Excessive newborn hyperbilirubinemia can cause permanent brain damage, that is, chronic bilirubin encephalopathy (BE), also known as kernicterus. The effort to understand and treat neonatal hyperbilirubinemia is for the most part an effort to prevent kernicterus and bilirubin-induced neurological dysfunction (BIND), the latter referring to subtle neurodevelopmental disabilities without classical findings of kernicterus.1–4 Kernicterus is a matter of concern for pediatricians and neonatologists. Historically, kernicterus caused a significant number of cases of cerebral palsy (CP), particularly the athetoid or dystonic type. Kernicterus remains a significant problem in underdeveloped countries where bilirubin screening and treatment of excessive hyperbilirubinemia is not routinely available as highlighted in Chapter 13 Neonatal Jaundice in Low-Middle-Income Countries. The “classic” literature on kernicterus evolved during an era when Rh disease was the main cause and therapeutic options for treatment were limited. The resulting acute bilirubin encephalopathy (ABE) was dramatic, with prominent central nervous system (CNS) signs of lethargy, ophthalmoplegia and setting sun sign (impairment of upward gaze), high-pitched cry, opisthotonus, and seizures.5 Both the basal ganglia, with yellow staining (icterus) of the deep nuclei or “kernel” of the brain, and brainstem auditory pathways were recognized as being particularly vulnerable.5,6

The association between high levels of unconjugated bilirubin in the blood and kernicterus was recognized7 in the 1950s. In newborns with Rh hemolytic disease (gestation not provided), Mollison and Cutbush8 described kernicterus in 1/13 or 8% of term infants with peak total serum bilirubin (TSB) levels of 19–24 mg/dL, 4/12 (33%) with TSB 25–29 mg/dL, and 8/11 (73%) with TSB 30–40 mg/dL. The authors note, however, that “in many cases only two blood samples were taken during the period of maximum jaundice …,” so it is likely that the maximum TSB concentrations were actually higher. As specific therapeutic criteria were developed first to treat and then to prevent severe hyperbilirubinemia and Rh disease, the incidence of kernicterus fell dramatically. However, the level of bilirubin that is regarded as safe in human infants cannot be determined in isolation from other important risk factors, because it is bilirubin in the CNS, not bilirubin in blood bound to albumin, that is neurotoxic.

While clearly the risk of kernicterus rises as TSB rises, other risk factors, including free bilirubin, pH, albumin binding, infection, inflammation, and gestational age, may be important in combination with TSB to better predict neurotoxicity.

Pathology

Kernicterus is a pathological term originally used to describe the yellow staining (icterus) of the deep nuclei (kernel) of the brain, that is, the basal ganglia. More recently it has been used as a clinical term synonymous with chronic BE, the clinical syndrome encompassing long-term adverse neurodevelopmental sequelae corresponding to the pathological condition of kernicterus. The original pathological diagnosis included yellow staining and necrosis in the globus pallidus, subthalamic nucleus (STN), brainstem nuclei, hippocampal CA-2, and cerebellar Purkinje cells. Today, modern neuroimaging can identify characteristic, almost pathognomonic brain lesions in children with ABE and chronic BE and with clinical neurophysiology using the auditory brainstem response (ABR) we can objectively identify the characteristic findings of both ABE and chronic BE.

Clinicopathological Correlations

The clinical features of chronic BE range from deafness and severe dystonic/athetoid CP, seizures, or death (classic kernicterus) to subtle cognitive disturbances. The most extreme bilirubin-induced brain injury produces deafness and severe auditory neuropathy spectrum disorders (ANSD), extrapyramidal movement disorders and abnormal muscle tone, gaze abnormalities, and dental enamel dysplasia of the deciduous (baby) teeth.9–11 The classic movement disorder consists of athetosis and/or dystonia, the so-called athetoid CP. These relate to pathological lesions in the basal ganglia, namely, the globus pallidus and STN, the cerebellum, and brainstem including auditory nuclei (cochlear nuclei, superior olivary complex, lateral lemniscus, trapezoid body, and inferior colliculus),12,13 vestibular nuclei,14 the interstitial nucleus of Cajal (upward gaze center), Dieter’s nucleus (truncal tone),13 and cerebellar Purkinje cells.

The auditory system may be affected clinically with auditory neuropathy/dyssynchrony with or without hearing loss, and, as a result, there may be difficulty understanding speech in noisy environments, even when “hearing” as measured by audiograms is normal or near-normal. The neuropathology of elevated bilirubin in the auditory system is based primarily on autopsy studies of infants with classic kernicterus,15–17 and premature, low birth weight infants with “low-bilirubin kernicterus.”18 These studies have shown central auditory pathology, with involvement of brainstem auditory structures (e.g., the dorsal and ventral cochlear nuclei, the superior olivary complex, the nuclei of the lateral lemniscus, and the inferior colliculi), but no significant abnormalities of the inner ear structures.19,20

Neuroimaging

Lesions in the globus pallidus and STN can be seen on magnetic resonance imaging (MRI) scans of the brain (Figure 11-1).

In the globus pallidus, hyperintense lesions can be seen in both the external and internal portions; lesions in the STN are more difficult to visualize, but may also appear as hyperintense signals on MRI. Other lesions, such as those in auditory brainstem nuclei or cerebellum, are too small to be seen on routine MRI scans. In the context of a hyperbilirubinemic baby with a static encephalopathy, the MRI findings of bilateral hyperintensity of the globus pallidus and STN without other significant abnormalities are almost pathognomonic of BE.

Our experience is that MRIs done within a few weeks of peak bilirubin neurotoxicity in babies with ABE who go on to develop kernicterus often show striking bilateral T1 hyperintensities in the globus pallidus without significant T2 abnormalities; later, T2 and FLAIR images become hyperintense, sometimes with an intervening normal appearing MRIs. Others report a similar shift from T1 to T2 hyperintensity in the globus pallidus,22,23 and in five preterm and three term infants followed serially, Govaert et al.23 found that sometimes the signal changes were “subtle and easily overlooked.”

Auditory Testing

Evoked potentials identify abnormalities of neuronal function with a high degree of sensitivity. These include conduction delay, desynchronization, and loss of cells, which occur in a number of pathological conditions involving brain injury, metabolic disorders, and demyelination.24–26 ABRs, aka brainstem auditory evoked potentials (BAEPs) or responses (BAERs), are electrical potentials evoked by auditory stimulation and recorded noninvasively from the scalp. A series of characteristic waves, which arise from neural generators in the auditory nerve and brainstem fiber tracts and nuclei,27–30 can be distinguished from the background electrical activity (electroencephalogram) by averaging the responses to many stimuli. Each ABR wave is generated by a small subpopulation of synchronously firing neural elements; thus, each component of the ABR wave reflects the activation of specific but temporally overlapping anatomical regions of the brainstem. The time between ABR waves is known as the interwave interval (IWI). This interval reflects the time it takes for nerve impulses to travel from one anatomical location to another. Dysfunction in these neural pathways causes delayed or abnormal conduction of impulses and manifests as increased IWIs, that is, the times between specific ABR waves. Desynchronization or loss of nerve cell activity also produces changes in amplitudes and morphology of the ABR waves. Thus, alterations of latencies, IWIs, and wave amplitudes indicate neuronal dysfunction.

ABRs were first measured in 1979 in studies of older children and adults with chronic BE31,32 and abnormal function of the auditory nerve and the brainstem was found. In these patients, however, cochlear microphonic (CM) recordings were normal. These recordings assess the electrical output of the outer hair cells, part of the efferent auditory system in the inner ear.31 In hyperbilirubinemic human newborns, increases in IWIs and decreases in amplitudes were found,31,33–36 abnormalities that could be reversed when the TSB decreased spontaneously or in response to phototherapy or exchange transfusion.35,37,38 ABR changes correlate significantly with serum levels of total and free bilirubin in the newborn period34 and at follow-up.39

In 1996, patients were described with hearing impairment, normal evoked otoacoustic emissions (OAEs; a test of the mechanical integrity of the basilar membrane of the inner ear), normal CM responses, and absent or abnormal ABRs, and the term “auditory neuropathy” was coined.40 We and others prefer the term auditory neuropathy/dyssynchrony to better describe the condition and reflect the concern that the term “neuropathy” is inappropriate for pathologies that may only affect central auditory pathways.41–43 Recently, the term ANSD has been applied to this condition.44 The pathophysiology of ANSD involves inner hair cells, spiral ganglion cells, or their processes in the auditory portion of the eighth nerve or the auditory brainstem, all or any of which in theory could preserve OAEs and cochlear (CM) responses while producing severely abnormal ABRs.

Kernicterus and neonatal hyperbilirubinemia are associated with ANSD, functionally defined as absent or abnormal ABRs and normal tests of cochlear function (CMs and OAEs). Initially normal, ANSD and OAEs may become abnormal with time while CMs remain normal.

The combination of absent ABRs and normal CM responses described in 1979 in children with hearing loss due to hyperbilirubinemia31 is thought to be the first reported case of what is now called ANSD. Notably, a history of hyperbilirubinemia and prematurity is found in over half of patients with ANSD45 without other reported signs of kernicterus. Previously, CM responses were obtained from a transtympanic electrode; CMs are now usually obtained noninvasively from scalp recordings during the ABR, using two techniques to distinguish CM from electrical artifacts: (1) a tube from the speaker to the tympanic membrane to introduce an acoustic delay and (2) using reversing polarity of stimuli (CM responses change polarity with the stimuli, while ABR waves do not).

ANSD prevalence was found to occur in 11% of a group of children with permanent hearing deficit.46 With the increased recognition of ANSD through neonatal programs that utilize ABR or automatic ABR screening, the incidence of diagnosed cases of ANSD is likely to increase. A recent report of universal screening found that 24% of 477 graduates from a regional perinatal center neonatal intensive care unit (NICU) fit the ANSD profile of absent ABR and present OAEs and had more hyperbilirubinemia than those infants not fitting an ANSD profile.47 ANSD was detected by universal newborn hearing screening in 9 of 52 infants with hearing loss in 14,807 consecutively screened cases in Singapore—6/10,000 screened, and 17.3% of hearing loss.48 Of the many possible risk factors assessed, only hyperbilirubinemia and administration of vancomycin or furosemide were more frequent in the ANSD group.

Any discussions of the outcome of neonatal hyperbilirubinemia and assessment of new methods to predict outcome depend on a good, objective, and clear definition of the outcome variable, in this case kernicterus. In this section we focus on defining kernicterus and developing diagnostic criteria.

Traditional Definitions

Acute Bilirubin Encephalopathy

The Subcommittee on Hyperbilirubinemia of the American Academy of Pediatrics (AAP)49 recommends that the term “ABE” be used “to describe the acute manifestations of bilirubin toxicity seen in the first weeks after birth and that the term ‘kernicterus’ be reserved for the chronic and permanent clinical sequelae of bilirubin toxicity.” Clinically, ABE has a progression of symptomatology. Initially neonates show lethargy and decreased feeding, then variable abnormal tone with both hypotonia and hypertonia, often alternating over the course of minutes, a high-pitched or shrill cry, and then truncal arching (opisthotonus) with extension of the neck (retrocollis). Neonates develop downward deviation of the eyes from impairment of vertical upward gaze, known as the setting sun sign. As they become more neurotoxic, they may develop fever, seizures, and death from cardiovascular collapse. In the acute stage, ABR changes will occur, starting with abnormalities of waves III and V from the brainstem, followed in severe cases by the loss of all ABR waves. In the acute phase MRI will show increased signal on T1-weighted images. Recently, Slusher et al. have described a characteristic “kernicterus facies,” a “scared” look that combines the setting sun sign with facial dystonia and eyelid retraction, suggesting a dorsal midbrain syndrome combined with dystonia from basal ganglia dysfunction.50

Kernicterus or Chronic Bilirubin Encephalopathy

It is not difficult to diagnose severe chronic BE or classical kernicterus in older children and adults. Clinically there is a tetrad of (1) severe dystonia with or without athetosis, (2) severe hearing impairment or deafness due to severe auditory neuropathy/dyssynchrony, (3) impairment of the oculomotor function, especially upward gaze, and (4) dental enamel dysplasia of the deciduous (baby) teeth. Currently, laboratory studies are available to support the diagnosis. MRI scans showing abnormal signal intensity in the globus pallidus, STN (if the quality of the scan is good enough), and audiological studies show abnormalities of ABRs with normal CM responses, consistent with a diagnosis of auditory neuropathy/dyssynchrony. Other abnormalities that have been described are hypotonia and sensorimotor disturbances.

The movement disorders, athetosis (slow writhing movement) and, more commonly, dystonia (abnormal muscle tone resulting in abnormal position or postures), correspond to the lesions in the globus pallidus and subthalamic nuclei in the basal ganglia.

In classic kernicterus, there is audiometric evidence for a predominantly high-frequency hearing loss that is usually bilateral and symmetric, with recruitment and abnormal loudness growth functions.10,51–57 Central auditory system abnormalities, either alone or in combination with sensory loss, are suggested by reports of decreased binaural fusion, auditory aphasia and imperception, word deafness, and numerous instances of patients labeled as “deaf” when objective tests show normal thresholds.9,10,53,55–57 While deafness is a feature of classical kernicterus, studies have shown an association between moderate-to-severe hearing loss and central auditory dysfunction and elevated bilirubin levels in high-risk, low birth weight newborns in the absence of kernicterus.58–60 Both the amount and duration of hyperbilirubinemia are risk factors.58,59

With current understanding and ABR and CM testing, the typical clinical auditory abnormality in chronic kernicterus is ANDS and relates to abnormalities in the brainstem auditory nuclei including the cochlear nucleus, superior olivary complex, medial nucleus of the trapezoid body, and inferior colliculus. It is also possible that bilirubin toxicity may affect the cell bodies of the auditory nerve in the spiral ganglia, or selectively affect large, heavily myelinated fibers of the auditory nerve.61 Severe ANSD can cause a child to be deaf with absent ABRs, yet can be distinguished from the more common types of sensory deafness with ABR, CM, and other auditory testing.

The oculomotor abnormalities include impairment of upward gaze, which can be difficult to detect on physical examination in infants, and other oculomotor abnormalities including strabismus, esotropia, and exotropia. The disturbance of vertical gaze, especially upward gaze, is likely due to the selective involvement of the interstitial nucleus of Cajal in the brainstem.14 Finally dental enamel dysplasia of the deciduous teeth may be present. An important pathological consideration is that, for the most part, bilirubin toxicity does not affect the cerebral cortex and most children with kernicterus, absent other etiologies, comorbidities, and concurrent damage (such as hypoxia–ischemia), will have normal intelligence. Learning disorders related to auditory processing problems or sensory integration or sensorimotor integration perhaps at the level of the basal ganglia may be present, and oculomotor problems may manifest as difficulties with reading and tracking visually.

Even though etiologies for hyperbilirubinemia may differ, there is still a remarkable similarity in the clinical picture of classical kernicterus from case to case. With the exception of kernicterus in extremely premature infants (see comments later regarding auditory-predominant subtype associated with prematurity), almost all cases of kernicterus have variations in tone. Many have greater or lesser amounts of truncal hypotonia. We suggest that bilirubin neurotoxicity is more likely to affect the auditory nervous system in prematurely born infants and that motor abnormalities and perhaps more cerebellar findings may be seen than with bilirubin neurotoxicity in term infants, as preterm infants may have longer but relatively lower levels of hyperbilirubinemia.

Subtle Kernicterus

Subtle neurodevelopmental disabilities related to neonatal hyperbilirubinemia, including mild neurological abnormalities and cognitive disorders, have been recognized for some time,62–67 as have isolated hearing loss58,68 and ANSD.46,69–74 More recently this has been termed BIND.2,75 Children with kernicterus generally have normal intelligence but are trapped or locked inside dysfunctional bodies, sometimes with severe disabling movement disorders, abnormal control of eye movements, and deafness.

New Definitions

Defining kernicterus is important because it can help us to understand the risk of neurological sequelae from hyperbilirubinemia and to design the appropriate research studies. No matter how carefully designed and novel prospective studies are, the validity of the results depends on the quality and objectivity of the outcome measures, that is, the dependent variables. Other authors have discussed how bilirubin (the independent variable) and other risk factors such as gestational age, infection, inflammation, and hemolysis can affect the outcome. I will focus on the dependent variable, kernicterus, that is, brain damage due to bilirubin neurotoxicity. It is important to attempt to quantify, as best one can, the definitions of kernicterus and BIND, since pairing excellent independent variables with poorly defined, imprecise, or subjective definitions of the dependent variables for outcome measures affects the quality and reliability of the studies. Thus, I have attempted to define kernicterus and BIND in at least semi-objective terms, so that outcome researchers can use similar terminology.

We lack a consistent definition of kernicterus. The absence of a single clinical sign (or combination of clinical and neurophysiological findings) that defines kernicterus makes an objective definition difficult. Perhaps for this reason, studies that attempt to relate neonatal events, including excessive neonatal hyperbilirubinemia, to an outcome of kernicterus rarely, if ever, define kernicterus. In my experience, there is a wide range of manifestations of kernicterus, varying from mild to moderate to severe, and from localized or system-specific kernicterus to classical kernicterus, including the entire triad or tetrad. The well-described differences between ABE, sub-ABE, and chronic BE (kernicterus) are also seen, as are changes that occur during the first year of life. I will attempt to define kernicterus and to establish semi-objective criteria for its diagnosis and severity. I will also describe some of the subtypes seen.

As proposed by Perlstein in 196010 and later by Volpe,76 varied but distinctive patterns of sequelae following BE represent “clinical aggregates in a continuation of syndromes and the possible major predominance of one site of damage over another in the auditory or extrapyramidal category.” Perlstein noted, for example, that motor involvement can range from the very severe to so mild as to be virtually unrecognizable except under the broad terms of being “awkward” or “clumsy.”10 Volpe reviewed more recent literature and suggested that impairment of auditory function is the most consistent abnormality associated with chronic postkernicteric BE, especially in premature infants, and that the auditory pathways constitute the most sensitive neural system to bilirubin injury.76 I have seen patients with impairment of auditory function with neither athetosis nor a significant associated movement disorder and recently proposed new clinical definitions of chronic kernicterus by localization, severity, and timing, where localization was characterized as isolated, mixed, or classical and severity as mild, moderate, or severe.2 I have suggested that kernicterus can be classified according to three dimensions of severity, location, and time. Although I had originally conceived that the time dimension would reflect time in relation to the bilirubin neurotoxic damage, that is, acute, subacute, and chronic encephalopathy, the time dimension could also represent the stage of the infant’s neurodevelopment (i.e., postmenstrual age) at which the CNS is exposed to bilirubin neurotoxicity, which I believe may be an important determinant of selective susceptibility.