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PubMed1997

Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect.

Gilbert syndrome is a common genetic disorder associated with mild unconjugated hyperbilirubinemia and no clinical illness. In contrast, Crigler-Najjar syndrome types I and II are rare genetic disorders associated with severe unconjugated hyperbilirubinemia and a life-long risk of kernicterus. Patients with Gilbert syndrome have low levels of a normal form of uridinediphosphoglucuronate glucuronosyltransferase because of a defect in the promoter region of both alleles, whereas patients with Crigler-Najjar syndrome are homozygous for a defect that yields an abnormal form of the enzyme that has limited or no activity. This case report describes a young adult with Crigler-Najjar syndrome type II in whom kernicterus developed after a laparoscopic cholecystectomy. The development of kernicterus was the result of a largely preventable series of events that lead to an increase in the free fraction of his serum bilirubin. Analysis of his genetic defect showed that he was homozygous for the mutation associated with Gilbert syndrome and heterozygous for a second mutation in the open reading frame of one allele of the bilirubin uridinediphosphoglucuronate glucuronosyltransferase gene. The combined defect leads to severe hyperbilirubinemia and shows how seemingly benign genetic defects, when combined, can cause serious clinical disease.

Adult↗
PubMed2006

Kernicterus in late preterm infants cared for as term healthy infants.

OBJECTIVE: To compare the clinical profile and health care experiences related to management of newborn jaundice and hyperbilirubinemia in preterm infants (<37(0/7) weeks gestation) who are cared for as term infants (> or =37(0/7) weeks) and develop acute and/or chronic posticteric sequelae. METHODS: Retrospective study of a convenient sample of term and near term infants voluntarily reported to the Pilot Kernicterus Registry (1992-2003). Study infants were required to meet the clinical definitions for acute bilirubin encephalopathy (moderate or advanced severity) and/or the classical signs of kernicterus. Main outcome measures were the comparison of etiology, severity and duration of extreme hyperbilirubinemia (TSB levels >20 mg/dL), response to interventions of intensive phototherapy and exchange transfusion, and health care delivery experiences in preterm as compared with term infants. RESULTS: No targeted attention was accorded to preterm infants during their neonatal health care experiences as related to predischarge risk assessment, feeding, discharge follow-up instructions, or breastfeeding, regardless of the known vulnerability of preterm infants to safely transition during the first week after birth. The TSB levels, age at re-hospitalization, and birth weight distribution were similar for late preterm and term infants. Large for gestational age and late preterm infants disproportionately developed kernicterus as compared with those who were appropriate for gestational age and term. Clinical management of extreme of hyperbilirubinemia, by the attending clinical providers, was not impacted or influenced by the gestational age, clinical signs, or risk assessment. This resulted in severe posticteric sequelae which was more severe and frequent in late preterm infants. CONCLUSIONS: Late prematurity (34(0/7) to 36(6/7) weeks) of healthy infants was not recognized as a risk factor for hazardous hyperbilirubinemia by clinical practitioners. Unsuccessful lactation experience was the most frequent experience; being large for gestational age as well as the other known biologic risk factors for hyperbilirubinemia and bilirubin neurotoxicity were not identified by the clinical care providers either before discharge or at immediate postdischarge follow up.

Birth Weight↗
PubMed2002

Kernicterus: an international perspective.

Kernicterus occurs in all parts of the world. The risk is increased in countries where glucose-6-phosphate dehydrogenase-deficiency is common. In the 1990's more case reports of infants who developed kernicterus were published than in the previous decades. A combination of reduced concern for jaundice in newborns, early discharge with inadequate follow-up and a decreased awareness of the signs that may herald serious toxicity may have contributed to the apparent increase in the incidence of kernicterus. Although most jaundiced newborns do not need aggressive evaluation or treatment, physicians who deal with such infants still need to be vigilant. We lack the necessary tools to distinguish infants who may be particularly vulnerable to the effects of bilirubin on the brain from those who may tolerate high serum bilirubin levels without harm. Therefore it is imperative that each infant with significant jaundice be conscientiously evaluated and a plan for testing and, if necessary, therapy be formulated. Transcutaneous measurement of bilirubin is a simple tool that significantly reduces the need for invasive tests. Signs of possible neurotoxicity must never be disregarded or neglected. Any jaundiced infant who shows signs of possible neurotoxicity should receive intensive phototherapy as an emergency procedure while further evaluation continues. Further studies regarding bilirubin toxicity and neonatal jaundice are needed, both in the basic science as well as in the clinical arena.

Aftercare↗
PubMed2003

Kernicterus and G6PD deficiency--a case series from Oman.

The relationship between glucose-6 phosphate dehydrogenase (G6PD) deficiency and jaundice in the newborn period is well recognized. However, there is concern about the increasing incidence of kernicterus being reported worldwide, especially due to unrecognized G6PD deficiency and early discharge from hospital after birth. We report a case series of kernicterus from a set-up where the high prevalence rate of G6PD deficiency is known. Fourteen cases of kernicterus were seen during a time period of 6 years, 71 per cent of them had G6PD deficiency. Recent literature is reviewed and possible preventive measures in the light of current information and practices are suggested.

Female↗
PubMed2006

Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns.

PURPOSE: We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake. METHODS: A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus. RESULTS: There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake. CONCLUSIONS: Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.

Bilirubin↗
PubMed1987

Neonatal bilirubin toxicity. A review of kernicterus and the implications of drug-induced bilirubin displacement.

Kernicterus, the primary manifestation of neonatal bilirubin toxicity, remains an important complication of unconjugated hyperbilirubinaemia despite advances made with phototherapy and exchange transfusions. It results from the penetration of bilirubin into neuronal tissues of the CNS with subsequent damage to the mitochondrion. A number of factors may modify or potentiate bilirubin toxicity, including drugs administered to the infant. The importance of drug-bilirubin interactions in the pathogenesis of kernicterus was first realised quite inadvertently in the 1950s, and the potential risk for significant drug-bilirubin interactions has since become an important consideration in neonatal drug therapy. All drugs intended for use in newborn infants should be evaluated for their capacity to displace bilirubin. A number of techniques have been developed which have facilitated investigation of the mechanisms mediating the bilirubin-displacing effects of drugs and the pharmacokinetics of drug-bilirubin interactions. Further, the clinical risk for inducing kernicterus has been investigated for many of the drugs to which neonates may be exposed by direct administration, transplacentally, or through breast milk. This review summarises the available knowledge concerning the physicochemical properties and toxicities of bilirubin, reviews the methodologies used in evaluating drug-bilirubin interactions, and focuses on the mechanisms, pharmacokinetics and clinical significance of the bilirubin displacing effects of antibiotics, anticonvulsants, diuretics, and other important drug classes used in the treatment of neonates.

Bilirubin↗
PubMed1992

[Clinical study on the prevention of kernicterus caused by hereditary glucose-6-phosphate dehydrogenase deficiency].

A combined preventive scheme was conducted in four hospitals in Guangzhou to lower the rate of kernicterus and mental retardation caused by related neonatal jaundice due to G6PD deficiency. Observation was focused on 330 G6PD deficient infants, and the effects were measured according to the incidence of hyperbilirubinemia and kernicterus. The results, as compared to those of a retrospective study, showed that the incidence of hyperbilirubinemia was significantly decreased (51.4% to 21.2%), and neither kernicterus nor mental retardation infant was found in this series (12.5% in the control group). The authors conclude that this combined scheme is extremely effective and can be used in any large population area in which there is a high gene frequency of G6PD deficiency.

Female↗
PubMed1995

Kernicterus in otherwise healthy, breast-fed term newborns.

OBJECTIVE: To document the occurrence of classical kernicterus in full-term, otherwise healthy, breast-fed infants. METHODS: We reviewed the files of 22 cases referred to us by attorneys throughout the United States during a period of 18 years, in which neonatal hyperbilirubinemia was alleged to be responsible for brain damage in apparently healthy, nonimmunized, full-term infants. To qualify for inclusion, these infants had to be born at 37 or more weeks' gestation, manifest the classic signs of acute bilirubin encephalopathy, and have the typical neurologic sequelae. RESULTS: Six infants, born between 1979 and 1991, met the criteria for inclusion. Their peak recorded bilirubin levels occurred 4 to 10 days after birth and ranged from 39.0 to 49.7 mg/dL. All had one or more exchange transfusions. One infant had an elevated reticulocyte count (9%) but no other evidence of hemolysis. The other infants had no evidence of hemolysis, and no cause was found for the hyperbilirubinemia (other than breast-feeding). CONCLUSIONS: Although very rare, classic kernicterus can occur in apparently healthy, full-term, breast-fed newborns who do not have hemolytic disease or any other discernible cause for their jaundice. Such extreme elevations of bilirubin are rare, and we do not know how often infants with similar serum bilirubin levels escape harm. We also have no reliable method for identifying these infants early in the neonatal period. Closer follow-up after birth and discharge from the hospital might have prevented some of these outcomes, but rare, sporadic cases of kernicterus might not be preventable unless we adopt an approach to follow-up and surveillance of the newborn that is significantly more rigorous than has been practiced. The feasibility, risks, costs, and benefits of this type of intervention need to be determined.

Breast Feeding↗
PubMed1986

Kernicterus in an adult.

A 43-year-old woman was initially seen because of icterus. Clinical investigations revealed severe hepatic damage probably due to non-A, non-B hepatitis. She was treated with extracorporeal charcoal-column perfusion but died two weeks later in a hepatic coma. At autopsy, the brain showed kernicterus with typical discoloration of the hippocampus, the subthalamic nuclei, and the cerebellar dentate nuclei. Kernicterus in an adult is very rare. In this case, extracorporeal charcoal-column perfusion treatment led repeatedly to severe depletion of fibrinogen, with extensive hemorrhages. Overload of the already reduced hepatic glucuronyl-transferase capacity resulted in high serum levels of unconjugated bilirubin, an apparent prerequisite for the development of bilirubin encephalopathy.

Adult↗
PubMed1999

MR findings in a patient with Kernicterus.

We report on a 2.5-year-old boy with severe mental retardation, choreoathetosis, dystonia, muscle rigidity, opisthotonus and severe hearing impairment. He had history of severe hyperbilirubinaemia immediately after birth presumably due to ABO incompatibility. The history and the clinical picture suggested the diagnosis of Kernicterus. The MR imaging examination upon admission revealed bilateral signal intensity increase in the globus pallidum on T2-weighted sequences. Additionally, our patient showed signal intensity changes within the subthalamic nuclei, which is known to be another characteristic area of bilirubin deposition in Kernicterus.

Abnormalities, Multiple↗
PubMed2005

Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin.

The serum total bilirubin concentration at any point in time represents the amount of bilirubin being produced minus that being excreted. Hyperbilirubinemia develops when bilirubin production exceeds the body's capacity to excrete it, primarily by conjugation. When extreme, hyperbilirubinemia may lead to the development of free bilirubin, that form of bilirubin which may cross the blood-brain barrier and enter and damage the basal nuclei of the brain. This rare, though devastating complication, may result in irreversible bilirubin induced brain damage termed kernicterus. In this paper, adjuncts to the interpretation of the serum total bilirubin are discussed, with the purpose of singling out those few neonates in real danger of bilirubin encephalopathy. Interpretation of the serum total bilirubin should be performed in conjunction with factors unique to the particular infant being evaluated. Understanding the mechanisms and dangers of severe neonatal hyperbilirubinemia should facilitate recognition of an emergency situation and optimize the speed with which bilirubin testing is performed and blood for exchange transfusion prepared. Hyperbilirubinemia is a condition of major importance and a source of concern to all involved in the management of the newborn. Its prevention and management should be based on the recently revised American Academy of Pediatric guidelines, with special attention paid to neonates manifesting risk factors for kernicterus. Close cooperation between the clinical laboratory and the medical team managing the newborn is an essential component in the management of a hyperbilirubinemic baby.

Bilirubin↗
PubMed2005

Neurological complications of kernicterus.

OBJECTIVE AND BACKGROUND: Prevention of bilirubin encephalopathy relies on the detection of newborns who are at risk of developing serious hyperbilirubinemia. The objective of this study was to reassess the clinical syndrome of kernicterus as neurodiagnostic studies have become more readily available and can be used to evaluate these infants. METHODS: The study population was neonates born at term or near term admitted to The Hospital for Sick Children in Toronto, Ontario, Canada, between January 1990 and May 2000. During the study period, there were 9776 admissions (average number of admissions per year--888 infants). The inclusion criteria were that patients had total serum bilirubin levels of >400 micromol/L at the time of diagnosis and no evidence of hypoxic ischemic encephalopathy. Records were reviewed to establish neurodevelopment outcomes. RESULTS: Twelve neonates (nine males) were identified. Bilirubin levels at the time of diagnosis ranged from 405 to 825 micromol/L. Causes of these elevated levels included glucose-6-phosphate dehydrogenase deficiency (seven patients), dehydration (three patients), sepsis (one patient), and was undetermined in one patient. Abnormal visual evoked potentials were found in three of nine patients and abnormal brainstem auditory evoked potentials in seven of ten patients. Abnormal electroencephalograms were documented in five patients studied. Brain magnetic resonance imaging results were abnormal in three of four patients. CONCLUSIONS: Magnetic resonance imaging typically showed an increased signal in the posteromedial aspect of the globus pallidus and was, therefore, useful in the assessment of the structural changes of chronic bilirubin encephalopathy after kernicterus.

Behavior↗
PubMed2002

Breast-feeding, neonatal jaundice and kernicterus.

Despite the many advantages of breast-feeding, there is ample documentation of the strong association between breast-feeding and an increase in the risk of neonatal hyperbilirubinaemia. Breast-fed infants have higher bilirubin levels than formula-fed infants. Suggested mechanisms for these findings include poor fluid and caloric intake, inhibition of hepatic excretion of bilirubin, and intestinal absorption of bilirubin (enterohepatic circulation). On rare occasions, breast-fed infants without evidence of haemolysis have developed extreme hyperbilirubinaemia and kernicterus. Because almost all of the cases of kernicterus reported in the last 15 years have occurred in fully or partially breast-fed newborns, it is important that these infants be followed closely. Appropriate support and advice must be provided to the lactating mother so that successful breast-feeding can be established and the risk of severe hyperbilirubinaemia reduced.

Bilirubin↗
PubMed2000

Kernicterus in term and near-term infants--the specter walks again.

UNLABELLED: Diagnostic and therapeutic intervention is common in newborns with neonatal jaundice, motivated by the fear of bilirubin-associated brain damage, kernicterus. In recent years, a resurgence of kernicterus has been noted in countries in which this complication had essentially disappeared. Both early postnatal discharge and relaxation of attitudes to neonatal jaundice have been implicated. Guidelines for the management of neonatal jaundice show significant disparity, attesting to our inadequate understanding of the underlying biology. Aggressive guidelines expose infants to unnecessary risks, risks that are significant when it comes to exchange transfusion, and may also involve improper use of limited resources. Relaxed guidelines, on the other hand, may expose infants to increased risk of brain toxicity. CONCLUSION: At present we have no tools for ensuring certain identification of individuals with increased vulnerability to bilirubin toxicity. Relaxation of guidelines which have been proven safe through prolonged use should therefore be undertaken only in an atmosphere of increased vigilance. Guidelines that allow for a range of therapeutic and diagnostic options underline the need for careful assessment of each case on its individual merits.

Bilirubin↗
PubMed2000

Recurrence of kernicterus in term and near-term infants in Denmark.

UNLABELLED: Classical acute bilirubin encephalopathy (kernicterus) in term and near-term infants had not been seen in Denmark for at least 20 y until 1994. From 1994 to 1998. however, six cases were diagnosed. Aetiology of the hyperbilirubinaemia was known in two infants; spherocytosis and galactosaemia, most likely known in two infants; possible A-O blood type immunization, and unknown in two infants. However, one of these last-mentioned infants had a gestational age of only 36 wk. The maximum plasma total bilirubin concentrations were 531-745 micromol/L. The increase in the number of cases of kernicterus was considered to have been caused by: (i) a decreased awareness of the pathological signs, (ii) a change in the assessment of the risk of bilirubin encephalopathy, (iii) early discharge of the infants from the maternity ward, (iv) so-called breastfeeding-associated jaundice, (v) demonstration of bilirubin being an antioxidant, and (vi) difficulty in estimating the degree of jaundice in certain groups of immigrants. Accordingly, for prevention: (a) Attempt to change the healthcare workers' understanding of the risk of bilirubin encephalopathy, (b) give further instructions, both orally and in writing, to mothers before discharge from the maternity ward, (c) be more liberal in giving infant formula supplements, (d) conduct home visits by the community nurse at an earlier stage, (e) follow authorized guidelines for phototherapy and exchange transfusion, (f) lower plasma bilirubin concentration limits as an indication for phototherapy and exchange transfusion, (g) screen all term and near-term infants, and (h) measure the skin's yellow colour with a device that corrects for the skin's melanin content. CONCLUSIONS: Audit of the six cases presented indicates that measures are necessary in both the primary and secondary healthcare sectors if the risk of kemicterus is to be avoided. Screening may be considered, but in order to identify the problems it would first be reasonable to perform a larger prospective study in which audit is performed on all newborn infants, born at term and near-term, who develop a plasma bilirubin concentration above the exchange transfusion limit.

Adult↗
PubMed1997

Newborn infants with yellow brains: the discovery of kernicterus in Germany, 1875-1908.

Kernicterus, described in the period just before Kinnier Wilson's publication of his study of hepatolenticular degeneration, served him as a model of liver dysfunction associated with neurological disorder. The work of the early investigators of kernicterus, especially their descriptions of the pathological changes in the brain, led Wilson to postulate that a hepatotoxin was responsible for the neurological entity that he elucidated.

Brain↗
PubMed1953

Studies on the pathogenesis of kernicterus, with special reference to the nature of kernicteric pigment and its deposition under natural and experimental conditions.

Kernicteric pigment was extracted by means of chloroform from the brains of 3 infants. Solutions of it gave a positive diazo reaction, and, as determined electrophotometrically, gave maximum absorption of light having a wavelength of 425 mmicro, being identical in these properties with chloroform solutions of crystalline mesobilirubin. Experimental kernicterus was regularly induced by injecting crystalline mesobilirubin intracerebrally in newborn kittens, the pigment staining the cerebral tissues a bright canary-yellow and being deposited abundantly in the nerve cells, as microscopic examinations showed, although these latter were otherwise intact. Bilirubin, likewise injected intracerebrally in newborn kittens, had no such effects. The possibility is discussed that the blood-brain barrier is altered in some infants with hyperbilirubinemia in such a way that bilirubin crosses it and is then reduced within the brain to mesobilirubin thus giving rise to the cerebral pigmentation of kernicterus. The fact that the pigment itself does not seem to damage the neurons, as the present studies show, makes it necessary to seek some other cause for the neuronal damage that is sometimes seen, in association with the pigmentation, in the naturally occurring disease.

Bilirubin↗