Kernicterus

1. Kernicterus Developmental Pediatrics Louis Meng, PL2 November 12th 2002

2. 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

3. 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

4. Bilirubin Conjugation

5. 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

6. 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

7. 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

8. MRI of an infant who suffered from severe Erythroblastosis Fetalis

9. 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

10. 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.

11. 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.

12. 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

13. 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

15. 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.

16. 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

17. 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

18. 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

19. Follow Up: Gaze Abnormality • Early involvement of ophthalmology • Strabismus surgery as needed • Correction/patching as needed

20. 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

21. 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

22. 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.

23. 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.

24. 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.