Special Feature - Nature

Special Feature Definition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND) Steven M. Shapiro, MD

Kernicterus, currently used to describe both the neuropathology of bilirubininduced brain injury and its associated clinical findings, is a complex syndrome. The neurobiology of kernicterus, including the determinants and mechanisms of neuronal injury, is discussed along with traditional and evolving definitions ranging from classical kernicterus with athetoid cerebral palsy, impaired upward gaze and deafness, to isolated conditions, for example, auditory neuropathy or dys-synchrony (AN/AD), and subtle bilirubin-induced neurological dysfunction (BIND). The clinical expression of BIND varies with location, severity, and time of assessment, influenced by the amount, duration and developmental age of exposure to excessive free bilirubin. Although total serum bilirubin (TSB) is important, kernicterus cannot be defined based solely on TSB. For study purposes kernicterus may be defined in term and near-term infants with TSB Z20 mg/dl using abnormal muscle tone on examination, auditory testing diagnostic of AN/ AD, and magnetic resonance imaging showing bilateral lesions of globus pallidus±subthalamic nucleus. Journal of Perinatology (2005) 25, 54–59. doi:10.1038/sj.jp.7211157 Published online 2 December 2004

INTRODUCTION Although kernicterus is a pathological term that describes the yellow staining of the deep nuclei of the brain, it is currently used to describe not only the neuropathology of bilirubin-induced brain injury, but in addition, its associated clinical findings. The term bilirubin encephalopathy is used to denote the clinical condition associated with elevated bilirubin. While classical kernicterus is well defined, we are beginning to develop definitions for more subtle forms of kernicterus and the means to diagnose them. These include partial or isolated forms of bilirubin encephalopathy. In this paper, the neurobiology of kernicterus including the determinants and mechanisms of neuronal injury, and traditional

Division of Child Neurology, Departments of Neurology and Pediatrics, Medical College of Virginia Campus, Virginia Commonwealth University Medical Center, Richmond, VA, USA Address correspondence and reprint requests to Steven M. Shapiro, MD, Division of Pediatric Neurology, Departments of Neurology, Medical College of Virginia Campus, Virginia Commonwealth University Medical Center, PO Box 980211, Richmond, VA 33298-0211, USA.

and evolving definitions of bilirubin-induced brain injury are discussed.

DETERMINANTS OF NEURONAL INJURY BY BILIRUBIN The risk of neuronal injury by bilirubin is primarily determined by the concentration of unbound or ‘‘free’’ unconjugated bilirubin (Bf) and hydrogen ion (pH) in blood. Unconjugated bilirubin (UCB) enters brain tissue as Bf when the blood’s bilirubin-binding capacity is exceeded, or when other displacing substances, for example, sulfonamides, compete for bilirubin-binding sites on albumin. Other important risk factors for kernicterus relate to neuronal susceptibility, including gestational age, infection or sepsis, and hemolysis, especially Rh isoimmunization. Sepsis, other neonatal inflammatory conditions, and prematurity may decrease the bilirubin-binding affinity of albumin. Since total serum bilirubin (TSB) or UCB measures the bilirubin not in the brain but in the blood, the overwhelming majority of which is bound to albumin, it is difficult to accurately determine a ‘‘safe’’ level of TSB at which kernicterus or bilirubininduced 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 ATPdependent export by transporter molecules, acts as a pump to remove Bf from the brain and maintain the concentration gradient of UCB from plasma to CSF.2 A meta-analysis of in vitro studies3 found that Bf, at slightly above aqueous solubility, impairs mitochondrial function and the viability of astrocytes, and induces apoptosis in neurons. Higher concentrations impair mitochondrial function and cellular proliferation in neurons, and inhibit uptake of glutamate in astrocytes. The authors favor a role for small, soluble UCB aggregates present at moderately supersaturated Bf levels in the often-reversible damage to mitochondria and possibly plasma 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 hypothesized that a high concentration of UCB for a short time is not equivalent to a low UCB for a long exposure. Another important determinant of toxicity is neuronal susceptibility. We examined cerebella of jaundiced Gunn rats made Journal of Perinatology 2005; 25:54–59 r 2005 Nature Publishing Group All rights reserved. 0743-8346/05 $30

54

www.nature.com/jp

Definition and Clinical Spectrum of Kernicterus

toxic at various developmental ages and found that neurons undergoing differentiation at the time of exposure were the most susceptible to cell death, while those that were slightly more or less mature showed only transient changes and seemed much less sensitive.4 This supports the presence of a critical or sensitive period when elevated bilirubin may be most toxic to neuronal development. Necrosis is one mechanism of brain cell injury from bilirubin. There is now good evidence from in vitro studies that bilirubin induces apoptosis, supporting previous in vivo observations showing neuroanatomical changes. Bilirubin also interferes with intracellular calcium homeostasis through several mechanisms such as altering function and expression of calcium/calmodulin kinase II.5,6 selectively decreasing calcium binding proteins in susceptible brainstem areas,7,8 and increasing intracellular calcium in cultured neurons.9 Another possibility is that it sensitizes the cell to other injuries, triggering apoptosis. Bilirubin may also kill cells by causing neuronal hyperexcitability perhaps via excitatory amino-acid neurotoxicity, or it may have other membrane or neurotransmitter effects. Finally, it may act by interfering with mitochondrial respiration and energy production. Overall, one can hypothesize that bilirubin damages brain tissue cells via necrosis and apoptosis, either alone or in combination, in a neuroanatomical distribution dependent on the amount, duration, and the developmental timing of exposure of sensitive brain tissue to free bilirubin. With this perspective, one expects the neuroanatomical and clinical expression of injury to be complex, with different patterns of neuropathological damage and a range of clinical expression. Different patterns of expression may relate to (1) the amount and duration of exposure to free bilirubin (highlevel, short-duration exposure may produce a different pattern of 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 susceptible to other stressors, either at the time of hyperbilirubinemia or afterwards.

NEUROPATHOLOGY OF KERNICTERUS Kernicterus causes selective yellow staining in the basal ganglia, especially the globus pallidus and subthalamic nucleus. Brainstem nuclei, especially the auditory (cochlear nucleus, inferior colliculus, superior olivary complex), oculomotor and vestibular nuclei are especially vulnerable. Other susceptible areas are the cerebellum, especially Purkinje cells, and the hippocampus especially the CA2 sector. The basal ganglia lesions are clinically correlated with the movement disorders of dystonia and athetosis. Abnormalities of the auditory brainstem nuclei are associated with deafness, hearing loss, and a recently described entity known as Journal of Perinatology 2005; 25:54–59

Shapiro

auditory neuropathy (AN), also known as auditory dys-synchrony (AD). Abnormalities of the brainstem oculomotor nuclei are associated with strabismus and gaze palsies, especially paresis of upgaze. In the auditory system, bilirubin does not appear to affect either inner or outer hair cells, although it may affect the cell bodies of the auditory nerve in the spiral ganglia. The most sensitive area in the auditory system seems to be in the brainstem auditory nuclei. The auditory pathways in the thalamus and cortex do not seem to be affected. These auditory brainstem nuclei cannot be imaged with currently available techniques, but can be assessed neurophysiologically. The mechanical structure of the inner ear is assessed clinically with otoacoustic emissions (OAEs), and the outer hair cells of the inner ear are tested with cochlear microphonic responses (CMs). Both OAEs and CMs are normal in neonates with bilirubin-induced injury. The auditory brainstem response (ABR), a.k.a. brainstem auditory evoked potential (BAEP) or response (BAER), is absent or abnormal, reflecting damage to the auditory nerve (wave I) and/or, more likely, auditory brainstem nuclei (waves III and V). The basal ganglia can be imaged with magnetic resonance imaging (MRI), the signature of which is bilateral damage of the globus pallidus. The subthalamic nucleus can sometimes be seen and is characteristically affected. One hypothesis is that destroying the output of the globus pallidus reduces inhibitory input to the motor thalamus, and dysinhibition of the thalamus leads to the excessive movements of athetosis and dystonia in kernicterus.10 The MRI damage of kernicterus differs from that of hypoxia– ischemia, which damages thalamus, cortex and periventricular white matter, and the caudate and putamen, areas of the basal ganglia that are not affected in kernicterus.

DEFINITIONS OF KERNICTERUS AND DIAGNOSTIC TOOLS Classic Kernicterus 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), highpitched cry, retrocollis and opisthotonus, setting sun sign, fever, seizures, and death. Laboratory evidence ranges from increased abnormal ABR interwave intervals I–III and I–V and decreased amplitude waves III and V to absent ABRs, and MRI shows acute abnormalities in the globus pallidus and subthalamic nucleus. Volpe has described three phases of ABE: initial, intermediate and advanced.11 Abnormal ABRs may improve or normalize with exchange transfusion.12,13 A bilirubin-induced neurological dysfunction (BIND) scoring scale has been proposed as a tool to objectify the neonatal neurological exam in infants with hyperbilirubinemia. The BIND 55

Shapiro

Score has not yet been validated, but could be a useful and simple research tool. Chronic bilirubin encephalopathy is a clinical tetrad consisting of (1) a movement disorder consisting of not only of athetosis and dystonia, but may also include spasticity and hypotonia, (2) auditory dysfunction consisting of deafness or hearing loss and AN or AD, (3) oculomotor impairments especially impairment of upgaze, but also lateral gaze impairments including strabismus, and (4) dental enamel hypoplasia of the deciduous teeth. The neurological findings correspond to the neuropathological lesions in (1) basal ganglia, specifically the globus pallidus, subthalamic nucleus, cerebellum and brainstem nuclei involved with truncal tone and posture, (2) auditory brainstem nuclei and perhaps the auditory nerve, and (3) brainstem oculomotor nuclei. In the ‘‘athetoid’’ form of cerebral palsy due to kernicterus, the abnormal muscle tone does not usually lead to fixed postures and contractions, and the sparing of the cortex and subcortical white matter tracts usually results in normal intelligence, however, there may be specific learning disorders and abnormal sensory function or sensorimotor integration. In the most severe cases, individuals may appear to have severe mental retardation but in fact have normal or superior intelligence but are trapped in immobile, dysfunctional bodies and cannot voluntarily move, hear, sign, type or communicate effectively. Auditory system abnormalities with hyperbilirubinemia have been reviewed recently,14 and found to primarily involve brainstem nuclei, as well as frequently being associated with hearing loss or deafness. The newly described term, ‘‘auditory neuropathy (AN)’’,15,16 also called ‘‘auditory dys-synchrony,’’17,18 functionally defined as absent or abnormal ABRs with normal tests of inner ear function, was described in children with hearing loss due to hyperbilirubinemia in 1979.19 The ABR (a.k.a. BAEP) is a noninvasive, scalp-recorded response to an auditory stimulus, usually a click. It may be used for hearing screening in newborns, or to assess neurological dysfunction. Preceding the ABR is a cochlear microphonic (CM) response, arising from the outer hair cells of the inner ear. In AN the CM response persists even when the ABR is totally abolished. ‘‘Giant’’ CM responses have been reported with AN 17 which may be misinterpreted to be ABR waves, giving the false impression of a normal ABR. Abnormal ABRs may improve after exchange transfusion. Another method of hearing screening is called otoacoustic emissions (OAEs), an echo recorded in the ear canal that assesses the mechanical integrity of the inner ear. Commonly, children with hearing loss have abnormal function of the inner ear and abnormal OAE. However, in AN hearing loss localized either in the inner hair cells of the inner ear, in the auditory nerve, or centrally in the brainstem, then the OAE (and CM) is normal. Since hyperbilirubinemia affects the auditory brainstem and perhaps the auditory nerve, OAEs along with CM will be normal in children 56


deaf due to hyperbilirubinemia and kernicterus. OAE hearing screening alone will miss AN. Inexplicably, a number of children with AN have lost OAE responses with time; in these children the CM remains. The impaired upgaze of kernicterus may be difficult to detect, and may improve with age. There is anecdotal evidence of a central visual impairment, which may be related to and need to be distinguished from an oculomotor apraxia due to nuclear or supranuclear involvement of oculomotor pathways. Dental dysplasia affects only the deciduous (baby) teeth, and with proper dental care, the permanent teeth are unaffected. The enamel flakes off and may be discolored and a line of demarcation may appear between normal and abnormal. Kernicterus may be a comorbidity in children with dramatic illnesses requiring emergency surgery who fail to receive treatment for hyperbilirubinemia during the perioperative period. Subtle Kernicterus There is evidence that less severe hyperbilirubinemia can produce subtle encephalopathy, referred to as BIND, as noted above.20.Subtle bilirubin encephalopathies consisting of neurological, cognitive, learning and perhaps movement disorders,21–26 isolated hearing loss,27,28 and auditory dysfunction, for example, AN29,30 are associated with less severe hyperbilirubinemia and bilirubin neurotoxicity. There is an association of isolated hearing loss27,31,32 and cognitive dysfunction22,24,33 with hyperbilirubinemia without classical kernicterus, and measures of Bf predict these outcomes better than TSB or UCB.22,24 Hyperbilirubinemia can also produce isolated AN without other classic signs of kernicterus.16,29,30,34,35 An important clinical concern regarding subtle kernicterus or BIND is AN, defined as an absent or abnormal ABR, and a normal OAE or CM. Although there is usually some hearing loss, children with AN may not have hearing loss, and may have a normal audiogram, even though they have abnormal processing of sound. Conduction in the large, heavily myelinated, fast conducting afferent auditory pathways is not synchronized. Individuals with this disorder have problems with sound localization, discriminating speech in noise without visual cues, for example, using the telephone. The pure-tone audiogram may be normal. Some abnormal ABRs early in development become normal, but this does not necessarily mean the auditory system has become normal, and a central auditory processing disorder may be expressed later in life. Preliminary reports indicate that many cases of AN due to hyperbilirubinemia do not improve.36,37 Children with AN and profound hearing loss appear to respond favorably to cochlear implantation.38 With AN due to hyperbilirubinemia, the responsible lesion in the brain stem or auditory nerve is likely to be proximal to the cochlear implant, but several previously deaf children with AN due to hyperbilirubinemia are able to hear and speak after implantation. Journal of Perinatology 2005; 25:54–59


There have also been suggestions of a relationship of moderate levels of hyperbilirubinemia to the subsequent development of other disorders such as attention deficit hyperactivity disorder (ADHD), Parkinson disease, and even autism, but so far, there is no evidence to support these contentions.

PROPOSED DEFINITIONS OF KERNICTERUS Three factors appear to be important in classifying children and adults with kernicterus: location, severity, and time. Taken together, these three factors form a more complex, threedimensional picture of kernicterus and BIND (Figure 1). Location may vary from isolated to mixed or classic. Isolated kernicterus encompasses isolated symptoms limited to only one system, either isolated auditory symptoms, for example, AN with no motor (movement) problems or isolated motor symptoms with a normal auditory system. However, most are not strictly isolated but have findings in another system. These can then more properly be classified as mixed, either auditory- or motor-predominate. Auditory-predominate kernicterus may manifest as moderate or severe AN, with or without a hearing loss, with minimal or mild motor symptoms and perhaps a normal or slightly abnormal globus pallidus or a subthalamic nucleus as seen in MRI. Similarly, patients with athetosis, dystonia and other movement disorders may have minimal auditory problems, and may be classified as motor-predominant kernicterus.

Shapiro

The severity of kernicterus varies from mild, moderate to severe, with a wide range of severity manifested in both children and adults. Some are very mildly affected, some moderately affected with athetoid or choreoathetoid movements and dystonic postures. These patients may be able to talk, and, with difficulty, feed and ambulate unassisted. Severely affected individuals are wheelchairbound, talk with great difficultly, and have severe spasticity and painful muscle cramps. Simultaneously, AN and hearing loss may vary from mild to severe. The factor time may refer to the time at which the injury is assessed, acute, subacute or chronic, and has been described above. Another use of the term time can refer to the developmental time of injury, that is, the neurodevelopmental age (conceptual age ¼ gestational age plus chronological age) at the time of exposure to bilirubin neurotoxicity. However, developmental time of injury may best be considered an important independent variable that may affect outcome, rather than used as part of a clinical definition. Kernicterus subtypes and the pattern of involvement may relate to factors such as developmental age, and the amount and duration of exposure to bilirubin. In a preliminary review of 18 cases of kernicterus, AN with no or minimal motor involvement, was seen in four children, three of whom were r34 weeks gestation at birth, and had peak TSBs of r24 mg/dl.37 Since the auditory system develops and myelinates earlier than motor 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 auditorypredominant 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

Figure 1. Three factors important in classifying children and adults with kernicterus (see text for details). Note that the heights of the bars do not represent a relationship between location and time and the severity of the response, but merely represent illustrated that three factors, severity, location and time, can be used to catagorize clinical kernicterus. Journal of Perinatology 2005; 25:54–59

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 of age. For research purposes, we propose defining kernicterus in term or near-term infants with peak TSB Z20 mg/dl at 3 months as ‘‘certain kernicterus’’ if there is (1) abnormal muscle tone on examination, (2) an abnormal ABR with a normal OAE or CM, plus (3) an abnormal MRI with the specific abnormality in the 57

Shapiro

globus pallidus and/or the subthalamic nucleus. If two of three are present, with one being an abnormality of muscle tone, we propose calling this ‘‘probable kernicterus’’. If any one of three were abnormal, it would be classified as ‘‘possible kernicterus’’. At 9–18 months of age, the classification of ‘‘probable kernicterus’’ at 3 months becomes certain if now there is (a) a hyperkinetic dystonia, for example, athetoid or dystonic CP, (b) abnormal vertical gaze, and (c) dental enamel dysplasia. If the diagnosis was ‘‘possible’’ at 3 months and any two of the three above are abnormal at 9–18 months, the diagnosis would become ‘‘probable.’’ Finally, if the classification was ‘‘not kernicterus’’ at 3 months and now two of the three abnormalities above are present at 9–18 months, the classification would change to ‘‘possible kernicterus’’. It should be emphasized that these are proposed working definitions and research questions that are based on clinical experience and the literature, but must be validated with prospective and perhaps retrospective studies. In conclusion, kernicterus is a complex clinical and neuropathological syndrome ranging from isolated conditions such as AN and subtle BIND to classical kernicterus with athetoid CP, impaired upgaze, and deafness. The clinical expression of bilirubin neurotoxicity varies with location, severity, and time of assessment, and is influenced by factors including the amount, duration and developmental age of exposure to excessive free bilirubin. Although total serum bilirubin is an important risk factor, kernicterus cannot be defined based on total serum bilirubin alone. We suggest that kernicterus may be defined for study purposes in term and near-term infants with total bilirubin Z20 mg/dl using abnormal muscle tone on neurological examination, auditory neurophysiological testing (ABR a.k.a. BAEP), and MRI. There are also a number of unresolved issues regarding the neurobiology of kernicterus, clinical definition and classification as noted in this paper.

References 1. Levine RL, Fredericks WR, Rapoport SI. Clearance of bilirubin from rat brain after reversible osmotic opening of the blood–brain barrier. Pediatr Res 1985;19(10):1040–3. 2. Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts of bilirubin encephalopathy. Eur J Clin Invest 2003;33(11):988–97. 3. Ostrow JD, Pascolo L, Tiribelli C. Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro. Pediatr Res 2003;54(1):98–104. 4. Conlee JW, Shapiro SM. Development of cerebellar hypoplasia in jaundiced Gunn rats treated with sulfadimethoxine: a quantitative light microscopic analysis. Acta Neuropathol 1997;93:450–60. 5. Churn SB, DeLorenzo RJ, Shapiro SM. Bilirubin induces a calciumdependent inhibition of multifunctional Ca2+/calmodulin-dependent kinase II activity in vitro. Pediatr Res 1995;38:949–54. 6. Conlee JW, Shapiro SM, Churn SB. Expression of the alpha and beta subunits of Ca2+/calmodulin kinase II in the cerebellum of jaundiced 58


7.

8.

9.

10.

11. 12.

13.

14. 15. 16.

17. 18.

19.

20. 21.

22.

23. 24.

25.

Gunn rats during development: a quantitative light microscopic analysis. Acta Neuropathol (Berl) 2000;99(4):393–401. Shaia WT, Shapiro SM, Heller AJ, Galiani DL, Sismanis A, Spencer RF. Immunohistochemical localization of calcium-binding proteins in the brainstem vestibular nuclei of the jaundiced Gunn rat. Hear Res 2002;173(1–2):82–90. Spencer RF, Shaia WT, Gleason AT, Sismanis A, Shapiro SM. Changes in calcium-binding protein expression in the auditory brainstem nuclei of the jaundiced Gunn rat. Hear Res 2002;171(1–2):129–41. Shapiro SM, Churn SB, Pal S, Limbrick DD, De Lorenzo RJ. Bilirubin alters intracellular calcium homeostasis. Pediatr Res 1998;42(42, Part 2):195A. Johnston MV, Hoon Jr AH. Possible mechanisms in infants for selective basal ganglia damage from asphyxia, kernicterus, or mitochondrial encephalopathies. J Child Neurol 2000;15(9):588–91. Volpe JJ. Bilirubin and brain injury. In: Volpe JJ. editor. Neurology of the Newborn. Philadelphia: WB Saunders; 2001. p. 490–514. Wennberg RP, Ahlfors CE, Bickers R, McMurtry CA, Shetter JL. Abnormal auditory brainstem response in a newborn infant with hyperbilirubinemia: improvement with exchange transfusion. J Pediatr 1982;100(4):624–6. Nwaesei CG, Van Aerde J, Boyden M, Perlman M. Changes in auditory brainstem responses in hyperbilirubinemic infants before and after exchange transfusion. Pediatr 1984;74(5):800–3. Shapiro SM, Nakamura H. Bilirubin and the auditory system. J Perinatol 2001;21(Suppl 1):S52–5 (discussion S59–62). Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy. Brain 1996;119(Part 3):741–53. Deltenre P, Mansbach AL, Bozet C, Clercx A, Hecox KE. Auditory neuropathy: a report on three cases with early onsets and major neonatal illnesses. Electroencephalogr Clin Neurophysiol 1997;104(1):17–22. Berlin CI, Bordelon J, St John P, et al. Reversing click polarity may uncover auditory neuropathy in infants. Ear Heart 1998;19(1):37–47. Berlin CI, Morlet T, Hood LJ. Auditory neuropathy/dyssynchrony: its diagnosis and management. Pediatr Clin North Am 2003;50(2):331–40 vii–viii. Chisin R, Perlman M, Sohmer H. Cochlear and brain stem responses in hearing loss following neonatal hyperbilirubinemia. Ann Otol 1979;88: 352–7. Volpe JJ. Bilirubin and brain injury. In: Volpe JJ. editor. Neurology of the Newborn. Philadelphia: WB Saunders Co; 1981. p. 336–56. Hyman CB, Keaster J, Hanson V, et al. CNS abnormalities after neonatal hemolytic disease or hyperbilirubinemia. A prospective study of 405 patients. Am J Dis Child 1969;117:395–405. Johnson L, Boggs TR. Bilirubin-dependent brain damage: Incidence and indications for treatment. In: Odell GB, Schaffer R, Sionpoulous AP. editors. Phototherapy in the Newborn: An Overview 1974. Washington: National Academy of Sciences. p. 122–49. Naeye RL. Amniotic fluid infections, neonatal hyperbilirubinemia and psychomotor impairment. Pediatr 1978;62:497–503. Odell GB, Storey GN, Rosenberg LA. Studies in kernicterus III. The saturation of serum proteins with bilirubin during neonatal life and its relationship to brain damage at five years. J Pediatr 1970;76:12–21. Rubin RA, Balow B, Fisch RO. Neonatal serum bilirubin levels related to cognitive development at ages 4 through 7 years. J Pediatr 1979;94(4): 601–4. Journal of Perinatology 2005; 25:54–59


26. Scheidt PC. Toxicity to bilirubin in neonates: infant development during first year in relation to maximal neonatal serum bilirubin concentration. J Pediatr 1977;92:292–7. 27. Bergman I, Hirsch RP, Fria TJ, Shapiro SM, Holzman I, Painter MJ. Cause of hearing loss in the high-risk premature infant. J Pediatr 1985;106(1):5–101. 28. Salamy A, Eldredge L, Tooley WH. Neonatal status and hearing loss in highrisk infants. J Pediatr 1989;114(5):847–52. 29. Rance G, Beer DE, Cone-Wesson B, et al. Clinical findings for a group of infants and young children with auditory neuropathy. Ear Heart 1999;20(3):238–52. 30. Simmons JL, Beauchaine KL. Auditory neuropathy: case study with hyperbilirubinemia. J Am Acad Audiol 2000;11(6):337–47. 31. de Vries LS, Lary S, Whitelaw AG, Dubowitz LM. Relationship of serum bilirubin levels and hearing impairment in newborn infants. Early Hum Dev 1987;15(5):269–77. 32. de Vries LS, Lary S, Dubowitz LMS. Relationship of serum bilirubin levels to ototoxicity and deafness in high-risk, low birth-weight infants. Pediatr 1985;76(3):351–4.

Journal of Perinatology 2005; 25:54–59

Shapiro

33. Seidman DS, Paz I, Stevenson DK, Laor A, Danon YL, Gale R. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age. Pediatr 1991;88(4):828–33. 34. Yilmaz Y, Degirmenci S, Akdas F, et al. Prognostic value of auditory brainstem response for neurologic outcome in patients with neonatal indirect hyperbilirubinemia. J Child Neurol 2001;16(10):772–5. 35. Stein L, Tremblay K, Pasternak J, Banerjee S, Lindemann K. Auditory brainstem neuropathy and elevated bilirubin levels. Semin Hearing 1996;17:197–213. 36. Shapiro SM, Rosen JR, Dixon KT. Auditory brainstem response (ABR) abnormalities and auditory neuropathy in children with kernicterus. Pediatr Res 2002;51(4 Part 2):340A. 37. Shapiro SM, Daymont MJ. Patterns of kernicterus related to neonatal hyperbilirubinemia and gestational age. Pediatr Res 2003;53(4 Part 2):398A–9A. 38. Shallop JK, Peterson A, Facer GW, Fabry LB, Driscoll CL. Cochlear implants in five cases of auditory neuropathy: postoperative findings and progress. Laryngoscope 2001;111(4 Part 1):555–62.

59