Synonym: bilirubin encephalopathy
Kernicterus is a complication of neonatal jaundice. The word kernicterus means yellow kern, kern being the structures of the brain that are most commonly affected. They are the basal ganglia, hippocampus, geniculate bodies and cranial nerve nuclei, especially the oculomotor, vestibular and cochlear. The cerebellum can also be affected. The presence of yellow staining and damage to the brain caused by unconjugated bilirubin was first described by Hervieux in 1847. At postmortem examination a characteristic yellow stain is seen in those structures. Schmorl used the term kernicterus in 1903. Acute bilirubin encephalopathy is the clinical manifestation of bilirubin toxicity. There is hypotonia followed by hypertonia, opisthotonus (backward arching of the neck), or retrocollis (backward arching of the back) or both. Bilirubin encephalopathy is taken as synonymous with kernicterus.
Much of the traditional teaching about neonatal jaundice and kernicterus has been revised. It is the premature baby who is at risk and kernicterus rarely affects a term infant unless bilirubin levels are exceptionally high. A high level of physiological jaundice, especially in breast-fed babies, seems benign and resolves spontaneously without complications.
Kernicterus occurs in all parts of the world but is more frequent where glucose-6-phosphate dehydrogenase (G6PD) deficiency is common. Numbers fell in the 1970s and 1980s only to rise again in the 1990s. This has been attributed to early discharge of term babies with lack of follow-up but term babies are at very low risk. However, large numbers at low risk can produce a significant number of affected individuals. For many years paediatricians have been concerned that their increasing ability to save the lives of babies at earlier and earlier gestations may be resulting in an unacceptable level of morbidity in survivors. It would seem that the cause of the rise is multifactorial.
Risk factors include:
- Rapidly rising level of bilirubin
- Diseases that cause haemolysis
Diseases that increase risk include:
However, those at recognised risk may well be treated so that kernicterus occurs more often in those of lower risk in whom the process was not recognised. A register of babies with chronic kernicterus was formed in the USA between 1984 and 1998 and analysis shows that all babies on the register had been discharged from the hospital before 72 hours old. 60% of the babies had delivered at term. Total serum bilirubin levels at presentation with the classical features of kernicterus ranged from 26 to 50 mg/dL. 95% were breast-fed. Haemolytic disease, mainly rhesus isoimmunisation, was identified in 19 of the 80 babies. 18 had G6PD dehydrogenase deficiency, two had galactosaemia and one had Crigler-Najjar syndrome. Sepsis was the cause in nine. In 21 out of 74 infants, no predisposing factor for the severe hyperbilirubinaemia was found.
In June 2003, the Royal College of Paediatrics and Child Health announced a surveillance programme of cases of severe neonatal hyperbilirubinemia following anecdotal reports of increasing observation of kernicterus; however, no recent reports on the incidence of kernicterus in the United Kingdom have been formally published.
High levels of bilirubin may induce haemolysis, thus producing a vicious circle.
The presentation in the premature baby may be rather different from the presentation at term.
- In the early baby it may be difficult to distinguish neurological features of the disease from other neurological conditions that may be present. The risk of damage from bilirubin seems to be confined to the first few days of life in the term infant but may be rather longer with prematurity.
- There may be known risk factors such as prematurity, rhesus incompatibility or a family history of G6PD deficiency or spherocytosis. ABO incompatibility rarely causes severe problems.
- If the baby is feeding well and appears healthy and vigorous, this is reassuring. Babies who are breast-fed tend to get more jaundiced. Between 20 and 40% of women have high levels of beta-glucuronidase in their breast milk, which potentiates and prolongs hyperbilirubinaemia in their breast-fed babies.
There are 3 stages of kernicterus but, of those affected, 55 to 65% have the full picture, 25 to 35% display a limited variety of neurological changes and around 15% have no clinical abnormality.
- Phase 1 occurs in the first few days of life. There is reduced alertness, hypotonia and poor feeding. These are also features of many other conditions and so a high index of suspicion is essential if appropriate treatment is to be started. Convulsions are not typical with acute bilirubin encephalopathy.
- Phase 2 is variable in onset and duration. Hypertonia of the extensor muscles succeeds hypotonia. Retrocollis, opisthotonus or both may occur. This may lead to long-term neurological problems.
- Phase 3 occurs in children over a week old and is hypotonia.
- Chronic bilirubin encephalopathy develops over the first few years of life. The first phase occurs in the first year of life with hypotonia, hyperreflexia and delayed physical milestones. The tonic neck reflex can also be present. In children over one year the classical features develop, which include abnormalities in the extrapyramidal, visual and auditory systems. Minor intellectual deficits may be present.
- Extrapyramidal signs may occur and the most common and most severe is athetosis, although chorea can also occur. Upper extremities are more severely affected than the lower ones and bulbar nerves may also be involved. Chronic bilirubin encephalopathy causes damage to the basal ganglia.
- Visual problems most commonly affect ocular movements, resulting in upward gaze, although horizontal gaze abnormalities and gaze palsies can also occur. These are due to damage to the cranial nerve nuclei in the brain stem.
- Hearing problems are the most consistent feature of chronic bilirubin encephalopathy and can occur in the absence of any other characteristic features. The most common problem is high-frequency hearing loss, ranging from mild to severe. Both the cochlear nuclei in the brain stem and the auditory nerve appear to be very sensitive to bilirubin, even at relatively low levels. This may present as delayed language and so any baby at risk must have hearing assessed. The presenting feature of kernicterus may be childhood deafness.
- Cognitive defects do not feature prominently in kernicterus but athetosis or chorea along with hearing defects may give the false impression of mental handicap.
- Dental enamel shows some hypoplasia in about 75% of cases and some may show green staining of teeth.
- Jaundice can be detected clinically although this is more difficult in babies with dark skin. Clinical assessment is not enough and estimation of serum bilirubin is required, although a technique of transcutaneous measurement of bilirubin has shown value in preventing unnecessary readmissions to hospital.
- Transcutaneous bilirubinometry is a non-invasive technique that is currently being explored.
- Both direct and indirect bilirubin should be measured. This gives an indication of the level of free bilirubin, although direct measurement of this is not possible. It is free bilirubin that crosses the blood-brain barrier. The test may need repeating with a frequency dependent upon the levels found, gestational age and age since birth. Nomograms have been produced to try to anticipate maximum levels.
- Both mother and baby should have blood tested for ABO and rhesus groups as well as minor groups.
- Neonates have a slightly higher reticulocyte count than older children but an elevated level for age suggests an ongoing problem of haemolysis.
- The direct Coombs' test detects antibody on the surface of the erythrocyte. A positive result indicates that antibody is on the red cells and so they are at risk of immune haemolysis. This is a qualitative test that does not indicate the amount of antibody or the degree of haemolysis although the reticulocyte count may indicate this.
- A blood smear should be examined for spherocytosis or elliptocytosis
- Check U&E. Dehydration seems a risk factor for kernicterus and may be a feature in babies re-admitted with hypernatraemia and elevated bilirubin.
- A differential white count may indicate sepsis. If there is any suggestion of this, a lumbar puncture should be performed.
- Imaging of the brain does not help in the diagnosis, except by excluding other causes. Ultrasound is portable and useful. CT does not provide so much information as MRI. There may be some subtle changes in the MRI scan in kernicterus but the value of this is uncertain.
- Brainstem auditory evoked response (BAER) can be used to assess hearing at a very early stage and long before the presentation of delayed language.
Management is aimed at preventing neurotoxicity. The management of hyperbilirubinaemia by both phototherapy and exchange transfusion is discussed in the separate article Neonatal Jaundice. In 1994, the American Academy of Pediatrics (AAP) published practice parameters for the management of hyperbilirubinaemia in the healthy term infant. Some people think that their criteria for exchange transfusion are too aggressive. However, authors involved in a review of the American register, advocate a 'crash-cart' approach and consider that speedy intervention with exchange transfusion and phototherapy considerably reduces the incidence of kernicterus.
There is no such consensus in the UK but a review by the National Institute for Clinical Excellence (NICE) is awaited. A Cochrane review examined the difference between single volume exchange transfusion and the traditional double volume. It failed to draw a conclusion. Phenobarbital may induce enzyme induction to accelerate the conjugation of bilirubin to its harmless state.
Jaundice tends to be deeper in breast-fed babies but formula feeding or giving dextrose in water does not improve the prognosis. Therefore, because of the many other advantages of breast-feeding, it should not be stopped.
Babies that are thought to have neurological damage should be referred early for neurodevelopmental assessment and remedial help.
There is no correlation between level of bilirubin and clinical outcome. Of the 80 babies on the kernicterus register three died but it is impossible to know how many may have died with kernicterus and not been reported. Of those on the register, 66 out of 77 (86%) had chronic kernicterus, 61 of which had severe disease. 10 of 77 (13%) had no apparent abnormalities when over one year old.
Prevention of kernicterus is based on the identification and adequate treatment of hyperbilirubinaemia in neonates.
- Kernicterus is unlikely in a term or near term baby but it can occur and represented 60% of those on the American register.
- Attention needs to be paid to those who are premature, to those who are known to have a family history of G6PD deficiency or other disorders that may produce neonatal haemolysis and to any baby that seems to develop rapid and unexpected jaundice. The Newborn Jaundice and Kernicterus Meeting in Siena recently called for a global expansion of neonatal G6PD screening.
- Breast-feeding increases levels of bilirubin but it may actually be protective for kernicterus.
If the size of a population at low risk is very much larger than a high-risk group, then the total number affected may contain more individuals from the low-risk than the high-risk group. This is especially likely if the high-risk group is carefully monitored and treated but the low-risk group is ignored.
- It is very important that if there are signs of abnormality in the low risk group that investigation with a view to treatment should not be overlooked.
- With early discharge it has been suggested that bilirubin should be checked and a nomogram used, as discharge is before the peak of physiological jaundice and this may help to identify those who will have problems. Neonatal jaundice is common but kernicterus is rare.
- Questions have been raised about the cost-effectiveness of routine predischarge serum or transcutaneous bilirubin screening and one study concluded that it could be falsely reassuring. Predischarge bilirubin does, however, have a greater predictive value than a clinical risk factor score.
- When jaundice is deeper than expected it must be taken seriously, as the consequences of kernicterus are devastating and life-long. Infection also needs to be excluded. Breast-feeding might increase levels of bilirubin but it should be encouraged with a regime for identifying babies at risk. Nevertheless it is difficult to overlook the fact that in the American register 95% were breast-fed and this must be well above the national average. Indeed, the evidence of one systematic review recommends substituting formula for breast milk in babies with significant hyperbilirubinaemia.
- A recent synopsis report from the American register suggested that the incidence of kernicterus could be reduced if families had better access to healthcare in the early stages of neonatal jaundice.
- Some babies develop kernicterus with unexpectedly low levels of bilirubin.
Further reading & references
- Springer SC; Kernicterus; emedicine 2008.
- Hansen TW; Kernicterus: an international perspective. Semin Neonatol. 2002 Apr;7(2):103-9.
- Watchko JF; Vigintiphobia revisited. Pediatrics. 2005 Jun;115(6):1747-53.
- Johnson L, Brown AK: A pilot registry for acute and chronic kernicterus in term and near-term infants.; Pediatrics 1999 Sep; 104:(3): 736
- Alexandra Brito M, Silva RF, Brites D; Bilirubin toxicity to human erythrocytes: a review. Clin Chim Acta. 2006 Dec;374(1-2):46-56. Epub 2006 Jun 17.
- Petersen JR, Okorodudu AO, Mohammad AA, et al; Association of transcutaneous bilirubin testing in hospital with decreased readmission rate for hyperbilirubinemia. Clin Chem. 2005 Mar;51(3):540-4.
- Johnson L, Bhutani VK, Karp K, et al; Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol. 2009 Feb;29 Suppl 1:S25-45.
- No authors listed; Practice parameter: management of hyperbilirubinemia in the healthy term newborn. American Academy of Pediatrics. Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Pediatrics. 1994 Oct;94(4 Pt 1):558-65.
- Rennie JM, Sehgal A, De A, et al; Range of UK practice regarding thresholds for phototherapy and exchange transfusion in neonatal hyperbilirubinaemia. Arch Dis Child Fetal Neonatal Ed. 2009 Sep;94(5):F323-7. Epub 2008 Nov 10.
- Thayyil S, Milligan DW; Single versus double volume exchange transfusion in jaundiced newborn infants. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004592.
- Kaplan M, Hammerman C; The need for neonatal glucose-6-phosphate dehydrogenase screening: a global perspective. J Perinatol. 2009 Feb;29 Suppl 1:S46-52.
- Bhutani VK, Johnson LH, Keren R; Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am. 2004 Aug;51(4):843-61, vii.
- Slaughter J, Annibale D, Suresh G; False-negative results of pre-discharge neonatal bilirubin screening to predict severe hyperbilirubinemia: a need for caution. Eur J Pediatr. 2009 Mar 3.
- Keren R, Bhutani VK, Luan X, et al; Identifying newborns at risk of significant hyperbilirubinaemia: a comparison of two recommended approaches. Arch Dis Child. 2005 Apr;90(4):415-21.
- No authors listed; Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316.
- Ip S, Glicken S, Kulig J, et al; Management of neonatal hyperbilirubinemia. Evid Rep Technol Assess (Summ). 2002 Nov;(65):1-5.
- Bhutani VK, Johnson L; Synopsis report from the pilot USA Kernicterus Registry. J Perinatol. 2009 Feb;29 Suppl 1:S4-7.
|Original Author: Dr Laurence Knott||Current Version: Dr Laurence Knott|
|Last Checked: 22/01/2010||Document ID: 2355 Version: 22||© EMIS|
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