Special Feature Deﬁnition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND)

Steven M. Shapiro, MD and evolving deﬁnitions of bilirubin-induced brain injury are discussed.

Kernicterus, currently used to describe both the neuropathology of bilirubin- DETERMINANTS OF NEURONAL INJURY BY BILIRUBIN induced brain injury and its associated clinical findings, is a complex syndrome. The neurobiology of kernicterus, including the determinants and The risk of neuronal injury by bilirubin is primarily determined by mechanisms of neuronal injury, is discussed along with traditional and the concentration of unbound or ‘‘free’’ unconjugated bilirubin evolving definitions ranging from classical kernicterus with athetoid (Bf) and hydrogen ion (pH) in blood. Unconjugated bilirubin cerebral palsy, impaired upward gaze and deafness, to isolated conditions, (UCB) enters brain tissue as Bf when the blood’s bilirubin-binding for example, auditory neuropathy or dys-synchrony (AN/AD), and subtle capacity is exceeded, or when other displacing substances, for bilirubin-induced neurological dysfunction (BIND). The clinical expression example, sulfonamides, compete for bilirubin-binding sites on of BIND varies with location, severity, and time of assessment, influenced by albumin. Other important risk factors for kernicterus relate to the amount, duration and developmental age of exposure to excessive free neuronal susceptibility, including gestational age, infection or bilirubin. Although total serum bilirubin (TSB) is important, kernicterus sepsis, and hemolysis, especially Rh isoimmunization. Sepsis, other cannot be defined based solely on TSB. For study purposes kernicterus may neonatal inflammatory conditions, and prematurity may decrease be defined in term and near-term infants with TSB Z20 mg/dl using the bilirubin-binding affinity of albumin. abnormal muscle tone on examination, auditory testing diagnostic of AN/ Since total serum bilirubin (TSB) or UCB measures the AD, and magnetic resonance imaging showing bilateral lesions of globus bilirubin not in the brain but in the blood, the overwhelming pallidus±subthalamic nucleus. majority of which is bound to albumin, it is difficult to accurately Journal of Perinatology (2005) 25, 54–59. doi:10.1038/sj.jp.7211157 determine a ‘‘safe’’ level of TSB at which kernicterus or bilirubin- Published online 2 December 2004 induced brain injury will not occur. The blood–brain barrier has been considered to play an important role in protection of the brain from bilirubin toxicity; however, its disruption produces diffuse yellow staining, not the specific pattern of kernicterus.1 It has been recently suggested that the blood–brain barrier, through ATP- INTRODUCTION dependent export by transporter molecules, acts as a pump to Although kernicterus is a pathological term that describes the remove Bf from the brain and maintain the concentration gradient yellow staining of the deep nuclei of the brain, it is currently used of UCB from plasma to CSF.2 3 to describe not only the neuropathology of bilirubin-induced brain A meta-analysis of in vitro studies found that Bf, at slightly injury, but in addition, its associated clinical findings. The term above aqueous solubility, impairs mitochondrial function and the bilirubin encephalopathy is used to denote the clinical condition viability of astrocytes, and induces apoptosis in neurons. Higher associated with elevated bilirubin. While classical kernicterus is concentrations impair mitochondrial function and cellular well defined, we are beginning to develop definitions for more proliferation in neurons, and inhibit uptake of glutamate in subtle forms of kernicterus and the means to diagnose them. These astrocytes. The authors favor a role for small, soluble UCB include partial or isolated forms of bilirubin encephalopathy. In aggregates present at moderately supersaturated Bf levels in the this paper, the neurobiology of kernicterus including the often-reversible damage to mitochondria and possibly plasma determinants and mechanisms of neuronal injury, and traditional membranes of CNS cells that characterize the early stages of bilirubin encephalopathy. Owing to the multiple physical states of unbound UCB, including monomers, oligomers, charge-stabilized colloidal microsuspension and visible aggregates, the authors Division of Child Neurology, Departments of Neurology and Pediatrics, Medical College of Virginia Campus, Virginia Commonwealth University Medical Center, Richmond, VA, USA hypothesized that a high concentration of UCB for a short time is not equivalent to a low UCB for a long exposure. Address correspondence and reprint requests to Steven M. Shapiro, MD, Division of Pediatric Neurology, Departments of Neurology, Medical College of Virginia Campus, Virginia Another important determinant of toxicity is neuronal Commonwealth University Medical Center, PO Box 980211, Richmond, VA 33298-0211, USA. susceptibility. We examined cerebella of jaundiced Gunn rats made

toxic at various developmental ages and found that neurons auditory neuropathy (AN), also known as auditory dys-synchrony undergoing differentiation at the time of exposure were the most (AD). Abnormalities of the brainstem oculomotor nuclei are susceptible to cell death, while those that were slightly more or less associated with strabismus and gaze palsies, especially paresis of mature showed only transient changes and seemed much less upgaze. sensitive.4 This supports the presence of a critical or sensitive period In the auditory system, bilirubin does not appear to affect either when elevated bilirubin may be most toxic to neuronal inner or outer hair cells, although it may affect the cell bodies of development. the auditory nerve in the spiral ganglia. The most sensitive area in Necrosis is one mechanism of brain cell injury from bilirubin. the auditory system seems to be in the brainstem auditory nuclei. There is now good evidence from in vitro studies that bilirubin The auditory pathways in the thalamus and cortex do not seem to induces apoptosis, supporting previous in vivo observations be affected. These auditory brainstem nuclei cannot be imaged showing neuroanatomical changes. Bilirubin also interferes with with currently available techniques, but can be assessed intracellular calcium homeostasis through several mechanisms neurophysiologically. The mechanical structure of the inner ear is such as altering function and expression of calcium/calmodulin assessed clinically with otoacoustic emissions (OAEs), and the outer kinase II.5,6 selectively decreasing calcium binding proteins in hair cells of the inner ear are tested with cochlear microphonic susceptible brainstem areas,7,8 and increasing intracellular calcium responses (CMs). Both OAEs and CMs are normal in neonates with in cultured neurons.9 Another possibility is that it sensitizes the cell bilirubin-induced injury. The auditory brainstem response (ABR), to other injuries, triggering apoptosis. Bilirubin may also kill cells a.k.a. brainstem auditory evoked potential (BAEP) or response by causing neuronal hyperexcitability perhaps via excitatory (BAER), is absent or abnormal, reﬂecting damage to the auditory amino-acid neurotoxicity, or it may have other membrane or nerve (wave I) and/or, more likely, auditory brainstem nuclei neurotransmitter effects. Finally, it may act by interfering with (waves III and V). mitochondrial respiration and energy production. The basal ganglia can be imaged with magnetic resonance Overall, one can hypothesize that bilirubin damages brain tissue imaging (MRI), the signature of which is bilateral damage of the cells via necrosis and apoptosis, either alone or in combination, in globus pallidus. The subthalamic nucleus can sometimes be seen a neuroanatomical distribution dependent on the amount, and is characteristically affected. One hypothesis is that destroying duration, and the developmental timing of exposure of sensitive the output of the globus pallidus reduces inhibitory input to the brain tissue to free bilirubin. With this perspective, one expects the motor thalamus, and dysinhibition of the thalamus leads to the neuroanatomical and clinical expression of injury to be complex, excessive movements of athetosis and dystonia in kernicterus.10 with different patterns of neuropathological damage and a range of The MRI damage of kernicterus differs from that of hypoxia– clinical expression. Different patterns of expression may relate to ischemia, which damages thalamus, cortex and periventricular (1) the amount and duration of exposure to free bilirubin (high- white matter, and the caudate and putamen, areas of the basal level, short-duration exposure may produce a different pattern of ganglia that are not affected in kernicterus. damage than a lower level, long-duration exposure), (2) variation in susceptibility of the developing nervous system, (3) the relative amount of necrosis vs apoptosis produced, and (4) whether surviving neurons become functionally normal or are more DEFINITIONS OF KERNICTERUS AND DIAGNOSTIC TOOLS susceptible to other stressors, either at the time of Classic Kernicterus hyperbilirubinemia or afterwards. The classical clinical expression of kernicterus can be divided into acute and chronic bilirubin encephalopathy. Acute bilirubin encephalopathy (ABE) consists of decreased feeding, lethargy, variable abnormal tone (hypotonia and/or hypertonia), high- NEUROPATHOLOGY OF KERNICTERUS pitched cry, retrocollis and opisthotonus, setting sun sign, fever, Kernicterus causes selective yellow staining in the basal ganglia, seizures, and death. Laboratory evidence ranges from increased especially the globus pallidus and subthalamic nucleus. Brainstem abnormal ABR interwave intervals I–III and I–V and decreased nuclei, especially the auditory (cochlear nucleus, inferior amplitude waves III and V to absent ABRs, and MRI shows acute colliculus, superior olivary complex), oculomotor and vestibular abnormalities in the globus pallidus and subthalamic nucleus. nuclei are especially vulnerable. Other susceptible areas are the Volpe has described three phases of ABE: initial, intermediate and cerebellum, especially Purkinje cells, and the hippocampus advanced.11 Abnormal ABRs may improve or normalize with especially the CA2 sector. The basal ganglia lesions are clinically exchange transfusion.12,13 correlated with the movement disorders of dystonia and athetosis. A bilirubin-induced neurological dysfunction (BIND) scoring Abnormalities of the auditory brainstem nuclei are associated with scale has been proposed as a tool to objectify the neonatal deafness, hearing loss, and a recently described entity known as neurological exam in infants with hyperbilirubinemia. The BIND

Journal of Perinatology 2005; 25:54–59 55 Shapiro Deﬁnition and Clinical Spectrum of Kernicterus

Score has not yet been validated, but could be a useful and simple deaf due to hyperbilirubinemia and kernicterus. OAE hearing research tool. screening alone will miss AN. Inexplicably, a number of children Chronic bilirubin encephalopathy is a clinical tetrad consisting with AN have lost OAE responses with time; in these children the of (1) a movement disorder consisting of not only of athetosis and CM remains. dystonia, but may also include spasticity and hypotonia, (2) The impaired upgaze of kernicterus may be difficult to detect, auditory dysfunction consisting of deafness or hearing loss and AN and may improve with age. There is anecdotal evidence of a central or AD, (3) oculomotor impairments especially impairment of visual impairment, which may be related to and need to be upgaze, but also lateral gaze impairments including strabismus, distinguished from an oculomotor apraxia due to nuclear or and (4) dental enamel hypoplasia of the deciduous teeth. The supranuclear involvement of oculomotor pathways. Dental neurological findings correspond to the neuropathological lesions dysplasia affects only the deciduous (baby) teeth, and with proper in (1) basal ganglia, specifically the globus pallidus, subthalamic dental care, the permanent teeth are unaffected. The enamel flakes nucleus, cerebellum and brainstem nuclei involved with truncal off and may be discolored and a line of demarcation may appear tone and posture, (2) auditory brainstem nuclei and perhaps the between normal and abnormal. auditory nerve, and (3) brainstem oculomotor nuclei. Kernicterus may be a comorbidity in children with dramatic In the ‘‘athetoid’’ form of cerebral palsy due to kernicterus, the illnesses requiring emergency surgery who fail to receive treatment abnormal muscle tone does not usually lead to fixed postures and for hyperbilirubinemia during the perioperative period. contractions, and the sparing of the cortex and subcortical white matter tracts usually results in normal intelligence, however, there Subtle Kernicterus may be specific learning disorders and abnormal sensory function There is evidence that less severe hyperbilirubinemia can produce or sensorimotor integration. In the most severe cases, individuals subtle encephalopathy, referred to as BIND, as noted above.20.Subtle may appear to have severe mental retardation but in fact have bilirubin encephalopathies consisting of neurological, cognitive, normal or superior intelligence but are trapped in immobile, learning and perhaps movement disorders,21–26 isolated hearing dysfunctional bodies and cannot voluntarily move, hear, sign, type loss,27,28 and auditory dysfunction, for example, AN29,30 are or communicate effectively. associated with less severe hyperbilirubinemia and bilirubin Auditory system abnormalities with hyperbilirubinemia have neurotoxicity. There is an association of isolated hearing loss27,31,32 been reviewed recently,14 and found to primarily involve brainstem and cognitive dysfunction22,24,33 with hyperbilirubinemia nuclei, as well as frequently being associated with hearing loss or without classical kernicterus, and measures of Bf predict these deafness. The newly described term, ‘‘auditory neuropathy outcomes better than TSB or UCB.22,24 Hyperbilirubinemia can also (AN)’’,15,16 also called ‘‘auditory dys-synchrony,’’17,18 functionally produce isolated AN without other classic signs of defined as absent or abnormal ABRs with normal tests of inner ear kernicterus.16,29,30,34,35 function, was described in children with hearing loss due to An important clinical concern regarding subtle kernicterus or hyperbilirubinemia in 1979.19 BIND is AN, defined as an absent or abnormal ABR, and a normal The ABR (a.k.a. BAEP) is a noninvasive, scalp-recorded response OAE or CM. Although there is usually some hearing loss, children to an auditory stimulus, usually a click. It may be used for hearing with AN may not have hearing loss, and may have a normal screening in newborns, or to assess neurological dysfunction. audiogram, even though they have abnormal processing of sound. Preceding the ABR is a cochlear microphonic (CM) response, Conduction in the large, heavily myelinated, fast conducting arising from the outer hair cells of the inner ear. In AN the CM afferent auditory pathways is not synchronized. Individuals with response persists even when the ABR is totally abolished. ‘‘Giant’’ this disorder have problems with sound localization, discriminating CM responses have been reported with AN 17 which may be speech in noise without visual cues, for example, using the misinterpreted to be ABR waves, giving the false impression of a telephone. The pure-tone audiogram may be normal. Some normal ABR. Abnormal ABRs may improve after exchange abnormal ABRs early in development become normal, but this does transfusion. not necessarily mean the auditory system has become normal, and Another method of hearing screening is called otoacoustic a central auditory processing disorder may be expressed later in emissions (OAEs), an echo recorded in the ear canal that assesses life. Preliminary reports indicate that many cases of AN due to the mechanical integrity of the inner ear. Commonly, children hyperbilirubinemia do not improve.36,37 with hearing loss have abnormal function of the inner ear and Children with AN and profound hearing loss appear to respond abnormal OAE. However, in AN hearing loss localized either in the favorably to cochlear implantation.38 With AN due to inner hair cells of the inner ear, in the auditory nerve, or centrally hyperbilirubinemia, the responsible lesion in the brain stem or in the brainstem, then the OAE (and CM) is normal. Since auditory nerve is likely to be proximal to the cochlear implant, but hyperbilirubinemia affects the auditory brainstem and perhaps the several previously deaf children with AN due to hyperbilirubinemia auditory nerve, OAEs along with CM will be normal in children are able to hear and speak after implantation.

56 Journal of Perinatology 2005; 25:54–59 Deﬁnition and Clinical Spectrum of Kernicterus Shapiro

There have also been suggestions of a relationship of moderate The severity of kernicterus varies from mild, moderate to severe, levels of hyperbilirubinemia to the subsequent development of with a wide range of severity manifested in both children and other disorders such as attention deficit hyperactivity disorder adults. Some are very mildly affected, some moderately affected (ADHD), Parkinson disease, and even autism, but so far, there is with athetoid or choreoathetoid movements and dystonic postures. no evidence to support these contentions. These patients may be able to talk, and, with difficulty, feed and ambulate unassisted. Severely affected individuals are wheelchair- bound, talk with great difficultly, and have severe spasticity and PROPOSED DEFINITIONS OF KERNICTERUS painful muscle cramps. Simultaneously, AN and hearing loss may Three factors appear to be important in classifying children and vary from mild to severe. adults with kernicterus: location, severity, and time. Taken The factor time may refer to the time at which the injury is together, these three factors form a more complex, three- assessed, acute, subacute or chronic, and has been described dimensional picture of kernicterus and BIND (Figure 1). Location above. Another use of the term time can refer to the may vary from isolated to mixed or classic. Isolated kernicterus developmental time of injury, that is, the neurodevelopmental encompasses isolated symptoms limited to only one system, either age (conceptual age ¼ gestational age plus chronological age) at isolated auditory symptoms, for example, AN with no motor the time of exposure to bilirubin neurotoxicity. However, (movement) problems or isolated motor symptoms with a normal developmental time of injury may best be considered an important auditory system. However, most are not strictly isolated but have independent variable that may affect outcome, rather than used as findings in another system. These can then more properly be part of a clinical definition. classified as mixed, either auditory- or motor-predominate. Kernicterus subtypes and the pattern of involvement may relate Auditory-predominate kernicterus may manifest as moderate or to factors such as developmental age, and the amount and severe AN, with or without a hearing loss, with minimal or mild duration of exposure to bilirubin. In a preliminary review of 18 motor symptoms and perhaps a normal or slightly abnormal cases of kernicterus, AN with no or minimal motor involvement, was seen in four children, three of whom were r34 weeks globus pallidus or a subthalamic nucleus as seen in MRI. 37 Similarly, patients with athetosis, dystonia and other movement gestation at birth, and had peak TSBs of r24 mg/dl. Since the disorders may have minimal auditory problems, and may be auditory system develops and myelinates earlier than motor classified as motor-predominant kernicterus. pathways, we hypothesize that earlier exposure to bilirubin toxicity during development preferentially affects the auditory nervous system. There is some preliminary evidence that premature infants with lower levels of hyperbilirubinemia tend to develop auditory- predominant kernicterus:37 four of 18 patients referred to above had auditory-predominant kernicterus, and three of these four were r34 weeks gestation with TSBs of 20–24 mg/dl, and the fourth child was a term, Rh sensitized neonate with a rapid rise of bilirubin followed by two double volume exchange transfusions.

PROPOSED RESEARCH DEFINITIONS OF KERNICTERUS A small group of investigators, Dr. Michael J. Painter, past president and representative of the Child Neurology Society, Dr. Lois Johnson and Dr. Vinod K. Bhutani and the author met to establish definitions of kernicterus that could be used for research on infants with exposure to hyperbilirubinemia. We searched for key, objective factors that can be assessed at three, 9 and 18 months Figure 1. Three factors important in classifying children and adults of age. with kernicterus (see text for details). Note that the heights of the bars For research purposes, we propose defining kernicterus in term do not represent a relationship between location and time and the or near-term infants with peak TSB Z20 mg/dl at 3 months as severity of the response, but merely represent illustrated that three ‘‘certain kernicterus’’ if there is (1) abnormal muscle tone on factors, severity, location and time, can be used to catagorize clinical examination, (2) an abnormal ABR with a normal OAE or CM, kernicterus. plus (3) an abnormal MRI with the specific abnormality in the

Journal of Perinatology 2005; 25:54–59 57 Shapiro Deﬁnition and Clinical Spectrum of Kernicterus

globus pallidus and/or the subthalamic nucleus. If two of three are Gunn rats during development: a quantitative light microscopic analysis. present, with one being an abnormality of muscle tone, we propose Acta Neuropathol (Berl) 2000;99(4):393–401. calling this ‘‘probable kernicterus’’. If any one of three were 7. Shaia WT, Shapiro SM, Heller AJ, Galiani DL, Sismanis A, Spencer RF. abnormal, it would be classified as ‘‘possible kernicterus’’. Immunohistochemical localization of calcium-binding proteins in the At 9–18 months of age, the classification of ‘‘probable brainstem vestibular nuclei of the jaundiced Gunn rat. Hear Res kernicterus’’ at 3 months becomes certain if now there is (a) a 2002;173(1–2):82–90. hyperkinetic dystonia, for example, athetoid or dystonic CP, (b) 8. Spencer RF, Shaia WT, Gleason AT, Sismanis A, Shapiro SM. Changes in calcium-binding protein expression in the auditory brainstem nuclei of the abnormal vertical gaze, and (c) dental enamel dysplasia. If the jaundiced Gunn rat. Hear Res 2002;171(1–2):129–41. diagnosis was ‘‘possible’’ at 3 months and any two of the three 9. Shapiro SM, Churn SB, Pal S, Limbrick DD, De Lorenzo RJ. Bilirubin above are abnormal at 9–18 months, the diagnosis would become alters intracellular calcium homeostasis. Pediatr Res 1998;42(42, ‘‘probable.’’ Finally, if the classification was ‘‘not kernicterus’’ at Part 2):195A. 3 months and now two of the three abnormalities above are present 10. Johnston MV, Hoon Jr AH. Possible mechanisms in infants for selective basal at 9–18 months, the classification would change to ‘‘possible ganglia damage from asphyxia, kernicterus, or mitochondrial encephalo- kernicterus’’. It should be emphasized that these are proposed pathies. J Child Neurol 2000;15(9):588–91. working definitions and research questions that are based on 11. Volpe JJ. Bilirubin and brain injury. In: Volpe JJ. editor. Neurology of the clinical experience and the literature, but must be validated with Newborn. Philadelphia: WB Saunders; 2001. p. 490–514. prospective and perhaps retrospective studies. 12. Wennberg RP, Ahlfors CE, Bickers R, McMurtry CA, Shetter JL. Abnormal In conclusion, kernicterus is a complex clinical and auditory brainstem response in a newborn infant with hyperbilirubinemia: neuropathological syndrome ranging from isolated conditions such improvement with exchange transfusion. J Pediatr 1982;100(4):624–6. as AN and subtle BIND to classical kernicterus with athetoid CP, 13. Nwaesei CG, Van Aerde J, Boyden M, Perlman M. Changes in auditory brainstem responses in hyperbilirubinemic infants before and after impaired upgaze, and deafness. The clinical expression of bilirubin exchange transfusion. Pediatr 1984;74(5):800–3. neurotoxicity varies with location, severity, and time of assessment, 14. Shapiro SM, Nakamura H. Bilirubin and the auditory system. J Perinatol and is influenced by factors including the amount, duration and 2001;21(Suppl 1):S52–5 (discussion S59–62). developmental age of exposure to excessive free bilirubin. Although 15. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy. total serum bilirubin is an important risk factor, kernicterus Brain 1996;119(Part 3):741–53. cannot be defined based on total serum bilirubin alone. We suggest 16. Deltenre P, Mansbach AL, Bozet C, Clercx A, Hecox KE. Auditory neuropathy: that kernicterus may be defined for study purposes in term and a report on three cases with early onsets and major neonatal illnesses. near-term infants with total bilirubin Z20 mg/dl using abnormal Electroencephalogr Clin Neurophysiol 1997;104(1):17–22. muscle tone on neurological examination, auditory 17. Berlin CI, Bordelon J, St John P, et al. Reversing click polarity may uncover neurophysiological testing (ABR a.k.a. BAEP), and MRI. There are auditory neuropathy in infants. Ear Heart 1998;19(1):37–47. also a number of unresolved issues regarding the neurobiology of 18. Berlin CI, Morlet T, Hood LJ. Auditory neuropathy/dyssynchrony: its kernicterus, clinical definition and classification as noted in this diagnosis and management. Pediatr Clin North Am 2003;50(2):331–40 vii–viii. paper. 19. Chisin R, Perlman M, Sohmer H. Cochlear and brain stem responses in hearing loss following neonatal hyperbilirubinemia. Ann Otol 1979;88: 352–7. References 20. Volpe JJ. Bilirubin and brain injury. In: Volpe JJ. editor. Neurology of the 1. Levine RL, Fredericks WR, Rapoport SI. Clearance of bilirubin from rat Newborn. Philadelphia: WB Saunders Co; 1981. p. 336–56. brain after reversible osmotic opening of the blood–brain barrier. Pediatr 21. Hyman CB, Keaster J, Hanson V, et al. CNS abnormalities after neonatal Res 1985;19(10):1040–3. hemolytic disease or hyperbilirubinemia. A prospective study of 405 patients. 2. Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts of bilirubin Am J Dis Child 1969;117:395–405. encephalopathy. Eur J Clin Invest 2003;33(11):988–97. 22. Johnson L, Boggs TR. Bilirubin-dependent brain damage: Incidence and 3. Ostrow JD, Pascolo L, Tiribelli C. Reassessment of the unbound indications for treatment. In: Odell GB, Schaffer R, Sionpoulous AP. editors. concentrations of unconjugated bilirubin in relation to neurotoxicity in Phototherapy in the Newborn: An Overview 1974. Washington: National vitro. Pediatr Res 2003;54(1):98–104. Academy of Sciences. p. 122–49. 4. Conlee JW, Shapiro SM. Development of cerebellar hypoplasia in jaundiced 23. Naeye RL. Amniotic fluid infections, neonatal hyperbilirubinemia and Gunn rats treated with sulfadimethoxine: a quantitative light microscopic psychomotor impairment. Pediatr 1978;62:497–503. analysis. Acta Neuropathol 1997;93:450–60. 24. Odell GB, Storey GN, Rosenberg LA. Studies in kernicterus III. The 5. Churn SB, DeLorenzo RJ, Shapiro SM. Bilirubin induces a calcium- saturation of serum proteins with bilirubin during neonatal life and its dependent inhibition of multifunctional Ca2+/calmodulin-dependent relationship to brain damage at five years. J Pediatr 1970;76:12–21. kinase II activity in vitro. Pediatr Res 1995;38:949–54. 25. Rubin RA, Balow B, Fisch RO. Neonatal serum bilirubin levels related to 6. Conlee JW, Shapiro SM, Churn SB. Expression of the alpha and beta cognitive development at ages 4 through 7 years. J Pediatr 1979;94(4): subunits of Ca2+/calmodulin kinase II in the cerebellum of jaundiced 601–4.

58 Journal of Perinatology 2005; 25:54–59 Deﬁnition and Clinical Spectrum of Kernicterus Shapiro

26. Scheidt PC. Toxicity to bilirubin in neonates: infant development during 33. Seidman DS, Paz I, Stevenson DK, Laor A, Danon YL, Gale R. Neonatal first year in relation to maximal neonatal serum bilirubin concentration. J hyperbilirubinemia and physical and cognitive performance at 17 years of Pediatr 1977;92:292–7. age. Pediatr 1991;88(4):828–33. 27. Bergman I, Hirsch RP, Fria TJ, Shapiro SM, Holzman I, Painter MJ. Cause of 34. Yilmaz Y, Degirmenci S, Akdas F, et al. Prognostic value of auditory hearing loss in the high-risk premature infant. J Pediatr 1985;106(1):5–101. brainstem response for neurologic outcome in patients with neonatal 28. Salamy A, Eldredge L, Tooley WH. Neonatal status and hearing loss in high- indirect hyperbilirubinemia. J Child Neurol 2001;16(10):772–5. risk infants. J Pediatr 1989;114(5):847–52. 35. Stein L, Tremblay K, Pasternak J, Banerjee S, Lindemann K. Auditory 29. Rance G, Beer DE, Cone-Wesson B, et al. Clinical findings for a group of brainstem neuropathy and elevated bilirubin levels. Semin Hearing infants and young children with auditory neuropathy. Ear Heart 1996;17:197–213. 1999;20(3):238–52. 36. Shapiro SM, Rosen JR, Dixon KT. Auditory brainstem response (ABR) 30. Simmons JL, Beauchaine KL. Auditory neuropathy: case study with abnormalities and auditory neuropathy in children with kernicterus. Pediatr hyperbilirubinemia. J Am Acad Audiol 2000;11(6):337–47. Res 2002;51(4 Part 2):340A. 31. de Vries LS, Lary S, Whitelaw AG, Dubowitz LM. Relationship of serum 37. Shapiro SM, Daymont MJ. Patterns of kernicterus related to neonatal bilirubin levels and hearing impairment in newborn infants. Early Hum hyperbilirubinemia and gestational age. Pediatr Res 2003;53(4 Part Dev 1987;15(5):269–77. 2):398A–9A. 32. de Vries LS, Lary S, Dubowitz LMS. Relationship of serum bilirubin levels to 38. Shallop JK, Peterson A, Facer GW, Fabry LB, Driscoll CL. Cochlear implants ototoxicity and deafness in high-risk, low birth-weight infants. Pediatr in five cases of auditory neuropathy: postoperative findings and progress. 1985;76(3):351–4. Laryngoscope 2001;111(4 Part 1):555–62.

Journal of Perinatology 2005; 25:54–59 59