5 -  Kernicterus and other additive factors

According to Maisels (2006), "Jaundice is an important
clinical sign seen in most healthy newborns" [1, p 807].
Jaundice is the result of high bilirubin levels in the
blood, but Maisels points out that this is a transient
event, as are many other parameters like rapid
breathing and rapid heart rate in the newborn period;
bilirubin is a problem only in infants who have suffered
compromise, for example by premature birth  [1].  
Harris et al. (1958) observed damage caused by
bilirubin in the brain (kernicterus) in premature infants
with low concentrations of bilirubin in the blood [2].

The earliest descriptions of kernicterus made special
note that yellow-staining was not uniform throughout
the brain, but selectively affected only the subcortical
nuclei that were known predilection sites for anoxic
injury [3-7].  These reports appear to be totally
unknown to many present-day neonatologists, and the
misconception that bilirubin is directly toxic to the brain
appears to be one major motivation for the recent
protocol to clamp the umbilical cord immediately at
birth [8,9].

Kernicterus, the brain damage caused in the past by
bilirubin in infants born to Rh-negative mothers, was
found to involve primarily subcortical structures [3-7].  
In experiments with newborn animals, Rozdilsky and
Olszewski (1961) found that in kittens the inferior
colliculus was consistently affected by bilirubin
injections, and in dogs this was the site of the earliest
pathologic lesion [10].  Lucey et al. (1964)
investigated the effects of bilirubin in neonatal
monkeys and observed a similar pattern of damage
[7], which also reflected the rank order of brainstem
nuclei found by Ranck & Windle (1959) and Myers
(1972) to be affected by asphyxia at birth [11, 12].  
However, in neonatal monkeys bilirubin produced
brain damage only if preceded by asphyxia [7].

The finding of Lucey et al. that bilirubin is damaging
only when accompanied by asphyxia at birth is an
example of dual mechanisms each compounding the
effect of the other.  Unfortunately in real life
complications of this type happen, and may partly
explain why a brief period of anoxia around the time of
birth is harmless to most infants, but in combination
with any toxic factor can affect brain function and lead
to disability.

Bodier et al (2001) in a study of 295 birth records of
children with autism found a 34 percent incidence of
perinatal difficulties in children with associated medical
disorders, which suggests a likely interplay of anoxia
and toxic byproducts of faulty metabolism [13].  One
third of the children investigated by Bodier et al had
no associated medical disorders, but in this group 77
percent had a history of perinatal problems.

I am not trying to assert that all or most cases of
autism are the result of birth injury, but damage to the
inferior colliculi, and the rank-order of other
metabolically active subcortical nuclei, by a brief
period of asphyxia at birth cannot be dismissed as
unlikely.  The inferior colliculus is clearly vulnerable to
asphyxia and other factors that cause metabolic
compromise.  Autism has many etiologies, and the
inferior colliculus as the common site affected in the
brain should be considered.

In progress...
  1. Maisels MJ. (2006) What's in
    a name? Physiologic and
    pathologic jaundice: the
    conundrum of defining
    normal bilirubin levels in the
    newborn.
  2. Harris, R.C. et al. (1958).
    Kernicterus in premature
    infants associated with low
    concentrations of bilirubin in
    the plasma.
  3. Orth J (1875) Ueber das
    Vorkommen von
    Bilirubinkrystallen bei
    neugebornen Kindern.  
  4. Schmörl G (1904) Zur
    Kenntnis des Ikterus
    neonatorum, insbesondere
    der dabie auftretenden
    Gehirn veränderungen.  
  5. Zimmerman HM & Yannet H
    (1933). Kernicterus: jaundice
    of the nuclear masses of the
    brain.  
  6. Dublin WB (1951) Neurologic
    lesions of erythroblastosis
    fetalis in relation to nuclear
    deafness.
  7. Lucey JF et al. (1964)
    Kernicterus in asphyxiated
    newborn monkeys.
  8. Saigal S et al. (1972)
    Placental transfusion and
    hyperbilirubinemia in the
    premature.
  9. Kinmond S et al. (1993).
    Umbilical cord clamping and
    preterm infants: a
    randomised trial.
  10. Rozdilsky B & Olszewski J
    (1961). Experimental study of
    the toxicity of bilirubin in
    newborn animals.
  11. Ranck JB & Windle WF
    (1959). Brain damage in the
    monkey, Macaca mulatta, by
    asphyxia neonatorum.
  12. Myers RE (1972) Two
    patterns of perinatal brain
    damage and their conditions
    of occurrence.
  13. Bodier C et al. (2001)
    Autisme et pathologies
    associées. Étude clinique de
    295 cas de troubles
    envahissants du
    development [Autism and
    associated pathologies.
    Clinical study of 295 cases
    involving development
    disorders].
Full References
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Chronological references

  1. Shapiro SM. Bilirubin toxicity in the developing nervous system. Pediatr
    Neurol. 2003 Nov;29(5):410-21.
  2. Hansen TW. Mechanisms of bilirubin toxicity: clinical implications. Clin
    Perinatol. 2002 Dec;29(4):765-78,
  3. Hansen TW. Bilirubin brain toxicity. J Perinatol. 2001 Dec;21 Suppl 1:S48-51
  4. Wickham, Sara (2002) Anti-D in midwifery : panacea or paradox? LC call no.
    RG629.E78 W53 2001
  5. Hansen TW. Kernicterus in term and near-term infants--the specter walks
    again. Acta Paediatr. 2000 Oct;89(10):1155-7.
  6. Hansen TW. Pioneers in the scientific study of neonatal jaundice and
    kernicterus. Pediatrics. 2000 Aug;106(2):E15.
  7. Wennberg RP (2000) The blood-brain barrier and bilirubin encephalopathy.
    Cell Mol Neurobiol. 2000 Feb;20(1):97-109.
  8. Pearson HA. (1998) Commentary: Replacement transfusion as a treatment of
    erythroblastosis fetalis, by Louis K. Diamond, MD, Pediatrics, 1948;2:520-524.
    Pediatrics. 102 (supplement):203-5.
  9. Valaes T, Koliopoulos C, Koltsidopoulos A. The impact of phototherapy in the
    management of neonatal hyperbilirubinemia: comparison of historical cohorts.
    Acta Paediatr. 1996 Mar;85(3):273-6.
  10. Worley G, Erwin CW, Goldstein RF, Provenzale JM, Ware RE (1996) Delayed
    development of sensorineural hearing loss after neonatal hyperbilirubinemia:
    a case report with brain magnetic resonance imaging. Developmental
    Medicine and Child Neurology 38:271-277.
  11. Roger C, Koziel V, Vert P, Nehlig A (1996) Autoradiographic mapping of local
    cerebral permeability to bilirubin in immature rats: effects of
    hyperbilirubinemia. Pediatric Research 39:64-71.
  12. Roger C, Koziel V, Vert P, Nehlig A (1995) Regional cerebral metabolic
    consequences of bilirubin in rat depend upon post-gestational age at the time
    of hyperbilirubinemia. Brain Research. Developmental Brain Research 87:194-
    202.
  13. Ebbesen F, Knudsen A. The possible risk of bilirubin encephalopathy as
    predicted by plasma parameters in neonates with previous severe asphyxia.
    Eur J Pediatr. 1992  Dec;151(12):910-2.
  14. Valaes T. Bilirubin toxicity: the problem was solved a generation ago.
    Pediatrics. 1992 May;89(5 Pt 1):819-21.
  15. Mittendorf R, Williams MA (1991). Rho(D) immunoglobulin (RhoGAM): how it
    came into being. Obstetrics and Gynecology. 77:301-3.
  16. Connolly AM, Volpe JJ. Clinical features of bilirubin encephalopathy. Clin
    Perinatol. 1990 Jun;17(2):371-9.
  17. Valaes T, Gellis SS. Is kernicterus always the definitive evidence of bilirubin
    toxicity? Pediatrics. 1981 Jun;67(6):940-1.
  18. Doshi N, Klionsky B, Fujikura T, MacDonald H. Pulmonary yellow hyaline
    membranes in neonates. Hum Pathol. 1980 Sep;11(5 Suppl):520-
  19. Saigal S, O'Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and
    hyperbilirubinemia in the premature. Pediatrics. 1972 Mar;49(3):406-19.
  20. Dunn PM. The placental venous pressure during and after the third stage of
    labour following early cord ligation. J Obstet Gynaecol Br Commonw. 1966 Oct;
    73(5):747-56.
  21. Chen H (1964) Kernicterus in the Chinese newborn. A morphological and
    spectrophotometric study.  Journal of Neuropathology and Experimental
    Neurology 23:527-549.
  22. Lucey JF, Hibbard E, Behrman RE, Esquival FO, Windle WF (1964)
    Kernicterus in asphyxiated newborn monkeys.  Experimental Neurology 9:43-
    58.
  23. Rozdilsky B and Olszewski J (1961). Experimental study of the toxicity of
    bilirubin in newborn animals. Journal of Neuropathology and Experimental
    Neurology, 20, 193-205.
  24. Margoles C, Katami K, Moloney Wc, Pentschew A, Sutow Ww, Haymaker W.
    Kernicterus in Japanese infants. II. Pathologic data in 25 cases of kernicterus
    and in 20 cases of systemic icterus without kernicterus.World Neurol. 1960
    Sep;1:254-71.
  25. Ranck JB Jr, Windle WF. Brain damage in the monkey, macaca mulatta, by
    asphyxia neonatorum. Exp Neurol. 1959 Jun;1(2):130-54.
  26. Gerrard J. Kernicterus.  Brain. 1952 Dec;75(4):526-70.
  27. Dublin WB (1951) Neurologic lesions of erythroblastosis fetalis in relation to
    nuclear deafness. Am J Clin Pathol. 1951 Oct;21(10):935-9
  28. Zimmerman HM and Yannet H (1933). Kernicterus: jaundice of the nuclear
    masses of the brain.  American Journal of Diseases of Children, 45, 740-759.
  29. Schmörl G (1904) Zur Kenntnis des Ikterus neonatorum, insbesondere der
    dabie auftretenden Gehirn veränderungen.  Verhandlung der deutschen
    pathologischen Gesellschaft 6:109-115.
  30. Orth J (1875) Ueber das Vorkommen von Bilirubinkrystallen bei neugebornen
    Kindern.  Archiv für pathologische Anatomie und Physiologie und für klinische
    Medicin 63:447-462
References
Additional references of possible interest

  • [No authors listed] Neonatal hyperbilirubinaemia. Lancet. 1958 Nov 29;2(7057):1162-4.
  • Onishi S, Kawade N, Itoh S, Isobe K, Sugiyama S. Postnatal development of uridine
    diphosphate glucuronyltransferase activity towards bilirubin and 2-aminophenol in human
    liver. Biochem J. 1979 Dec 15;184(3):705-7.
  • Eidelman AI, Schimmel MS. Phototherapy--1988. A green light for a new approach? J
    Perinatol. 1989 Mar;9(1):69-71.
  • LESTER R, SCHMID R. BILIRUBIN METABOLISM. N Engl J Med. 1964 Apr 9;270:779-86.
  • Stern L. Adaptation to extrauterine life. Int Anesthesiol Clin. 1968 Fall;6(3):875-909.
  • Lazar MA.East meets West: an herbal tea finds a receptor. J Clin Invest. 2004 Jan;113(1):23-
    5.
  • Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance
    by activating the nuclear receptor CAR. J Clin Invest. 2004 Jan;113(1):137-43.
  • ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 348, November
    2006: Umbilical cord blood gas and acid-base analysis. Obstet Gynecol. 2006 Nov;108(5):
    1319-22.
  1. Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of
    defining normal bilirubin levels in the newborn. Pediatrics. 2006 Aug;118(2):805-7.
  2. Harris, R.C., Lucey, J.F., & MacLean, J.R. (1958). Kernicterus in premature infants
    associated with low concentrations of bilirubin in the plasma. Pediatrics, 21, 875-884.
  3. Orth J (1875) Ueber das Vorkommen von Bilirubinkrystallen bei neugebornen Kindern.  
    Archiv für pathologische Anatomie und Physiologie und für klinische Medicin 63:447-462
  4. Schmörl G (1904) Zur Kenntnis des Ikterus neonatorum, insbesondere der dabie
    auftretenden Gehirn veränderungen.  Verhandlung der deutschen pathologischen
    Gesellschaft 6:109-115.
  5. Zimmerman HM and Yannet H (1933). Kernicterus: jaundice of the nuclear masses of the
    brain.  American Journal of Diseases of Children, 45, 740-759.
  6. Dublin WB (1951) Neurologic lesions of erythroblastosis fetalis in relation to nuclear
    deafness. Am J Clin Pathol. 1951 Oct;21(10):935-9.
  7. Lucey JF, Hibbard E, Behrman RE, Esquival FO, Windle WF (1964) Kernicterus in
    asphyxiated newborn monkeys.  Experimental Neurology 9:43-58.
  8. Saigal S, O'Neill A, Surainder Y, Chua LB, Usher R. Placental transfusion and
    hyperbilirubinemia in the premature. Pediatrics. 1972 Mar;49(3):406-19.
  9. Kinmond S, Aitchison TC, Holland BM, Jones JG, Turner TL, Wardrop CA.Umbilical cord
    clamping and preterm infants: a randomised trial. BMJ. 1993 Jan 16;306(6871):172-5.
  10. Rozdilsky B and Olszewski J (1961). Experimental study of the toxicity of bilirubin in
    newborn animals. Journal of Neuropathology and Experimental Neurology, 20, 193-205.
  11. Ranck JB, Windle WF (1959). Brain damage in the monkey, Macaca mulatta, by asphyxia
    neonatorum.  Experimental Neurology 1:130-154.
  12. Myers RE (1972) Two patterns of perinatal brain damage and their conditions of
    occurrence.  American Journal of Obstetrics and Gynecology 112:246-276.
  13. Bodier C, Lenoir P, Malvy J, Barthélemy C, Wiss M, Sauvage D. (2001) Autisme et
    pathologies associées. Étude clinique de 295 cas de troubles envahissants du
    development [Autism and associated pathologies. Clinical study of 295 cases involving
    development disorders]. Presse Médicale 30(24 Pt 1):1199-203.
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