OBJECTIVES: To study the clinical and imaging features of children with influenza-associated encephalopathy (IAE), and to investigate the influencing factors for prognosis. METHODS: A retrospective analysis was conducted on the medical data (clinical data, laboratory examinations, imaging data, and prognosis) of 23 children with IAE who were diagnosed and treated in Children's Hospital of Nanjing Medical University from May 2022 to April 2023. RESULTS: Among the 23 patients, 18 (78%) had influenza A and 5 (22%) had influenza B. All patients had fever and encephalopathy, and 20 patients (87%) had seizures, while 11 patients (48%) had persistent convulsions. There were 10 patients (43%) with an increase in alanine aminotransferase, 14 (61%) with an increase in aspartate aminotransferase, and 18 (78%) with an increase in lactate dehydrogenase. Abnormal imaging findings were observed in 20 patients (87%), among whom 10 (43%) had acute necrotizing encephalopathy. All 23 patients received peramivir or oseltamivir. Of all patients, 12 (52%) achieved complete recovery, 5 (22%) had varying degrees of neurological dysfunction, and 6 (26%) died. Compared with the good prognosis group, the poor prognosis group had significantly higher levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (P<0.05). CONCLUSIONS Fever and convulsions are the most common symptoms of children with IAE, and acute necrotizing encephalopathy is the most common clinical imaging syndrome. Increases in alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase have a certain value in predicting poor prognosis.
Humans ; Influenza, Human/complications* ; Male ; Prognosis ; Female ; Child, Preschool ; Retrospective Studies ; Infant ; Child ; Brain Diseases/etiology*

OBJECTIVES: The neurotoxicity of carbon monoxide (CO) to the central nervous system is a key pathogenesis of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP). Our previous study found that retinoic acid (RA) can suppress the neurotoxic effects of CO. This study further explores, in vivo and in vitro, the molecular mechanisms by which RA alleviates CO-induced central nervous system damage. METHODS: A cytotoxic model was established using the mouse hippocampal neuronal cell line HT22 and primary oligodendrocytes exposed to CO, and a DEACMP animal model was established in adult Kunming mice. Cell viability and apoptosis of hippocampal neurons and oligodendrocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin V/propidium iodide (PI) double staining. The transcriptional and protein expression of each gene was detected using real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting. Long noncoding RNA (lncRNA) SNHG15 and LINGO-1 were knocked down or overexpressed to observe changes in neurons and oligodendrocytes. In DEACMP mice, SNHG15 or LINGO-1 were knocked down to assess changes in central nervous tissue and downstream protein expression. RESULTS: RA at 10 and 20 μmol/L significantly reversed CO-induced apoptosis of hippocampal neurons and oligodendrocytes, downregulation of SNHG15 and LINGO-1, and upregulation of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) (all P<0.05). Overexpression of SNHG15 or LINGO-1 weakened the protective effect of RA against CO-induced cytotoxicity (all P<0.05). Knockdown of SNHG15 or LINGO-1 alleviated CO-induced apoptosis of hippocampal neurons and oligodendrocytes and upregulated BDNF and TrkB expression levels (all P<0.05). Experiments in DEACMP model mice showed that knockdown of SNHG15 or LINGO-1 mitigated central nervous system injury in DEACMP (all P<0.05). CONCLUSIONS RA alleviates CO-induced apoptosis of hippocampal neurons and oligodendrocytes, thereby reducing central nervous system injury and exerting neuroprotective effects. LncRNA SNHG15 and LINGO-1 are key molecules mediating RA-induced inhibition of neuronal apoptosis and are associated with the BDNF/TrkB pathway. These findings provide a theoretical framework for optimizing the clinical treatment of DEACMP and lay an experimental foundation for elucidating its molecular mechanisms.
Animals ; RNA, Long Noncoding/physiology* ; Brain-Derived Neurotrophic Factor/genetics* ; Carbon Monoxide Poisoning/complications* ; Mice ; Tretinoin/pharmacology* ; Nerve Tissue Proteins/metabolism* ; Membrane Proteins/metabolism* ; Apoptosis/drug effects* ; Hippocampus/cytology* ; Receptor, trkB/metabolism* ; Neurons/drug effects* ; Male ; Brain Diseases/etiology* ; Oligodendroglia/drug effects* ; Signal Transduction ; Cell Line

The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Subarachnoid Hemorrhage/complications* ; Inflammasomes/metabolism* ; Rats ; Mice ; Neuroinflammatory Diseases/metabolism* ; WNK Lysine-Deficient Protein Kinase 1/genetics* ; Male ; Humans ; Chlorides/metabolism* ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Brain Injuries/metabolism* ; Microglia/metabolism* ; Protein Serine-Threonine Kinases

A growing interest in the comprehensive pathogenic mechanisms of psychiatric disorders from the perspective of the microbiome has been witnessed in recent decades; the intrinsic link between microbiota and brain function through the microbiota-gut-brain axis or other pathways has gradually been realized. However, little research has focused on viruses-entities characterized by smaller dimensions, simpler structures, greater diversity, and more intricate interactions with their surrounding milieu compared to bacteria. To date, alterations in several populations of bacteriophages and viruses have been documented in both mouse models and patients with psychiatric disorders, including schizophrenia, major depressive disorder, autism spectrum disorder, and Alzheimer's disease, accompanied by metabolic disruptions that may directly or indirectly impact brain function. In addition, eukaryotic virus infection-mediated brain dysfunction provides insights into the psychiatric pathology involving viruses. Efforts towards virus-based diagnostic and therapeutic approaches have primarily been documented. However, limitations due to the lack of large-scale cohort studies, reliability, clinical applicability, and the unclear role of viruses in microbiota interactions pose a challenge for future studies. Nevertheless, it is conceivable that investigations into viruses herald a new era in the field of precise psychiatry.
Humans ; Mental Disorders/virology* ; Animals ; Brain/virology* ; Gastrointestinal Microbiome/physiology* ; Viruses ; Virus Diseases/complications*

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, referring to a diffuse brain dysfunction caused by sepsis in the absence of direct central nervous system (CNS) infection. SAE occurs in up to 70% of patients with sepsis. Globally, the annual incidence of sepsis ranges from 30.0 to 48.9 million cases, resulting in approximately 11 million deaths per year, which accounts for 20% of all global mortalities. SAE is identified as an independent risk factor contributing to the increased mortality rate among these patients. Early diagnosis of SAE and related cerebral protection interventions hold significant clinical importance. Currently, the main indicators of brain function for sepsis patients include Glasgow coma score (GCS), confusion assessment method for the intensive care unit (CAM-ICU), electroencephalogram (EEG), brain CT or magnetic resonance imaging (MRI) and other related imaging changes, which have the problems of low sensitivity, poor specificity, and non-objective evaluation of the results of the diagnosis of SAE. This article focuses on the latest progress in the pathogenesis of SAE and systematically reviews potential biomarkers related to the onset of SAE from multiple aspects, including inflammatory markers, endothelial and neuronal injury markers, and metabolic markers. This will provide new insights for the clinical diagnosis and treatment of SAE.
Humans ; Sepsis-Associated Encephalopathy/therapy* ; Biomarkers ; Sepsis/complications* ; Magnetic Resonance Imaging ; Electroencephalography ; Brain Diseases/etiology*

Cerebral small vessel disease (CSVD) is a senile brain lesion caused by the abnormal structure and function of arterioles, venules and capillaries in the aging brain. The etiology of CSVD is complex, and disease is often asymptomatic in its early stages. However, as CSVD develops, brain disorders may occur, such as stroke, cognitive dysfunction, dyskinesia and mood disorders, and heart, kidney, eye and systemic disorders. As the population continues to age, the burden of CSVD is increasing. Moreover, there is an urgent need for better screening methods and diagnostic markers for CSVD, in addition to preventive and asymptomatic- and mild-stage treatments. Integrative medicine (IM), which combines the holistic concepts and syndrome differentiations of Chinese medicine with modern medical perspectives, has unique advantages for the prevention and treatment of CSVD. In this review, we summarize the biological markers, ultrasound and imaging features, disease-related genes and risk factors relevant to CSVD diagnosis and screening. Furthermore, we discuss IM-based CSVD prevention and treatment strategies to stimulate further research in this field.
Humans ; Integrative Medicine ; Brain/pathology* ; Cerebral Small Vessel Diseases/pathology* ; Stroke/complications* ; Cognitive Dysfunction/complications* ; Magnetic Resonance Imaging

Objective: To investigate the clinical features and short-term prognosis of patients with SARS-CoV-2 infection associated acute encephalopathy (AE). Methods: Retrospective cohort study. The clinical data, radiological features and short-term follow-up of 22 cases diagnosed with SARS-CoV-2 infection associated AE in the Department of Neurology, Beijing Children's Hospital from December 2022 to January 2023 were retrospectively analyzed. The patients were divided into cytokine storm group, excitotoxic brain damage group and unclassified encephalopathy group according to the the clinicopathological features and the imaging features. The clinical characteristics of each group were analyzed descriptively. Patients were divided into good prognosis group (≤2 scores) and poor prognosis group (>2 scores) based on the modified Rankin scale (mRS) score of the last follow-up. Fisher exact test or Mann-Whitney U test was used to compare the two groups. Results: A total of 22 cases (12 females, 10 males) were included. The age of onset was 3.3 (1.7, 8.6) years. There were 11 cases (50%) with abnormal medical history, and 4 cases with abnormal family history. All the enrolled patients had fever as the initial clinical symptom, and 21 cases (95%) developed neurological symptoms within 24 hours after fever. The onset of neurological symptoms included convulsions (17 cases) and disturbance of consciousness (5 cases). There were 22 cases of encephalopathy, 20 cases of convulsions, 14 cases of speech disorders, 8 cases of involuntary movements and 3 cases of ataxia during the course of the disease. Clinical classification included 3 cases in the cytokine storm group, all with acute necrotizing encephalopathy (ANE); 9 cases in the excitotoxicity group, 8 cases with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and 1 case with hemiconvulsion-hemiplegia syndrome; and 10 cases of unclassified encephalopathy. Laboratory studies revealed elevated glutathione transaminase in 9 cases, elevated glutamic alanine transaminase in 4 cases, elevated blood glucose in 3 cases, and elevated D-dimer in 3 cases. Serum ferritin was elevated in 3 of 5 cases, serum and cerebrospinal fluid (CSF) neurofilament light chain protein was elevated in 5 of 9 cases, serum cytokines were elevated in 7 of 18 cases, and CSF cytokines were elevated in 7 of 8 cases. Cranial imaging abnormalities were noted in 18 cases, including bilateral symmetric lesions in 3 ANE cases and "bright tree appearance" in 8 AESD cases. All 22 cases received symptomatic treatment and immunotherapy (intravenous immunoglobulin or glucocorticosteroids), and 1 ANE patient received tocilizumab. The follow-up time was 50 (43, 53) d, and 10 patients had a good prognosis and 12 patients had a poor prognosis. No statistically significant differences were found between the two groups in terms of epidemiology, clinical manifestations, biochemical indices, and duration of illness to initiate immunotherapy (all P>0.05). Conclusions: SARS-CoV-2 infection is also a major cause of AE. AESD and ANE are the common AE syndromes. Therefore, it is crucial to identify AE patients with fever, convulsions, and impaired consciousness, and apply aggressive therapy as early as possible.
Child ; Female ; Male ; Humans ; Retrospective Studies ; Cytokine Release Syndrome ; COVID-19/complications* ; SARS-CoV-2 ; Brain Diseases/etiology* ; Prognosis ; Seizures ; Cytokines

OBJECTIVES: To study the clinical characteristics and prognosis of SARS-CoV-2 Omicron variant infection-associated acute necrotizing encephalopathy (ANE) in children . METHODS: A retrospective analysis was conducted on the medical data of 12 children with SARS-CoV-2 Omicron variant infection-associated ANE who were admitted to the Pediatric Intensive Care Unit, Qingdao Women and Children's Hospital from December 18 to 29, 2022. The children were divided into two groups based on outcomes: death group (7 cases) and survival group (5 cases). The clinical manifestations and auxiliary examination results were compared between the two groups. RESULTS: The median age of the 12 patients was 30 months, with a male-to-female ratio of 1:1. All patients presented with persistent high fever, with a median highest body temperature of 41℃. The median time from fever onset to seizure or consciousness disturbance was 18 hours. The death group had a higher proportion of neurogenic shock, coagulation dysfunction, as well as elevated lactate, D-dimer, interleukin-6, interleukin--8, and interleukin-10 levels compared to the survival group (P<0.05). CONCLUSIONS Children with SARS-CoV-2 Omicron variant infection-associated with ANE commonly present with persistent high fever, rapidly progressing disease, and have a high likelihood of developing consciousness disorders and multiorgan dysfunction within a short period. The occurrence of neurogenic shock, coagulation dysfunction, and significantly elevated cytokine levels suggests an increased risk of mortality.
Humans ; Female ; Child ; Male ; Infant ; SARS-CoV-2 ; Retrospective Studies ; COVID-19/complications* ; Brain Diseases/etiology* ; Prognosis ; Fever ; Blood Coagulation Disorders

Humans ; Spinal Cord Injuries/complications* ; Paralysis/etiology* ; Nervous System Diseases ; Brain

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS 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.
Humans ; Male ; Child ; Female ; Infant ; Child, Preschool ; SARS-CoV-2 ; Interleukin-6 ; Retrospective Studies ; Critical Illness ; COVID-19/complications* ; Procalcitonin ; Inflammation ; Brain Diseases/diagnostic imaging*