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Bilirubin Encephalopathy

Kernicterus

Bilirubin encephalopathy is primarily described in neonates and infants who develop symptoms due to toxic effects of bilirubin on the nervous system. Patients present with jaundice, motor abnormalities, feeding difficulties, fever, and convulsions. A variable degree of hearing impairment, difficulties in maintaining an upward vertical gaze, poor teeth development, together with intellectual disability, are potential long-term sequelae of both acute and chronic form of bilirubin encephalopathy (kernicterus). Clinical, biochemical, and imaging criteria are necessary to establish the diagnosis.


Presentation

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]
  • Abnormal neurodevelopment was defined as either (i) cerebral palsy or (ii) abnormal DDST or (iii) abnormal BERA. The mean bilirubin at admission was 37 mg dl(-1). MRI and BERA were abnormal in 61% and 76%.[ncbi.nlm.nih.gov]
  • At follow-up, 5 infants developed classic choreoathetoid cerebral palsy, 6 had spectrum of neurologic dysfunction and developmental delay (as described by the reporting physician), and 3 were healthy.[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]
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]
  • 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]
  • 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]
  • 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
  • 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
  • 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]
  • Patients present with jaundice, motor abnormalities, feeding difficulties, fever, and convulsions.[symptoma.com]
  • In recent years, changes in health care practices including the early discharge of newborns have transformed the management of neonatal jaundice into an outpatient problem.[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]
  • Abstract Jaundice is the most common and one of the most annoying problems that can occur in the newborn.[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]
  • In recent years, changes in health care practices including the early discharge of newborns have transformed the management of neonatal jaundice into an outpatient problem.[ncbi.nlm.nih.gov]
  • The management of neonatal jaundice requires that therapy begins when total serum bilirubin levels are significantly below the levels at which kernicterus is considered an immediate threat.[ncbi.nlm.nih.gov]
  • Yasuo_Hachiya@member.metro.tokyo.jp Abstract Bilirubin encephalopathy (BE), which includes acute (kernicterus) and chronic (postkernicteric) forms, results from severe neonatal jaundice.[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]
  • 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]
  • 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]
  • .); 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]
  • 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]
  • Babies may also present with retrocollis or opisthotonus. Some infants have no neurologic signs.[atlases.muni.cz]
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
  • 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]

Workup

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

  • 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]
  • 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 Mild jaundice may not require treatment, but if his 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]

Prognosis

  • 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]
  • 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]

Etiology

  • Unconjugated hyperbilirubinaemia is the etiology of kernicterus, especially when total bilirubin levels exceed 35 mg/dL 1,2,5 .[radiopaedia.org]
  • 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]
  • Significant hyperbilirubinemia ( 95th percentile for age in hours) occurs in 8 to 11% of infants. 1 , 2 The etiological basis for progressive hyperbilirubinemia is multifactorial and due to excessive bilirubin production and/or decrease its elimination[nature.com]

Epidemiology

  • 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.com]
Sex distribution
Age distribution

Pathophysiology

  • 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]
  • 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]

Prevention

  • […] of chronic bilirubin encephalopathy, performed at the request of the US Preventive Services Task Force (USPSTF).[ncbi.nlm.nih.gov]
  • 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[ncbi.nlm.nih.gov]
  • Prevention of bilirubin encephalopathy is based on the detection of infants at risk of developing a significant hyperbilirubinemia.[ncbi.nlm.nih.gov]
  • OBJECTIVE: To systematically review the effectiveness of specific screening modalities to prevent neonatal bilirubin encephalopathy.[ncbi.nlm.nih.gov]
  • This case report emphasises the need for timely suspicion and diagnosis of this disease for prevention of chronic morbidity.[ncbi.nlm.nih.gov]

References

Article

  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.

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Last updated: 2019-06-28 10:17