Kernicterus: a re-emerging problem?

1. Kernicterus: a re-emerging problem? N. Ambalavanan MD Division of Neonatology University of Alabama at Birmingham May 2003

2. Overview • What is kernicterus? • Is it a problem? • Why is it a problem? • What can we do about it?

3. Kernicterus • Kernicterus: Schmorl (1904) described yellow staining of the basal ganglia in the brain of infants who died with severe jaundice and called it “kernikterus”. Also noted by Orth in 1875. • Extreme hyperbilirubinemia causes bilirubin encephalopathy and toxicity to basal ganglia and brainstem nuclei. • Rare but preventable cause of severe morbidity in otherwise normal infants.

4. Stages of kernicterus • Acute bilirubin encephalopathy: 3 distinct clinical phases: • First phase (first few days): Stupor, hypotonia, and poor sucking. • Second phase: Hypertonia (retrocollis – backward arching of neck, opisthotonus – arching of trunk) and fever. All infants who develop this will develop chronic encephalopathy. • Third phase (after first week): Disappearance of hypertonia. Muscle rigidity, paralysis of upward gaze, periodic oculogyric crisis, and irregular respirations are present in the terminal phase. 4% die in acute phase (data from USA)

5. Stages of kernicterus • Chronic bilirubin encephalopathy • First year: Poor feeding, high pitched cry. Hypotonia but good deep tendon reflexes. Tonic neck reflex, righting reflex persist. Slow motor skills (up to 5 years to walk). • After first year: Main clinical features are: • extrapyramidal disorder (athetosis, ballismus, tremor, dysarthria) • hearing loss (damage to cochlear nuclei in brainstem) • gaze abnormalities (limitation of upward gaze) Athetosis normally develops 18 months- 8 years of age. Hearing loss may be the only symptom in some children.

6. Investigations (Volpe JJ:. 3rd Ed., 1995) • Clinical features • Bilirubin (unconjugated) level • Magnetic Resonance Imaging (MRI) • Increased signal intensity in the globus pallidus (+ putamen + thalamus) on T2-weighted images

7. Is kernicterus a problem? • Major problem in the 1950’s -1970’s • Rh-hemolytic disease was common, and kernicterus had a high incidence • Exchange transfusion, Rh-immunoglobulin, and phototherapy markedly reduced kernicterus by 1980’s. • Less emphasis on jaundice in 1990’s • An increase in kernicterus recently

8. What is the incidence? • Kernicterus registry in the United States: 90 cases from 1984 to 2001 • True incidence unknown, as not all cases are identified or reported • JCAHO (Joint Commission on Accreditation of Healthcare Organizations) issued a ‘Sentinel Event Alert’ on kernicterus recently (Apr 2001)

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10. Why is kernicterus a problem? • Jaundice in the newborn is common • Extreme hyperbilirubinemia that can cause kernicterus is rare • Assessment of risk of extreme hyperbilirubinemia has been inadequate or unreliable, and bilirubin levels have not always been measured, or measured in time

11. Risk factors for hyperbilirubinemia in full-term newborns • Jaundice within first 24 hours of birth • A sibling who was jaundiced as a neonate • Unrecognized hemolysis (ABO- or Rh- incompatibility) • Non-optimal sucking/nursing • Deficiency in G6PD • Infection • Cephalhematomas/bruising • East Asian or Mediterranean descent MMWR Vol 50, No. 23, 491-4, June 15, 2001

12. Pathophysiology • Physiologic hyperbilirubinemia • Increased bilirubin production • Decreased bilirubin conjugation • Decreased excretion • Average peak in full term: 5-6 mg/dL • Exaggerated physiological: 7-17 mg/dL • Pathologic hyperbilirubinemia:>17 mg/dL Dennery et al. NEJM 344:581, 2001

13. Pathophysiology

14. Pathophysiology • Factors affecting neurotoxicity • Concentration of bilirubin in the brain • Duration of exposure to bilirubin • Correlation between serum bilirubin and neurotoxicity is weak, except in infants with hemolysis Dennery et al. NEJM 344:581, 2001

15. Problems with serum bilirubin • No estimate of duration • Not a good estimate of • tissue concentration • bilirubin production • albumin-bound bilirubin in serum • Phototherapy creates photo-isomer that is excreted

16. Serum Bilirubin and Kernicterus Kernicterus in Rh-isoimmunization: Serum level Incidence 10-18 mg/dL 0 % 19-24 mg/dL 8 % 25-29 mg/dL 33 % 30-40 mg/dL 73 % Volpe JJ: Neurology of the Newborn. 3rd Ed. pp 490-514, 1995

17. Is there a safe serum bilirubin level in the absence of hemolysis? Management of Hyperbilirubinemia in the Healthy Term Newborn. Pediatrics 94: 558, 1994

18. Is a serum bilirubin of 20-25 mg/dL safe? • 9.8% of babies with serum bilirubin between 20-25 mg/dl had kernicterus Dhaded et al. Indian Pediatr 33: 1059, 1996 • Prospective observational study of 94 infants admitted with bilirubin >18 mg/dL • Exchange transfusion done at level >20 mg/dL • 28 excluded as 24 had hemolysis and 4 had malformations • 14 (22%) of remaining 64 developed kernicterus (> stage II) • Total bilirubin 18-25 mg/dL: 14 % incidence 25-29 mg/dL: 18 % incidence >30 mg/dL: 43 % incidence • Problem: Admitted in declining phase, after damage is done? Murki et al. Indian Pediatr 38: 757, 2001

19. Root cause analysis • Four patient care processes: • Patient assessment • Continuum of care • Patient and family education • Treatment JCAHO Sentinel Event Alert April 2001

20. Root cause: Patient assessment • The unreliability of visual assessment of jaundice in newborns with dark skin • Failure to recognize jaundice- or its severity- based on visual assessment, and measure a bilirubin level before the infant’s discharge from the hospital or during a follow-up visit • Failure to measure the bilirubin level in an infant who is jaundiced within the first 24 hours

21. Root cause: Continuum of care • Early discharge (before 48 hours) with no follow-up within 1 or 2 days of discharge (particularly important for infants <38 wks gestation) • Failure to provide early follow-up with physical assessment for infants who are jaundiced before discharge • Failure to provide ongoing lactation support to ensure adequacy of intake for breast-fed newborns

22. Root cause: Patient and Family education • Failure to provide appropriate information to parents about jaundice and failure to respond appropriately to parental concerns about a jaundiced newborn, poor feeding, lactation difficulties, and change in newborn behavior and activity.

23. Root cause: Treatment • Failure to recognize, address, or treat rapidly rising bilirubin • Failure to aggressively treat severe hyperbilirubinemia in a timely manner with intensive phototherapy or exchange transfusion

24. Early identification: Nomograms Bhutani et al. Pediatrics 103:6, 1999

25. How good is the nomogram? For predicting values >95th percentile Bhutani et al. Pediatrics 103:6, 1999

26. Transcutaneous measurement • New multiwavelength spectral analysis devices (e.g. Bilicheck) • Infants with predischarge BiliCheck values above the 75th percentile on the bilirubin nomogram at high risk for hyperbilirubinemia -> Negative predictive value = 100%; positive predictive value = 33%; sensitivity = 100%; specificity = 88% Bhutani et al. Pediatrics 106:E17, 2000

27. Transcutaneous measurement A recent study in a predominantly hispanic population showed that skin measurement underestimated serum levels, especially for levels >10 mg/dL Engle et al. Pediatrics 110:61, 2002

28. Early identification: CO COStat End-tidal breath analyzer (Natus Medical) • Carbon monoxide production is an index of bilirubin production • Devices available to measure CO production in exhaled air (ETCOc) • Does not add much predictive ability to serum bilirubin measurements Stevenson et al. Pediatrics 108:175, 2001

29. Newer methods of prevention • Metalloporphyrins inhibit bilirubin production • Tin-mesoporphyrin (SnMP; 6 mM/kg) within 24 h of birth in 517 preterm infants decreased peak bilirubin by 41% and need for phototherapy by 76% (Valaes et al. Pediatrics 93:1, 1994) • SnMP reduced need for phototherapy (Bili>19.5) in term infants with levels 15-18 mg/dL at 24-48 hrs of age (0 of 40 in SnMP gp vs. 12 of 44 in controls) (Martinez et al. Pediatrics 103:1, 1999) • Other trials also show efficacy in term infants (Dennery et al. NEJM 344:581, 2001) • Not yet approved for use in newborn; no oral formulation yet

30. Early treatment is required! • Phototherapy (>12 mW/cm2/nm) • Blue light/White light fluorescent bulbs • Bili-blanket • High intensity LED (blue, blue-green) gallium nitride • Exchange transfusion • Only after trial of optimal phototherapy, if bilirubin >20-25 mg/dL • About 2% mortality, 12% complications

31. Summary • Kernicterus still occurs, and is preventable • Prevention is important: • Evaluate risk factors (JAUNDICE) • Evaluate serum bilirubin (low threshold) • Adequate feeding (especially breast fed) • Early follow-up (1-2 days after discharge if <48 hours of age) • Instructions to parents • Aggressive treatment (early phototherapy)