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1.
N Engl J Med ; 387(2): 148-159, 2022 07 14.
Article in English | MEDLINE | ID: covidwho-1931553

ABSTRACT

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).


Subject(s)
Erythropoietin , Hypothermia, Induced , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Administration, Intravenous , Cerebral Palsy/etiology , Double-Blind Method , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Erythropoietin/therapeutic use , Humans , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/adverse effects , Neuroprotective Agents/therapeutic use
2.
Childs Nerv Syst ; 38(9): 1727-1734, 2022 09.
Article in English | MEDLINE | ID: covidwho-1888856

ABSTRACT

PURPOSE: To evaluate change in the severity of hypoxic-ischemic encephalopathy (HIE) and associated morbidities between pre- and during COVID-19 pandemic periods in Canada. METHODS: We conducted a retrospective cohort study extracting the data from level-3 NICUs participating in Canadian Neonatal Network (CNN). The primary outcome was a composite of death in the first week after birth and/or stage 3 HIE (Sarnat and Sarnat). Secondary outcomes included rate and severity of HIE among admitted neonates, overall mortality, brain injury on magnetic resonance imaging (MRI), neonates requiring resuscitation, organ dysfunction, and therapeutic hypothermia (TH) usage. We included 1591 neonates with gestational age ≥ 36 weeks with HIE during the specified periods: pandemic cohort from April 1st to December 31st of 2020; pre-pandemic cohort between April 1st and December 31st of 2017, 2018, and 2019. We calculated the odds ratio (OR) and confidence intervals (CI). RESULTS: We observed no significant difference in the primary outcome (15% vs. 16%; OR 1.08; 95%CI 0.78-1.48), mortality in the first week after birth (6% vs. 6%; OR 1.10, 95%CI 0.69-1.75), neonates requiring resuscitation, organ dysfunction, TH usage, or rate of brain injury. In the ad hoc analysis, per 1000 live births, there was an increase in the rate of infants with HIE and TH use. CONCLUSIONS: Severity of HIE, associated morbidities, and mortality were not significantly different during the pandemic lockdown compared to a pre-pandemic period in Canada. Anticipated risks and difficulties in accessing healthcare have not increased the mortality and morbidities in neonates with HIE in Canada.


Subject(s)
Brain Injuries , COVID-19 , Hypothermia, Induced , Hypoxia-Ischemia, Brain , Brain Injuries/complications , Canada/epidemiology , Cohort Studies , Communicable Disease Control , Humans , Hypoxia-Ischemia, Brain/epidemiology , Hypoxia-Ischemia, Brain/pathology , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Multiple Organ Failure/complications , Multiple Organ Failure/therapy , Pandemics , Retrospective Studies
3.
BMJ Open ; 12(4): e057073, 2022 04 26.
Article in English | MEDLINE | ID: covidwho-1854347

ABSTRACT

INTRODUCTION: Neonatal hypoxic-ischaemic encephalopathy (HIE) is an important illness associated with death or cerebral palsy. This study aims to assess the safety and tolerability of the allogenic human multilineage-differentiating stress-enduring cell (Muse cell)-based product (CL2020) cells in newborns with HIE. This is the first clinical trial of CL2020 cells in neonates. METHODS AND ANALYSIS: This is a single-centre, open-label, dose-escalation study enrolling up to 12 patients. Neonates with HIE who receive a course of therapeutic hypothermia therapy, which cools to a body temperature of 33°C-34°C for 72 hours, will be included in this study. A single intravenous injection of CL2020 cells will be administered between 5 and 14 days of age. Subjects in the low-dose and high-dose cohorts will receive 1.5 and 15 million cells per dose, respectively. The primary outcome is the occurrence of any adverse events within 12 weeks after administration. The main secondary outcome is the Bayley Scales of Infant and Toddler Development Third Edition score and the developmental quotient per the Kyoto Scale of Psychological Development 2001 at 78 weeks. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The Nagoya University Hospital Institutional Review Board (No. 312005) approved this study on 13 November 2019. The results of this study will be published in peer-reviewed journal and reported in international conferences. TRIAL REGISTRATION NUMBERS: NCT04261335, jRCT2043190112.


Subject(s)
Hypothermia, Induced , Hypoxia-Ischemia, Brain , Body Temperature , Humans , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Protective Devices , Research
4.
Neurobiol Dis ; 161: 105561, 2021 12.
Article in English | MEDLINE | ID: covidwho-1510138

ABSTRACT

Coronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain/metabolism , COVID-19/metabolism , Hypoxia-Ischemia, Brain/metabolism , Hypoxia/metabolism , Inflammation/metabolism , Pericytes/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Actins/metabolism , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/genetics , Animals , Brain/blood supply , COVID-19/physiopathology , Calcium Signaling , Collagen Type I/metabolism , Fibronectins/metabolism , Humans , Hypoxia-Ischemia, Brain/physiopathology , Lipid Peroxidation/drug effects , Lipid Peroxidation/genetics , Macrophage Migration-Inhibitory Factors/drug effects , Macrophage Migration-Inhibitory Factors/metabolism , Mice , Mice, Transgenic , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , Myofibroblasts , NF-kappa B/drug effects , NF-kappa B/metabolism , Nasal Mucosa , Nitrosative Stress , Oxidative Stress , Pericytes/cytology , Pericytes/drug effects , Phenotype , Receptor, Notch3/metabolism , Receptors, Coronavirus/drug effects , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/pharmacology
5.
Brain ; 144(9): 2696-2708, 2021 10 22.
Article in English | MEDLINE | ID: covidwho-1185655

ABSTRACT

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.


Subject(s)
Brain Infarction/pathology , Brain/pathology , COVID-19/pathology , Hypoxia-Ischemia, Brain/pathology , Intracranial Hemorrhages/pathology , Acute Kidney Injury/complications , Acute Kidney Injury/physiopathology , Acute Kidney Injury/therapy , Adult , Aged , Aged, 80 and over , Bacteremia/complications , Brain/metabolism , Brain Infarction/complications , COVID-19/complications , COVID-19/physiopathology , Coronavirus Nucleocapsid Proteins/metabolism , Female , Humans , Hypoxia-Ischemia, Brain/complications , Inflammation , Intensive Care Units , Intracranial Hemorrhages/complications , Male , Microglia/pathology , Middle Aged , Neurons/pathology , Phagocytosis , Phosphoproteins/metabolism , Pulmonary Embolism/complications , Pulmonary Embolism/physiopathology , RNA, Viral/metabolism , Renal Dialysis , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Survival Rate , T-Lymphocytes/pathology , Venous Thrombosis/complications , Venous Thrombosis/physiopathology
6.
medrxiv; 2021.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2021.03.16.21253167

ABSTRACT

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT- PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.


Subject(s)
9653 , 33768 , 59585 , 12092 , 50504 , 7678 , 50503 , 34255 , 37050 , 53982 , 15059 , 33354 , 7398 , 7426
8.
ssrn; 2021.
Preprint in English | PREPRINT-SSRN | ID: ppzbmed-10.2139.ssrn.3742286

ABSTRACT

Background: Despite the expanding literature that discusses insights into the clinical picture and mechanisms by which the SARS‐CoV‐2 virus invades the nervous system, data on the neuropathologic findings of patients who died following SARS-CoV-2 infection is limited.Methods: A broad literature search was done for published articles that reported on histopathological findings of the brain in patients with COVID-19 in PUBMED by Medline, EMBASE, and CENTRAL by the Cochrane Library, and SCOPUS from December 31, 2019 to October 31, 2020.Results: The systematic literature search strategy used resulted in a total of 1608 articles of which 14 were included in the analysis (PROSPERO registration number: CRD42020221022). There were ten case series, two case reports, one retrospective cohort, and one prospective cohort. The age of the subjects ranged between 38-90 years old, most of them older than 65-years-old (n=66, 45.2%) and males (n=79, 54.1%). Most tested negative in SARS-CoV-2 immunohistochemistry (n=70, 47.9%). The striking pathologic changes included diffuse edema (n=25, 17.1%), gliosis with diffuse activation of microglia and astrocytes (n=52, 35.6%), infarctions involving cortical and subcortical areas of the brain (n=4, 2.7%), intracranial bleed (subarachnoid hemorrhage and punctate hemorrhages) (n=18, 12.4%), arteriosclerosis (n=43, 29.5%), hypoxic-ischemic injury (n=41, 28.1%), and signs of inflammation (n=52, 35.6%). The cause of death was mainly attributed to the cardiorespiratory system (n=66, 45.2%).Conclusions: The neuropathologic changes observed likely represent direct cytopathic effects and indirect effects secondary to host-specific inflammatory response induced by the viral infection. Further studies however are required to better elucidate the pathologic mechanism.Funding Statement: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.Declaration of Interests: None.


Subject(s)
6054 , 34255 , 59585 , 1166 , 21079 , 13733
9.
Neurology ; 95(10): 454-457, 2020 09 08.
Article in English | MEDLINE | ID: covidwho-616669
10.
Neurology ; 95(2): 77-84, 2020 07 14.
Article in English | MEDLINE | ID: covidwho-146855

ABSTRACT

OBJECTIVE: The emergence of coronavirus disease 2019 (COVID-19) presents a challenge for neurologists caring for patients with preexisting neurologic conditions hospitalized for COVID-19 or for evaluation of patients who have neurologic complications during COVID-19 infection. We conducted a scoping review of the available literature on COVID-19 to assess the potential effect on neurologists in terms of prevalent comorbidities and incidence of new neurologic events in patients hospitalized with COVID-19. METHODS: We searched MEDLINE/PubMed, CINAHL (EBSCO), and Scopus databases for adult patients with preexisting neurologic disease who were diagnosed and hospitalized for COVID-19 or reported incidence of secondary neurologic events following diagnosis of COVID-19. Pooled descriptive statistics of clinical data and comorbidities were examined. RESULTS: Among screened articles, 322 of 4,014 (8.0%) of hospitalized patients diagnosed and treated for COVID-19 had a preexisting neurologic illness. Four retrospective studies demonstrated an increased risk of secondary neurologic complications in hospitalized patients with COVID-19 (incidence of 6%, 20%, and 36.4%, respectively). Inconsistent reporting and limited statistical analysis among these studies did not allow for assessment of comparative outcomes. CONCLUSION: Emerging literature suggests a daunting clinical relationship between COVID-19 and neurologic illness. Neurologists need to be prepared to reorganize their consultative practices to serve the neurologic needs of patients during this pandemic.


Subject(s)
Coronavirus Infections/epidemiology , Hospitalization , Nervous System Diseases/epidemiology , Pneumonia, Viral/epidemiology , Respiratory Distress Syndrome/epidemiology , Betacoronavirus , COVID-19 , Cerebrovascular Disorders/epidemiology , Comorbidity , Coronavirus Infections/complications , Coronavirus Infections/physiopathology , Dementia/epidemiology , Epilepsy/epidemiology , Guillain-Barre Syndrome/epidemiology , Guillain-Barre Syndrome/etiology , Humans , Hypoxia-Ischemia, Brain/epidemiology , Hypoxia-Ischemia, Brain/etiology , Intensive Care Units , Leukoencephalitis, Acute Hemorrhagic/epidemiology , Leukoencephalitis, Acute Hemorrhagic/etiology , Pandemics , Parkinson Disease/epidemiology , Pneumonia, Viral/complications , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Stroke/epidemiology , Stroke/etiology
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