Kernicterus

Early detection and treatment of neonatal hyperbilirubinemia is important in the prevention of bilirubin-induced encephalopathy. In this study, we evaluated the New Jersey pediatricians' practices and beliefs regarding the management of neonatal hyperbilirubinemia and their compliance with the recommendations made by the American Academy of Pediatrics (AAP) in 1994. A survey questionnaire was mailed to a random sample of 800 pediatricians selected from a list of 1623 New Jersey Fellows of the AAP initially in October 2003 and then in February 2004 for the non-respondents. In addition to the physicians' demographic characteristics, the questionnaire addressed various aspects of neonatal hyperbilirubinemia management including the diagnosis, treatment, and follow up as well as the pediatricians' beliefs regarding the significance of risk factors in the development of severe hyperbilirubinemia. The adjusted response rate of 49.1% (n = 356) was calculated from the 725 eligib...

Rhesus haemolytic disease of the newborn can lead to complications such as hyperbilirubinaemia, kernicterus and anaemia. Postnatal management consists mainly of intensive phototherapy, exchange transfusion and blood transfusion. During the last decades, significant progress in prenatal care strategies for patients with Rhesus haemolytic disease has occurred. New prenatal management options have led to a remarkable reduction in perinatal mortality. As a result of the increase in perinatal survival, attention is now shifting towards short-term and long-term morbidity. This review focuses on the management of neonatal and paediatric complications associated with Rhesus haemolytic disease, discusses postnatal treatment options and summarizes the results of studies on short-term and long-term outcome.

aundice is a common and mostly benign condition in neonates but because of the potential toxicity of bilirubin, neonates must be monitored to identify those who might develop severe hyperbilirubinemia and, in rare cases, acute bilirubin encephalopathy or kernicterus. Over 60 percent of term and 80 percent of preterm babies develop clinical jaundice during the first week of life. Clinical jaundice, in neonates appears first on the face at a serum bilirubin concentration of 5 mg per dl in contrast to adults who appear jaundiced when the serum bilirubin is greater than 2 mg per dl.

To characterize discrepancies between transcutaneous bilirubin (TcB) measurements and total serum bilirubin (TSB) levels among newborns receiving care at multiple nursery sites across the United States. Medical records were reviewed to obtain data on all TcB measurements collected during two 2-week periods on neonates admitted to participating newborn nurseries. Data on TSB levels obtained within 2 hours of a TcB measurement were also abstracted. TcB - TSB differences and correlations between the values were determined. Data on demographic information for individual newborns and TcB screening practices for each nursery were also collected. Multivariate regression analysis was used to identify characteristics independently associated with the TcB - TSB difference. Data on 8319 TcB measurements were collected at 27 nursery sites; 925 TSB levels were matched to a TcB value. The mean TcB - TSB difference was 0.84 ± 1.78 mg/dL, and the correlation between paired measurements was 0.78. In...

Neonatal jaundice is the occurrence of elevated bilirubin levels in the blood. It may be physiological or pathological. If the concentration of non-conjugated bilirubin in the blood is too high, it breaches the blood brain barrier and bilirubin encephalopathy occurs with serious consequences for the child. The aim of the research was to examine the incidence frequency of unconjugated pathologic jaundice in newborns and connect it to some epidemiological variations (medical, social, demographic) as well as to prove the increased frequency of jaundice in children born by stimulation and labour induction. The study included 800 infants: 198 (24.8%) of them did, and 602 (75.2%) did not suffer from jaundice. Statistical analysis confirmed the association between the onset of jaundice in newborns and the following parameters: gestational age, birth weight, maternal infections and other illnesses during pregnancy and premature rupture of membranes as complications during labor and the mode...

Revised concepts of bilirubin encephalopathy have been revealed by studies of bilirubin toxicity in cultured CNS cells and in congenitally jaundiced Gunn rats. Bilirubin neurotoxicity is related to the unbound (free) fraction of unconjugated bilirubin (Bf), of which the dominant species at physiological pH is the protonated diacid, which can passively diffuse across cell membranes. As the binding affinity of plasma albumin for bilirubin decreases strikingly as albumin concentration increases, previously reported Bf values were underestimated. Newer diagnostic tests can detect reversible neurotoxicity before permanent damage occurs from precipitation of bilirubin (kernicterus). Early toxicity can occur at Bf only modestly above aqueous saturation and affects astrocytes and neurons, causing mitochondrial damage, resulting in impaired energy metabolism and apoptosis, plus cell-membrane perturbation, which causes enzyme leakage and hampers transport of neurotransmitters. The concentrations of unbound bilirubin in the cerebro-spinal fluid and CNS cells are probably limited mainly by active export of bilirubin back into plasma, mediated by ABC transporters present in the brain capillary endothelium and choroid plexus epithelium. Intracellular bilirubin levels may be diminished also by oxidation, conjugation and binding to cytosolic proteins. These new concepts may explain the varied susceptibility of neonates to develop encephalopathy at any given plasma bilirubin level and the selective distribution of CNS lesions in bilirubin encephalopathy. They also can suggest better strategies for predicting, preventing and treating this syndrome.

Preterm neonates with increased bilirubin production loads are more likely to sustain adverse outcomes due to either neurotoxicity or overtreatment with phototherapy and/or exchange transfusion. Clinicians should rely on expert consensus opinions to guide timely and effective interventions until there is better evidence to refine bilirubin-induced neurologic dysfunction or benefits of bilirubin. In this article, we review the evolving evidence for bilirubin-induced brain injury in preterm infants and highlight the clinical approaches that minimize the risk of bilirubin neurotoxicity.

Crigler-Najjar syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by a deficiency of uridine diphospho-glucuronosyl transferase 1A1. Current therapy relies on phototherapy to prevent kernicterus, but liver transplantation presently is the only permanent cure. Gene therapy is a potential alternative, and recent work has shown that helper-dependent adenoviral (HD-Ad) vectors, devoid of all viral coding sequences, induce prolonged transgene expression and exhibit significantly less chronic toxicity than early-generation Ad vectors. We used a HD-Ad vector to achieve liver-restricted expression of human uridine diphospho-glucuronosyl transferase 1A1 in the Gunn rat, a model of the human disorder. Total plasma bilirubin levels were reduced from >5.0 mg/dl to <<1.4 mg/dl for >2 yr after a single i.v. administration of vector expressing the therapeutic transgene at a dose of 3 x 10(12) viral particles per kg. HPLC analysis of bile from treated rats showed the presence of bilirubin glucuronides at normal WT levels >2 yr after one injection of vector, and i.v. injection of bilirubins IIIalpha and XIIIalpha in the same animals revealed excess bilirubin-conjugating capacity. There was no significant elevation of liver enzymes (alanine aminotransferase) and only transient, moderate thrombocytopenia after injection of the vector. A clinically significant reduction in serum bilirubin was observed with a dose as low as 6 x 10(11) viral particles per kg. We conclude that complete, long-term correction of hyperbilirubinemia in the Gunn rat model of Crigler-Najjar syndrome can be achieved with one injection of HD-Ad vector and negligible chronic toxicity.

Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. The lack of a monogenetic source for this risk of bilirubin neurotoxicity suggests that disease progression is dependent upon an overall decrease in the functionality of one or more essential genetically controlled metabolic pathways. In other words, a "load" is placed on key pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load (PGL) that affects the response to a specific insult has been previously reported as a PGL score. We hypothesize that the PGL score can be used to investigate whether increased susceptibility to bilirubin-induced CNS damage in neonates is due to a mutational load being placed on key genetic pathways important to the central nervous system's response to bilirubin neurotoxicity. We propose a modification of the PGL score method that replaces the use of a canonical pathway with custom gene lists organized into three tiers with descending levels of evidence combined with the utilization of single nucleotide polymorphism (SNP) causality prediction methods. The PGL score has the potential to explain the genetic background of complex bilirubin induced neurological disorders (BIND) such as kernicterus and could be the key to understanding ranges of outcome severity in complex diseases. We anticipate that this method could be useful for improving the care of jaundiced newborns through its use as an at-risk screen. Importantly, this method would also be useful in uncovering basic knowledge about this and other polygenetic diseases whose genetic source is difficult to discern through traditional means such as a genome-wide association study.

Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood–brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction.

To characterize discrepancies between transcutaneous bilirubin (TcB) measurements and total serum bilirubin (TSB) levels among newborns receiving care at multiple nursery sites across the United States. Medical records were reviewed to obtain data on all TcB measurements collected during two 2-week periods on neonates admitted to participating newborn nurseries. Data on TSB levels obtained within 2 hours of a TcB measurement were also abstracted. TcB - TSB differences and correlations between the values were determined. Data on demographic information for individual newborns and TcB screening practices for each nursery were also collected. Multivariate regression analysis was used to identify characteristics independently associated with the TcB - TSB difference. Data on 8319 TcB measurements were collected at 27 nursery sites; 925 TSB levels were matched to a TcB value. The mean TcB - TSB difference was 0.84 ± 1.78 mg/dL, and the correlation between paired measurements was 0.78. In...

Objective. We report serial magnetic resonance (MR) and sonographic behavior of globus pallidus in 5 preterm and 3 term infants with kernicterus and describe the clinical context in very low birth weight preterm infants. On the basis of this information, we suggest means of diagnosis and prevention. Methods. Charts and MR and ultrasound images of 5 preterm infants and 3 term infants with suspected bilirubin-associated brain damage were reviewed. Included were preterm infants with severe hearing loss, quadriplegic hypertonia, and abnormal hypersignal of globus pallidus on T2-weighted MR imaging (MRI). In 1 infant who died on day 150, the diagnosis was confirmed during the neonatal period. The others were picked up as outpatients and scanned at 12 or 22 months’ corrected age. Three instances of term kernicterus were included for comparison of serial MRI in the neonatal period and early infancy: they were caused by glucose-6-phosphate dehydrogenase deficiency, urosepsis, and dehydratio...

To identify the predictors of repeat exchange transfusion among infants with severe hyperbilirubinemia. Retrospective cross-sectional study. A referral children&amp;amp;amp;amp;amp;#39;s hospital in inner-city Lagos, Nigeria. Infants who received exchange transfusion for severe hyperbilirubinemia from January 2012 to December 2014. None. The predictors of repeat exchange transfusion were identified among all infants who had at least one exchange transfusion using multivariable logistic regression. A total of 352 infants with mean peak total serum bilirubin of 26.32 ± 7.96 mg/dL received exchange transfusion; of these, 49 (13.9%) with mean peak total serum bilirubin of 32.85 ± 10.54 mg/dL had repeat exchange transfusion. More than two thirds of infants who received exchange transfusion and repeat exchange transfusion were male, and at least one third had ABO incompatibility. No infant had more than two exchange transfusions. The mean age of admission was approximately 5 days (range, 1-14 d). Peak total serum bilirubin greater than or equal to 30 mg/dL (odds ratio, 2.88; 95% CI, 1.46-5.70) and acute bilirubin encephalopathy (odds ratio, 2.37; 95% CI, 1.18-4.77) were predictive of repeat exchange transfusion. Acute bilirubin encephalopathy and excessive total serum bilirubin levels at least 30 mg/dL are predictive of repeat exchange transfusion. A risk assessment framework that combines total serum bilirubin levels, acute bilirubin encephalopathy status, and risk factors of neurotoxicity should be considered for the timely detection and monitoring of infants at risk of repeat exchange transfusion.