Exploring Kernicterus Spectrum Disorders

This is the era of spectrum disorders . Increased awareness of the clinical complexities of many conditions has led to a lack of clarity about how to relate to those with partial manifestations of classic conditions. This, added to the ambiguity in terminology, has created the need to re-categorize as spectrum disorders those entities that were once seen as binary . Far beyond offering catchy new titles, viewing an entity as a spectrum disorder allows for a deeper understanding of the pathophysiology of the condition. This review will focus on kernicterus spectrum disorders (KSD).

The wide spectrum of clinical manifestations in patients with kernicterus presents us precisely with the need to clarify the nomenclature. In this review, the authors will define and unify the clinical and pathophysiological aspects of TEKs and unravel the terminological quagmire. They propose focusing on the newest and most controversial aspects of TEK.

Initially, the term “kernicterus” referred to the pathological finding of yellow staining of the deep nuclei of the brain that was diagnosed at autopsy. Advanced laboratory testing, such as auditory brainstem response (ABR) and magnetic resonance imaging (MRI) findings, including globus pallidus hyperintensity, along with increased attention to the evolution of clinical signs, have given resulting in the ability to confer a clinical diagnosis of kernicterus without absolute pathological evidence provided only at autopsy. The ability to provide a clinical diagnosis for patients with kernicterus is especially crucial for those infants who survive and have bilirubin-associated lesions.

> Encephalopathy/Kernicterus

The classic clinical syndrome of kernicterus is described as a tetrad characterized by 1) poor motor control and abnormal movements, 2) an alteration of auditory processing that may or may not be accompanied by hearing loss, 3) impaired oculomotor function, especially known as paralysis of the ascending part of the vertical gaze (sign of the setting sun), and 4) dysplasia of the enamel of primary (baby) teeth. (1)

However, over the years, the term "kernicterus" has come to be used interchangeably to refer to patients with severe illness and/or mild neurological dysfunction following severe hyperbilirubinemia, infants with acute bilirubin encephalopathy (ABE), and/or chronic bilirubin encephalopathy (CBE), and/or those individuals with isolated motor and/or auditory dysfunction without distinguishing between subtypes. (1)(2) Attempts to differentiate between kernicterus subtypes have resulted in a large number of overlapping and confusing terms, including bilirubin neurotoxicity, EAB, ECB, bilirubin-induced neurological dysfunction (NIBD), and auditory neuropathy. .

Recognizing that kernicterus is symptomatically broad and diverse, Le Pichon and colleagues (3) have proposed that use of the term “kernicterus spectrum disorders” can encompass all aspects of bilirubin neurotoxicity by viewing it as a kind of continuum, while Modifiers are used to distinguish between subtypes and degrees of severity.

> Variants of nomenclature: past, present and future

Acute bilirubin encephalopathy ( ABE) describes “acute” clinical signs associated with extreme hyperbilirubinemia.

Early signs include lethargy and poor feeding, which are not specific for bilirubin encephalopathy, but if associated with extreme jaundice, may portend serious neurotoxic damage. At this stage, if jaundice is treated properly, the condition can be reversed. However, as the disease process progresses, high-pitched crying develops. Muscle tone can fluctuate between hypotonia and hypertonia and, eventually, spasms of the extensor muscles, which can manifest as arching of the back, opisthotonus, retrocolis and altered upward gaze.

In this context, the term acute bilirubin encephalopathy (ABE) appropriately describes the signs associated with acute bilirubin neurotoxicity at the time of exposure, signs that may still be reversible as long as the hyperbilirubinemia is appropriately and immediately treated. As the definition implies, these signs may be transitory and therefore do not necessarily predict the outcome. (4)(5)(6) EAB, therefore, is not synonymous with kernicterus.

Chronic bilirubin encephalopathy ( CBE) is essentially a misnomer as it implies an encephalopathy secondary to chronic or continuous exposure to bilirubin. This is almost never the case. In reality, BCE is intended to refer to the long-term consequences of an acute hyperbilirubinemic insult, continuing long after the acute hyperbilirubinemic insult has resolved.

Bilirubin-induced neurological dysfunction ( DNIB ) is a particularly confusing term. From the name one might assume that DNIB would refer to all neurological conditions secondary to exposure to high levels of bilirubin, and indeed it has been used this way by some. (2)(3)(7)(8)(9) However, the term DNIB has also been used to designate only individuals with relatively mild neurological damage due to bilirubin, i.e., subtle kernicterus. (10) Finally, DNIB is also used to refer to a scoring system that quantitatively characterizes the progressive stages of EAB. (11) (12)

Involvement of a single basal ganglia: improvements in neuroimaging have allowed the visualization of abnormalities of isolated and specific structures of the basal ganglia. The clinical implications of single basal ganglia damage are not yet defined.

Many of the aforementioned terms have been used interchangeably over the years, without recognizing finer distinctions in definition. In proposing the inclusion of the term “TEK,” Le Pichon and colleagues (3) also suggested that other confusing terminology be abandoned and that the term “TEK” should be used with modifiers such as predominantly auditory or predominantly motor, acute or chronic, and severe or mild to specify and describe more precisely the corresponding pathophysiology. Furthermore, they suggested focusing on the classification of kernicterus based primarily on the auditory and motor aspects of the disease, which are considered the most significant and easily quantifiable clinical features. (3) The remaining components, along with additional aspects described as “kernicterus plus”, will be discussed later.

TEK is evaluated by clinical examination and history, neurophysiological tests such as RATE (also known as auditory brainstem evoked response), and advanced imaging techniques such as MRI. Shapiro (1) proposed and validated (13) a TEK diagnostic toolkit to objectively assess severity and improve prognostic predictions.

> TEK subtypes

Kernicterus motor. Motor kernicterus is characterized by extrapyramidal movement disorders of athetosis (slow, writhing movements), dystonia (abnormal tone, fixed postures, co-contraction of agonist and antagonist muscles), variable hypo/hypertonia, spasticity, ataxia, and incoordination. The severity of motor TEK is determined by the amount and severity of these involuntary movements along with the limitations of voluntary movements. For example, children who can ambulate, although with abnormal gait with or without a walker, and can feed themselves have moderate motor TEK, while children who do not ambulate, without the ability to feed themselves and with severe movement restriction voluntary movement have severe motor TEK. The most severe cases of motor TEK include children without voluntary movements, with very limited communication, both verbal and non-verbal, and with dystonic seizures. These kids are practically locked up.

Auditory neuropathy spectrum disorder. The auditory system is extremely sensitive to the effects of bilirubin, ranging from mild speech processing abnormalities to complete deafness. As with many aspects of TEK, definitions of hearing dysfunction are fraught with controversy and are therefore potentially confusing. The term “neuropathy” generally refers to an abnormality of a peripheral nerve. However, bilirubin-associated auditory dysfunction includes lesions of both peripheral and central nerves and their central pathways. (14) (15) Kernicterus clearly affects auditory nuclei of the brainstem (16) and most likely also the peripheral auditory nerve (Gunn rat animal model), especially the large myelinated fibers that are responsible for neuronal synchrony. (17) Clinically, auditory kernicterus can range from mildly abnormal to no RATE accompanied by mild to profound hearing loss.

To further complicate matters, auditory neuropathy spectrum disorder (AND) also encompasses a central auditory processing disorder, that is, a central nervous system deficit in the perceptual, visual-motor, and auditory functions of speech and language. despite normal IQ scores and absence of sensorineural hearing loss. (18) Therefore, there appears to be a “functional TENA” that occurs either in conjunction with or apart from neurosensory pathology.

TEK and prematurity

Premature babies are at increased risk for bilirubin-associated neurodevelopmental harm, sometimes occurring even at bilirubin levels considered safe. There appears to be a correlation between the severity of neonatal hyperbilirubinemia along with the gestational age of exposure and neurological outcome, type and severity. Developmental windows of central nervous system vulnerability to bilirubin toxicity exist, (1) (19) and neurodevelopmental age at the time of bilirubin brain injury influences the location of selective neuropathological damage. (20) (21) In fact, premature infants may present clinical evidence of kernicterus at serum total bilirubin (TSB) levels that have traditionally been considered safe. (22)

Because the ascending auditory system develops before extrapyramidal motor control pathways, experts have hypothesized that exposure to elevated levels of bilirubin early during development may preferentially affect the auditory system. Powers and colleagues (23) reviewed 36 cases of kernicterus and found that most cases of predominantly auditory kernicterus occurred in infants ≤34 weeks’ gestation and with peak BST levels ≤24 mg/dL (410.50 mmol/L). ).

While the auditory-predominant subtype of kernicterus is prevalent in infants whose bilirubin levels peak at an earlier gestational age, the motor-predominant subtype of kernicterus typically develops in infants older than 34 weeks’ gestation. (1)

In contrast, Okumura et al (24) described the cases of 8 premature infants who developed mixed motor and auditory TEK. None of the infants showed neurological symptoms characteristic of classic EAB during the neonatal period. (24) All patients were observed to have extrapyramidal motor impairment only after discharge. Dystonic posture and abnormal muscle tone were first universally recognized within 6 months of corrected age. Athletic movement disorders gradually became apparent. No patient in their series was able to sit without support at the last follow-up. All but one also had abnormal or absent RATEs, which were always bilateral.

The lack of early and acute neurological symptoms is characteristic of premature newborns with kernicterus.

It is possible that the acute signs seen in full-term infants, including abnormalities in level of consciousness, muscle tone, movement, and brainstem function, such as feeding and crying, may be more difficult to observe in preterm infants who are naturally hypotonic and inactive. It is also possible that neurological signs are more subtle or take longer to develop early in pregnancy. In fact, in Okumura’s cohort, not only did no clinical signs appear from the beginning, but MRI during the neonatal period also showed no abnormal findings. (24)

It has been suggested that the developmental nature of signal abnormalities compounded by normal developmental changes in the preterm infant may affect the sensitivity and signal specificity of MRI changes during the subacute phase. (25) Kitai et al (26) studied the evolution of MRI changes over time in premature infants with TEK and recommended performing diagnostic MRI in premature infants with suspected TEK only at a corrected age of 6 to 18. months.

> Neuropathology/Neuroimaging

BST is the sum of circulating conjugated bilirubin, BNC, plus the small fraction of BNC that is not bound to albumin and free bilirubin (Bl). The blood-brain barrier is designed to exclude the entry of large molecules into the central nervous system. However, it does not protect against Bl, the fraction of bilirubin that actually enters the brain. Because Bl is lipophilic, this compound can interact with lipids and enter cells by passive diffusion. While it is generally recognized that Bl is responsible for neurological damage, (27) it is not easy to measure. As such, clinical risk management is primarily based on BST levels.

Even once Bl enters the brain, its ability to cause damage is selective, that is, bilirubin has a propensity to damage specific regions of the brain during limited windows of development. In autopsies of infants who died with severe hyperbilirubinemia, the cerebral distribution of bilirubin was often nonspecific. Attempts to resolve these seemingly contradictory observations have suggested that the selectivity of specific brain areas lies not in distribution but rather in the vulnerability of specific areas to bilirubin-induced damage during particular stages of development. (28)

Early neuronal changes (within the first few days of bilirubin-induced injury) are characterized by swollen cytoplasm with prominent yellow pigment. At the end of the first week, atrophy of the globus pallidus is observed. There may also be atrophy of the hippocampus, thalamus, hypothalamus, and subthalamic nucleus. (29) Brites (19) described neuronal death by BNC as derived from “excitotoxicity, oxidative stress, alterations in neuronal arborizations, synaptotoxicity and apoptosis mediated by alterations in mitochondrial dynamics and caspase activation.” Neurogenesis and cells Mother neural and young neurons are more susceptible to BNC damage compared to mature and older neurons, therefore, further contributing to the increased vulnerability of preterm infants.

These changes result in signal abnormalities, characteristically a chronic, bilateral, symmetric increase in T2 signal in the globus pallidus and subthalamic nucleus. But, as described above, the nature of these signal abnormalities tends to vary over time and a normal MRI, especially in the early stages, does not exclude the diagnosis of TEK. However, in the first few days after the onset of EAB (i.e., the subacute phase), there is often increased T1 signal in the globus pallidus and subthalamic nucleus, while T2-weighted images of these regions are more subtle and increases over time. (30)

> DNIB Score

A numerical scoring system , the DNIB score, has been developed (11) and verified (31) to quantify the degree of DNIB. The score consists of a 9-point scale that assesses mental status, muscle tone, and crying patterns. A DNIB score of 0 is normal, while a DNIB score of 1 to 3, 4 to 6, and 7 to 9 correspond to mild, moderate, and severe EAB, respectively.

El Houchi et al (32) studied the predictive ability of the DNIB score and found that a DNIB score ≥4 had a specificity of 87% and a sensitivity of 97% in predicting poor neurological outcome, and a specificity of 87% and sensitivity 93% to predict long-term hearing impairment. Interestingly, however, 4 infants with high BST levels (≥36 mg/dL [615.74 mmol/L]) but low DNIB scores had normal outcomes during follow-up.

> Findings associated with TEK beyond auditory and motor kernicterus

As mentioned above, classic kernicterus includes additional clinical signs not specified in the auditory or motor TEK classifications. Oculomotor dysfunction, particularly upward gaze palsy, and dental enamel dysplasia are frequently present. Additionally, other findings associated with TEK are often found in children with severe TEK, including the following:

• Gastroesophageal reflux with vomiting that can be quite severe.

• Failure to thrive as a result of a combination of dysphasia and uncoordinated swallowing, along with increased caloric needs due to dystonia. (3) (33)

• Sleep disorders are an almost universal problem with frequent nighttime awakenings and difficulty maintaining sleep. Recent studies in animals and adults with Parkinson’s disease, which may be applicable, implicate a role for the globus pallidus in sleep maintenance and sleep-wake control. (33)

• Dystonic state with severe and prolonged episodic dystonia is often caused by intercurrent illness or malaise.

• Neuroorthopedic conditions such as scoliosis and hip dysplasia that occur due to persistent dystonia.

• Generalized seizures may occur during EAB, but often do not persist. Antiseizure medications can usually be stopped. However, there may be an overall increase in seizures in children with kernicterus. (34) (35) (36) Retrospective analysis of kernicterus registry data from 125 patients found that 41 patients (33%) were clinically diagnosed with neonatal seizures or suspected seizures. Of the 20 patients with follow-up data, 10 had chronic seizures. Thus, 10 (8%) of 125 developed epilepsy. (36)

It should be noted that although episodic dystonic activity can be easily confused with tonic-clonic seizures, it can be distinguished from seizures by recording video electroencephalography during the episodes.

• Assessment of cognitive function is extremely challenging in patients with severe movement disorders and deafness, and patients with kernicterus may be incorrectly classified as cognitively impaired due to their contorted face and twisted limbs. It is noteworthy, however, that the neocortex is primarily spared in bilirubin-associated neurotoxicity and significant cognitive impairment occurs only in a minority of kernicterus patients. (37) A 17-year retrospective study of 1,948 Israeli military recruits (38) reported on the effect of neonatal hyperbilirubinemia on long-term cognitive ability. Logistic regression analysis adjusted for potentially confounding variables found no direct linear association between maximum neonatal bilirubin levels and IQ scores or school performance at 17 years of age. However, the risk of low IQ scores (<85) was found to be significantly higher (P=0.014) in full-term male infants with neonatal serum bilirubin levels greater than 20 mg/dL (342.08 mmol/L). .

> Kernicterus subtle

Although difficult to define, there appears to be an additional constellation of subtle neurodevelopmental disabilities that do not meet full classical definitions of kernicterus that, after careful evaluation and exclusion of other possibilities, appear to be associated with bilirubin neurotoxicity. (10) These may include 1) mild to moderate movement disorders (e.g., incoordination, clumsiness, gait abnormalities, disturbances in static and dynamic balance, impairment of fine motor skills, and ataxia), 2) milder alterations in muscle tone and 3) impairment of sensorimotor integration. Subtle kernicterus may be so mild that it may be virtually unrecognizable except under the broad descriptive terms of being “gawky” and “clumsy.” (27)

> TEK Plus

Additionally, there are neurological findings that are not generally considered directly related to bilirubin neurotoxicity . This combination of TEK and other neurological conditions is known as TEK plus (TEK+). For example, spasticity is not considered a neurological sequelae of bilirubin neurotoxicity. Therefore, the finding of spasticity in conjunction with TEK suggests alternative etiologies in addition to TEK. Other suggestions that the encephalopathy is not due to bilirubin neurotoxicity include microcephaly, appearance of clinical signs before there is a significant increase in serum bilirubin levels, and MRI abnormalities that are not typically seen in TEK (e.g. e.g., lesions of the cerebral cortex, periventricular leukomalacia or ventriculomegaly).

Although exposure to extreme hyperbilirubinemia is clearly a necessary precursor to developing kernicterus, it is not sufficient to determine a serious neurodevelopmental outcome. Indeed, major studies to date have failed to identify a bilirubin level above which neurotoxicity occurs, and 8% to 9% of reported cases of kernicterus occurred with maximum BST of ≤25 mg/dL (427 .60 mmol/L). (39) Thus, comorbidity and/or associated risk factors are often involved in mediating neurotoxicity in the face of hyperbilirubinemia. The neurological outcome may be modified by factors such as the maturation of the central nervous system at the time of exposure, the aggressiveness of hemolysis, the conjugation and elimination of bilirubin, inflammation and acidosis, as well as underlying genetic factors. (40)

In the next section, the authors will focus on the possible exacerbating role of some of these genetic factors as a possible prototype for such interactions.

Genetic characteristics that potentially contribute to extreme neonatal hyperbilirubinemia

It is increasingly clear that much of the control of bilirubin metabolism lies within genetic control. The role of genes controlling both the production and elimination of bilirubin has recently been reviewed. (41) Here, some aspects of the bilirubin conjugating gene, UDP-glucuronosyltransferase (UGT) 1A1, will be highlighted to allow the reader to appreciate the enhancing role of genetic polymorphisms in the development of extreme hyperbilirubinemia. This is especially important for understanding the pathophysiology of extreme hyperbilirubinemia associated with glucose-6-phosphatase dehydrogenase (G6PD) deficiency, a condition associated with bilirubin neurotoxicity (42) and therefore of great importance in a discussion on TEK.

Bilirubin conjugation is inherently lower in newborns and progressively lower as gestational age decreases. UGT1A1 encodes the UDP bilirubin-conjugating enzyme UGT1A1. As such, it plays a cardinal role in controlling the conjugation of bilirubin from the unconjugated (indirect) to conjugated (direct) form, a change that makes the bilirubin molecule soluble in water, thus facilitating its removal from the body. organism.

The coding area of ​​the gene includes variable exon 1A1, which is specific for bilirubin conjugation and the only variable exon known to regulate bilirubin conjugation. This variable exon functions together with common exons 2 to 5 for the synthesis of the UDP enzyme UGT1A1. Mutations in the coding area of ​​the exons involved in bilirubin conjugation can lead to structural alterations in the UGT1A1 enzyme per se with absent conjugation capacity (Crigler-Najjar syndrome, also associated with kernicterus) in extreme cases.

On the other hand, polymorphisms in the non-coding promoter area decrease the expression of a normally structured enzyme. Decreased expression will further decrease neonatal bilirubin conjugation, which already functions poorly. (43) Decreased bilirubin conjugation with resulting decreased elimination increases the body’s bilirubin reserve, contributing to hyperbilirubinemia.

UGT1A1(TA)7 promoter polymorphism

The UGT1A1 promoter contains a TATA box nucleic acid sequence. The wild-type promoter contains 6 TA nucleotide sequences, designated (TA)6. Longer TATA polymorphisms, such as the not uncommon (TA)7 or the rare (TA)8, are associated with decreased enzyme expression and, as a result, reduced bilirubin conjugation. Gilbert syndrome in adults and hyperbilirubinemia in newborns is associated with homozygosity for the (TA)7 promoter, also known as UGT1A1*28. The latter occurs primarily when coexpressed with additional icterogenic factors, of which G6PD deficiency is the best documented.

Using reversed-phase high-performance liquid chromatography technology, Kaplan and colleagues (44) (45) demonstrated decreased bilirubin conjugation in G6PD-deficient neonates with moderate hyperbilirubinemia, as well as in G6PD-deficient neonates who were not hyperbilirubinemia at the time of sampling, but who later developed hyperbilirubinemia. Decreased bilirubin conjugation in newborns with G6PD deficiency was related to the (TA)7 UGT1A1 promoter polymorphism. In an interesting study by Kaplan and colleagues (46), neither G6PD deficiency in and of itself, nor the (TA)7 promoter polymorphism alone, increased the initial incidence of hyperbilirubinemia, defined as BST ≥15 mg/dL ( 256.56 mmol/L).

However, the combination of G6PD deficiency with heterozygosity or homozygosity for UGT1A1*28 led to a progressive and gradual increase in the incidence of hyperbilirubinemia from baseline from 9.7% to 31.6% in heterozygotes and up to 50 % in UGT1A1*28 homozygotes. Coexpression of G6PD deficiency and UGT1A1*28 may also contribute to the extreme hyperbilirubinemia and high incidence of kernicterus-associated G6PD deficiency frequently found in neonates with G6PD deficiency. (47) (48) (49) (50)

Gly71Arg mutation

UGT1A1 promoter polymorphisms are rare in Asians, while the G>A mutation at nucleotide 211 is associated with Gilbert syndrome in Asians. This gene variant, G71R, is known as UGT1A1*6. This mutation is associated with neonatal hyperbilirubinemia in Asian newborns in the absence of other additional factors. Huang and colleagues (51) demonstrated an interaction between UGT1A1*6 and G6PD deficiency, with overlap of the 2 genes leading to an increased risk of hyperbilirubinemia.

TEK continues to plague the modern world. (41)(42) (43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53) The Global Burden of Disease Study demonstrated that neonatal hyperbilirubinemia It ranked seventh globally among all causes of deaths in the first week after birth, representing 1,309 deaths per 100,000 live births in 2016 and Bhutani et al (54) estimated that 18% (24 million) of Globally, 134 million babies born in 2010 developed clinically significant jaundice, 481,000 late preterm and full-term newborns developed extreme hyperbilirubinemia (BST >25 mg/dL [427.60 mmol/L]), 114,000 died, and more than 63,000 survivors had neurological deterioration. moderate to severe long-term resulting from bilirubin neurotoxicity.

Factors contributing to the incidence of kernicterus in developing countries include inadequate screening for neonatal jaundice, inadequate measurement of BST levels, and a high prevalence of high-risk medical conditions, such as G6PD deficiency, Rh isoimmunization, and sepsis. .

In developing countries, these factors are often compounded by delays in the referral of newborns with jaundice to treatment facilities, environments that lack effective light sources and electricity, and limited availability of whole blood, safe practices. in blood banks or both to perform an exchange transfusion in infants with extremely high bilirubin levels or early evidence of acute bilirubin toxicity. (55) (56) Many of these risk factors are reversible and therefore can be prevented.

The main goal of prevention is to avoid extreme hyperbilirubinemia.

This goal can be achieved through active surveillance and early treatment of neonatal jaundice through a multipronged approach aimed at increasing the availability of resources in the developing world. Such an approach should include the following:

• Increased widespread availability of low-cost point-of-care instruments to measure BST levels without the need for a laboratory. This would allow for more rapid identification of potentially toxic bilirubin levels and facilitate earlier treatment.

• Greater availability of intensive phototherapy instruments.

• Further development of mobile phone technology to improve out-of-hospital bilirubin monitoring.

• Early referral of newborns with jaundice to treatment centers with adequate facilities.

• Rh disease prevention programs.

• Intensive education of both parents and medical caregivers aimed at increasing awareness and early identification of infants with associated medical conditions such as isoimmune hemolysis, G6PD deficiency, and spherocytosis that are likely to exacerbate hyperbilirubinemia.

Although we are not surprised that TEK remains out of control in developing countries with underdeveloped medical systems and that healthcare organizations are rendered ineffective due to the ravages of war, its continued prevalence in industrialized countries is disconcerting . (55) (56) (57) (58) Reports, all published after the year 2000, emanating from the United States, Canada and all of Europe document that, far from being resolved, the problem continues well into the third millennium.

In the industrialized world, post-discharge surveillance may be more criticized in prevention. In many Western countries, the mother/newborn dyad is discharged at approximately 48 hours of age after vaginal delivery. It is evident from reading the bilirubin nomogram that bilirubin continues to rise after this age, peaking at approximately 4 or 5 days.

Recent studies have confirmed that short hospital stay is associated with an increased risk of readmission. (58) (59) (60) It is not surprising that neonatal jaundice is the most common reason for readmission of a newborn. (55) (62) In fact, many newborns who were readmitted with extreme hyperbilirubinemia or bilirubin encephalopathy on or around postnatal day 5 had been discharged healthy from their birth hospitalization. (53) (54) (55) (56) (57) (58) (59) (60) (61) (62) (63) (64)

It is essential, therefore, to comply with post-discharge follow-up recommendations designed to identify newborns in whom jaundice may be developing or worsening after discharge.

In a recent study conducted in Israel, where the Israel Neonatal Society recommends universal community follow-up after discharge, (64) (65) the compliance rate for early neonatal follow-up was only 32%. It is notable, however, that for those who were specifically ordered to return to the hospital for a blood bilirubin test, the compliance rate was almost 100%. (64) (65) These results suggest that providing parents with a specific date, time, and location for follow-up is effective.

Without a doubt, the best therapeutic approach for TEK is prevention by avoiding dangerous levels of hyperbilirubinemia.

Aggressive interventions to reduce bilirubin levels may also be helpful in the early stages of EAB. Standard approaches to achieving this have been extensively reviewed elsewhere and will not be discussed here. Rather, the authors will focus on current, novel, and exciting therapies that can be implemented once bilirubin encephalopathy has occurred.

Symptomatic treatments can target specific TEK targets. TENA is not synonymous with hearing loss, but is characterized by an abnormal and dyssynchronous disorder in signal processing at the auditory level of the brainstem, with or without concomitant hearing loss. The initial approach to language development in these patients is based on “cued speech,” (66) a visual communication system that uses hand shapes and placements in combination with mouth movements and speech to assist in the recognition and distinction between the phonemes of spoken language. In severe cases with associated sensorineural hearing loss, cochlear implants may be useful. (67)

Severe and uncontrollable motor dysfunction is probably the most debilitating aspect of TEK. Motor dysfunction in TEK is due to the neurotoxic effect of bilirubin in the basal ganglia. While physical therapy and occupational therapy can be helpful, unfortunately there are few established options for the relief of severe dystonia and abnormal movements. Therapies such as benzodiazepines, GABAB receptor agonists, anticholinergic medications and dopaminergic agents, which aim to modulate neuronal output from the basal ganglia and thus improve abnormal movements, have been suggested in an attempt to reduce dystonia and restore functional voluntary movements. However, to date they have had limited benefits in clinical studies.

More generalized therapies for TEK have been derived from those used to treat similar symptoms in people without TEK, with minimal specific evidence regarding their effectiveness in TEK. For example, therapeutic hypothermia has been shown to be neuroprotective in hypoxic-ischemic encephalopathy. Its effectiveness against bilirubin neurotoxicity has been demonstrated only in vitro where lower temperatures (32°C – 34°C) decreased neuronal cell death. Similarly, Deliktas and colleagues (68) demonstrated that caffeine decreased bilirubin-induced apoptosis in a rat model.

Novel experimental modalities to reduce bilirubin neurotoxicity

Trihexyphenidyl is a selective muscarinic antagonist. Muscarinic receptors in the basal ganglia appear to segregate with dopamine receptors. Thus, it has been postulated that its inhibition would also modulate the general activity of dopamine output and help to improve the dopaminergic-cholinergic balance, thus improving dystonia. Still the clinical evidence for the use of trihexyphenidyl comes from children with dystonic cerebral palsy, and the evidence in kernicterus is limited to anecdotal reports. (69)

Minocycline, a second-generation tetracycline with anti-inflammatory and neuroprotective properties, has been shown in a rat model of hyperbilirubinemia to preserve normal motor coordination abilities and reduce lethality. (70) This effect was mediated through a reduction in neurodegeneration and neuroinflammation, without affecting plasma bilirubin levels. (71) Treated mice showed a dose-dependent reduction in cerebellar neuron apoptosis and a bilirubin-induced decrease in microglia. Although minocycline is unlikely to be used due to its side effects, the application of other anti-inflammatory medications may confer protection against bilirubin-induced neurological damage and death.

Benzodiazepines, which modulate GABAA receptor activity, and intrathecal baclofen (a GABAB receptor agonist), may improve dystonia and muscle spasm in other dystonic conditions; however, experience in treating kernicterus is limited. Botulinum toxin injection can provide sustained symptomatic relief for cases of focal dystonia. Deep brain stimulation has successfully improved tone and voluntary movements in primary dystonia, and evidence is accumulating for its effectiveness in cases of choreoathetosis and dystonia, which are commonly seen in TEK. (72) Finally, anecdotal reports of successful autologous stem cell therapy in TEK in both animal models and humans are emerging. (73)

In conclusion, more than a century has passed since the first case of bilirubin encephalopathy was reported. Despite being potentially preventable and despite efforts to eliminate the irreversible brain damage of bilirubin encephalopathy and kernicterus, these conditions have been with us into the third millennium. TEK continues to be widespread, not only in developing countries with poorly developed medical systems but also in industrialized countries. Treatment options, although expanding, remain limited and evidence of effectiveness is anecdotal, emphasizing the need for prevention. 

The present study highlights that kernicterus continues to be a public health problem worldwide, both in developed and developing countries. The different subtypes of the kernicterus spectrum are discussed, including predominantly motor, neurosensory auditory dysfunction, subtle kernicterus, and kernicterus plus. On the other hand, the authors reviewed the multiple genetic factors that increase the risk of developing kernicterus spectrum disorder, and emphasized the need for its prevention in all areas since therapeutic options continue to be scarce and unsatisfactory.