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Kernicterus. Developmental Pediatrics Louis Meng, PL2 November 12 th 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

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kernicterus

Kernicterus

Developmental Pediatrics

Louis Meng, PL2

November 12th 2002

history
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
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
pathophysiology newborn hyperbilirubinemia
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
pathophysiology exaggerated hyperbilirubinemia
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
pathophysiology7
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
clinical manifestations bilirubin encephalopathy
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 encephalopathy10
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
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
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
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
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
  • 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
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
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
Follow Up: Gaze Abnormality
  • Early involvement of ophthalmology
    • Strabismus surgery as needed
    • Correction/patching as needed
follow up cognitive delays
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
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
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.
sources23
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.
sources24
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.