Kernicterus
Developmental Pediatrics
Louis Meng, PL2
November 12th 2002
History
• Earliest work on jaundice from Baumes1785, and Hervieux-1847
• Kernicterus was first described by Johannes
Orth, 1875
– He postulated that jaundice might have
hematologic origins
– He noted that the brain in jaundiced adults wasn’t
affected
• Christian Schmorl coined the term in 1904
– Translated, Kernicterus means jaundice of the
“kern” or nuclear region of the brain
Pathophysiology
• RBCs are broken down
• Bilirubin is an end product of heme
metabolism
• Bilirubin is conjugated in the liver
– Enzyme: UDP-Glucuronyl Transferase
• Conjugated bili is excreted via the GI tract
– Enzyme: Beta-Glucuronidase can unconjugate
bili in the small intestine and bili is reabsorbed
Bilirubin Conjugation
Pathophysiology
Newborn Hyperbilirubinemia
• Relatively high hematocrit; more cells to
break down
• UDP-Glucuronyl Transferase is not fully
functional until 3-4 months of life
• Relative starvation state and slow transit
time, especially in breastfeeders
• Breastmilk contains beta-glucuronidase;
enterohepatic circulation is increased
Pathophysiology
Exaggerated Hyperbilirubinemia
• Polycythemia
• Hemolysis
– Rh incompatibility
– ABO incompatibility
– Abnormal RBCs—G6PD, spherocytosis, thalassemia
• Birth Trauma—Bruising, Cephalohematoma
• Metabolic Abnormalities—Crigler Najjar, Gilbert
Syndrome, Galactosemia
• Medications—Sulfonamides
– Displaces bilirubin from albumin; same binding site
Pathophysiology
• UCB is lipophilic and crosses the Blood-Brain Barrier
– In vitro, free UCB will not precipitate out of solution unless in
the presence of a polar lipid membrane
– In theory, only free UCB crosses, albumin-bound does not.
– BBB of infants is more permeable than adults, and acidosis
causes it to be even more permeable.
• UCB has an affinity for the basal ganglia, hippocampus,
cranial nerve nuclei
– Mechanism is widely studied, but still unknown
• UCB interrupts metabolism in glial cells and causes
apoptosis of neurons
– Exact mechanisms are unknown, but definitely separate
pathways.
– Age of the cell is inversely proportional to susceptibility
MRI of an infant who suffered from
severe Erythroblastosis Fetalis
Clinical Manifestations
Bilirubin Encephalopathy
• Acute Bilirubin Encephalopathy
– 1st phase: hypotonia, poor suck-present in the first
few days
– 2nd phase: Hypertonia (retrocollis and opisthotonos),
fever
– 3rd phase: Gradual disappearance of the hypertoniaUp to years after the first week
Clinical Manifestations:
Bilirubin Encephalopathy
• Chronic Encephalopathy:
(Perlstein’s Tetrad: Extrapyramidal Abnormalities, Hearing Loss, Gaze
abnormality, and Dental Dysplasia)
– Extrapyramidal abnormalities: Facial grimacing,
drooling, dysarthria, and athetosis--may develop by
18mo or delayed to 8or9 years.
– Hearing loss is usually due to injury of the cochlear
nuclei in the brainstem. It may be the only
manifestation
– Gaze abnormalities: Limitation of upward gaze, palsies
– Cerebral cortex is relatively spared, so intelligence is
often close to normal.
Diagnosis
• Kernicterus is a pathologic diagnosis, not
clinical. Post-mortem exam of the brain is
the definitive diagnosis
• Clinically, kernicterus is suspected based on
the history of hyperbilirubinemia and the
clinical manifestations as mentioned above.
– The degree of hyperbilirubinemia does not
correlate well with the development or severity
of kernicterus.
Laboratory Measures
• There is currently no lab value that correlates well with
the development of kernicterus; there seem to be many
factors that lead to its development
• Guidelines for initiating therapy for hyperbilirubinemia
currently include the variables of UCB and age of baby.
– There are no good guidelines for preterm infants
– An unconjugated bilirubin level of 25 or less in TERM,
HEALTHY babies has not been correlated with kernicterus
– Pediatrics 1995; Case reports of Term, Healthy, Breastfed
babies—UCB levels associated with clinical Kernicterus were
39-50
• It has been hypothesized that measuring UNBOUND
UCB can be correlated, but not well supported as of yet
Prevention: Treatment of
Hyperbilirubinemia
• Phototherapy
– Initiate based on UCB level and baby’s age
– Isomerizes UCB to Lumirubin, soluble in water and
excreted via the kidney
• Exchange transfusion
– Initiate if phototherapy fails, repeat as needed
– Incidence of kernicterus has dropped since the advent
• Sn-Mesoporphyrin
– Inhibits Heme-oxygenase, which is the rate-limiting
enzyme in heme catabolism.
– Only case reports thus far, where exchange transfusion
was refused
Incidence and Prognosis
• True incidence is not well known
– Using pathologic criteria, one-third of all
infants with untreated hemolytic diseases that
have bilirubin levels >25 will develop
Kernicterus
• Prognosis depends of severity of effects
– Wide spectrum of manifestations, those with
early overt neurologic signs usually die.
Treatment
• Treatment of clinically suspected
kernicterus is centered around early
intervention from multiple disciplines
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–
–
–
–
–
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Neurodevelopmental Pediatrics
Neurology
Physical and Occupational Therapy
Audiology
Ophthalmology
Speech Therapy
School, County, EFMP
Follow Up: Spasticity/Dystonia
• Botox, Baclofen for severe posturing
• Physical therapy for training of muscles and
teaching stretching techniques
• Occupational Therapy for independence and
activities of daily living
• Speech Therapy
• Equipment—Appropriate chairs, braces, etc
Follow Up: Hearing Deficit
• Early Diagnosis
– Brainstem Auditory Evoked Response
• Long-Term follow up by audiology
– Sign Language and other alternative means for
communication
– Hearing aids as appropriate
– Cochlear implants as appropriate
• Speech therapy as needed
Follow Up: Gaze Abnormality
• Early involvement of ophthalmology
– Strabismus surgery as needed
– Correction/patching as needed
Follow Up: Cognitive Delays
• Cerebral cortex is usually relatively spared,
but cognitive delays may be present
– Neurodevelopmental Pediatrician to continually
reassess for these delays
– Early diagnosis of learning disabilities
– Early intervention, special schools, IEPs as
appropriate
Summary
• Kernicterus remains an important topic for
discussion
– Incidence is down due to advances in
recognition and treatment
– Making a small resurgance due to higher
survivial rates from the NICU
• Kernicterus is better understood than ever,
but still many mysteries remain and
research continues
• Therapy for clinically suspected Kernicterus
centers around multidisciplinary early
intervention
Sources
• Ahlfors, CE: Unbound Bilirubin Associated with
Kernicterus: A Historical Approach. Journal of
Pediatrics 2000; 137(4): 540-544.
• Brodersen, R and L. Stern: Deposition of Bilirubin
Acid in the CNS—A Hypothesis for the Development
of Kernicterus: Acta Paediatr Scand 1990; 79: 12-19.
• Hansen, TR: Pioneers in the Scientific Study of
Neonatal Jaundice and Kernicterus. Pediatrics 2000;
106(2): e15.
• Kappas, A, et al: Sn-Mesoporphyrin Interdiction of
Severe Hyperbilirubinemia in Jehovah’s Witness
Newborns as an Alternative to Exchange Transfusion.
Pediatrics 2001; 108(6): 1374-1377.
Sources
• Kernicterus. Nelson’s Textbook of Pediatrics:
Behrman, Ed: pp 517-519.
• Kim, MH, et al: Lack of Predictive Indices in
Kernicterus. Pediatrics 1980; 66(6): 852-858.
• Maisels, MJ; et al: Kernicterus in Otherwise Healthy,
Breast-fed Term Newborns. Pediatrics 1995; 96(4):
730-733.
• Rodrigues, CM, et al: Aging Confers Different
Sensitivity to the Neurotoxic Properties of
Unconjugated Bilirubin. Pediatric Research 2002;
51(1): 112-118.
Sources
• Rosenbloom, L: Diagnosis and Management of
Cerebral Palsy. Archives of Disease in Childhood
1995; 72: 350-354.
• Rui, FM, et al: Rat Cultured Neuronal and Glial
Cells Respond Differently to Toxicity of
Unconjugated Bilirubin. Pediatric Research 2002;
51(4): 535-541.
• Turkel, SB, et al: A Clinical Pathologic
Reappraisal of Kernicterus. Pediatrics 1982;
69(3): 267-272.
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Kernicterus - NCC Pediatrics Residency at Walter Reed