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

  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]

  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]

  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]

  Kernicterus: A disorder that is due to severe jaundice in the newborn, with deposition of the pigment bilirubin in the brain that causes damage to the brain, potentially leading to athetoid cerebral palsy, hearing loss, vision problems, or mental retardation [medicinenet.com]

  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]

• High-Pitched Cry

  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]

  cry are manifestations encountered of more severe intoxications. [symptoma.com]

  The initial phase is characterized by the infant not feeding well, being lethargic with a decreased muscle tone (mild hypotonia) and a high pitched cry. [g6pddf.org]

  Symptoms of kernicterus include excessive sleepiness, high-pitched crying, muscle spasms and arching in the neck and back. The sympto ms can become life-threatening if treatment is delayed. [childbirthinjuries.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]

• Pain

  Unfortunately, determination of serum bilirubin is a painful procedure, and is not very accurate since there is a high variability in laboratory measurements. [ncbi.nlm.nih.gov]

  The patient's chief complaint as communicated by the mother was pain in lower left back tooth region of the patient since 2 days. Pain aggravated on chewing food and on drinking cold water. [jorr.org]

  The lawsuits filed on behalf of kernicterus patients and families seek damages for medical bills, loss of earning potential, pain and suffering, and loss of the pleasures of life. [feldmanshepherd.com]

  Our law firm has successfully handled many medical malpractice cases involving birth injuries and can help you get the compensation you deserve for you pain, suffering and medical bills. Call us today for an immediate consultation. [knopfbigger.com]

  If you or someone in your care has chest pains, difficulty breathing, or severe bleeding, it could be a life-threatening emergency. Call 9-1-1 or the local emergency number immediately. [healthlinkbc.ca]

• Weakness

  The baby may seem "floppy" and weak. Sometimes this is followed by periods when the baby's muscles flex in a way that is not normal. The baby may be stiff and arch his or her back and head. A fever that occurs along with any of these other symptoms. [myhealth.alberta.ca]

  Other symptoms of Kernicterus include: Lethargy (the baby is not alert, difficult to wake up or can’t be kept awake) Shrill, high-pitched cry Weak, limp or floppy appearance Tendency to lie unnaturally in bed, with body arching or bowing upward when lying [feldmanshepherd.com]

  ABE has been categorized into three phases: Phase 1 typically begins around 3-5 days of life, and may involve decreased alertness, feeding problems, hypotonia, and a weak Moro reflex. [abclawcenters.com]

  Pathophysiology Factors affecting neurotoxicity Concentration of bilirubin in the brain Duration of exposure to bilirubin Correlation between serum bilirubin and neurotoxicity is weak, except in infants with hemolysis Dennery et al. [slideshare.net]

• 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

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

  What Are the Risk Factors for Jaundice and Kernicterus? Some newborn babies are more likely than others to develop jaundice, which if left undiagnosed and untreated can lead to kernicterus. [feldmanshepherd.com]

  Generally, this includes: Identifying risks for jaundice complications (i.e. risk factors such as race, previous birth with a child with jaundice, darker skin, and premature birth). [edwardskirby.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]

  Prevention Treating jaundice or conditions that may lead to it can help prevent kernicterus. Infants with the first signs of jaundice have bilirubin level measured within 24 hours. [nicklauschildrens.org]

• 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]

  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]

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

  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]

• Lethargy

  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 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]

  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]

  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]

  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]

• Opisthotonus

  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]

  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 may also present with retrocollis or opisthotonus. Some infants have no neurologic signs. [atlases.muni.cz]

  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]

• 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]

  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]

  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]

• 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].

• Gliosis

  Microscopically, they show neuronal necrosis (eosinophilic neurons similar to HIE) and, in burned-out cases, neuronal loss, gliosis and atrophy. Bilirubin binds to cell membranes and is toxic to neurons and oligodendroglia. [neuropathology-web.org]

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 - When treatment is necessary, our clinic offers pharmacological and non-pharmacological treatments and referrals. [childrensmercy.org]

Fortunately, prompt treatment can stop brain damage from progressing. Kernicterus Treatment Kernicterus is a medical emergency and requires immediate treatment. [childbirthinjuries.com]

Postponing treatment for reasons which deviate from accepted standards. Not performing any treatment at all. Other Forms of Negligence Failing to treat risk factors, including hypoxic ischemic encephalopathy. [edwardskirby.com]

The most common treatments for BE include: Light Therapy – Light therapy is the most common form of treatment for elevated bilirubin levels. [birthinjuryguide.org]

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]

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]

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]

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

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

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]

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.com]

[…] 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]

Accurately detecting and monitoring jaundice, performing necessary tests, and appropriately treating the condition is absolutely critical to preventing Kernicterus. [edwardskirby.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.