Skip to main content

Advertisement

SpringerLink
Log in

Bilirubin Encephalopathy

  • Neurology of Systemic Diseases (J. Biller, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Hyperbilirubinemia is commonly seen in neonates. Though hyperbilirubinemia is typically asymptomatic, severe elevation of bilirubin levels can lead to acute bilirubin encephalopathy and progress to kernicterus spectrum disorder, a chronic condition characterized by hearing loss, extrapyramidal dysfunction, ophthalmoplegia, and enamel hypoplasia. Epidemiological data show that the implementation of universal pre-discharge bilirubin screening programs has reduced the rates of hyperbilirubinemia-associated complications. However, acute bilirubin encephalopathy and kernicterus spectrum disorder are still particularly common in low- and middle-income countries.

Recent Findings

The understanding of the genetic and biochemical processes that increase the susceptibility of defined anatomical areas of the central nervous system to the deleterious effects of bilirubin may facilitate the development of effective treatments for acute bilirubin encephalopathy and kernicterus spectrum disorder. Scoring systems are available for the diagnosis and severity grading of these conditions. The treatment of hyperbilirubinemia in newborns relies on the use of phototherapy and exchange transfusion. However, novel therapeutic options including deep brain stimulation, brain-computer interface, and stem cell transplantation may alleviate the heavy disease burden associated with kernicterus spectrum disorder.

Summary

Despite improved screening and treatment options, the prevalence of acute bilirubin encephalopathy and kernicterus spectrum disorder remains elevated in low- and middle-income countries. The continued presence and associated long-term disability of these conditions warrant further research to improve their prevention and management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Ansong-Assoku B, Shah SD, Adnan M, Ankola PA. Neonatal jaundice. Treasure Island: StatPearls; 2022.

    Google Scholar 

  2. Mitra S, Rennie J. Neonatal jaundice: aetiology, diagnosis and treatment. Br J Hosp Med (Lond). 2017;78(12):699–704. https://doi.org/10.12968/hmed.2017.78.12.699.

    Article  Google Scholar 

  3. Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med. 2010;15(3):157–63. https://doi.org/10.1016/j.siny.2009.12.004.

    Article  PubMed  Google Scholar 

  4. Orth J. Ueber das Vorkommen von Bilirubinkrystallen bei neugebornen Kindern. In: Virchows Arch Path Anat. 1875(63):S. 447–62.

  5. American Academy of Pediatrics Subcommittee on H. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297–316. https://doi.org/10.1542/peds.114.1.297.

    Article  Google Scholar 

  6. • Le Pichon JB, Riordan SM, Watchko J, Shapiro SM. The neurological sequelae of neonatal hyperbilirubinemia: definitions, diagnosis and treatment of the kernicterus spectrum disorders (KSDs). Curr Pediatr Rev. 2017;13(3):199–209. https://doi.org/10.2174/1573396313666170815100214. This paper clarifies terminology, proposes the term KSD, and outlines available treatment options. The authors identify diagnostic criteria and systemic nomenclature for KSD using the KSD-Toolkit clinical scoring system.

  7. Vidavalur R, Devapatla S. Trends in hospitalizations of newborns with hyperbilirubinemia and kernicterus in United States: an epidemiological study. J Matern Fetal Neonatal Med. 2021:1–6. https://doi.org/10.1080/14767058.2021.1960970.

  8. Greco C, Arnolda G, Boo NY, Iskander IF, Okolo AA, Rohsiswatmo R, et al. Neonatal jaundice in low- and middle-income countries: lessons and future directions from the 2015 Don Ostrow Trieste Yellow Retreat. Neonatology. 2016;110(3):172–80. https://doi.org/10.1159/000445708.

    Article  CAS  PubMed  Google Scholar 

  9. Dong XY, Wei QF, Li ZK, Gu J, Meng DH, Guo JZ, et al. Causes of severe neonatal hyperbilirubinemia: a multicenter study of three regions in China. World J Pediatr. 2021;17(3):290–7. https://doi.org/10.1007/s12519-021-00422-3.

    Article  CAS  PubMed  Google Scholar 

  10. • Olusanya BO, Osibanjo FB, Slusher TM. Risk factors for severe neonatal hyperbilirubinemia in low and middle-income countries: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117229. https://doi.org/10.1371/journal.pone.0117229. This systematic review and meta-analysis examines studies from 1990 to 2014 to identify key risk factors for BE in LMIC.

  11. • Usman F DU, Shapiro SM, Le Pichon JB, Slusher TM. Acute bilirubin encephalopathy and its progression to kernicterus: current perspectives. Res Rep Neonatol. 2018;8:33–44. This review describes terminology, clinical manifestations, pathogenesis, diagnosis, and treatment options for BE.

  12. • Karimzadeh P, Fallahi M, Kazemian M, Taslimi Taleghani N, Nouripour S, Radfar M. Bilirubin induced encephalopathy. Iran J Child Neurol. 2020;14(1):7–19. This paper is a recent summary on the incidence, clinical manifestations, BIND scoring system, and few management options for BE.

  13. Olds C, Oghalai JS. Audiologic impairment associated with bilirubin-induced neurologic damage. Semin Fetal Neonatal Med. 2015;20(1):42–6. https://doi.org/10.1016/j.siny.2014.12.006.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Oghalai JS. The cochlear amplifier: augmentation of the traveling wave within the inner ear. Curr Opin Otolaryngol Head Neck Surg. 2004;12(5):431–8. https://doi.org/10.1097/01.moo.0000134449.05454.82.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Shapiro SM, Bhutani VK, Johnson L. Hyperbilirubinemia and kernicterus. Clin Perinatol. 2006;33(2):387–410. https://doi.org/10.1016/j.clp.2006.03.010.

    Article  PubMed  Google Scholar 

  16. Xia A, Song Y, Wang R, Gao SS, Clifton W, Raphael P, et al. Prestin regulation and function in residual outer hair cells after noise-induced hearing loss. PLoS ONE. 2013;8(12):e82602. https://doi.org/10.1371/journal.pone.0082602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Choi CH, Oghalai JS. Perilymph osmolality modulates cochlear function. Laryngoscope. 2008;118(9):1621–9. https://doi.org/10.1097/MLG.0b013e3181788d72.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Shapiro SM, Nakamura H. Bilirubin and the auditory system. J Perinatol. 2001;21 Suppl 1:S52–5; discussion S9–62. https://doi.org/10.1038/sj.jp.7210635.

  19. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy. Brain. 1996;119(Pt 3):741–53. https://doi.org/10.1093/brain/119.3.741.

    Article  PubMed  Google Scholar 

  20. Farouk ZL, Muhammed A, Gambo S, Mukhtar-Yola M, Umar Abdullahi S, Slusher TM. Follow-up of children with kernicterus in Kano, Nigeria. J Trop Pediatr. 2018;64(3):176–82. https://doi.org/10.1093/tropej/fmx041.

    Article  PubMed  Google Scholar 

  21. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344(8):581–90. https://doi.org/10.1056/NEJM200102223440807.

    Article  CAS  PubMed  Google Scholar 

  22. Hamza A. Kernicterus. Autops Case Rep. 2019;9(1):e2018057. https://doi.org/10.4322/acr.2018.057.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kaplan M, Hammerman C. Understanding severe hyperbilirubinemia and preventing kernicterus: adjuncts in the interpretation of neonatal serum bilirubin. Clin Chim Acta. 2005;356(1–2):9–21. https://doi.org/10.1016/j.cccn.2005.01.008.

    Article  CAS  PubMed  Google Scholar 

  24. • Riordan SM, Shapiro SM. Review of bilirubin neurotoxicity I: molecular biology and neuropathology of disease. Pediatr Res. 2020;87(2):327–31. https://doi.org/10.1038/s41390-019-0608-0. This review summarizes current and recent advances in the understanding of the neuropathology and molecular biology of bilirubin neurotoxicity.

  25. Rawat V, Bortolussi G, Gazzin S, Tiribelli C, Muro AF. Bilirubin-induced oxidative stress leads to DNA damage in the cerebellum of hyperbilirubinemic neonatal mice and activates DNA double-strand break repair pathways in human cells. Oxid Med Cell Longev. 2018;2018:1801243. https://doi.org/10.1155/2018/1801243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brouillard RP. Measurement of red blood cell life-span. JAMA. 1974;230(9):1304–5.

    Article  CAS  Google Scholar 

  27. Brites D, Fernandes A. Bilirubin-induced neural impairment: a special focus on myelination, age-related windows of susceptibility and associated co-morbidities. Semin Fetal Neonatal Med. 2015;20(1):14–9. https://doi.org/10.1016/j.siny.2014.12.002.

    Article  PubMed  Google Scholar 

  28. Brites D. Bilirubin injury to neurons and glial cells: new players, novel targets, and newer insights. Semin Perinatol. 2011;35(3):114–20. https://doi.org/10.1053/j.semperi.2011.02.004.

    Article  PubMed  Google Scholar 

  29. Silva RF, Rodrigues CM, Brites D. Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr Res. 2002;51(4):535–41. https://doi.org/10.1203/00006450-200204000-00022.

    Article  CAS  PubMed  Google Scholar 

  30. Ostrow JD, Pascolo L, Brites D, Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity. Trends Mol Med. 2004;10(2):65–70. https://doi.org/10.1016/j.molmed.2003.12.003.

    Article  CAS  PubMed  Google Scholar 

  31. Cayabyab R, Ramanathan R. High unbound bilirubin for age: a neurotoxin with major effects on the developing brain. Pediatr Res. 2019;85(2):183–90. https://doi.org/10.1038/s41390-018-0224-4.

    Article  CAS  PubMed  Google Scholar 

  32. Falcao AS, Silva RF, Pancadas S, Fernandes A, Brito MA, Brites D. Apoptosis and impairment of neurite network by short exposure of immature rat cortical neurons to unconjugated bilirubin increase with cell differentiation and are additionally enhanced by an inflammatory stimulus. J Neurosci Res. 2007;85(6):1229–39. https://doi.org/10.1002/jnr.21227.

    Article  CAS  PubMed  Google Scholar 

  33. Vaz AR, Delgado-Esteban M, Brito MA, Bolanos JP, Brites D, Almeida A. Bilirubin selectively inhibits cytochrome c oxidase activity and induces apoptosis in immature cortical neurons: assessment of the protective effects of glycoursodeoxycholic acid. J Neurochem. 2010;112(1):56–65. https://doi.org/10.1111/j.1471-4159.2009.06429.x.

    Article  CAS  PubMed  Google Scholar 

  34. Bertini G, Dani C, Pezzati M, Rubaltelli FF. Prevention of bilirubin encephalopathy. Biol Neonate. 2001;79(3–4):219–23. https://doi.org/10.1159/000047095.

    Article  CAS  PubMed  Google Scholar 

  35. Silva R, Mata LR, Gulbenkian S, Brito MA, Tiribelli C, Brites D. Inhibition of glutamate uptake by unconjugated bilirubin in cultured cortical rat astrocytes: role of concentration and pH. Biochem Biophys Res Commun. 1999;265(1):67–72. https://doi.org/10.1006/bbrc.1999.1646.

    Article  CAS  PubMed  Google Scholar 

  36. Fernandes A, Silva RF, Falcao AS, Brito MA, Brites D. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS. J Neuroimmunol. 2004;153(1–2):64–75. https://doi.org/10.1016/j.jneuroim.2004.04.007.

    Article  CAS  PubMed  Google Scholar 

  37. Grojean S, Koziel V, Vert P, Daval JL. Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons. Exp Neurol. 2000;166(2):334–41. https://doi.org/10.1006/exnr.2000.7518.

    Article  CAS  PubMed  Google Scholar 

  38. Grojean S, Lievre V, Koziel V, Vert P, Daval JL. Bilirubin exerts additional toxic effects in hypoxic cultured neurons from the developing rat brain by the recruitment of glutamate neurotoxicity. Pediatr Res. 2001;49(4):507–13. https://doi.org/10.1203/00006450-200104000-00012.

    Article  CAS  PubMed  Google Scholar 

  39. McDonald JW, Shapiro SM, Silverstein FS, Johnston MV. Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model. Exp Neurol. 1998;150(1):21–9. https://doi.org/10.1006/exnr.1997.6762.

    Article  CAS  PubMed  Google Scholar 

  40. Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromol Med. 2003;3(2):65–94. https://doi.org/10.1385/NMM:3:2:65.

    Article  CAS  Google Scholar 

  41. Rodrigues CM, Sola S, Castro RE, Laires PA, Brites D, Moura JJ. Perturbation of membrane dynamics in nerve cells as an early event during bilirubin-induced apoptosis. J Lipid Res. 2002;43(6):885–94.

    Article  CAS  Google Scholar 

  42. Rodrigues CM, Sola S, Brites D. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons. Hepatology. 2002;35(5):1186–95. https://doi.org/10.1053/jhep.2002.32967.

    Article  CAS  PubMed  Google Scholar 

  43. Seubert JM, Darmon AJ, El-Kadi AO, D’Souza SJ, Bend JR. Apoptosis in murine hepatoma Hepa 1c1c7 wild-type, C12, and C4 cells mediated by bilirubin. Mol Pharmacol. 2002;62(2):257–64. https://doi.org/10.1124/mol.62.2.257.

    Article  CAS  PubMed  Google Scholar 

  44. Ahdab-Barmada M. Kernicterus in the premature neonate. J Perinatol. 1987;7(2):149–52.

    CAS  PubMed  Google Scholar 

  45. Ahdab-Barmada M, Moossy J. The neuropathology of kernicterus in the premature neonate: diagnostic problems. J Neuropathol Exp Neurol. 1984;43(1):45–56. https://doi.org/10.1097/00005072-198401000-00004.

    Article  CAS  PubMed  Google Scholar 

  46. Conlee JW, Shapiro SM. Morphological changes in the cochlear nucleus and nucleus of the trapezoid body in Gunn rat pups. Hear Res. 1991;57(1):23–30. https://doi.org/10.1016/0378-5955(91)90070-p.

    Article  CAS  PubMed  Google Scholar 

  47. Shapiro SM, Conlee JW. Brainstem auditory evoked potentials correlate with morphological changes in Gunn rat pups. Hear Res. 1991;57(1):16–22. https://doi.org/10.1016/0378-5955(91)90069-l.

    Article  CAS  PubMed  Google Scholar 

  48. Conlee JW, Shapiro SM. Development of cerebellar hypoplasia in jaundiced Gunn rats: a quantitative light microscopic analysis. Acta Neuropathol. 1997;93(5):450–60. https://doi.org/10.1007/s004010050639.

    Article  CAS  PubMed  Google Scholar 

  49. Conlee JW, Shapiro SM, Churn SB. Expression of the alpha and beta subunits of Ca2+/calmodulin kinase II in the cerebellum of jaundiced Gunn rats during development: a quantitative light microscopic analysis. Acta Neuropathol. 2000;99(4):393–401. https://doi.org/10.1007/s004010051141.

    Article  CAS  PubMed  Google Scholar 

  50. Shaia WT, Shapiro SM, Heller AJ, Galiani DL, Sismanis A, Spencer RF. Immunohistochemical localization of calcium-binding proteins in the brainstem vestibular nuclei of the jaundiced Gunn rat. Hear Res. 2002;173(1–2):82–90. https://doi.org/10.1016/s0378-5955(02)00631-7.

    Article  CAS  PubMed  Google Scholar 

  51. Spencer RF, Shaia WT, Gleason AT, Sismanis A, Shapiro SM. Changes in calcium-binding protein expression in the auditory brainstem nuclei of the jaundiced Gunn rat. Hear Res. 2002;171(1–2):129–41. https://doi.org/10.1016/s0378-5955(02)00494-x.

    Article  CAS  PubMed  Google Scholar 

  52. Shaia WT, Shapiro SM, Spencer RF. The jaundiced Gunn rat model of auditory neuropathy/dyssynchrony. Laryngoscope. 2005;115(12):2167–73. https://doi.org/10.1097/01.MLG.0000181501.80291.05.

    Article  PubMed  Google Scholar 

  53. Zhang L, Liu W, Tanswell AK, Luo X. The effects of bilirubin on evoked potentials and long-term potentiation in rat hippocampus in vivo. Pediatr Res. 2003;53(6):939–44. https://doi.org/10.1203/01.PDR.0000061563.63230.86.

    Article  CAS  PubMed  Google Scholar 

  54. Gazzin S, Zelenka J, Zdrahalova L, Konickova R, Zabetta CC, Giraudi PJ, et al. Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups. Pediatr Res. 2012;71(6):653–60. https://doi.org/10.1038/pr.2012.23.

    Article  CAS  PubMed  Google Scholar 

  55. Hegeman DJ, Hong ES, Hernandez VM, Chan CS. The external globus pallidus: progress and perspectives. Eur J Neurosci. 2016;43(10):1239–65. https://doi.org/10.1111/ejn.13196.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Kita H. Parvalbumin-immunopositive neurons in rat globus pallidus: a light and electron microscopic study. Brain Res. 1994;657(1–2):31–41. https://doi.org/10.1016/0006-8993(94)90950-4.

    Article  CAS  PubMed  Google Scholar 

  57. Mallet N, Micklem BR, Henny P, Brown MT, Williams C, Bolam JP, et al. Dichotomous organization of the external globus pallidus. Neuron. 2012;74(6):1075–86. https://doi.org/10.1016/j.neuron.2012.04.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nobrega-Pereira S, Gelman D, Bartolini G, Pla R, Pierani A, Marin O. Origin and molecular specification of globus pallidus neurons. J Neurosci. 2010;30(8):2824–34. https://doi.org/10.1523/JNEUROSCI.4023-09.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71:537–92. https://doi.org/10.1146/annurev.biochem.71.102301.093055.

    Article  CAS  PubMed  Google Scholar 

  60. Johnson AD, Kavousi M, Smith AV, Chen MH, Dehghan A, Aspelund T, et al. Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet. 2009;18(14):2700–10. https://doi.org/10.1093/hmg/ddp202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Watchko JF, Lin Z. Exploring the genetic architecture of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med. 2010;15(3):169–75. https://doi.org/10.1016/j.siny.2009.11.003.

    Article  PubMed  Google Scholar 

  62. Brites D. The evolving landscape of neurotoxicity by unconjugated bilirubin: role of glial cells and inflammation. Front Pharmacol. 2012;3:88. https://doi.org/10.3389/fphar.2012.00088.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Fernandes A, Falcao AS, Silva RF, Brito MA, Brites D. MAPKs are key players in mediating cytokine release and cell death induced by unconjugated bilirubin in cultured rat cortical astrocytes. Eur J Neurosci. 2007;25(4):1058–68. https://doi.org/10.1111/j.1460-9568.2007.05340.x.

    Article  PubMed  Google Scholar 

  64. Fernandes A, Falcao AS, Silva RF, Gordo AC, Gama MJ, Brito MA, et al. Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin. J Neurochem. 2006;96(6):1667–79. https://doi.org/10.1111/j.1471-4159.2006.03680.x.

    Article  CAS  PubMed  Google Scholar 

  65. Barateiro A, Miron VE, Santos SD, Relvas JB, Fernandes A, Ffrench-Constant C, et al. Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination. Mol Neurobiol. 2013;47(2):632–44. https://doi.org/10.1007/s12035-012-8364-8.

    Article  CAS  PubMed  Google Scholar 

  66. Barateiro A, Vaz AR, Silva SL, Fernandes A, Brites D. ER stress, mitochondrial dysfunction and calpain/JNK activation are involved in oligodendrocyte precursor cell death by unconjugated bilirubin. Neuromol Med. 2012;14(4):285–302. https://doi.org/10.1007/s12017-012-8187-9.

    Article  CAS  Google Scholar 

  67. Riordan SM, Bittel DC, Le Pichon JB, Gazzin S, Tiribelli C, Watchko JF, et al. A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy. Front Neurosci. 2016;10:376. https://doi.org/10.3389/fnins.2016.00376.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant > or =35 weeks’ gestation: an update with clarifications. Pediatrics. 2009;124(4):1193–8. https://doi.org/10.1542/peds.2009-0329.

    Article  PubMed  Google Scholar 

  69. Cat FC, Cat A, Cicek T, Gulec SG. Evaluation of the relationship between transcutaneous bilirubin measurement and total serum bilirubin in neonatal patients followed for jaundice. Sisli Etfal Hastan Tip Bul. 2021;55(2):262–7. https://doi.org/10.14744/SEMB.2020.79837.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Khan DS, Mirza A, Bhatti A, Shabbir A, Tariq B, Rizvi A. Effectiveness of transcutaneous bilirubin measurement in high-risk neonates and to evaluate validity of transcutaneous bilirubin with total serum bilirubin levels in both low and high-risk neonates at a tertiary care center in a developing country. Cureus. 2021;13(3):e13685. https://doi.org/10.7759/cureus.13685.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Jegathesan T, Campbell DM, Ray JG, Shah V, Berger H, Hayeems RZ, et al. Transcutaneous versus total serum bilirubin measurements in preterm infants. Neonatology. 2021;118(4):443–53. https://doi.org/10.1159/000516648.

    Article  CAS  PubMed  Google Scholar 

  72. Panda SK, Gaurav A, Das P, Swain N, Rath S. A comparison between transcutaneous bilirubin and total serum bilirubin levels for the management of jaundice in preterm neonates by Bland-Altman plot. Cureus. 2021;13(10):e18442. https://doi.org/10.7759/cureus.18442.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kumar D, Kumar D. Can serum albumin level affect the transcutaneous bilirubinometry in term neonates? J Neonatal Perinatal Med. 2022. https://doi.org/10.3233/NPM-210958.

    Article  PubMed  Google Scholar 

  74. Ho SR, Lin YC, Chen CN. The impact of phototherapy on the accuracy of transcutaneous bilirubin measurements in neonates: optimal measurement site and timing. Diagnostics (Basel). 2021;11(9).https://doi.org/10.3390/diagnostics11091729.

  75. Olusanya BO, Slusher TM, Imosemi DO, Emokpae AA. Maternal detection of neonatal jaundice during birth hospitalization using a novel two-color icterometer. PLoS ONE. 2017;12(8):e0183882. https://doi.org/10.1371/journal.pone.0183882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Taylor JA, Stout JW, de Greef L, Goel M, Patel S, Chung EK, et al. Use of a smartphone app to assess neonatal jaundice. Pediatrics. 2017;140(3). https://doi.org/10.1542/peds.2017-0312.

  77. Hegyi T, Kleinfeld A, Huber A, Weinberger B, Memon N, Shih W, et al. Unbound bilirubin measurements by a novel probe in preterm infants. J Matern Fetal Neonatal Med. 2019;32(16):2721–6. https://doi.org/10.1080/14767058.2018.1448380.

    Article  CAS  PubMed  Google Scholar 

  78. Huber AH, Zhu B, Kwan T, Kampf JP, Hegyi T, Kleinfeld AM. Fluorescence sensor for the quantification of unbound bilirubin concentrations. Clin Chem. 2012;58(5):869–76. https://doi.org/10.1373/clinchem.2011.176412.

    Article  CAS  PubMed  Google Scholar 

  79. Johnson L, Brown AK, Bhutani VK. BIND - a clinical score for bilirubin induced neurologic dysfunction in newborns. Pediatrics. 1999;104(3):746–7.

    Google Scholar 

  80. Radmacher PG, Groves FD, Owa JA, Ofovwe GE, Amuabunos EA, Olusanya BO, et al. A modified bilirubin-induced neurologic dysfunction (BIND-M) algorithm is useful in evaluating severity of jaundice in a resource-limited setting. BMC Pediatr. 2015;15:28. https://doi.org/10.1186/s12887-015-0355-2.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Dasari VR, Shapiro SM, Yeh HW, Gelineau-Morel R. Kernicterus Spectrum Disorders Diagnostic Toolkit: validation using retrospective chart review. Pediatr Res. 2021. https://doi.org/10.1038/s41390-021-01755-5.

    Article  PubMed  Google Scholar 

  82. Coskun A, Yikilmaz A, Kumandas S, Karahan OI, Akcakus M, Manav A. Hyperintense globus pallidus on T1-weighted MR imaging in acute kernicterus: is it common or rare? Eur Radiol. 2005;15(6):1263–7. https://doi.org/10.1007/s00330-004-2502-2.

    Article  PubMed  Google Scholar 

  83. Wang X, Wu W, Hou BL, Zhang P, Chineah A, Liu F, et al. Studying neonatal bilirubin encephalopathy with conventional MRI, MRS, and DWI. Neuroradiology. 2008;50(10):885–93. https://doi.org/10.1007/s00234-008-0423-5.

    Article  PubMed  Google Scholar 

  84. Mao J, Fu JH, Chen LY, Wang XM, Xue XD. Changes of globus pallidus in the newborn infants with severe hyperbilirubinemia. Zhonghua Er Ke Za Zhi. 2007;45(1):24–9.

    PubMed  Google Scholar 

  85. Cece H, Abuhandan M, Cakmak A, Yildiz S, Calik M, Karakas E, et al. Diffusion-weighted imaging of patients with neonatal bilirubin encephalopathy. Jpn J Radiol. 2013;31(3):179–85. https://doi.org/10.1007/s11604-012-0166-4.

    Article  PubMed  Google Scholar 

  86. Wu M, Shen X, Lai C, You Y, Zhao Z, Wu D. Detecting acute bilirubin encephalopathy in neonates based on multimodal MRI with deep learning. Pediatr Res. 2021. https://doi.org/10.1038/s41390-021-01560-0.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Wu W, Zhang P, Wang X, Chineah A, Lou M. Usefulness of (1) H-MRS in differentiating bilirubin encephalopathy from severe hyperbilirubinemia in neonates. J Magn Reson Imaging. 2013;38(3):634–40. https://doi.org/10.1002/jmri.23995.

    Article  PubMed  Google Scholar 

  88. Wisnowski JL, Panigrahy A, Painter MJ, Watchko JF. Magnetic resonance imaging of bilirubin encephalopathy: current limitations and future promise. Semin Perinatol. 2014;38(7):422–8. https://doi.org/10.1053/j.semperi.2014.08.005.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Stevenson DK, Wong RJ, Arnold CC, Pedroza C, Tyson JE. Phototherapy and the risk of photo-oxidative injury in extremely low birth weight infants. Clin Perinatol. 2016;43(2):291–5. https://doi.org/10.1016/j.clp.2016.01.005.

    Article  PubMed  Google Scholar 

  90. Lightner DA, Linnane WP 3rd, Ahlfors CE. Bilirubin photooxidation products in the urine of jaundiced neonates receiving phototherapy. Pediatr Res. 1984;18(8):696–700. https://doi.org/10.1203/00006450-198408000-00003.

    Article  CAS  PubMed  Google Scholar 

  91. Hansen TW. The role of phototherapy in the crash-cart approach to extreme neonatal jaundice. Semin Perinatol. 2011;35(3):171–4. https://doi.org/10.1053/j.semperi.2011.02.012.

    Article  PubMed  Google Scholar 

  92. Olusanya BO, Imam ZO, Emokpae AA, Iskander IF. Revisiting the criteria for exchange transfusion for severe neonatal hyperbilirubinemia in resource-limited settings. Neonatology. 2016;109(2):97–104. https://doi.org/10.1159/000441324.

    Article  CAS  PubMed  Google Scholar 

  93. Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012;32(9):660–4. https://doi.org/10.1038/jp.2012.71.

    Article  CAS  PubMed  Google Scholar 

  94. Murki S, Kumar P. Blood exchange transfusion for infants with severe neonatal hyperbilirubinemia. Semin Perinatol. 2011;35(3):175–84. https://doi.org/10.1053/j.semperi.2011.02.013.

    Article  PubMed  Google Scholar 

  95. Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed. 2003;88(1):F6-10. https://doi.org/10.1136/fn.88.1.f6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Suresh GK, Martin CL, Soll RF. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev. 2003;(2):CD004207. https://doi.org/10.1002/14651858.CD004207.

  97. Martinez JC, Garcia HO, Otheguy LE, Drummond GS, Kappas A. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics. 1999;103(1):1–5. https://doi.org/10.1542/peds.103.1.1.

    Article  CAS  PubMed  Google Scholar 

  98. Kappas A, Drummond GS, Henschke C, Valaes T. Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns. Pediatrics. 1995;95(4):468–74.

    Article  CAS  Google Scholar 

  99. Kappas A, Drummond GS, Munson DP, Marshall JR. Sn-Mesoporphyrin interdiction of severe hyperbilirubinemia in Jehovah’s Witness newborns as an alternative to exchange transfusion. Pediatrics. 2001;108(6):1374–7. https://doi.org/10.1542/peds.108.6.1374.

    Article  CAS  PubMed  Google Scholar 

  100. Rice AC, Chiou VL, Zuckoff SB, Shapiro SM. Profile of minocycline neuroprotection in bilirubin-induced auditory system dysfunction. Brain Res. 2011;1368:290–8. https://doi.org/10.1016/j.brainres.2010.10.052.

    Article  CAS  PubMed  Google Scholar 

  101. Vodret S, Bortolussi G, Iaconcig A, Martinelli E, Tiribelli C, Muro AF. Attenuation of neuro-inflammation improves survival and neurodegeneration in a mouse model of severe neonatal hyperbilirubinemia. Brain Behav Immun. 2018;70:166–78. https://doi.org/10.1016/j.bbi.2018.02.011.

    Article  CAS  PubMed  Google Scholar 

  102. Bortolussi G, Baj G, Vodret S, Viviani G, Bittolo T, Muro AF. Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicity in vivo in mice. Dis Model Mech. 2014;7(9):1057–68. https://doi.org/10.1242/dmm.016535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Deliktas M, Ergin H, Demiray A, Akca H, Ozdemir OMA, Ozdemir MB. Caffeine prevents bilirubin-induced cytotoxicity in cultured newborn rat astrocytes. J Matern Fetal Neonatal Med. 2019;32(11):1813–9. https://doi.org/10.1080/14767058.2017.1419175.

    Article  CAS  PubMed  Google Scholar 

  104. Kuter N, Aysit-Altuncu N, Ozturk G, Ozek E. The neuroprotective effects of hypothermia on bilirubin-induced neurotoxicity in vitro. Neonatology. 2018;113(4):360–5. https://doi.org/10.1159/000487221.

    Article  CAS  PubMed  Google Scholar 

  105. De Siati RD, Rosenzweig F, Gersdorff G, Gregoire A, Rombaux P, Deggouj N. Auditory neuropathy spectrum disorders: from diagnosis to treatment: literature review and case reports. J Clin Med. 2020;9(4). https://doi.org/10.3390/jcm9041074.

  106. • Shapiro SM, Riordan SM. Review of bilirubin neurotoxicity II: preventing and treating acute bilirubin encephalopathy and kernicterus spectrum disorders. Pediatr Res. 2020;87(2):332–7. https://doi.org/10.1038/s41390-019-0603-5. This review summarizes current and possible novel methods to prevent bilirubin neurotoxicity and treat ABE and KSDs.

  107. Sanger TD, Liker M, Arguelles E, Deshpande R, Maskooki A, Ferman D, et al. Pediatric deep brain stimulation using awake recording and stimulation for target selection in an inpatient neuromodulation monitoring unit. Brain Sci. 2018;8(7). https://doi.org/10.3390/brainsci8070135.

  108. Yuan H, Li Y, Yang J, Li H, Yang Q, Guo C, et al. State of the art of non-invasive electrode materials for brain-computer interface. Micromachines (Basel). 2021;12(12). https://doi.org/10.3390/mi12121521.

  109. Foldes ST, Chandrasekaran S, Camerone J, Lowe J, Ramdeo R, Ebersole J, et al. Case study: mapping evoked fields in primary motor and sensory areas via magnetoencephalography in tetraplegia. Front Neurol. 2021;12:739693. https://doi.org/10.3389/fneur.2021.739693.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Oxley TJ, Yoo PE, Rind GS, Ronayne SM, Lee CMS, Bird C, et al. Motor neuroprosthesis implanted with neurointerventional surgery improves capacity for activities of daily living tasks in severe paralysis: first in-human experience. J Neurointerv Surg. 2021;13(2):102–8. https://doi.org/10.1136/neurintsurg-2020-016862.

    Article  PubMed  Google Scholar 

  111. Yang FC, Riordan SM, Winter M, Gan L, Smith PG, Vivian JL, et al. Fate of neural progenitor cells transplanted into jaundiced and nonjaundiced rat brains. Cell Transplant. 2017;26(4):605–11. https://doi.org/10.3727/096368917X694840.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Yang FC, Draper J, Smith PG, Vivian JL, Shapiro SM, Stanford JA. Short term development and fate of MGE-like neural progenitor cells in jaundiced and non-jaundiced rat brain. Cell Transplant. 2018;27(4):654–65. https://doi.org/10.1177/0963689718766327.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Amini N, Vousooghi N, Soleimani M, Samadikuchaksaraei A, Akbari M, Safakheil H, et al. A new rat model of neonatal bilirubin encephalopathy (kernicterus). J Pharmacol Toxicol Methods. 2017;84:44–50. https://doi.org/10.1016/j.vascn.2016.10.002.

    Article  CAS  PubMed  Google Scholar 

  114. Amini N, Vousooghi N, Hadjighassem M, Bakhtiyari M, Mousavi N, Safakheil H, et al. Efficacy of human adipose tissue-derived stem cells on neonatal bilirubin encephalopathy in rats. Neurotox Res. 2016;29(4):514–24. https://doi.org/10.1007/s12640-016-9599-3.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology and Rehabilitation, University of Illinois at Chicago College of Medicine, 912 S Wood St, Chicago, IL, 60612, USA

    Shuo Qian, Prateek Kumar & Fernando D. Testai

Authors
  1. Shuo Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prateek Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernando D. Testai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuo Qian.

Ethics declarations

Conflict of Interest

Shuo Qian, Prateek Kumar, and Fernando D Testai each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neurology of Systemic Diseases

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qian, S., Kumar, P. & Testai, F.D. Bilirubin Encephalopathy. Curr Neurol Neurosci Rep 22, 343–353 (2022). https://doi.org/10.1007/s11910-022-01204-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-022-01204-8

Keywords

Search

Navigation