Encephalopathy Group Research Articles

Brivaracetam use in children with epilepsy: A retrospective multicenter study

PurposeThis retrospective multicenter study aimed to assess the efficacy and safety of brivaracetam (BRV) in pediatric epilepsy. MethodsOur cohort consisted of 93 children (mean age 11.5 ± 7.5 years) with a wide spectrum of pediatric epilepsy, including epileptic encephalopathy and generalized epilepsy. Of these, 61 (60.4%) were diagnosed with focal epilepsy, 19 (15.8%) with generalized epilepsy, and 16 (15.8%) with combined epilepsy, while 8 patients (7.9%) had an unknown epilepsy type. The cohort included rare epilepsy syndromes: 8 patients with Lennox-Gastaut syndrome, 3 with Dravet syndrome, and 1 with Rasmussen syndrome. Patients had a history of various antiseizure medications (ASMs) (6.42 ± 3.15), and on average, were being treated with more than two (2.57 ± 1.16) drugs at the time of BRV deployment. ResultsRetention rates were high, with 80.6% of patients adhering to treatment at 3 months, 66.7% at 6 months, and 45.2% at 12 months. In 29 patients (30.1%), BRV was added in an overnight switch from levetiracetam (LEV), resulting in a reduction of behavioral adverse effects (AEs) in 5 patients (17.2%). The response rate was 25.8% at 3 months, 16.1% at 6 months, and 17.2% at 12 months, with no responders in the epileptic encephalopathy group. Therapy tolerance was notable, with 70 patients (75.3%) reporting no AEs. Transient AEs occurred in 10 patients (10.7%), and in 13 cases (14.0%), the AEs warranted dose adjustment or discontinuation of BRV. ConclusionApproximately one-fifth of pediatric patients with drug-resistant epilepsy responded to BRV, with the best response observed in patients with focal seizures. However, the impact on patients with epileptic encephalopathy was limited.

Analysis of the risk factors of the radiation-induced encephalopathy in nasopharyngeal carcinoma: A retrospective cohort study.

To analyze the related factors of radiation-induced encephalopathy in nasopharyngeal carcinoma (NPC) to identify the risk factors and their clinical significance. This retrospective cohort study included 707 NPC patients. They had undergone conventional and enhanced computed tomography or magnetic resonance imaging scans. They were divided into the radiation-induced encephalopathy group and the no encephalopathy group according to the imaging examination. Detailed clinical information was collected. The incidence of radiation-induced encephalopathy in NPC was 22.2%, in which 124 were radiation-induced encephalopathy and 33 were reirradiation patients. We found that age, pathological type, radiation method, hypertension, radiation course, relapse, carotid/cerebral arteriosclerosis, clinical stage, and radiotherapy dose were statistically significant between the two groups (p < 0.05). Multiple logistic regression showed that clinical stage, age, radiotherapy method, hypertension, carotid/cerebral arteriosclerosis, and radiation courses after a reoccurrence of NPC were risk factors for radiation-induced encephalopathy. The more advanced the clinical stage was and the older the patient, the greater the risk. Radiotherapy method, radiation course, hypertension, carotid/cerebral arteriosclerosis, age, and clinical stage were the risk factors associated with radiation-induced encephalopathy in NPC.

Brain-Derived Neurotrophic Factor as a Potential Diagnostic Marker in Minimal Hepatic Encephalopathy

Abstract Background Based on the etiology, liver cirrhosis is sub-classified into viral hepatitis (hepatitis B, C, and D), due to toxins (alcohol and drugs), autoimmune hepatitis, Cholestatic (primary biliary cholangitis, and primary sclerosing cholangitis), vascular (Budd-Chiari syndrome, sinusoidal obstruction syndrome, and cardiac cirrhosis), and metabolic causes (hemochromatosis, NASH, Wilson disease, alpha-1 antitrypsin deficiency, cryptogenic cirrhosis). Aim of the Work The aim of the current study is to detect Minimal Hepatic Encephalopathy (MHE) among cirrhotic patients of Child C with no or clinically manifest encephalopathy using Brain-Derived Neurotrophic Factor (BDNF) and study the diagnostic value of BDNF serum marker versus Psychometric Hepatic Encephalopathy Score (PHES) in detecting MHE. Patients and Methods 90 patients were enrolled into a clinical cross-sectional study. All patients gave informed written consent. Patients are divided equally into 3 groups, 30 patients each. Patients are either in-patient or out-patients in Ain shams University Hospitals. Group 1 The Examined Group (EG): includes 30 patients diagnosed as hepatitis C, cirrhotic, Child class C with no overt or clinically manifest encephalopathy. Group 2 The Hepatic Encephalopathy Group (HEG): includes 30 patients diagnosed as hepatitis C, cirrhotic, Child class C with overt or clinically manifest encephalopathy. Group 3 The Control Group (CG): includes 30 healthy individuals (volunteers). Results In the present study among the whole sample (n = 90), there was a significant positive correlation between PHES score &amp; BDNF serum level with Hb, platelet count and albumin. While, there was a significant negative correlation between PHES score and BDNF serum level with AST, ALT, total bilirubin, direct bilirubin, INR and Child’s Score. On the other hand, Stawicka et al. 2021, reported that BDNF had a negative correlation with bilirubin (R = –0.35, p = 0.005) and international normalized ratio (INR) (R = –0.37, p = 0.003), and positive with platelets (R = 0.36, p = 0.004), while no associations with age, sex, body mass index (BMI), waist-hip ratio (WHR), creatinine and ammonia. Conclusion MHE constitutes a significant medical problem in a common patient population. Unfortunately, it is often underdiagnosed, likely related to the notion that testing is time consuming requiring highly specialized personnel. Additionally, the term ‘MHE’ may create the impression that this condition has limited impact on patient’s wellbeing; however, it has been shown that MHE has clinical implications on the patient as well as public safety concerns. Diagnosing and treating MHE is difficult owing to the subclinical nature of the disease. The use of Psychometric Hepatic Encephalopathy Score (PHES) and Brain-Derived Neurotrophic Factor could be of great help in early detection of the condition and to give suitable preventive treatment.

Analysis of clinical and genetic characteristics of the severe liver disease phenotype in patients with hepatolenticular degeneration

Objective: To investigate the clinical and genetic characteristics and predictive role of the severe liver disease phenotype in patients with hepatolenticular degeneration (HLD). Methods: Inpatients with HLD confirmed at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine from January 1989 to December 2022 were selected as the research subjects. Clinical classification was performed according to the affected organs. Patients with liver disease phenotypes were classified into the liver disease group and further divided into the severe liver disease group and the ordinary liver disease group. The clinical characteristics and genetic variations were compared in each group of patients. The predictive indicators of patients with severe liver disease were analyzed by multiple regression. Statistical analysis was performed using the t-test, Mann-Whitney U test, or χ(2) test according to different data. Results: Of the 159 HLD cases, 142 were in the liver disease group (34 in the severe liver disease group and 108 in the ordinary liver disease group), and 17 were in the encephalopathy group. The median age of onset was statistically significantly different between the liver disease group and the encephalopathy group [12.6 (7.0, 13.3) years versus 16.9 (11.0, 21.5) years, P<0.01]. 156 ATP7B gene mutation sites were found in 83 cases with genetic testing results, of which 54 cases carried the p.Arg778Leu gene mutation (allele frequency 46.2%). Compared with patients with other types of gene mutations (n=65), patients with homozygous p.Arg778Leu mutations (n=18) had lower blood ceruloplasmin and albumin levels, a higher prognostic index, Child-Pugh score, an international normalized ratio, and prothrombin time (P<0.05). Hemolytic anemia, corneal K-F ring, homozygous p.Arg778Leu mutation, and multiple laboratory indexes in the severe liver disease group were statistically significantly different from those in the ordinary liver disease group (P<0.05). Multivariate logistic regression analysis showed that the predictive factors for severe liver disease were homozygous p.Arg778Leu mutation, total bilirubin, and bile acids (ORs=16.512, 1.022, 1.021, 95% CI: 1.204-226.425, 1.005-1.039, and 1.006-1.037, respectively, P<0.05). The drawn ROC curve demonstrated a cutoff value of 0.215 3, an AUC of 0.953 2, and sensitivity and specificity of 90.91% and 92.42%, respectively. Conclusion: Liver disease phenotypes are common in HLD patients and have an early onset. Total bilirubin, bile acids, and the homozygous p.Arg778Leu mutation of ATP7B is related to the severity of liver disease in HLD patients, which aids in predicting the occurrence and risk of severe liver disease.

History of Depression is Associated With Higher Prevalence of Hepatic Encephalopathy in Patients With Advanced Liver Disease

BackgroundDepression and hepatic encephalopathy are common in patients with advanced liver disease. Although these are distinct entities, they share several clinical features. In this analysis, we evaluated whether having a history of depression was associated with developing hepatic encephalopathy in patients with advanced liver disease. MethodsWe performed a retrospective cohort study of patients with cirrhosis referred for liver transplant. Patients were categorized into 1 of 2 groups: “history of depression” or “no history of depression.” Multivariable logistic regression was used to evaluate history of depression as a potential independent predictor of hepatic encephalopathy. ResultsA total of 447 patients were included, of which 158 (35%) had a history of depression and 233 (52%) had experienced hepatic encephalopathy. Hepatic encephalopathy was more common in patients with a history of depression (63% vs 46%, P < .01). On multivariate analyses, depression history was independently associated with hepatic encephalopathy (aOR 2.3, 95% CI 1.4-3.6), along with alcohol associated cirrhosis (aOR 2.0, 95% CI 1.3-3.2), history of ascites (aOR 3.5, 95% CI 2.1-5.9) and presence of a trans-jugular intra-hepatic shunt (aOR 9.2, 95% CI 2.6-32.6). The relationship between history of depression and hepatic encephalopathy remained significant in a subgroup of patients with alcohol associated liver disease (P = .04). Among those with a history of depression, SNRI prescription was more common in the hepatic encephalopathy group (14% vs 3%), and SNRI prescription was as an independent predictor of hepatic encephalopathy in the multivariable model (OR 4.8, 95% CI 1.0-24.6) ConclusionsPatients with a history of depression were significantly more likely to experience hepatic encephalopathy. Patients with cirrhosis who have a history of depression should be closely monitored for the development of hepatic encephalopathy. Further research is needed to understand the nuances of this relationship and whether the use of certain psychiatric medications may modify the relationship between depression and hepatic encephalopathy.

Predicting factors for acute encephalopathy in febrile seizure children with SARS-CoV-2 omicron variant: a retrospective study

BackgroundSARS-CoV-2 posed a threat to children during the early phase of Omicron wave because many patients presented with febrile seizures. The study aimed to investigate predicting factors for acute encephalopathy of children infected by SARS-CoV-2 Omicron variant presenting with febrile seizures.MethodsThe retrospective study analyzed data from pediatric patients who visited the emergency department of Chang Gung Memorial Hospital in Taiwan between April and July 2022. We specifically focused on children with COVID-19 who presented with febrile seizures, collecting demographic, clinical, and laboratory data at the pediatric emergency department, as well as final discharge diagnoses. Subsequently, we conducted a comparative analysis of the clinical and laboratory characteristics between patients diagnosed with acute encephalopathy and those with other causes of febrile seizures.ResultsOverall, 10,878 children were included, of which 260 patients presented with febrile seizures. Among them, 116 individuals tested positive for SARS-CoV-2 and of them, 14 subsequently developed acute encephalopathy (12%). Those with acute encephalopathy displayed distinctive features, including older age (5.1 vs. 2.6 years old), longer fever duration preceding the first seizure (1.6 vs. 0.9 days), cluster seizure (50% vs. 16.7%), status epilepticus (50% vs. 13.7%) and occurrences of bradycardia (26.8% vs. 0%) and hypotension (14.3% vs. 0%) in the encephalopathy group. Besides, the laboratory findings in the encephalopathy group are characterized by hyperglycemia (mean (95% CI) 146 mg/dL (95% CI 109–157) vs. 108 mg/dL (95% CI 103–114) and metabolic acidosis (mean (95% CI) pH 7.29(95% CI 7.22–7.36) vs. 7.39 (95%CI 7.37–7.41)).ConclusionsIn pediatric patients with COVID-19-related febrile seizures, the occurrence of seizures beyond the first day of fever, bradycardia, clustered seizures, status epilepticus, hyperglycemia, and metabolic acidosis should raise concerns about acute encephalitis/encephalopathy. However, the highest body temperature and the severity of leukocytosis or C-reactive protein levels were not associated with poor outcomes.

Bone Marrow Nucleated Cells and Bone Marrow-Derived CD271+ Mesenchymal Stem Cell in Treatment of Encephalopathy and Drug-Resistant Epilepsy.

The broad spectrum of brain injuries in preterm newborns and the plasticity of the central nervous system prompts us to seek solutions for neurodegeneration to prevent the consequences of prematurity and perinatal problems. The study aimed to evaluate the safety and efficacy of the implantation of autologous bone marrow nucleated cells and bone marrow mesenchymal stem cells in different schemes in patients with hypoxic-ischemic encephalopathy and immunological encephalopathy. Fourteen patients received single implantation of bone marrow nucleated cells administered intrathecally and intravenously, followed by multiple rounds of bone marrow mesenchymal stem cells implanted intrathecally, and five patients were treated only with repeated rounds of bone marrow mesenchymal stem cells. Seizure outcomes improved in most cases, including fewer seizures and status epilepticus and reduced doses of antiepileptic drugs compared to the period before treatment. The neuropsychological improvement was more frequent in patients with hypoxic-ischemic encephalopathy than in the immunological encephalopathy group. Changes in emotional functioning occurred with similar frequency in both groups of patients. In the hypoxic-ischemic encephalopathy group, motor improvement was observed in all patients and the majority in the immunological encephalopathy group. The treatment had manageable toxicity, mainly mild to moderate early-onset adverse events. The treatment was generally safe in the 4-year follow-up period, and the effects of the therapy were maintained after its termination.

Remodeling of extracranial veins and venous-arterial imbalance in extrinsic stenosis and hypoplasia of the internal jugular veins

The aim of the study was to compare hemodynamic parameters, the sequence of remodeling of the jugular and extrajugular outflow tracts of cerebral venous circulation in extrinsic stenosis and hypoplasia of the internal jugular vein (IJV). Material and methods. Groups with external compression and IJV stenosis (n = 50), with IJV hypoplasia (n = 27), and after IJV ligation/resection (n = 6) as a model of IJV occlusion with a minimal cerebral venous insufficiency and venous encephalopathy and control group (n = 31) were compared. All patients underwent a neurological examination, ultrasound duplex scanning of the IJV (J2 and at the level of stenosis), common carotid and vertebral artery (V2), 2DToF or 3DToF magnetic resonance venography of the neck veins. The degree of stenosis of the IJV, the crosssectional area and the time average blood flow velocity, the calculated indicator of the venous-arterial balance (VAB) were determined according to the modified formula. Results and discussion. In the group of external compression of the IJV, stenosis averaged 64.52 %. The area of the IJV at the site of stenosis was 6 times, and at the standard place (J2) – 3 times less than the area of the opposite IJV. The hypoplastic IJV throughout its entire length (from J1 to J3) had the same area (0.21 ± 0.12 cm2 ), smooth contours, without local expansions or narrowings. A very low blood flow velocity (10.2 ± 11.67 cm/s) is characteristic for stenosis, in contrast to the normal velocity in the hypoplastic vein and in the control group. The blood flow velocity in the contralateral IJV with external stenosis does not differ from normal, but it is increased with hypoplasia (34.62 ± 12.23 cm/s). With MR venography, it is possible to detect a stenosing factor, symptoms of a filling defect, a decrease or loss of a blood flow signal, and an assessment of the overall picture of remodeling of the venous network of the neck. A decrease in the IJV area on the side of the lesion/anomaly corresponds to negative remodeling, while an expansion of the opposite IJV corresponds to positive remodeling. If the obstruction persists, the homolateral, then the contralateral external jugular vein expands, then the vertebral veins and plexuses, spinal epidural veins, anterior jugular and posterior cervical veins expand too. The magnitude of the IJV on the side of the anomaly/pathology with hypoplasia did not differ from the value with stenosis (9 %), but was slightly less than on the opposite IJV (53.39 ± 13.40 and 67.24 ± 18.02 %, respectively, p &lt; 0.06) and significantly less compared to the control (24.16 ± 8.06 % on the left and 33.15 ± 8.27 % on the right, p &lt; 0.0001), which makes this indicator a good additional criterion for outflow abnormality according to the IJV of one side.

Clinicobiochemical Profile and Outcome of Children with Small Molecule Neurometabolic Disorders: A Tertiary Care Hospital Experience from India

AbstractInborn Errors of Metabolism (IEM), though heterogenous, are not uncommon. Neurologic manifestations predominate. Without universal newborn screening, early diagnosis and treatment may lessen neuromorbidity. Hence, this study was done to understand small molecule neurometabolic disorders' presentation, diagnostic clues, and outcome.Small molecule neurometabolic disorder was diagnosed in 45 children (postneonatal onset) over 14 years (2008–2022) in a tertiary care hospital. Clinical and laboratory data were retrospectively analyzed.There were 26 boys and 19 girls. The median age at diagnosis was 19 months (interquartile range [IQR] 8–38 months). The median diagnostic delay was 12 months in chronic encephalopathy (IQR 1–24 months) and 1 month (IQR 0.2–5.5 months) in the acute encephalopathy group (p ≤ 0.01). The presentation mode was chronic encephalopathy/myopathy in 29 (64.4%) and acute encephalopathy in 11 (24.4%). Diagnostic clues included unexplained developmental delay (n = 27, 60%), tone abnormalities (n = 26, 57.7%), movement disorder and ataxia (n = 16, 35.5%), acute encephalopathy (n = 11, 24.4%), neuroregression (n = 10, 22.2%), macrocephaly (n = 10, 22.2%), and alopecia (n = 4, 8.9%). Diagnostic/suggestive blood-spot tandem mass spectrometry (TMS) was seen in 34/38 (89.5%) children. Neuroimaging helped clinch the diagnosis in 17 (47%) children. Diagnostic categories were organic acidemias (n = 25, 55.6%), urea cycle disorders (n = 11, 24.4%), aminoacidopathies (n = 5, 11.1%), and fatty acid oxidation disorders (n = 4, 8.9%). The neurodevelopmental outcome was normal in 13 (28.8%), mild delay in 12 (26.6%), severe delay in 11 (24.4%), 3 deaths (6.6%), and 6 (13.3%) children being lost to follow-up. Overall, the outcome was favorable in 55% of cases.Unexplained developmental delay with tone abnormalities with or without movement disorders is a joint presentation of late-onset neurometabolic diseases. Neuroimaging studies and laboratory tests like blood-spot TMS help identify many small molecule disorders.

Artificial Intelligence-Enabled Stool Analysis for Lactulose Titration Assistance in Hepatic Encephalopathy Through a Smartphone Application.

Management of hepatic encephalopathy relies on self-titration of lactulose. In this feasibility trial, we assess an artificial intelligence-enabled tool to guide lactulose use through a smartphone application. Subjects with hepatic encephalopathy on lactulose captured bowel movement pictures during lead-in and intervention phases. During the intervention phase, daily feedback on lactulose titration was delivered through the application. Goals were determined according to number of bowel movement and Bristol Stool Scale reports. Subjects completed the study with more than 80% satisfaction. In the lead-in phase, less compliant subjects achieved Bristol Stool Scale goal on 62/111 (56%) of days compared with 107/136 (79%) in the intervention phase ( P = 0.041), while the most compliant subjects showed no difference. Severe/recurrent hepatic encephalopathy group achieved Bristol Stool Scale goal on 80/104 (77%) days in the lead-in phase and 90/110 (82%) days in the intervention phase ( P = NS), compared with 89/143 (62%) days and 86/127 (68%) days in the stable group. Dieta application is a promising tool for objective Bowel Movement/Bristol Stool Scale tracking for hepatic encephalopathy and may potentially be used to assist with lactulose titration.

INTERRELATIONSHIP BETWEEN INDICATORS OF LOCAL AND SYSTEMIC INFLAMMATORY REACTION IN NEWBORNS WITH NEONATAL ENCEPHALOPATHY

Introduction. Neonatal encephalopathy is one of the most common diseases in newborns. Several factors influence the development of neonatal encephalopathy including adverse obstetric history, fetal distress, meconium-containing amniotic fluid and cesarean section. In moderate and severe neonatal encephalopathy, damage to internal organs, local and systemic inflammation may occur. Cytokines, which are activated in the central nervous system and released in response to its damage, play an important role in brain inflammation caused by neonatal encephalopathy. C-reactive protein is also a possible biomarker of neonatal encephalopathy severity, being considered a protein of the innate immune system with anti-inflammatory properties. The state of the inflammatory response can be influenced by a local inflammatory reaction, as a result of which children with neonatal encephalopathy have been shown to have increased levels of fecal calprotectin in the first weeks of life. Also, one of the results of the transferred inflammatory reaction is a change in the composition of the neonatal intestinal microbiome. Objective. To study risk factors for neonatal encephalopathy in newborns, the features of the relationship between local and systemic inflammatory response parameters in asphyxia of varying degrees, and the features of severity and control of inflammatory response parameters. Materials and methods. The study was conducted in 119 full-term newborns, of which 87 children had neonatal encephalopathy and 32 healthy children. To determine the features of severity and control of inflammatory response parameters, group A was identified, which included 60 newborns, 46 of them with moderate neonatal encephalopathy, 14 with severe neonatal encephalopathy. The study was conducted using a culture method to determine the composition of the intestinal microbiome in feces. Using a semi-automated Thermo Scientific Multiskan FC enzyme immunoassay analyzer, the level of fecal calprotectin in feces and C-reactive protein and interleukins 1β and 10 in the blood serum were estimated by the enzyme immunoassay. The results were analyzed using SPSS version 28.0. The correlation between the parameters was analyzed using the Pearson correlation coefficient. The odds ratio was used to quantitatively describe the closeness of the relationship between the features in the statistical population. Binary logistic regression was used to determine the dependencies of the severity of the inflammatory reaction and create a model for calculating its severity. Results. Risk factors for neonatal encephalopathy included mother’s acute respiratory infections and fetal distress. Bifidobacterium levels were positively correlated throughout the study, and there was also a relationship with lactobacilli in the control and non-probiotic treated neonatal encephalopathy groups. E. coli values were positively associated with opportunistic pathogens in the control and probiotic treated groups. Fecal calprotectin was negatively correlated with birth weight and height, Apgar scores, and gestational age. Fecal calprotectin levels were positively correlated with E. coli and opportunistic pathogens in healthy neonates. In children with neonatal encephalopathy interleukin 1β and 10 values were positively associated with fecal calprotectin, interleukin 1β were positively correlated with interleukin 10 and C-reactive protein. Conclusions. The most significant risk factors for the development of neonatal encephalopathy are mother’s acute infectious diseases and fetal distress. The severity of hypoxia/asphyxia at birth correlated with the levels of interleukin 1β and 10 at 2 and 5 weeks of life, and Bifidobacterium at 2 weeks of life. The severity of the inflammatory response in the study population was characterized by a change in the level of interleukin 1β and Bifidobacterium at 2 weeks and a change in the level of interleukin 10 at 5 weeks

Long-term effect of indomethacin on a rat model of neonatal hypoxia ischemic encephalopathy through behavioral tests.

Many medical experts prescribe indomethacin because of its anti-inflammatory, analgesic, tocolytic, and duct closure effects. This article presents an evaluation of the enduring impact of indomethacin on neonatal rats with hypoxic-ischemic (HI) insults, employing behavioral tests as a method of assessment. The experiment was conducted on male Wistar-Albino rats weighing 10 to 15 g, aged between seven and 10 days. The rats were divided into three groups using a random allocation method as follows: hypoxic ischemic encephalopathy (HIE) group, HIE treated with indomethacin group (INDO), and Sham group. A left common carotid artery ligation and hypoxia model was applied in both the HIE and INDO groups. The INDO group was treated with 4mg/kg intraperitoneal indomethacin every 24 h for 3days, while the Sham and HIE groups were given dimethylsulfoxide (DMSO). After 72 h, five rats from each group were sacrificed and brain tissue samples were stained with 2,3,5-Triphenyltetrazolium chloride (TCC) for infarct-volume measurement. Seven rats from each group were taken to the behavioral laboratory in the sixth postnatal week (PND42) and six from each group were sacrificed for the Evans blue (EB) experiment for blood-brain barrier (BBB) integrity evaluation. The open field (OF) test and Morris water maze (MWM) tests were performed. After behavioral tests, brain tissue were obtained and stained with TCC to assess the infarct volume. The significant increase in the time spent in the central area and the frequency of crossing to the center in the INDO group compared with the HIE group indicated that indomethacin decreased anxiety-like behavior (p < 0.001, p < 0.05). However, the MWM test revealed that indomethacin did not positively affect learning and memory performance (p > 0.05). Additionally, indomethacin significantly reduced infarct volume and neuropathological grading in adolescence (p < 0.05), although not statistically significant in the early period. Moreover, the EB experiment demonstrated that indomethacin effectively increased BBB integrity (p < 0.05). In this study, we have shown for the first time that indomethacin treatment can reduce levels of anxiety-like behavior and enhance levels of exploratory behavior in a neonatal rat model with HIE. It is necessary to determine whether nonsteroidal anti-inflammatory agents, such as indomethacin, should be used for adjuvant therapy in newborns with HIE.

SCN8A epileptic encephalopathy: literature review and own observation

A genetic disease caused by pathogenetic nucleotide variants in the SCN8A gene (Sodium channel protein type 8 subunit alpha, also known as Nav1.6), encoding the α-subunit of the Na channel type 8, is included in the group of early epileptic encephalopathies. In most cases, this pathology is characterized by the development of polymorphic pharmacoresistant epileptic seizures over the first year of a child’s life, a lag in psychomotor development or regression, loss of skills. In some patients, seizures may appear during the first days of life, while in others they appear later (at the age of 2 to 7 months), against the background of a pronounced or slight developmental delay. Types of seizures may include generalized, tonic-clonic seizures, infantile spasms, absences and focal seizures. Other signs and symptoms of encephalopathy caused by mutations of the SCN8A gene may include low muscle tone (hypotension), high pain threshold, motor disorders (such as dystonia and ataxia), mild to severe mental retardation, sleep problems and autistic traits. In some people with SCN8A encephalopathy, various other pathological changes in the body have been reported, including hearing or vision impairment, scoliosis, and thermoregulation difficulties. The disease is inherited by an autosomal dominant type.&#x0D; To date, the disease in the OMIM system is referred to as «Developmental encephalopathy and epileptic encephalopathy type 13». Previously, the disease was called «Early infantile (infantile) epileptic encephalopathy, type 13». The serial number «13» indicates this form of early epileptic encephalopathy to be caused by a heterozygous mutation in the gene on the long arm of chromosome 12 in chromosome region 12q13.13.&#x0D; This report also presents a clinical description of a patient suffering from early infantile epileptic encephalopathy, type 13.

Inducing prion protein shedding as a neuroprotective and regenerative approach in pathological conditions of the brain: from theory to facts.

In the last decades, the role of the prion protein (PrP) in neurodegenerative diseases has been intensively investigated, initially in prion diseases of humans (e.g., Creutzfeldt-Jakob disease) and animals (e.g., scrapie in sheep, chronic wasting disease in deer and elk, or "mad cow disease" in cattle). Templated misfolding of physiological cellular prion protein (PrPC) into an aggregation-prone isoform (termed PrP "Scrapie" (PrPSc)), self-replication and spreading of the latter inside the brain and to peripheral tissues, and the associated formation of infectious proteopathic seeds (termed "prions") are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies. Later, key roles of the correctly folded PrPC were identified in more common human brain diseases (such as Alzheimer's disease or Parkinson's disease) associated with the misfolding and/or accumulation of other proteins (such as amyloid-β, tau or α-synuclein, respectively). PrPC has also been linked with neuroprotective and regenerative functions, for instance in hypoxic/ischemic conditions such as stroke. However, despite a mixed "bouquet" of suggested functions, our understanding of pathological and, especially, physiological roles played by PrPC in the brain and beyond is certainly incomplete. Interactions with various other proteins at the cell surface or within intracellular compartments may account for the functional diversity linked with PrPC. Moreover, conserved endogenous proteolytic processing of PrPC generates several defined PrPC fragments, possibly holding intrinsic functions in physiological and pathological conditions, thus making the "true and complete biology" of this protein more complicated to be elucidated. Here, we focus on one of those released PrPC fragments, namely shed PrP (sPrP), generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surface. Similar to other soluble PrPC fragments (such as the N1 fragment representing PrP's released N-terminal tail upon the major α-cleavage event) or experimentally employed recombinant PrP, sPrP is being suggested to act neuroprotective in Alzheimer's disease and other protein misfolding diseases. Several lines of evidence on extracellular PrPC (fragments) suggest that induction of PrPC release could be a future therapeutic option in various brain disorders. Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM10, based on ligands binding to cell surface PrPC, may further set the stage for research into this direction.

Iatrogenic encephalopathies are not so rare in psychiatry: A retrospective study about 5217 EEG examinations

ObjectivesEncephalopathy is a severe pathological process induced by multiple factors, which is typically associated with electroencephalogram (EEG) abnormalities. Early diagnosis, management, and treatment improve the patient's prognosis. Psychotropic treatments are a risk for drug-induced encephalopathies. In this study, the prevalence of encephalopathies in a psychiatric hospital has been studied for 5 years (2012 to 2016) using 5217 EEG records. MethodsEEGs were performed i) systematically on patient admission, ii) in response to inexplicable modifications of consciousness or behavior, or when metabolic anomalies occurred, and iii) to perform therapeutic monitoring in outpatient consultations. When encephalopathy was suspected, the clinical data (age, sex and concomitant treatment) and biological data (plasma levels of medications) were collected. ResultsEncephalopathy was suspected in 189 patients. Following EEG examination, and monitoring of clinical course, encephalopathy was subsequently determined to be highly probable for 52 patients, (giving a prevalence of 1% per year), and low suspicion of encephalopathy in the other 137 patients. The suspicion of encephalopathy was made on both clinical (n=28) and non-clinical (n=24) signs. Involved drugs were mainly valproic acid (n=14), lithium (n=11) and clozapine (n=11) in the highly probable encephalopathy group. ConclusionsOur study demonstrates the importance of EEG in the diagnosis and monitoring of encephalopathies in a psychiatric hospital. Clinical symptoms of encephalopathies are polymorphic and sometimes atypical. This diagnosis is underestimated in a context where behavior or consciousness disorders are generally not attributed to psychotropic drugs used in psychiatry.

Generation of an iPSC line (FINi001-A) from a girl with developmental and epileptic encephalopathy due to a heterozygous gain-of-function p.R1882Q variant in the voltage-gated sodium channel Nav1.2 protein encoded by the SCN2A gene

A range of epilepsies, including the most severe group of developmental and epileptic encephalopathies (DEEs), are caused by gain-of-function variants in voltage-gated channels. Here we report the generation and characterisation of an iPSC cell line from the fibroblasts of a girl with early infantile DEE carrying heterozygous missense gain-of-function mutation (R1882Q) in Nav1.2(SCN2A) protein, using transient transfection with a single mRNA molecule. The established iPSC line displays typical human primed pluripotent stem cell characteristics: typical colony morphology and robust expression of pluripotency-associated marker genes, ability to give rise to derivatives of all three embryonic germ layers, and normal karyotype without any SNP array-detectable copy number variations. We anticipate that this iPSC line will be useful for the development of neuronal hyperactivity-caused human stem cell-based DEE models, advancing both understanding and potential therapy development for this debilitating condition.

Clinical characteristics and short-term prognosis of 22 cases with SARS-CoV-2 infection associated acute encephalopathy

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.

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.

Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

Diagnostics Value of Quantitative Magnetic Resonance Imaging (MRI) in Neonatal Acute Bilirubin Encephalopathy.

Background: This study was designed to investigate the diagnostic value of relative signal intensity of globus pallidus on T1-weighted magnetic resonance imaging (MRI) in neonatal acute bilirubin encephalopathy (ABE). Methods: Participants who were recruited in hospital from April 2019 to May 2020 were grouped into mildly increased total serum bilirubin (TSB) group (n = 30), severely increased TSB group (n = 25), or extremely increased TSB group (n = 10) based on the total serum bilirubin level. Bilirubin-induced neurologic dysfunction scale score was used to determine if participants had acute bilirubin encephalopathy. All neonates underwent conventional brain MRI and the relative signal intensity of globus pallidus was measured on T1-weighted images. The diagnostic value of these 3 indices was assessed by receiver operating characteristic curve analysis. Results: There was a significant correlation between relative signal intensity of globus pallidus and total serum bilirubin level in neonates with hyperbilirubinemia (r = 0.551, P < .001). Relative signal intensity of globus pallidus in the extremely increased TSB group was significantly higher than that in severely increased TSB, mildly increased TSB, and healthy control groups. Relative signal intensity of globus pallidus in the acute bilirubin encephalopathy group was significantly higher than that in the non-acute bilirubin encephalopathy group (P < .01). The area under the receiver operating characteristic curve of the relative signal intensity of globus pallidus was 0.765 (P < .01), with sensitivity of 0.655 and specificity of 0.861. The area under the curve of the total serum bilirubin and visual inspection of globus pallidus signal was 0.621 and 0.579, respectively. The area under the curve of relative signal intensity was significantly greater than that of total serum bilirubin and visual inspection (P = .04 for both). Conclusion: Relative signal intensity of globus pallidus, which is an objective assessment, has the potential to be used as a diagnostic tool for acute bilirubin encephalopathy.

Severe pediatric acute encephalopathy syndromes related to SARS-CoV-2.

To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group (P < 0.01). Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.