Severe Encephalopathy Research Articles

Role of temporary portosystemic surgical shunt during liver resection to prevent a post-resection small for size-like syndrome

Liver resection stands as the gold-standard therapeutic approach for selected cases of hepatocellular carcinoma (HCC). The extent of resectable parenchyma hinges upon the underlying liver function and its regenerative potential. Consequently, cirrhosis may impede access to potentially curative interventions for HCC arising within this context. Cirrhotic patients undergoing liver resection face heightened susceptibility to post-hepatectomy liver failure (PHLF). The clinical profile of PHLF bears a resemblance to a well-documented syndrome within the liver transplant (LT) domain: Small-for-size syndrome (SFSS), a form of graft failure observed in the postoperative phase following LT with undersized or partial organs. Management of SFSS targets mitigating the overflow syndrome, achievable through diverse portal diversion techniques. Portal vein flow diversion encompasses procedures redirecting a variable proportion of portal vein flow towards systemic circulation. Consequently, derivative procedures aim to directly alleviate portal hypertension. Side-to-side portocaval shunts emerge as the most straightforward and efficacious means of decompressing the portal system. Furthermore, they afford flow calibration to diminish the incidence and severity of steal syndrome and hepatic encephalopathy, without compromising efficacy or hepatic function. Translating insights gleaned from LT complexities involving SFSS to liver resection, strategies involving portal flow diversion warrant consideration in efforts to forestall PHLF. This approach aims to extend the frontiers of liver surgery, broadening access to hepatectomy with curative intent, either as a standalone intervention or as part of a comprehensive treatment regimen where LT serves as a secondary option.

High antioxidant capacity may alter the severity and treatment of hypoxic-ischemic encephalopathy in newborns

High antioxidant capacity may alter the severity and treatment of hypoxic-ischemic encephalopathy in newborns

Unraveling Dravet Syndrome: Exploring the complex effects of sodium channel mutations on neuronal networks.

Dravet Syndrome (DS) is a severe developmental epileptic encephalopathy with frequent intractable seizures accompanied by cognitive impairment, often caused by pathogenic variants in SCN1A encoding sodium channel NaV1.1. Recent research utilizing in vitro patient-derived neuronal networks and accompanying in silico models uncovered that not just sodium-but also potassium-and synaptic currents were impaired in DS networks. Here, we explore the implications of these findings for three questions that remain elusive in DS: How do sodium channel impairments result in epilepsy? How can identical variants lead to varying phenotypes? What mechanisms underlie the developmental delay in DS patients? We speculate that impaired potassium currents might be a secondary effect to NaV1.1 mutations and could result in hyperexcitable neurons and epileptic networks. Moreover, we reason that homeostatic plasticity is actively engaged in DS networks, possibly affecting the phenotype and impairing learning and development when driven to extremes.

Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome.

Dravet syndrome is a severe infantile onset developmental and epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. Prospective data on long-term developmental and clinical outcomes are limited; this study seeks to evaluate the clinical course of Dravet syndrome over a 10-year period and identify predictors of developmental outcome. SCN1A mutation-positive Dravet syndrome patients were prospectively followed up in the UK from 2010 to 2020. Caregivers completed structured questionnaires on clinical features and disease burden; the Epilepsy & Learning Disability Quality of Life Questionnaire, the Adaptive Behavioural Assessment System-3 and the Sleep Disturbance Scale for Children. Sixty-eight of 113 caregivers (60%) returned posted questionnaires. Developmental outcome worsened at follow-up (4.45 [SD 0.65], profound cognitive impairment) compared to baseline (2.9 [SD 1.1], moderate cognitive impairment, P < 0.001), whereas epilepsy severity appeared less severe at 10-year follow-up (P = 0.042). Comorbidities were more apparent at 10-year outcome including an increase in autistic features (77% [48/62] versus 30% [17/57], χ2 = 19.9, P < 0.001), behavioural problems (81% [46/57] versus 38% [23/60], χ2 = 14.1, P < 0.001) and motor/mobility problems (80% [51/64] versus 41% [24/59], χ2 = 16.9, P < 0.001). Subgroup analysis demonstrated a more significant rise in comorbidities in younger compared to older patients. Predictors of worse long-term developmental outcome included poorer baseline language ability (P < 0.001), more severe baseline epilepsy severity (P = 0.003) and a worse SCN1A genetic score (P = 0.027). Sudden unexpected death in epilepsy had not been discussed with a medical professional in 35% (24/68) of participants. Over 90% of caregivers reported a negative impact on their own health and career opportunities. Our study identifies important predictors and potential biomarkers of developmental outcome in Dravet syndrome and emphasizes the significant caregiver burden of illness. The negative impact of epilepsy severity at baseline on long-term developmental outcomes highlights the importance of implementing early and focused therapies whilst the potential impact of newer anti-seizure medications requires further study.

Severe Posterior Reversible Encephalopathy Syndrome Secondary to Hyponatremia in a Patient with Water Intoxication.

Severe Posterior Reversible Encephalopathy Syndrome Secondary to Hyponatremia in a Patient with Water Intoxication.

Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review

PurposeSeizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. MethodWe analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. ResultThe proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00%), seizures (36/40, 90.00%), cranial deformity (27/40, 67.50%), facial deformity (22/40, 55.00%), hypotonia (22/40, 55.00%), abnormal interseizure EEG discharge (26/40, 65.00%), slow background activity (20/40, 50.00%), corpus callosum deformity (18/40, 45.00%). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. ConclusionThe compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

Analgesia and sedation strategies in neonates undergoing whole-body therapeutic hypothermia: A scoping review

Background Therapeutic hypothermia (TH) is a widely practiced neuroprotective strategy for neonates with hypoxic-ischemic encephalopathy. Induced hypothermia is associated with shivering, cold pain, agitation, and distress. Objective This scoping review determines the breadth of research undertaken for pain and stress management in neonates undergoing hypothermia therapy, the pharmacokinetics of analgesic and sedative medications during hypothermia and the effect of such medication on short- and long-term neurological outcomes. Methods We searched the following online databases namely, (i) MEDLINE, (ii) Web of Science, (iii) Cochrane Library, (iv) Scopus, (v) CINAHL, and (vi) EMBASE to identify published original articles between January 2005 and December 2022. We included only English full-text articles on neonates treated with TH and reported the sedation/analgesia strategy used. We excluded articles that reported TH on transport or extracorporeal membrane oxygenation, did not report the intervention strategies for sedation/analgesia, and reported hypoxic-ischemic encephalopathy in which hypothermia was not applied. Results The eligible publications (n = 97) included cohort studies (n = 72), non-randomized experimental studies (n = 2), pharmacokinetic studies (n = 4), dose escalation feasibility trial (n = 1), cross-sectional surveys (n = 5), and randomized control trials (n = 13). Neonatal Pain, Agitation, and Sedation Scale (NPASS) is the most frequently used pain assessment tool in this cohort. The most frequently used pharmacological agents are opioids (Morphine, Fentanyl), benzodiazepine (Midazolam) and Alpha2 agonists (Dexmedetomidine). The proportion of neonates receiving routine sedation-analgesia during TH is center-specific and varies from 40–100% worldwide. TH alters most drugs’ metabolic rate and clearance, except for Midazolam. Dexmedetomidine has additional benefits of thermal tolerance, neuroprotection, faster recovery, and less likelihood of seizures. There is a wide inter-individual variability in serum drug levels due to the impact of temperature, end-organ dysfunction, postnatal age, and body weight on drug metabolism. Conclusions No multidimensional pain scale has been tested for reliability and construct validity in hypothermic encephalopathic neonates. There is an increasing trend towards using routine sedation/analgesia during TH worldwide. Wide variability in the type of medication used, administration (bolus versus infusion), and dose ranges used emphasizes the urgent need for standardized practice recommendations and guidelines. There is insufficient data on the long-term neurological outcomes of exposure to these medications, adjusted for underlying brain injury and severity of encephalopathy. Future studies will need to develop framework tools to enable precise control of sedation/analgesia drug exposure customized to individual patient needs.

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased sCr\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{sCr}$$\\end{document} in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the sCr\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{sCr}$$\\end{document} synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher sCr\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{sCr}$$\\end{document} synthesis rate compared to no-AKI patients. Our findings show that the use of sCr\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\mathrm{sCr}$$\\end{document} as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.Graphical

COVID-19 and Brain complications in adult and pediatric patients: A review on neuroimaging findings

In this review, we will discuss the neuroimaging findings of patients with COVID-19 from the outbreak (late December 2019) to the end of October 2021. PubMed, Scopus, Google Scholar, Science Direct, ProQuest, Web of Science and the World Health Organization database (January 01, 2020, to October 30, 2021) were searched for related published articles. In each of the databases, the appendix search strategies were performed and the below keywords were used: COVID-19”OR“coronavirus disease 2019” AND “brain MRI” OR “brain magnetic resonance imaging” OR “brain CT” OR “neuroimaging”. In total, neuroimaging findings of 1550 patients, with ages from 1-96 years, were analyzed. Most brain neuroimaging findings include hyperintensity, Cerebral venous thrombosis, intraventricular and subarachnoid hemorrhage, infarction, leukoencephalopathy, acute ischemic strokes and posterior reversible encephalopathy syndrome (PRES) in adult patients and severe encephalopathy, stroke, infarction, CNS infection/demyelination, neuritis or polyradiculitis, venous thrombosis, Guillain-Barré syndrome, and longitudinally extensive myelitis, and myositis in pediatric patients. Our findings showed that the most important complication of the coronavirus is not just respiratory complications, because although transiently, COVID-19-related brain complications are seen in pediatrics as well as adults, and families should pay more attention to health care.

Severe hepatic encephalopathy with mechanical ventilation may inform waitlist priority in acute liver failure: A UNOS database analysis.

Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality. About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7). Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs.

Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial

ObjectiveTo study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE).DesignSecondary...

Minimal hepatic encephalopathy: clinical, neurophysiological, neuroimaging markers

Hepatic encephalopathy in the initial stages is a diagnostically challenging clinical phenomenon, based on the accumulation of ammonia. Symptoms of encephalopathy are extremely varied: from a slight cognitive decrease and minimal affective disorders to disorders of consciousness and coma in the terminal stages. However, the severity of liver pathology and neurophysiological and neuroimaging data do not always correlate with the severity of encephalopathy. The greatest difficulties in diagnosis arise at the initial stage of the disease, and a timely recognized and established diagnosis can not only slow down the progression of cognitive deficits and characterological changes, but also significantly improve the patient’s prognosis.

Hearing impairment after asphyxia and neonatal encephalopathy: a Norwegian population-based study.

The purpose of this study is to evaluate the association between perinatal asphyxia, neonatal encephalopathy, and childhood hearing impairment. This is a population-basedstudy including all Norwegian infants born ≥ 36weeks gestation between 1999 and 2014 and alive at 2years (n = 866,232). Data was linked from five national health registries with follow-up through 2019. Perinatal asphyxia was defined as need for neonatal intensive care unit (NICU) admission and an Apgar 5-min score of 4-6 (moderate) or 0-3 (severe). We coined infants with seizures and an Apgar 5-min score < 7 as neonatal encephalopathy with seizures. Infants who received therapeutic hypothermia were considered to have moderate-severe hypoxic-ischemic encephalopathy (HIE). The reference group for comparisons were non-admitted infants with Apgar 5-min score ≥ 7. We used logistic regression models and present data as adjusted odds ratios (aORs) with 95% confidence intervals (CI). The aOR for hearing impairment was increased in all infants admitted to NICU: moderate asphyxia aOR 2.2 (95% CI 1.7-2.9), severe asphyxia aOR 5.2 (95% CI 3.6-7.5), neonatal encephalopathy with seizures aOR 7.0 (95% CI 2.6-19.0), and moderate-severe HIE aOR 10.7 (95% CI 5.3-22.0). However, non-admitted infants with Apgar 5-min scores < 7 did not have increased OR of hearing impairment. The aOR for hearing impairment for individual Apgar 5-min scores in NICU infants increased with decreasing Apgar scores and was 13.6 (95% CI 5.9-31.3) when the score was 0. Conclusions: An Apgar 5-min score < 7 in combination with NICU admission is an independent risk factor for hearing impairment. Children with moderate-severe HIE had the highest risk for hearing impairment. What is Known: • Perinatal asphyxia and neonatal encephalopathy are associated with an increased risk of hearing impairment. • The strength of the association, and how other co-morbidities affect the risk of hearing impairment, is poorly defined. What is New: • Among neonates admitted to a neonatal intensive care unit (NICU), decreased Apgar 5-min scores, and increased severity of neonatal encephalopathy, were associated with a gradual rise in risk of hearing impairment. • Neonates with an Apgar 5-min score 7, but without NICU admission, did not have an increased risk of hearing impairment.

Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors.

MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling, and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in 2 siblings with microcephaly, epileptic encephalopathy, and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13, Mad2, and Rev7 binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated an identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early-deceased patient with low-level aneuploidy, severe epileptic encephalopathy, and frequent blood glucose elevations, likely corresponds to complete loss of function, as in Mad2l1bp-/- mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.

The incidence, indications, risk factors and pregnancy outcomes of peripartum hysterectomy at a tertiary hospital between 2013 and 2022.

To analyze the incidence, indications, risk factors and pregnancy outcomes of postpartum hemorrhage resulting in peripartum hysterectomy (PH). We retrospectively reviewed patients with postpartum hemorrhage requiring surgical procedures at ≥ 28weeks of gestation from January 1, 2013 to December 31, 2022 at a tertiary hospital in Shanghai, China. The patients were divided into a PH group and a non-PH group. Maternal clinical characteristics, the management of postpartum hemorrhage, pregnancy outcomes were compared between groups. Logistic regression was used to analyze the correlations between risk factors and PH. The incidence of hysterectomy was 0.2/1000 deliveries (31/150194). The variables significantly associated with PH were placenta previa with placenta increta/percreta (OR36.26), uterine rupture (OR266.16) and an estimated blood loss ≥ 3513mL (OR431.11). The proportion of cases involving hemorrhagic shock, disseminated intravascular coagulation, bladder injury, neonatal severe asphyxia, neonatal death and hypoxic-ischemic encephalopathy were significantly higher in the PH group (P < 0.05). The most common indications of PH were placental pathology. Efforts should be made to reduce the rate of cesarean deliveries and uterine curettage to lower the probability of abnormal placental invasion and appropriate medical indications for trial of labor after cesarean should be strictly followed to avoid the risk of uterine rupture.

Exploring the genetic landscape of neurotransmitter alterations in hypoxic-ischemic encephalopathy: A personalized medicine perspective

\textbf{Background:} Hypoxic-ischemic encephalopathy (HIE) is a neurological condition due to perinatal asphyxia, affecting brain areas with high metabolic rates and active myelination processes. The HIE has various origins and can be challenging to diagnose and treat. This study aimed to determine the origin of the clinical phenotype of patients who met the criteria for perinatal asphyxia at birth from personalized medicine. \textbf{Methods:} We evaluated 28 patients classified according to the SARNAT scale (i.e., clinical staging of HIE) and neurological anomalies by MRI scans. We used a next-generation sequencing panel for genes related to neurotransmitters and analyzed the statistical association between sequelae and other clinical variables using Fisher’s exact test. We also evaluated odds ratios (OR) with 95\% confidence intervals by binary logistic regression analysis adjusted for SARNAT, seizure, MRI scans, and genetic findings. \textbf{Results:} We identified 11 patients with neurotransmitter-related genetic alterations, such as glycine encephalopathy. Three had pathogenic variants (ALDH7A1, AMT, and SLC1A4), and eight had uncertain significance (TH, DBH, MYH2, CGH1, SLC6A5, ABAT, ALDH5A1, GLRB). One patient had 8p11.2 deletion, 14q11.2 deletion, and 10q11.22 duplication. Statistical analyses indicated that the presence or absence of mutations had a statistically significant association with sequelae (p-value = 0.054). Patients with a pathogenetic or uncertain mutation are associated with an increased risk of neurological sequelae (OR: 6.43; 95\% CI: 1.2 – 51.5; p-value = 0.044) regardless of clinical conditions such as the presence of seizures, severity of encephalopathy, alterations in the RMI or hypothermia therapy. \textbf{Conclusions:} Our findings suggest that neurotransmitter alterations are a critical factor significantly increasing the risk of HIE-related sequelae. Identifying these genetic alterations could lead to earlier and more precise diagnosis and treatment of HIE patients.

Evaluating clinical outcomes and prognosis in patients with cirrhosis and portal hypertension: a retrospective observational cohort study

ObjectiveCirrhosis describes the end-stage of chronic liver disease. Irreversible changes in the liver cause portal hypertension, which can progress to serious complications and death. Only a few studies with small...

Clinical and imaging analysis of neurological complications in critically ill children infected with SARS-CoV-2 Omicron

To summarize clinical predictors and imaging characteristics of critically ill children infected with SARS-CoV-2 Omicron with neurological complications in Shenzhen during the peak of the first round of infections. The clinical data of 11 critically ill children with neurological complications infected with SARS-CoV-2 Omicron in Shenzhen Children's Hospital from December 12 to 31, 2022, were retrospectively collected and analyzed. Laboratory test results related to liver parenchymal injury, histiocytic injury, inflammation, and coagulation function were collected, and imaging characteristics including CT and/or magnetic resonance imaging (MRI) were analyzed. The differences in CT/MRI score, acute necrotizing encephalopathy severity scale (ANE-SS) score and total score (CT/MRI score + ANE-SS score) were compared between the two groups with different prognosis during hospitation. Among 11 children, 7 were male and 4 were female. The age ranged from 10 months to 16 years. There were 5 cases of acute necrotizing encephalopathy (ANE) and 6 cases of acute fulminant cerebral edema (AFCE). During hospitalization, 3 patients survived and 8 patients died of multiple organ dysfunction syndrome (MODS), including 2 cases of ANE and 6 cases of AFCE. All cases had fever (> 38.5 centigrade), and 3 cases had ultra-high fever (> 41 centigrade). Within 48 hours of onset, all cases had disorders of consciousness and 9 cases had seizures. The 8 dead children had complications with multisystem involvement, including shock, respiratory failure, disseminated intravascular coagulation (DIC), liver failure, renal failure or myocardial damage, and the laboratory predictors related to hepatocellular injury [alanine aminotransferase (ALT), aspartate aminotransferase (AST)], histocyte injury [creatine kinase (CK), lactate dehydrogenase (LDH)], inflammation [procalcitonin (PCT), interleukin-6 (IL-6), serum ferritin (SF)], coagulation function (D-dimer) and blood glucose (Glu) increased in different quantities, of which PCT was specifically increased in 6 cases with AFCE, PLT was specifically decreased in 3 cases with AFCE, and ALT and LDH were significantly increased in 2 cases with ANE. Imaging analysis showed subarachnoid hemorrhage, basal ganglia and thalamus lesions in all 6 cases with AFCE, while thalamus lesions in all 5 cases with ANE. The ANE-SS score of 8 deceased children ranged from 2 to 7 (of which 6 cases were ≥ 5), and the ANE-SS score of 3 surviving children ranged from 0 to 2. Eight dead children had a CT/MRI score of 1-4 (of which 6 cases were 4), and 3 surviving children had a CT/MRI score of 1-2 (of which 2 cases were 1). The total score of 8 deceased children was 6-10 (of which 6 cases ≥ 8), and 3 surviving children was 1-4. The neurological complications of critically ill children infected with SARS-CoV-2 Omicron in Shenzhen progressed rapidly to ANE and AFCE, with high mortality. High fever (> 40 centigrade), convulsion/disturbance of consciousness, and multiple organ failure were the most common symptoms in ANE and AFCE cases. PCT increased and PLT decreased specifically in AFCE cases. Poor prognosis (death) was more common in age < 4 years old, predictors of ALT, AST, CK, LDH, PCT, D-dimer, Glu, IL-6 increased significantly, PLT decreased significantly. The common imaging feature of ANE and AFCE is the involvement of dorsal thalamus, a new imaging sign of AFCE (subarachnoid hemorrhage) was found. The higher the ANE-SS score, CT/MRI score and total score, the greater the risk of death.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial

Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks’ gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5–5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

A Novel Variant of ASL Gene Mutation in a Lebanese Neonate with Severe Argininosuccinic Aciduria Phenotype

Argininosuccinic aciduria is a urea cycle defect associated with deficiency in argininosuccinate lyase enzyme, leading to a severe hyperammonemic encephalopathy, epilepsy and hepatopathy. Only very few known mutations have been linked with a severe phenotype. Here we report the case of a Lebanese newborn child with a very early manifestation of argininosuccinic aciduria, his genetic studies confirmed the presence of a mutation in the ASL gene (c.697A&gt;C p. (Thr233Pro) at the homozygous state. To our knowledge, this is the first time this variant has been reported in literature.