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The Clinical Syndrome of Bilirubin-Induced Neurologic Dysfunction
Lois Johnson, MD, FAAP,* and Vinod K. Bhutani, MD, FAAP†
We believe that the syndrome of bilirubin-induced neurologic dysfunction [BIND] represents a spectrum of neurologic manifestations among vulnerable infants who have experienced an exposure to bilirubin of lesser degree than generally described in previous publications.Clinical neuro-motor manifestations extend to a range of subtle processing disorders with objective disturbances of visual-motor, auditory, speech, cognition, and language among infants with a previous history of moderate-to-severe hyperbilirubinemia of varied duration. Confounding effects include prematurity, hemolysis, perinatal-neonatal complications, altered bilirubin-albumin binding, severity andduration of bilirubin exposure, and the individual vulnerability of the infant related to genetic, family, social, and educational predilection, regardless of the cause of neonatal jaundice. Tools to better assess BIND specific domains of multisensory processing disorders, identified by pyschometric, audiologic, speech, language and visual-motor, and neuromotor examination would allow forprospective surveillance of infants at risk for the syndrome. Semin Perinatol 35:101-113 © 2011 Published by Elsevier Inc. KEYWORDS kernicterus, bilirubin induced neurologic dysfunction, jaundice, hyperbilirubinemia, bilirubin encephalopathy, newborn jaundice

nconjugated bilirubin is a known and well-established neurotoxin. At excessively high concentrations, it causes permanent neural damage in newborninfants, ie, “chronic bilirubin encephalopathy” or kernicterus.1-4 Listed in Table 1 are the definitions we use to categorize severity of hyperbilirubinemia as low risk (mild), significant (moderate), severe (high), extreme (excessive), and hazardous, qualified by their total serum bilirubin (TSB) percentiles for postnatal age in hours in term healthy infants.5 Studies in term infants withhyperbilirubinemia attributable to hemolysis6 from rhesus (Rh) blood type incompatibility have shown that kernicterus occurred in more than 50% of infants with TSB levels 30 mg/dL (513 mol/L) but rarely occurred at levels 20 mg/dL (427 mol/L). More recently, term infants with TSB levels 35 mg/dL (599 mol/L), regardless of etiology, rapidity of intervention or clinical assessment of severity of acutebilirubin toxicity (encephalopathy), either before or
*Pennsylvania Center for Kernicterus, Philadelphia, PA. †Division of Neonatal-Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Stanford, CA. Address reprint requests to Vinod K. Bhutani, MD, FAAP, Stanford University School of Medicine, Lucile Packard Children’sHospital, Department of Pediatrics, Division of Neonatal and Developmental Medicine, 750 Welch Ave #315, Stanford, CA 94304. E-mail: bhutani@stanford.edu

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after treatment, have been observed to develop some degree of irreversible sequelae.7 As assessed in the usual clinical setting, the diagnosis of acute bilirubin encephalopathy (ABE) may be a poor predictor of irreversible sequelae. Especially inthe preterm infant, its clinical signs are often subtle and indistinct.8 The precise threshold at which bilirubin may be neurotoxic in a given infant is unknown. A better understanding of the patho-physiology as it is related to the rate of hemolysis and bilirubin-albumin binding along with the expedited development of their respective assays will help resolve this uncertainty.9 The importanceand possibility of identifying individual differences in ability to destroy bilirubin in the brain and expedite or delay its neuronal exit, also needs to be addressed. Concerns regarding subtle manifestations of acute or chronic bilirubin-induced neurologic dysfunction (BIND), either because of hyperbilirubinemia that is not generally considered severe enough to need treatment or to prolonged...