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
pallidussubthalamic nucleus.
Journal of Perinatology (2005) 25, 5459. 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 bloods 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 bloodbrain 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 bloodbrain 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; 25:5459
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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; 25:5459

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 IIII and IV 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

Definition and Clinical Spectrum of Kernicterus

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,2126 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; 25:5459

Definition and Clinical Spectrum of Kernicterus

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 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 2024 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; 25:5459

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 918 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 918 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 918 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.

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