Kernicterus Developmental Pediatrics Louis Meng, PL2 November 12 th 2002.
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Transcript of Kernicterus Developmental Pediatrics Louis Meng, PL2 November 12 th 2002.
Kernicterus
Developmental Pediatrics
Louis Meng, PL2
November 12th 2002
History• Earliest work on jaundice from Baumes-
1785, 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
PathophysiologyNewborn 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
PathophysiologyExaggerated 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 ManifestationsBilirubin 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 hypertonia-
Up 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– 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.