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

  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]

  Other causes are certain types of drug therapy, cerebral palsy, and jaundice associated with prematurity. Symptoms of kernicterus include loss of the startle reflex, poor feeding, decreased movement, and seizures. [britannica.com]

  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]

• Anemia

  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]

  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]

  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

  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]

  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]

  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. [merckmanuals.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

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

  These cases provide a strong argument in favour of rapid and aggressive intervention in infants presenting with extreme jaundice and neurological symptoms. [ncbi.nlm.nih.gov]

• 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]

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

  Bertini G, Dani C, Tronchin M, Rubaltelli FF: Is breast feeding favoring early neonatal jaundice? Pediatrics, in press. [karger.com]

• 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]

  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]

  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]

  Initial symptoms of kernicterus in babies include: poor feeding irritability a high-pitched cry lethargy (sleepiness) brief pauses in breathing (apnoea) their muscles becoming unusually floppy, like a rag doll As kernicterus progresses, additional symptoms [nhs.uk]

  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]

• Seizure

  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]

  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]

  Management of kernicterus will include management of neurological complications, including seizures and sensory nerve deafness. [patient.info]

  […] kernicterus in babies include: poor feeding irritability a high-pitched cry 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]

• 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]

  These include lethargy, decreased feeding, hypotonia or hypertonia, a high-pitched cry, spasmodic torticollis, opisthotonus, setting sun sign, fever, seizures, and even death. [en.wikipedia.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

  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]

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

  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]

  Children affected with complications of hyperbilirubinemia can present with choreoathetoid cerebral palsy, dystonia, sensorineural hearing loss, paralysis of upward gaze, and dental enamel dysplasia. [cfp.ca]

  […] 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 resulting in muscle spasms (dystonia [rarediseases.org]

• 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].

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]

A blinded, retrospective chart review quantified the amount of weekly apnea and bradycardia events during the hospital stay, total duration of methylxanthine treatment, total duration of mechanical ventilation, CPAP, and/or nasal cannula, and risk factors [ncbi.nlm.nih.gov]

Fortunately, prompt treatment can stop brain damage from progressing. Kernicterus Treatment Kernicterus is a medical emergency and requires immediate treatment. [childbirthinjuries.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 - When treatment is necessary, our clinic offers pharmacological and non-pharmacological treatments and referrals. [childrensmercy.org]

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

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]

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]

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]

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

The study's authors contend that the risk of developing bilirubin encephalopathy from haemolytic diseases depends on the etiology of the disease. [natureasia.com]

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

Etiology Hyperbilirubinemia as a result of increased bilirubin production and decreased bilirubin elimination Immature blood-brain barrier of the neonates — the barrier is less well developed in the neonatal period than in adulthood. [atlases.muni.cz]

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 [currentpediatricreviews.com]

Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol. 2004 Oct. 24(10):650-62. [Medline]. Cashore WJ. Bilirubin and jaundice in the micropremie. Clin Perinatol. 2000 Mar. 27(1):171-9, vii. [emedicine.medscape.com]

Balances summaries of relevant pathophysiology with clear, practical clinical guidance to help you thoroughly understand the underlying science of diseases. [books.google.com]

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]

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]

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

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]

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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.