In newborn infants or neonates, the immature blood-brain-barrier (BBB) allows bilirubin in its conjugated form to reach the central nervous system (CNS) and exert toxic effect on neuronal cells and affect various metabolic processes (apoptosis, utilization of energy, and mitochondrial function) in the basal ganglia and the brainstem [1] [2]. Thus, signs of bilirubin-mediated toxicity may start during the first several weeks of life, in which case the term acute bilirubin encephalopathy is used [2] [3]. Jaundice as the most prominent finding, together with lethargy, feeding difficulties, and hypotonia followed by hypertonia are some of the earliest symptoms seen in acute disease, whereas abnormal extension of the neck (retrocollis), generalized aching and opisthotonus, fever, convulsions, and a very high-pitched cry are manifestations encountered of more severe intoxications [2] [4] [5]. In some cases, brainstem damage can induce life-threatening apnea due to diminished responses of the respiratory center to CO2 concentrations [4] [5]. Bilirubin encephalopathy may take a chronic course, and the term kernicterus is sometimes used to describe the long-term complications of this disorder. Disturbances in auditory function (total hearing loss is a possibility), dysplasia of deciduous teeth, inability to sustain an upward vertical gaze and persistent abnormalities of muscle tone and control are seen [2] [3] [5] [6]. Intellectual deficits, although being an uncommon finding, is one of the more debilitating sequelae of chronic bilirubin encephalopathy [3].

• Cerebral Palsy

  Bilirubin levels of 20 mg/dL or higher may cause choreoathetoid cerebral palsy, sensorineural hearing loss, eye disorders and enamel dysplasia in term infants; clinical picture compatible with kernicterus. [revistaschilenas.uchile.cl]

  Cerebral palsy epidemiology: Where are we now and where are we going? Dev Med Child Neurol 1992;34:547-51. 10. Cans C. Surveillance of cerebral palsy in Europe: A collaboration of cerebral palsy surveys and registers. [jorr.org]

  He had dyskinetic cerebral palsy, high frequency hearing loss and abnormalities in the globi pallidi on MRI of his brain. Very extensive investigations for other causes of dyskinetic cerebral palsy were negative. [fn.bmj.com]

  Two preterm infants with athetoid cerebral palsy due to bilirubin encephalopathy were examined by magnetic resonance spectroscopic imaging at age 3 years. An increased glutamate/glutamine complex/creatine ratio was found in the basal ganglia. [ncbi.nlm.nih.gov]

  If your child has been diagnosed with kernicterus or associated conditions such as cerebral palsy or epilepsy/a seizure disorder, it is likely a case of medical malpractice and you may be entitled to financial compensation. [abclawcenters.com]

• Anemia

  Transient hematologic manifestations including anemia, leukopenia, and thrombocytopenia are commonly encountered in neonatal lupus but isolated hemolytic anemia leading to severe hyperbilirubinemia in an otherwise asymptomatic newborn is an unusual presentation [jcnonweb.com]

  The infant was found to have a serum indirect bilirubin of 49 mg/dl secondary to isoimmune hemolytic anemia due to anti-c antibody. The infant survived but suffers from clinical manifestations of kernicterus. [ncbi.nlm.nih.gov]

  Kernicterus may occur because of Rh blood-group incompatibility between mother and child, as in erythroblastosis fetalis, where the mother’s immune system destroys fetal blood cells, resulting in severe anemia and jaundice in the newborn. [britannica.com]

  Moreover, neonates have much higher levels of bilirubin in their blood due to: Although the severe anemia of erythroblastosis fetalis is usually the cause of death, many children who barely survive the anemia exhibit permanent mental impairment or damage [en.wikipedia.org]

  The researchers found that children with no neurotoxicity risk factors, including: prematurity, anemia, significant lethargy, sepsis, acidosis, asphyxia, temperature instability, amongst others, could tolerate bilirubin levels higher than the standard [natureasia.com]

• Muscle Rigidity

  (soft spot) Seizures Late stage: High-frequency hearing loss Intellectual disability Muscle rigidity Speech difficulties Seizures Movement disorder Exams and Tests A blood test will show a high bilirubin level (greater than 20-25 mg/dL). [nicklauschildrens.org]

  (hypertonia) Poor feeding Late stage: Stupor or coma No feeding Shrill cry Muscle rigidity, markedly arched back with neck hyperextended backwards Seizures A blood test will show a high bilirubin level (greater than 20 to 25 mg/dL). [medlineplus.gov]

  (hypertonia) Poor feeding Late stage: Stupor or coma No feeding Shrill cry Muscle rigidity, markedly arched back with neck hyperextended backwards Seizures Exams and Tests A blood test will show a high bilirubin level (greater than 20 to 25 mg/dL). [stlukes-stl.com]

  Late Stage – Symptoms include shrill crying, seizures, muscle rigidity or arched back, coma, or no feeding at all. Late stage BE can be fatal if treatment is not administered in a timely manner, or is unsuccessful. [birthinjuryguide.org]

• Vomiting

  Early symptoms of kernicterus in term infants are lethargy, poor feeding, and vomiting. Opisthotonos, oculogyric crisis, seizures, and death may follow. [msdmanuals.com]

  Other symptoms of kernicterus include: high-pitched crying decreased appetite and less feeding than usual inconsolable crying floppy or limp body missing reflexes arching of the head and heels back, like a bow uncontrollable movements vomiting unusual [healthline.com]

  These symptoms may include lack of energy (lethargy), poor feeding habits, fever, and vomiting. [rarediseases.org]

  Kernicterus can cause: first few days: lethargy, poor feeding, vomiting, high pitched cry, seizures, decreased tone first week: opisthotonos, fever, increased tone, bulging fontanelles, pulmonary hemorrhage chronic: hearing damage, strabismus, mental [sharinginhealth.ca]

• Jaundice

  Feeding Difficulties A baby who is not eating, wetting, or stooling well in the first few days of life is more likely to get jaundice. Sibling with Jaundice A baby with a sister or brother that had jaundice is more likely to develop jaundice. [cdc.gov]

  Kernicterus is a rare kind of preventable brain damage that can happen in newborns with jaundice. Jaundice is a yellow coloring of the skin and other tissues that affects about 60%-80% of infants in the United States. [webmd.com]

  The most common clinical failure was a delay in measuring bilirubin in babies with visible jaundice, three of whom had a family history of neonatal jaundice and two of whom were jaundiced from very early in life. [fn.bmj.com]

  Patients present with jaundice, motor abnormalities, feeding difficulties, fever, and convulsions. [symptoma.com]

• Neonatal Jaundice

  jaundice due to other excessive hemolysis P58.0 Neonatal jaundice due to bruising P58.1 Neonatal jaundice due to bleeding P58.2 Neonatal jaundice due to infection P58.3 Neonatal jaundice due to polycythemia P58.4 Neonatal jaundice due to drugs or toxins [icd10data.com]

  The most common clinical failure was a delay in measuring bilirubin in babies with visible jaundice, three of whom had a family history of neonatal jaundice and two of whom were jaundiced from very early in life. [fn.bmj.com]

  The influence of breast-feeding on neonatal hyperbilirubinemia. Biol Neonate 1993;64:104–109. Nielsen HE, Haase P, Blaabjerg J, Stryhn H, Hilden J: Risk factors and sib correlation in physiological neonatal jaundice. [karger.com]

  Clinical experience with Sephadex gel filtration for evaluation of the bilirubin binding affinity of serum in neonatal jaundice is reported. [ncbi.nlm.nih.gov]

  For the vast majority this neonatal jaundice is a mild transitory phenomenon with no long-term consequences. The greatest fear associated with neonatal jaundice is kernicterus. [acutecaretesting.org]

• Lethargy

  It results from cerebral deposition of unconjugated bilirubin - globus pallidus (GP), subthalamic nucleus, hippocampus, putamen, cerebellar nuclei, and thalamus Relevant Clinical Information: Newborn (2–5 days-old) with jaundice, lethargy, hypotonia, [ajnr.org]

  The hypotonia, lethargy and poor sucking reflex of the first phase of kernicterus appeared highly significant because of the great importance of this phase concerning the infant's neurologic prognosis. [pediatrics.aappublications.org]

  […] a very high level of bilirubin in their blood the level of bilirubin in their blood is rising rapidly they do not receive any treatment Initial symptoms of kernicterus in babies include: poor feeding irritability a high-pitched cry no startle reflex lethargy [nhs.uk]

  Early symptoms of kernicterus in term infants are lethargy, poor feeding, and vomiting. Opisthotonos, oculogyric crisis, seizures, and death may follow. [msdmanuals.com]

  Jaundice as the most prominent finding, together with lethargy, feeding difficulties, and hypotonia followed by hypertonia are some of the earliest symptoms seen in acute disease, whereas abnormal extension of the neck (retrocollis), generalized aching [symptoma.com]

• Seizure

  Late stage: High-frequency hearing loss Intellectual disability Muscle rigidity Speech difficulties Seizures Movement disorder Exams and Tests A blood test will show a high bilirubin level (greater than 20-25 mg/dL). [nicklauschildrens.org]

  […] include: poor feeding irritability a high-pitched cry no startle reflex lethargy (sleepiness) brief pauses in breathing (apnoea) their muscles becoming unusually floppy, like a rag doll As kernicterus progresses, additional symptoms can include fits (seizures [nhs.uk]

  Symptoms of kernicterus include loss of the startle reflex, poor feeding, decreased movement, and seizures. If the infant survives, later effects of kernicterus may include movement disorders, hearing loss, and decreased mental ability. [britannica.com]

  Opisthotonos, oculogyric crisis, seizures, and death may follow. Kernicterus may result in intellectual disability, choreoathetoid cerebral palsy, sensorineural hearing loss, and paralysis of upward gaze later in childhood. [msdmanuals.com]

• Opisthotonus

  Jaundice as the most prominent finding, together with lethargy, feeding difficulties, and hypotonia followed by hypertonia are some of the earliest symptoms seen in acute disease, whereas abnormal extension of the neck (retrocollis), generalized aching and opisthotonus [symptoma.com]

  Babies with bilirubin encephalopathy are lethargic, hypotonic or hypertonic, and have a high pitched cry, opisthotonus, seizures, and may die if bilirubin is not lowered. The MRI shows high T2 signal in the globus pallidus. [neuropathology-web.org]

  mild to severe muscle spasms including those in which the head and heels are bent backward and the body bows forward (opisthotonus); and/or uncontrolled involuntary muscle movements (spasticity). [rarediseases.org]

  The advanced phase is characterized by an intens ification of the retrocollis and opisthotonus, producing arching, and inconsolable crying with a shrill cry. [g6pddf.org]

• Dystonia

  Dystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. [g6pddf.org]

  Both children have dystonia, athetosis, upward gaze palsy, and sensorineural hearing loss, with MRIs showing characteristic abnormal signal in the globus pallidus. [ncbi.nlm.nih.gov]

  Clinically, manifestations of CBE include: movement disorders - athetoid cerebral palsy and or dystonia, 60% have severe motor disability (unable to walk). auditory dysfunction - auditory neuropathy (ANSD) oculomotor impairments (nystagmus, strabismus [en.wikipedia.org]

  Acute bilirubin encephalopathy may ensue and progress to kernicterus (chronic bilirubin encephalopathy), a permanent disabling neurologic condition that is classically characterized by the extrapyramidal movement disorders of dystonia, choreoathetosis [blogs.nejm.org]

  Consequently, children diagnosed later in life with acute bilirubin encephalopathy present these developmental issues: Movement/motor disorders (dystonia and/or athetoid cerebral palsy) Hearing loss (auditory neuropathy) Eye/vision deficits ( strabismus [knopfbigger.com]

• Ataxia

  Wernicke's encephalopathy a neurological disorder characterized by confusion, apathy, drowsiness, ataxia of gait, nystagmus, and ophthalmoplegia; it is due to thiamine deficiency, usually from chronic alcohol abuse. [medical-dictionary.thefreedictionary.com]

  Patients surviving kernicterus have severe permanent neurologic symptoms ( choreoathetosis, spasticity, hearing loss, ataxia, mental retardation ). [neuropathology-web.org]

  Kernicterus is clinically characterized by chronic and permanent neurological manifestations in the infant, including 1 : choreoathetoid cerebral palsy cranial neuropathies, e.g. causing sensorineural hearing loss or gaze palsies ataxia intellectual disability [radiopaedia.org]

  As an affected infants ages, other symptoms and physical findings may develop including delayed and/or abnormal motions or motor development; convulsions or seizures; impaired ability to coordinate voluntary movements (ataxia); abnormal muscle rigidity [rarediseases.org]

Because of the complications that may arise from bilirubin encephalopathy, all newborn babies must be carefully monitored in their first several days of life in order to make an early diagnosis. In fact, guidelines advocate that physicians should check for jaundice every 8-12 hours [2], thus illustrating the importance of a proper physical examination and adequate clinical suspicion, perhaps the two most important components of the workup. If jaundice does appear, bilirubin encephalopathy must be ruled out, which can be done by measuring the total serum and total conjugated bilirubin (TSB and tcB, respectively) in blood [2]. These values must be interpreted according to the age of the newborn (in hours), and a value exceeding the 95% percentile yields solid evidence to make a presumptive diagnosis [2]. Since cholestasis, glucose-6-phosphate dehydrogenase (G6PD) deficiency (for newborns who received phototherapy), and hypothyroidism can be the underlying cause of bilirubin encephalopathy, a comprehensive laboratory workup encompassing these entities must be carried out [2]. Imaging studies of the endocranium, such as magnetic resonance imaging (MRI), are highly useful for determining the extent of damage caused by bilirubin [7]. Typical findings include high intensity of the subthalamic nuclei and globus pallidus on T1-weighed studies, but the use of more advanced methods - MR spectroscopy (MRS), and diffusion-weighted imaging (DWI) is advocated in order to recognize the ailment early on [7].

Treatment Mild jaundice may not require treatment, but if their bilirubin level is high, or if your baby has certain risk factors (like being born prematurely), treatment may be necessary. [webmd.com]

Treatment for kernicterus involves using an exchange transfusion as used in the treatment of newborn jaundice. [nhs.uk]

… it should be read widely by clinicians and public health officers confronted by issues related to the early diagnosis, treatment and rehabilitation of individuals suffering from kernicterus.” [amazon.es]

Many times, jaundice will go away without treatment. However, if treatment is required, the main treatment is a simple one. Babies are placed under special blue lights, called “ bili lights ,” for a number of hours, or wrapped in a “bili-blanket.” [feldmanshepherd.com]

Treatment Treatment depends on how old the baby is (in hours) and whether the baby has any risk factors (such as prematurity). [stlukes-stl.com]

Treatment and prognosis There is no disease-modifying treatment available, and prognosis is poor 1,2,6. [radiopaedia.org]

The hypotonia, lethargy and poor sucking reflex of the first phase of kernicterus appeared highly significant because of the great importance of this phase concerning the infant's neurologic prognosis. [pediatrics.aappublications.org]

Sections Continuing Education Activity Introduction Etiology Epidemiology Pathophysiology History and Physical Evaluation Treatment / Management Differential Diagnosis Pertinent Studies and Ongoing Trials Prognosis Complications Deterrence and Patient [pubmed.ncbi.nlm.nih.gov]

It may include: Light therapy (phototherapy) Exchange transfusions Outlook (Prognosis) Kernicterus is a serious condition. Many infants with late-stage nervous system complications die. [nicklauschildrens.org]

It may include: Light therapy (phototherapy) Exchange transfusions (removing the child's blood and replacing it with fresh donor blood or plasma) Outlook (Prognosis) BE is a serious condition. [stlukes-stl.com]

Unconjugated hyperbilirubinaemia is the etiology of kernicterus, especially when total bilirubin levels exceed 35 mg/dL 1,2,5. [radiopaedia.org]

Inherent neonatal deficiency of this enzyme is the principal etiology of physiologic jaundice. [emedicine.medscape.com]

The etiologic agent is also the cause of new variant Creutzfeldt-Jakob disease. [medical-dictionary.thefreedictionary.com]

Its etiology and pathogenesis overlap to some extent with HIE. [neuropathology-web.org]

Sections Continuing Education Activity Introduction Etiology Epidemiology Pathophysiology History and Physical Evaluation Treatment / Management Differential Diagnosis Pertinent Studies and Ongoing Trials Prognosis Complications Deterrence and Patient [pubmed.ncbi.nlm.nih.gov]

The objectives of this study were to establish the incidence of CBE in Canada and identify epidemiological and medical risk factors associated with its occurrence. [ncbi.nlm.nih.gov]

Public Health and Preventive Medicine, Ottawa, Ontario, Children`s Hospital of Eastern Ontario Research Institute - BORN Ontario, Ottawa, Ontario, University of Ottawa - School of Epidemiology, Public Health and Preventive Medicine, Ottawa, Ontario [eurekaselect.com]

Sections Continuing Education Activity Introduction Etiology Epidemiology Pathophysiology History and Physical Evaluation Treatment / Management Differential Diagnosis Pertinent Studies and Ongoing Trials Prognosis Complications Deterrence and Patient [pubmed.ncbi.nlm.nih.gov]

Sections Continuing Education Activity Introduction Etiology Epidemiology Pathophysiology History and Physical Evaluation Treatment / Management Differential Diagnosis Pertinent Studies and Ongoing Trials Prognosis Complications Deterrence and Patient [pubmed.ncbi.nlm.nih.gov]

Pathophysiology of kernicterus. In: Polin RA, Abman SH, Rowitch, DH, Benitz WE, Fox WW, eds. Fetal and Neonatal Physiology. 5th ed. Philadelphia, PA: Elsevier; 2017:chap 164. Kaplan M, Wong RJ, Sibley E, Stevenson DK. [medlineplus.gov]

Neonatology, Pathophysiology and Management of the Newborn. 5th ed. Philadelphia, PA: Lippincott; 1999. 765-819. Petersen JR, Okorodudu AO, Mohammad AA, et al. [emedicine.medscape.com]

Preventive Services Task Force (USPSTF). These statements address preventive health services for use in primary care clinical settings, including screening tests, counseling, and preventive medications. [aafp.org]

The aim of this rapid review is 1) to review the evidence for 1) predicting and preventing severe hyperbilirubinemia and bilirubin encephalopathy, 2) determining the efficacy of home/community treatments (home phototherapy) in the prevention of severe [eurekaselect.com]

[…] of chronic bilirubin encephalopathy, performed at the request of the US Preventive Services Task Force (USPSTF). [ncbi.nlm.nih.gov]

Kernicterus is Preventable Kernicterus is very preventable when high-risk infants are closely monitored and treated aggressively. [ezinearticles.com]

1. Ostrow JD, Pascolo L, Shapiro SM, Tiribelli C. New concepts in bilirubin encephalopathy. Eur J Clin Invest. 2003;33(11):988-997.
2. AAP Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.
3. Connolly AM, Volpe JJ. Clinical features of bilirubin encephalopathy. Clin Perinatol. 1990;17(2):371-379.
4. Amin SB, Bhutani VK, Watchko JF. Apnea in Acute Bilirubin Encephalopathy. Semin Perinatol. 2014;38(7):407-411.
5. Arnolda G, Nwe HM, Trevisanuto D, et al. Risk factors for acute bilirubin encephalopathy on admission to two Myanmar national paediatric hospitals. Matern Health Neonatol Perinatol. 2015;1:22.
6. Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med. 2010;15(3):157-163.
7. Wisnowski JL, Panigrahy A, Painter MJ, Watchko JF. Magnetic Resonance Imaging of Bilirubin Encephalopathy: Current Limitations and Future Promise. Semin Perinatol. 2014;38(7):422-428.