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kernicterus free bilirubin hypothesis ABR n a v i g a t o r kernicterus r e f e r e n c e s brain hearing clinical presentation ∆∆ pallidum > G6PD  histology Bhutani nomogram causes of hyper-bilirubinaemia genetics biochemistry imaging pallidum and subthalamus preterm kernicterus phototherapy Brain damage due to bilirubin toxicity was historically referred to as kernicterus, meaning ‘jaundice of the basal ganglia’. Yellow discoloration, particularly intense in the basal ganglia, was found during autopsy of infants who had died with pronounced neonatal jaundice. Neuronal cell loss, probably due to apoptosis, is region specific for unknown reasons. It follows membrane injury due to abnormally high free unconjugated bilirubin levels that crytallises into and destroys cell membranes. Acidosis and limitation in bilirubin-binding by albumin are important determinants in the process. There need not be disruption of the blood-brain barrier to cause kernicterus, although facilitated increase of bilirubin attached to albumin along a disrupted barrier may be an additional factor (Wennberg 2000). Permanent gliosis, developing in the course of a few weeks, may be detected by MRI in globus pallidus and subthalamic nucleus. Serum TSB levels withing the normally accepted range may still be associated with bilirubin toxicity.  Kernicterus, a clinicopathological term that describes the acute neonatal encephalopathy associated with brain toxicity due to unbound unconjugated bilirubin, stands out among other neonatal brain disorders by a characteristic multiregional damage pattern (Larroche 1977, Turkel et al. 1982, Friede 1989): globus pallidus, nucleus subthalamicus, geniculate nuclei, dentate nuclei, inferior olive, nucleus gracilis and cuneatus, hippocampus, corpora mammillaria, nucleus ruber, substantia nigra, cranial nerve nuclei, colliculi, vermis cerebelli. A pallido-subthalamic pattern of injury is distinct of the thalamo-striate pattern that is typical of acute total asphyxia (Leech and Alvord 1977, Hayashi et al. 1991). Often, therefore, confirmation of the existence and extent of nuclear damage (“kern”icterus) is sought in acute neonatal MRI. Due to uncertain description of extent and severity of neuronal injury, kernicterus is still a challenging disorder in neonatal imaging.  The main effects of bilirubin on neurons are decreased oxygen consumption and increased release of calcium and caspase 3, resulting in apoptosis (Watchko and Tiribelli 2013). A similar pattern is observed in oligodendrocytes, with increased apoptosis, oxidative stress and reduced synthesis of myelin. Microglia react to injury associated with bilirubin by release of proinflammatory cytokines and metalloproteinase activity as cells manifest the phagocytic phenotype. Once the intracellular concentration of bilirubin exceeds a toxic threshold, a metabolic cascade leading to neurotoxicity follows. Microglia react to toxic injury associated with bilirubin by increased release of proinflammatory cytokines and metalloproteinase activity as cells manifest the phagocytic phenotype. A similar pattern is observed in astrocytes, with enhanced release of glutamate and resultant apoptosis. At the same time, cells may reduce the intracellular concentration of bilirubin either by extruding the pigment through the ABC transporters or by increasing the formation of the less toxic bilirubin oxidation products (BOXes) through bilirubin oxidase, cytochrome P-450 enzymes (1a1 and 1a2, in particular), or both. These responses are protective, whereas all others result in cell damage; this suggests that once the intracellular concentration of bilirubin exceeds a toxic threshold, the polymorphic metabolic cascade leading to neurotoxicity ensues. The term cPARP denotes cleaved poly(adenosine diphosphate–ribose) polymerase, TNF-α tumor necrosis factor α, and TER transcellular resistance. This means that the signature of kernicterus in the brain in the acute stage is region specific and characteristic of apoptosis. Typically the neuronal swelling, that alters diffusion characteristics in MR sequences in the acute stage after asphyxia, is therefore absent in kernicterus, although more subtle alterations have been reported in the dentate to thalamus connections (Wisnowski et al. 2016). Globus pallidus and nucleus subthalamicus are hyperintense on T1 weighted MRI in the acute stage, but this is only a gradient of increased signal compared to normal and therefore not distinctive enough to be certain about the extent of neuronal death; after several weeks only a fine fibrillary astrogliotic scar permanently marks globus pallidus on T2 weighted MRI (Govaert et al. 2003).  Many but not all infants with an acute encephalopathic presentation (day 1-2: stupor, hypotonia, poor feeding, apnea, convulsions; day 3-7: extensor hypertonia, fever, high pitched cry, tongue protrusion, 2w-3m: hypotonia) go on to develop the typical outcome with dyskinetic cerebral palsy (extrapyramidal syndrome, vertical gaze palsy), dental dysplasia and hearing loss based on injury to the brainstem nuclei of the auditory system.  dyskinetic CP kernicterus: typical acute presentation in term infant < hight T1 signal in pallidum,normal T2 sgnal in acute phase normal diffusion MR sequence pallidum ——> Yi et al. 2023: relative low T1 value of putamen to pallidum AAP Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114: 297-316. Ahdab-Barmada, M., Moosy, J. (1984) The neuropathology of kernicterus in the premature neonate: diagnostic problems, Journal of Neuropathology and Experimental Neurology 43, 45-55. Ahlfors, C.E. (1994) Criteria for exchange transfusion in jaundiced newborns, Pediatrics 93, 488-494. Ahlfors, C.E. (2000) Unbound bilirubin associated with kernicterus: a historical approach, Journal of Pediatrics 137, 540-544. Barateiro A, Miron VE, Santos SD, Relvas JB, Fernandes A, Ffrench-Constant C, Brites D. Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination. Mol Neurobiol. 2013 Apr;47(2):632-44.  Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. 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Effect of postnatal age and clinical status of newborn infants on bilirubin-binding capacity. Biol Neonate. 1977;32(5-6):304-9.  Cashore, W.J., Oh, W. (1982) Unbound bilirubin and kernicterus in low-birth-weight infants, Pediatrics 69, 481-485. Cashore, W.J. (1990) The neurotoxicity of bilirubin, Clinics in Perinatology 17, 437-447. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014 Jun;146(7):1625-38. Friede RL (1989) Developmental neuropathology. Berlin: Springer-Verlag. Ch 7. Perinatal lesions of gray matter and Ch 9. Kernicterus.  Ginsberg MD, Myers RE. Fetal brain injury after maternal carbon monoxide intoxication. Clinical and neuropathologic aspects. Neurology. 1976 Jan;26(1):15-23.  Gourley GR, Li Z, Kreamer BL, Kosorok MR. A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics. 2005; 116:385-391. Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, De Rijke Y, Sinaasappel M, Barkovich J (2003) Changes in globus pallidus with (pre)term kernicterus. Pediatrics 112;6 Pt 1:1256-63. Hansen TWR (2002) Mechanism of bilirubin toxicity: clinical implications. Clin Perinatol 29:765-778. Hansen TWR. Acute management of extreme neonatal jaundice – the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation. Acta Paediatr 1997;86:843-846. Hansen TWR, Nietsch L, Norman E, Bjerre JV, Hascoet JM, Mreihil K, Ebbesen F. Apparent reversibility of acute intermediate phase bilirubin encephalopathy. Acta Paediatr 2009;98:1689-1694. Hayashi M, Satoh J, Sakamoto K (1991) Clinical and neuropathological findings in severe athetoid cerebral palsy: a comparative study of globo-Luysian and thalamo-putaminal groups. Brain Dev 13:47-51. Kamei A, Sasaki M, Akasaka M, Soga N, Kudo K, Chida S (2012) Proton Magnetic Resonance Spectroscopic Images in Preterm Infants with Bilirubin Encephalopathy. J Pediatr 2012; 160: 342-344. Kaplan M, Hammerman C. The need for neonatal glucose-6-phosphate dehydrogenase screening: a global perspective. J Perinatol. 2009 Feb;29 Suppl 1:S46-52.  Larroche J-Cl (1977) Developmental pathology of the neonate. North-Holland : Elsevier. Leech RW, Alvord EC (1977) Anoxic-ischemic encephalopathy in the human neonatal period. Arch Neurol 34:109-113.  Lequin M, Groenendaal F, Dudink J, Govaert P. Susceptibility weighted imaging can be a sensitive sequence to detect brain damage in neonates with kernicterus: a case report. BMC Neurol. 2023 Mar 11;23(1):104.  Levine, R.L., Fredericks, W.R., Rapoport, S.I. (1982) Entry of bilirubin into the brain due to opening of the blood brain barrier, Pediatrics 69, 255-259. Maisels MJ, Deridder JM, Kring EA, Balasubramaniam M. Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia. J Perinatol 2009;29: 612-617. Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR,  Watchko JF. Hyperbilirubinemia in the newborn infant ≥35 weeks’ gestation: an update with clarifications. Pediatrics 2009; 124: 1193-1198. Maisels MJ. Screening and early postnatal management strategies to prevent hazardous hyperbilirubinemia in newborns of 35 or more weeks of gestation. Semin Fetal Neonatal Med. 2010 Jun;15(3):129-35.  Oakden WK, Moore AM, Blaser S, Noseworthy MD. 1H MR spectroscopic characteristics of kernicterus: a possible metabolic signature.Am J Neuroradiol. 2005 Jun-Jul;26(6):1571-4.  Odell, G.B. (1980) Neonatal hyperbilirubinemia, Grune and Stratton, Monographs in Neonatology. Ostrow, J.D. (2001) Bilirubin tansport and cytotoxicity: new insight into an old problem, AGA state of the art lecture, ASPR, 2001. Resaz M, Pepe A, Tortora D, Rossi A, Ramenghi LA, Calandrino A. The Importance of Neuroimaging Follow-Up in Bilirubin-Induced Encephalopathy: A Clinical Case Review. Brain Sci. 2025 May 22;15(6):539. Robinson, P.J., Rapoport, S.I. (1987) Binding effect of albumin on uptake of bilirubin by brain, Pediatrics 79, 553-558. Schmorl G (1903) Zur Kennis des Ikterus neonatorum. Verh Dtsch Pathol Gesamte 6; 109-115. Shapiro SM. Definition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND). Journal of Perinatology 2005; 25:54–59 Shapiro SM. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin Fetal Neonatal Med. 2010 Jun;15(3):157-63. Silverman, W.A., Andersen, D.H., Blanc, W.A., Crozier, D.N. (1956) A difference in mortality rate incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens, Pediatrics 18, 614-625. Stern, L., Denton, R.L. (1965) Kernicterus in small premature infants, Pediatrics 35, 483-485. Turkel, S.B., Miller, C.A., Guttenberg, M.E., Moynes, D.R., Hodgman, J.E. (1982) A clinical pathologic reappraisal of kernicterus, Pediatrics 69, 267-272. Sari S, Yavuz A, Batur A, Bora A, Caksen H. Brain Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Findings of Children with Kernicterus Pol J Radiol, 2015; 80: 72-80 Slusher TM, Owa JA, Painter MJ, Shapiro SM. The kernicteric facies: facial features of acute bilirubin encephalopathy. Pediatr Neurol. 2011 Feb;44(2):153-4.   Turkel SB, Miller CA, Guttenberg ME (1982) A clinical pathologic reappraisal of kernicterus. Pediatrics 69:267-272. Van Bogaert L. La méthode histopathologique et les problèmes des maladies de la substance blanche [The histopathological method and the problems of white matter diseases]. J Belg Neurol Psychiatr. 1947 Feb;47(2):82-110. Watchko JF, Tiribelli C (2014) Bilirubin-induced neurologic damage. N Engl J Med 370(10):979. Wennberg, R.P. (2000) The blood-brain barrier and bilirubin encephalopathy, Cellular and Molecular Neurobiology 20, 97-109.  Wilson CI (2004) Basal ganglia. Ch 9 in “The synaptic organization of the brain”. Oxford University Press. (Gordon M. Shepherd, ed); pp 361-413. Wisnowski JL, Panigrahy A, Painter MJ, Watchko JF (2016) Magnetic Resonance Imaging Abnormalities in Advanced Acute Bilirubin Encephalopathy Highlight Dentato-Thalamo-Cortical Pathways. J Pediatr 174:260-3. 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 Sep;38(3):634-40.  Yi M, Lou J, Cui R, Zhao J. Globus pallidus/putamen T1WI signal intensity ratio in grading and predicting prognosis of neonatal acute bilirubin encephalopathy. Front Pediatr. 2023 Sep 29;11:1192126.  Zidan LK, Rowisha MA, Nassar MAE, Elshafey RA, El Mahallawi TH, Elmahdy HS. Magnetic resonance spectroscopy and auditory brain-stem response audiometry as predictors of bilirubin-induced neurologic dysfunction in full-term jaundiced neonates. Eur J Pediatr. 2024 Feb;183(2):727-738. kernicterus: references Based on experience with preterm and term kernicteric infants, the behaviour of globus pallidus on imaging has been reported. In preterms molar bilirubin/albumin ratios but not TSB levels were above the exchange transfusion thresholds recommended by Ahlfors in 1994.  Only postmortem studies could confirm kernicterus before the MR era.  Crucial to the diagnosis is recognition of the pallido-subthalamic type of selective neuronal injury with residual fibrillary gliosis, contrary to the putamino-thalamic type of hypoxic-ischemic injury. Pallidal involvement in asphyxia is not obligatory. In our patients no definite signal abnormality could be detected in other regions known to be vulnerable in kernicterus (except for the subthalamic nucleus): dentate nucleus, hippocampus, substantia nigra, hypothalamus, cranial nerve nuclei VIII and inferior olive.  Pallidal injury by bilirubin seems to be independent of maturation. Thalamic injury on the other hand is a characteristic marker for global asphyxia, in fetus and neonate. CO intoxication and mitochondriopathy are unlikely other causes of pallidal injury in sick preterm infants.  Kernicterus has been confirmed with MRI. T2-weighted images recognise of gliosis in globus pallidus and subthalamic nucleus after 6 months of age. Pallidal involvement, if partial, affects the medial posterior and inferior area of the nucleus. The images fit the description of dense fibrillary cell-poor gliosis as histological end stage.  In neonatally documented cases pallidal injury was only recognized from T1-hyperintensity and hypersignal in susceptibility weighted sequences. This may reflect astroglial gemistocytic reaction of the acute event and explain hyperechoic features of globus pallidus in one of our cases.   Mild hypersignal has already been suspected in globus pallidus on T2 at 16 and 18 days of age in term infants with classical kernicterus. Loss of the hyperintense T1-signal already occurs between the first and third week. The discernability of pallidum on T2-weighted images in the hyperacute stage is unusual and helpful only in association with relative increase of intensity on T1. The switch from easy detectability on T1 in the neonatal period, to mainly hypersignal on T2 in early childhood may not be typical of kernicterus, as it is also seen following birth asphyxia. fetal presentation kernicterus: imaging MRI chronic stage cranial ultrasound, preterm cranial ultrasound, preterm, subtle acute term MR presentation risk-acronymJ jaundice within 24 h of birth A another sib affected U unexpected hemolysis N non-optimal nutrition (poor breast feeding) D deficient G6PD  I infection C cephalhaematoma, bruising, other bleeding E East-Asian, Mediterranean add: high hematocrit maternal diabetes slow gut transit hemolysis warning signs: + Coombs Hcr < 40 % jaundice / 24 uur after birth fast increasing TSB high reticulocytosis multiple embolic strokes following exchange transfusion on umbilical venous catheter at term Maisels et al. 2010:receiver–operating characteristic curves for three different models for prediction of a serum bilirubin level of ≥17 mg per 100 mL (291 μmol/L) -> best predictor = GA + breastfeeding + Bhutani nomogram Neonatal hyperbilirubinemia may be present without jaundice, as visual detection of jaundice in a newborn is possible once the total serum bilirubin (TSB) level exceeds 80-100 µmol/L (≈ 5-6 mg/dL).  Neonatal jaundice is due to accumulation of unconjugated bilirubin, through a combination of transiently increased production combined with transiently low hepatic conversion capacity for bilirubin.  Bilirubin-induced brain toxicity typically evolves from an acute phase (ABE – acute bilirubin encephalopathy), characterized by increasing neurological symptoms and decreasing probability of being reversible, to chronic bilirubin encephalopathy, which encompasses kernicterus, but includes the newer concept BIND (bilirubin-induced neurological dysfunction, manifesting as a range of subtle processing disorders with disturbances of visual-motor and auditory function, speech, cognition, and language development)(Shapiro 2005). The yellow color is first seen on the forehead, with increasing TSB levels discernible further down the body towards the feet.This ‘cephalocaudal progression‘ has been used as an indicator of severity, i.e. jaundice visible on the feet strongly suggests the need to test for TSB. However, the ability to visually estimate jaundice in infants is very subjective (Hansen 2002). It is safer to rely on correct estimation of risk factors (one of the most important ones mild prematurity), discharge only after evaluation of TSB or TcB, and careful follow-up after discharge. Transcutaneous photometers work well as screening tools, to aid decisions as to whether a blood test is needed. The American Academy of Pediatrics recommends obtaining either a TSB, e.g. drawn concurrently with the metabolic screen, or a transcutaneous bilirubin measurement (TcB) prior to discharge of infants from the newborn nursery.  Jaundiced infants may be drowsy, less interested in feeding, suck poorly and exhibit reduced muscle tone. As jaundice progresses infants may become irritable, tone may increase, and moderate stupor may characterize the state of consciousness. When jaundice becomes extreme, increased tone of extensor muscles may lead to backward arching of neck and back (retrocollis and opisthotonos). Seizures may occur, and coma may ensue. Jaundiced infants in advanced stages of neurotoxicity are occasionally admitted from home to require emergency management. Phototherapy using white or blue light is the backbone of jaundice therapy in infants. In infants with pronounced jaundice, and especially in the presence of signs of neurotoxicity, phototherapy should be initiated as an emergency. The delivery of light energy should be maximized by i) positioning the lights as close as possible to the baby (no more than 10-20 cm away if using fluorescent lights); ii) exposing the maximum achievable area of skin to light by using reflecting white linen around the bed and phototherapy unit and by leaving the skin uncovered except for eye protection; iii) unless clinically contraindicated, provide enteral feeds in sufficient quantity to ensure that bilirubin excreted into the gut will be transported out rather than be reabsorbed by enterohepatic circulation.  Intravenous immune globulin (IVIG) 500-1000 mg/kg may be helpful in the treatment of jaundice due to blood group isoimmunization. In extreme jaundice with neurological symptoms, if evidence suggests isoimmunization, IVIG combined with intensive phototherapy may buy valuable time whilst waiting for blood for an exchange transfusion. Exchange transfusion has become less important as a treatment strategy due to more efficient phototherapy and IVIG. As fewer practitioners receive training in the performance of the procedure, the risk of complications is likely to increase. However, in infants threatened by intermediate to advanced stage acute bilirubin encephalopathy, exchange transfusion is still recommended. Phototherapy should also be continued during the exchange transfusion if the equipment allows. kernicterus: hyperbilirubinaemia <——------neuronal eosinophilia, nuclear pyknosis, loss of Nissl bodies subthalamus ——> At postmortem specific regional staining can be pathognomonic: globus pallidus, nucleus subthalamicus, geniculate nuclei, dentate nuclei, inferior olive, nucleus gracilis and cuneatus, hippocampus, corpora mammillaria, nucleus ruber, substantia nigra, cranial nerve nuclei, colliculi, vermis cerebelli. This staining in the acute stage has to be combined with neuronal death by apoptosis with limited initial cell response, leading later to fine fibrillary gliosis after several weeks. hippocampus —> fibrillary gliosis in subthalamus (Holzer stain, van Bogaert 1947) kernicterus: histology 1H-MRSI (E1 = short echotime, E2 = long echotime) in patient decreased NAA level, decreased myo-inositol level, decreased NAA/Choline ratio. Since bilirubin passes the placenta, any excess of bilirubin is usually cleared via the maternal circulation during pregnancy. Kernicterus of prenatal onset is believed to be extremely rare. This is an unpublished example of immediate postnatal pallidal injury within the context of fetal kernicterus. (courtesy dr Cornette, Brugge) The first pregnancy of a 25 year old Rh negative woman remained uneventful until 28 weeks, when intra-uterine growth restriction was noted. At 30 w PMA, growth was further restricted (percentile 5), and an indirect Coombs test was positive (1/256) owing to rhesus incompatibility. Serial ultrasound exams could not detect signs of fetal anaemia. The indirect Coombs test increased to a maximum of 1/4.096, proving Rh disease (anti-D, anti-C and anti-E). A preterm (35 weeks 3 days) male infant weighing 1860 g (centile 3) was born by cesarean section, because of placental abruption. The boy had Apgar scores of 1 at 1 min, 6 at seven min and 7 at 10 min. Umbilical cord pH were 7.07 (arterial) and 7.23 (venous). Marked fetal hydrops was present. He received intubation and mechanical ventilation. The first clinical seizures were noted at the age of one hour, treated with intravenous midazolam. Chest X-ray demonstrated bilateral pleural effusions, ascites and cardiomegaly. Hemoglobin level at birth was 8.6 g/dl. The direct Coombs test was positive. Lactate was increased up to 15.2 mmol/L. Total serum bilirubin level was 7.1 mg/dL at birth, further increasing to a maximum of 13.2 mg/dL at 30 hours of age, prompting an exchange transfusion.  Neonatal brain ultrasound as well as MR brain imaging during the first day of life already demonstrated bilateral signal changes within the globus pallidus, indicative of fetal kernicterus.  MR diffusion image and ADC maps were normal.  ADC values of the left and right globus pallidus were 1,16 x 10-³ and 1,35 x 10-³ mm²/sec, respectively. Metabolite analysis of N-actylaspartate (NAA – 2,012 ppm), creatine (Cr - 3,029 ppm), and choline (Cho – 3,21 ppm) had values of 0.037, 0,063 and 0,079 respectively. Drastic decreases of N-acetylaspartate (NAA), with a decreased NAA/Creatine (Cr) ratio indicate neuronal death.  Audiology: no reproducible trace was found at 90 dBnHL. A measurement with reversed polarity (condensation and rarefaction click) was performed, but no visible cochlear microphone potential was exposed. Finally OAE’s were bilaterally absent. term control kernicterus: fetal presentation <—— subthalamus ——> chronic stage high T1 intensity in pallidum and subthalamus kernicterus: chronic presentation  chronic stage high T2 intensity in pallidum and subthalamus chronic stage high proton density intensity in subthalamus excretion into bile: saturable, rate limiting, carrier mediatedmono- and diconjugates photo-isomers lumirubin ß and γ isomers kernicterus: bilirubin pathways transit time depends on ------------------------------- (1) endothelial permeability  (2) surface area, number of capillaries per tissue region, blood flow (3) dissociation rate from albumin   - level of Bf is very low, even in toxic states: absolute amount immediately taken up must be small, therefore higher CBFlow (more capillaries recruted), slower transit (congestion) and long duration of high levels of bilirubin must be relevant - hypercarbia not only increases CBF, it also equilibrates rapidly with CSF leading to brain acidosis and enhancing the formation of BH2-aggregates - max solubility 70 nMol/L at pH 7.4 - > 70 < 1000 nMol/L oligomers and metastable aggregates - self-aggreagation ongoing from about TSB 85 µMol/L - unsoluble macroprecipitates if Bf > 1000 nMol/L enterohepatic recirculationfollows deconjugation role of meconium evacuation calciumbinding kernicterus: pallidum (1), subthalamus (2), Ammon’s horn 1 A pallido-subthalamic pattern of injury is different than the thalamo-striate pattern that is typical of acute total asphyxia (Leech and Alvord 1977, Hayashi et al. 1991).  Some neurodegenerations may have to be excluded: pallidopyramidal degeneration (Hunt-van Bogaert: globus pallidus and pyramidal tract), pallido-Luysian atrophy (pallidum externum and subthalamus); panthotenate kinase associated neurodegeneration mitochondrial disorder 2 kernicterus: neuropathology 3 asphyxia: thalamus (1), putamen (2), subiculum, dentate gyrus, pontine, nuclei, neocortex (3) ∆∆ altered signal of pallidum on MRI -------------------------------------------------------------------------- asphyxia CO intoxication  manganese storage polycythaemia (T1 shortening = hypersignal) PRES hypoglycaemia organic acidaemias like glutaric aciduria mitochondrial disorder----------------------——————---------————————————————> cupper storage (Wilson disease) neurofibromatosis I succinic semialdehyde dehydrogenase deficiency acute stage, seizures, TSB > 700 µmol/L kernicterus: phototherapy - extrapyramidal syndrome (almost all: dyskinetic gait, drooling, dystonic grasp)- vertical gaze palsy (90 %)- dental dysplasia (baby teeth, > 80 %)- hearing loss (sometimes isolated. e.g.< 34 w GZ): auditory neuropathy (failed ABR, normal OAE = auditory neuropathy ☞ early cochlear implants (Shapiro et al. 2011) - 25 % cognitive dysfunction (no mental retardation) Proposed classification of kernicterus by location (Shapiro 2010) -----------------------------------------------------------------------------Classic kernicterus Classic triad or tetrad of: (1) auditory neuropathy/auditory dys-synchrony, hearing loss or deafness, (2) neuromotor symptoms e.g. dystonia, athetosis, hypertonia (3) oculomotor paresis of upward gaze, and (4) enamel dysplasia of the deciduous teeth. Oculomotor and dental criteria may be variably present or absent. Auditory kernicterus Predominantly auditory symptoms, i.e. auditory neuropathy/auditory dys-synchrony with minimal motor symptoms. Motor kernicterus Predominantly motor symptoms, e.g. dystonia athetosis with minimal auditory symptoms. Subtle kernicterus or bilirubin-induced neurological dysfunction (BIND) Subtle disabilities without classical findings of kernicterus that, after careful evaluation and consideration, appear to be due to bilirubin neurotoxicity. These may include disturbances of sensory and sensorimotor integration, central auditory processing, coordination and muscle tone. Are neurodevelopmental problems due to hyperbilirubinemia ? ------------------------------------------------------------------------------ Excessively high TSB      at  minimum: total bilirubin phototherapy level (15–20 mg/dL)      stronger evidence: total bilirubin > exchange trasfusion level           (20–25 mg/dL) - Neurological symptoms at time bilirubin high (tone, cry,      posturing, eye movements) - Other risk factors (duration, prematurity, sepsis, critically ill, Rh isoimmunization) - Abnormal tone and movements - Hearing loss, difficulty localizing sound or with sound in noise - Abnormal eye movements, especially decreased upward gaze - Dental enamel dysplasia (baby teeth) - Laboratory-specific ABR and MRI findings:      ABR absent or abnormal c/w AN/AD      MRI abnormal globus pallidus subthalamic nucleus         (hyperintensity T1 early, T2 later) Slusher et al. 2011: the kernicteric face in the late neonatal period % threshold loss kernicterus: clinical presentation sound frequency phase 1 (day 1-2): stupor, hypotonia, poor sucking, apnoea phase 2 (day 3-7): episodic extensor hypertonia with opisthotonos and retrocollis (extension in arms, flexion and pronation in forearms), fever parallel with hypertonia, oculogyric crises, apnoea, shrill cry, tongue protrusion; children reaching this stage always have brain injury phase 3 (2w-3m): hypotonia displacing drugs kernicterus: the free bilirubin hypothesis - albumin binding Cashore et al. 1977: decrease of binding capacity of albumin in sick newborns ------------------------------------------------------------------------ sick = one or more of - RDS: FiO2 > 30 % - pHa < 7.3 for > 12 hours and/or present at moment of study - core body temperature < 36 °C prior to or at moment of study - glycaemia < 30 mg/dL prior to or at moment of study - postasphyctic seizures - sepsis Ahlfors et al. 1994 ------------------------------------------------------------------------ suggestions for treatment of jaundice by exchange transfusion based on serum molar ratios between bilirubin and albumin; phototherapy usually starts at around 6/10 of the level for which exchange trasnfusion is advised different units have different strategies for serum albumin determination, but when cohorts are compared around 3-5 % of these ratios are above 0.5 Odell 1980: the free bilirubin hypothesis does not depend on free UCB (Bf) to line up near the endothelial wall: Bf bound to alb may present the molecule as well; the hypothesis does rely on penetration of bilirubin in acid form, first as amorphous bilirubin, at higher [ ] as bilirubin crystals - this process is going on in every sick preterm infant: injury will depend on the rate of deposition and acidosis mainly- serum Bf is low in normal circumstances (< 5 nanogram/mL) - the threshold to kernicterus lies above 12 nanogram/mL, based on displacement studies (Ahlfors 2000) - in VLBW preterms an effect on ABR maturation has been suggested at Bf from 5 nanogram/mL  (B/A ratios 0.3 to 0.4) binding sites: - primary binding site with high affinity (no significant displacement by drugs or anions) - multiple secondary binding sites with low affinity, used when the molar ratio B/A exceeds 1;  displacement at these sites possible by drugs and anions - binding sites for free fatty acids are at different locations, but at FFA/A ratios above 3 some displacing effect is possible kernicterus: graphic summary Watchko JF, Tiribelli C (2014) Bilirubin-induced neurologic damage. N Engl J Med 370(10):979. kernicterus: chronic presentation in preterm infant preterm GA 26w; BPD, subglottic stenosis; quiet baby on d40 term, asian, max TSB 33 mg/dL (560 µmol/L) on d4, no hemolysis, insufficient home supervision clear abnormality of pallidum signal in susceptibility weighted MR sequence (Lequin et al. 2023) kernicterus: acute presentation in term infant sublte late neonatal hyperechoic change of pallidum preterm GA 24w; IVH grade 3, bilateral cerebellar haemorrhage; CUS at PMA 36w, MRI at term equivalent age microconvex probe no T2 hypersignal in pallidum high resolution linear probe kernicterus: subtle presentation in preterm infant kernicterus: hemolysis and other effects of G6PD deficiency kernicterus: the bilirubin induced molecular injury cascade Brites et al. : the molecular cascades. Bhutani nomogram, Pediatrics 1999 kernicterus: prediction nomogram at early discharge glucuroconjugation - from 20 w gestation mainly glucose and xylose conjugates - monoglucuronide prevails around term, in adults > 80 % is diglucuronide - on day 3 diconjugates about 20 % of the conjugated fraction - adult levels achieved in preterms and terms after a few (5 ?) days; low levels contribute to early peak in physiological jaundice  - induction of UDPGT by phenobarbitone requires 2-5 days; phenobarbitone may alter brain bilirubin oxidation kernicterus: hepatic genetic causes of (un)conjugated hyperbilirubinaemia standard deviations days after birth kernicterus: preterm kernicterus kernicterus: ABR physiology <—— kernicterus effect kernicterus: central pathways for hearing kernicterus: ∆∆ with CO intoxication in utero - vulnerability increases with duration of gestation due to multiple mechanisms: indirect effect of maternal hypoxaemia due to binding of CO to maternal Hb; direct effect of transplacental CO binding much intenser with fetal Hb with shift to left of the dissociation curve; direct effect of CO by interfering with ATP synthesis through binding on cytochromes; indirect effect of fetal heart failure - specific vulnerability of globus pallidus internum and of substantia nigra (iron concentration high); also neuronal cell death in hippocampus, Purkinje cells, thalamus, subthalamic nucleus and putamen - non-specific ischaemic lesions in cortex and white matter neuropathological substrate (Ginsberg and Myers 1976) -------------------------------------------------------------------- septal agenesis (end of first trimester exposure) polymicrogyria cystic white matter destruction selective injury to pallidum, hypothalamus and substantia nigra dyskinetic cerebral palsy follows destruction of the pallidal and subthalamic functional stations in the striatum a disinhibition of thalamus leads to hypertonia and dystonia (largely based on Wilson 2004) <—— kernicterus kernicterus: globus pallidus and subthalamus in striatal functions Mac OS X  2°âATTRâ¼&¼com.apple.TextEncodingËcom.apple.quarantineutf-8;134217984q/0082;6a1f1d6d;Hype4;