings, with hemorrhage in 11 of the patients (42%), infarction in 13 of the patients (50%), and leukoencephalopathy in 7 of the patients (27%). Significant associations were seen between abnormal CT/MR imaging findings and intensive care unit admission (P = .039), intubation (P = .004), and acute kidney injury (P = .030). CONCLUSIONS: A spectrum of acute neuroimaging abnormalities was seen in our cohort of patients with coronavirus disease 2019, including hemorrhage, infarction, and leukoencephalopathy. Significant associations between abnormal neuroimaging studies and markers of disease severity (intensive care unit admission, intubation, and acute kidney injury) suggest that patients with severe forms of coronavirus disease 2019 may have higher rates of neuroimaging abnormalities.

Neurologic complications of COVID-19.

Patients with COVID-19 have a fairly high risk of neurologic complications, including encephalopathy, stroke, central nervous system infection, seizures, and neuromuscular diseases. Many report losing their senses of smell and taste, and many survivors report lingering neurocognitive impairment. The diagnosis and treatment of these complications does not differ from that in other patients, although sophisticated testing may not be readily available for a patient in intensive care and respiratory isolation. Clinicians should therefore be alert to these complications.

How SARS-Cov-2 can involve the central nervous system. A systematic analysis of literature of the department of human neurosciences of Sapienza University, Italy.

Italy is currently one of the countries most affected by the global emergency of COVID-19, a lethal disease of a novel coronavirus renamed as SARS-CoV-2. SARS-CoV-2 shares highly homological sequence with the most studied SARS-CoV, and causes acute, highly deadly pneumonia (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. Increasing evidence shows that these coronaviruses are not always confined to the respiratory tract and that they may also neuroinvasive and neurotropic, with potential neuropathological consequences in vulnerable populations. The aim of this study is to predict a likely CNS involvement by SARS-CoV-2 by studying the pathogenic mechanisms in common with other better known and studied coronaviruses with which it shares the same characteristics. Understanding the mechanisms of neuroinvasion and interaction of HCoV (including SARS-Cov-2) with the CNS is essential to evaluate potentially pathological short- and long-term consequences. Autopsies of the COVID-19 patients, detailed neurological investigation, and attempts to isolate SARS-CoV-2 from the endothelium of cerebral microcirculation, cerebrospinal fluid, glial cells, and neuronal tissue can clarify the role played by COVID-19 in CNS-involvement and in the ongoing mortalities as has been in the recent outbreak.

Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children.

Importance: Neurological manifestations have been reported in adults with coronavirus disease 2019 (COVID-19), which is caused by the highly pathogenic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objective: To report the neurological manifestations of children with COVID-19. Design, Setting, and Participants: In this case-series study, patients younger than 18 years who presented with SARS-CoV-2 infection and neurological symptoms to Great Ormond Street Hospital for Children (London, UK) between March 1, 2020, and May 8, 2020, were included after infection was confirmed by either a quantitative reverse transcription-polymerase chain reaction assay by nasopharyngeal swab or a positive test result for IgG antibodies against SARS-CoV-2 in serum. Main Outcomes and Measures: Clinical and paraclinical features were retrieved from electronic patient records. Results: Of the 27 children with COVID-19 pediatric multisystem inflammatory syndrome, 4 patients (14.8%) who were previously healthy had new-onset neurological symptoms. Symptoms included encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes. All 4 patients required intensive care unit admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome. Splenium signal changes were seen in all 4 patients on magnetic resonance imaging of the brain. In the 2 patients whose cerebrospinal fluid was tested, samples were acellular, with no evidence of infection on polymerase chain reaction or culture (including negative SARS-CoV-2 polymerase chain reaction results) and negative oligoclonal band test results. In all 3 patients who underwent electroencephalography, a mild excess of slow activity was found. Tests for N-methyl-d-aspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients. In all 3 patients who underwent nerve conduction studies and electromyography, mild myopathic and neuropathic changes were seen. Neurological improvement was seen in all patients, with 2 making a complete recovery by the end of the study. Conclusions and Relevance: In this case-series study, children with COVID-19 presented with new neurological symptoms involving both the central and peripheral nervous systems and splenial changes on imaging, in the absence of respiratory symptoms. Additional research is needed to assess the association of neurological symptoms with immune-mediated changes among children with COVID-19.