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Copyright H von Voss, Munich 2011 Hyperbilirubinemia-Intoxication- Encephalopathy-Syndrome Hubertus von Voss, Munich.

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Presentation on theme: "Copyright H von Voss, Munich 2011 Hyperbilirubinemia-Intoxication- Encephalopathy-Syndrome Hubertus von Voss, Munich."— Presentation transcript:

1 Copyright H von Voss, Munich 2011 Hyperbilirubinemia-Intoxication- Encephalopathy-Syndrome Hubertus von Voss, Munich

2 Copyright H von Voss, Munich 2011 Thanks to Mrs. Prof. Dr. Birgit Ertl – Wagner, Inst. for Clinical Radiology, Ludwig – Maximilians – University, Munich Dr. Andreas Nickisch and Mrs. Dr. Claudia Massinger, Kinderzentrum München von Voss Copyright 20102

3 History of Kernikterus

4 Copyright H von Voss, Munich 2011 Christian Georg Schmorl * 2. Mai 1861 in Mügeln; 14. August 1932 in Dresden2. Mai1861Mügeln14. August1932Dresden von Voss Copyright 20104

5 Copyright H von Voss, Munich 2011 Christian Georg Schmorl Zur Kenntnis des Ikterus neonatorum, insbesondere der dabei auftretenden Gehirnveränderungen. Verh Dtsch Pathol Ges 6, (1904) von Voss Copyright 20105

6 Copyright H von Voss, Munich 2011 Own Literature 1.MR-findings in a patient with kernicterus Steinborn M, Seelos KG, Heuck A, von Voss H, Reiser M Eur. Radiol. 1999, 9, 1913 – Pedaudiolgic findings after severe neonatal hyperbilirubinemia Nickisch A, Massinger C, Ertl – Wagner B, von Voss H Eur Arch Otorhinolaryngol. 2009, 266, von Voss Copyright 20106

7 Copyright H von Voss, Munich 2011 Kernikterus The term of KERNIKTERUS had been defined at the beginning of the last century by investigations of died newborns. Nowadays we have to define the Kernikterus – Syndrome on the basis of metabolismus functions and magnetic – resonance performance von Voss Copyright 20107

8 Copyright H von Voss, Munich 2011 Part I Physiology and pathophysiology of bilirubin

9 Copyright H von Voss, Munich 2011 Kernikterus Definition Yellow coloured regions in deep levels of the brain, especially basal ganglias: hippocampus, nucleus geniculatus, nuclei: nervus oculomotorius, vestibularis, abducens, cochlearis, formatio reticularis, cerebellum

10 Copyright H von Voss, Munich 2011 Kernikterus* Symptoms Part I Hypotonie, Hypertonia (Spasticity), athetosis, Chorea; epilepsia; fever Retrocollis auditory neuropathy** (OAE normal; BERA path.) eye movement disturbance balance - disorder mental retardation, disablities, functional dysregulations on learning *Pediatrics 1994; 94: **Int. J. Audiology 2004; 43:516 – 522

11 Copyright H von Voss, Munich 2011 Kernikterus Symptoms Part II Shrill crying,feeding problems, lethargy, fever Apnoe Convulsions Auditory neuropathy (one- or both- sided)

12 Copyright H von Voss, Munich 2011 Kernikterus* Symptoms Part I Hypotonia, Dystoniea, Hypertonia (Spasticity), Chorea; Epilepsia Retrocollis Auditory Neuropathy** (OAE normal; BERA pathological) Eye – movement - dysfunctions balance- und coordination- dysfunctions Sensoric – dysfunctions: orientation and long-time memory Mental dysfunctions, disabilities, learning disorders * Pediatrics 1994; 94: **Int. J. Audiology 2004; 43:516 – von Voss Copyright 2010

13 Copyright H von Voss, Munich 2011 Kernikterus - Intensity dependent of 1.beginning and intensity of bilirubin- increase 2.Increase of bilirubin intrauterin 3.hemolysis, anemia, hypoxia, acidosis, microcirculationdysfunctions, sepsis etc. 4.pregnancy – duration: maturity of organs and brain 5.duration of hyperbilirubinemia 6.etiology of hyperbilirubinemia von Voss Copyright

14 Copyright H von Voss, Munich 2011 Kernikterus Incidence bis patients (ESPED) Center for registration of rare diseases in Germany

15 Copyright H von Voss, Munich 2011 Kernikterus Reasons late detection of hyperbilirubinemia and late dectection of risks along pregnancy American Academy of Pediatrics Pediatrics Vol 94, 4. Oktober 1994, Seite

16 Copyright H von Voss, Munich 2011 Hyperbilirubinemia physiological ikterus prevalence: 60% in all newborns physiological ikterus beginning early, duration maximum 8 days, maximal bilirubin on 5 th day, maximum to 17 mg/ dl in normal babys 1 mg bilirubin/ dl = 17,1µmol/liter

17 Copyright H von Voss, Munich 2011 Typs of hyperbilirubinemia physiological ikterus: maximum 17 mg/dl pathological ikterus - types Icterus praecox: Bilirubin more than 7 mg within first 24 life - hours, or >12 mg/dl within first 36 life-hours Ikterus gravis 20 mg/dl Ikterus prolongatus 14 Tage Emergency case !! 6mg/dl in umbilical cord directly after birth

18 Copyright H von Voss, Munich 2011 Hyperbilirubinemia - Kernikterus Risks refering to outpatient and home-deliveries + investigation of newborns under artifical (NEON) - lightsGeburten

19 Copyright H von Voss, Munich 2011 BILIRUBIN Types lipophile fraktion of bilirubin = non conjugated bilirubin(indirect bilirubin) is toxic for newborns and especially preterms Characteristics penetrance to brain tissue. water soluble fraction of bilirubin = conjugated bilirubin which can be excreted by enzymatic functions of glukuronidase : excretion with the fluid of gall-bladder and urine. Albumin has capacities of binding the bilirubin but the capacity in newborns and especially preterms is not comparable to adults.

20 Copyright H von Voss, Munich 2011 Causes for hyperbilirubinemia Part I isoimmunisation/ inkompatibilities rhesus, ABO and subgroups (antibodies of rhesussystem: C, c, D, d, E, e, Kell, Duffy…) feto – fetal and materno - fetal transfusion glucose – 6 – phopsphatdehydrogenase – deficiency(G6- PDH), thalassemia severe coagulation disorders and hemolysis

21 Copyright H von Voss, Munich 2011 Causes for hyperbilirubinemia Part II Hypothyreosis Crigler – Najar Lucey – Driscoll Galaktosemia Cystic fibrosis alpha – 1 – antitrypsindeficiency Tyrosinosis Alagille- Syndrom biliare atresia: intra- and extrahepatic spherocytosis

22 Copyright H von Voss, Munich 2011 Causes for Hyperbilirubinämie Part III intrauterine infections sepsis toxoplasmosís,rubeola, cytomegaly, herpes, syphilis (lues) starvation and thirst

23 Copyright H von Voss, Munich 2011 Hyperbilirubinämie and preterms The risks for hyperbilirubinemia and following unwished side-effects increase especially in children with small for date premraturity, sick newborns and preterms with brain – bleeding and/ or sepsis. Indication for exchange transfusion and transfusion starts on bilirubin 18 mg% (310µmol/l or more)

24 Copyright H von Voss, Munich 2011 Hyperbilirubinemia and preterms Phototherapy with blue light (460 nm): These lights can be used only time – limited

25 Copyright H von Voss, Munich 2011 Early exchange transfusion Umbilical cord - bilirubin 6 mg/dl and more umbilicalcord - hemoglobin 12 g/dl (Hämatokrit 35%) direct Coombstest very positive (rhesus – Inkompatibility) postnatale bilirubin - increase 0,5mg/dl/ hour along for the first 48 life-hours

26 Copyright H von Voss, Munich 2011 Therapy recommendations (American Academy of Ped.) for hyperbilirubinemia – mg/ dl ; ()= µMol/ Liter) age (hours after birth) photo – therapy photo- therapy Indication Photo – therapy 4-6 Hours without pos. effects, exchange transfusion Exchancge transfusion (170) 15 (260) 20 (340) 25 (430) (260) 18 (310) 25 (430) 30 (510) (290) 20 (340) 25 (430) 30 (510) 26 von Voss Copyright 2010

27 Copyright H von Voss, Munich 2011 von Voss Copyright

28 Copyright H von Voss, Munich 2011 Early exchange blood transfusion conditions and indications umbilical cord - bilirubin 6 mg/dl and more umbilical – cord hemoglobin 12 g/dl (hematokrit 35%) direct Coombstest high - positiv (Rhesus – Inkompatibility) postnatale bilirubinincrease 0,5mg/dl/ hour within first 48 life - hours 28von Voss Copyright 2010

29 Copyright H von Voss, Munich 2011 Hyperbilirubinemia and phototherapy Phototherapy conditions intensive care of newborns increased fluid offer: plus 20 ml/kg body- weight/ 24 Stunden Aluminiumfolia over inkubator temperatur-control: incubator and on, child (rectal - measuring) Covering of eyes

30 Copyright H von Voss, Munich 2011 Part II Hyperbilirubinemia-Intoxication- Encephalopathy-Syndrome

31 Copyright H von Voss, Munich 2011 Casus I Tim, now 11 years 4th day of life: 31 mg % Bilirubin no exchange transfusion symptoms now: choreoathetosis, auditory neuropathy, learning disorder

32 Copyright H von Voss, Munich 2011 Casus II Felix, now 17 years old along pregancy non identified rhesus - incomaptibility BIRTH: hemoglobin 6 g%, bilirubin 9,8 mg/dl acidosis pH 6,9; base – excess minus 19, Reanimation: hydrops congenitus symptoms now high intelligence (IQ ~130=, musician (guitarr),one siedes auditory neuropathy, epilepsia, loss of short-memory, severe orientation - disorder

33 Casus I Prof. Dr. B. Ertl – Wagner, Radiological Institute Munich, Klinkum Grosshadern, LMU

34 Copyright H von Voss, Munich 2011

35

36 Casus II

37 Copyright H von Voss, Munich 2011 von Voss Copyright

38 Copyright H von Voss, Munich 2011 von Voss Copyright

39 Copyright H von Voss, Munich 2011 von Voss Copyright

40 Copyright H von Voss, Munich 2011 von Voss Copyright

41 Copyright H von Voss, Munich 2011 von Voss Copyright

42 Copyright H von Voss, Munich 2011 HIPPOCAMPUS aus WIKIPEDIA 2005 von Voss Copyright

43 Copyright H von Voss, Munich von Voss Copyright 2010

44 Copyright H von Voss, Munich 2011 HIPPOCAMPUS Zum Hippocampus (= Teil des Telencephalons (Großhirn) gehören: Gyrus dentatus Cornu ammonis Subiculum von Voss Copyright

45 Copyright H von Voss, Munich 2011 HIPPOCAMPUS aus WIKIPEDIA 2005 von Voss Copyright

46 Copyright H von Voss, Munich 2011 Hippocampus - functions conduction of sensoric informations: Consolidation of memory, storage and and transformation of short memory in parts of long-lasting memory orientation – abilities von Voss Copyright

47 Copyright H von Voss, Munich 2011 Pedaudiological findings in children with Kernikterus- syndro A. Nickisch, C. Massinger, H. von Voss Kinderzentrum München, Abteilung für Phoniatrie und Audiologie, Institut für Soziale Pädiatrie und Jugendmedizin der Ludwig-Maximilians-Universität München 47von Voss Copyright 2010

48 Copyright H von Voss, Munich 2011 Hyperbilirubinemia Bera unnormal in newborns Bilirubin 20mg%: Latenzretardation (IPL III-V), mostly reversible after effective therapy (casus 2, 7, 18, 19) newborns mature bilirubin 24mg% reversible (10) 48von Voss Copyright 2010

49 Copyright H von Voss, Munich 2011 Hyperbilirubinämia in newborns BERA- results -Bilirubin > 20mg%: Latenz- retardation or missing results: 50% (9, 14) irreversible (7, 11) additionaL neurological dysfunctions especially :choreoathetosis mental retardation(2, 6, 12, 14, 15) auditory Synapto-/Neuropathy (3, 14, 15) Bilirubinvalues are korrelating with the intensity of latence-reactions in BERA (2, 18, 20) 49von Voss Copyright 2010

50 Copyright H von Voss, Munich 2011 Hyperbilirubinemia in newborns auditory System shows early myelinisation, earlier than the motoric system Damage intensity depends on the time of bilirubin increase Perterms have a righ risk depending on Bilir mg% (5) bzw. Bilir. von 12-15mg% (8, 15, 16, 17) 50von Voss Copyright 2010

51 Copyright H von Voss, Munich 2011 Results and recommendations

52 Copyright H von Voss, Munich 2011 Which auditory results we find in children with Kernikterus-syndrome and hyperbilirubinemia >20mg% within first days of life 52von Voss Copyright 2010

53 Copyright H von Voss, Munich 2011 patient - Group n = 15 children with Kernikterus (n=8) and/ or hyperbilirubinemia >20mg% within first days of life (n=14) Control - group n = 15 children with hyperbilirubinämie 12,5-19,5mg% within first days of life (n=15) matched to pregnancy - duration 53von Voss Copyright 2010

54 Copyright H von Voss, Munich 2011 Maximum Bilirubinvalues (mg/dl) in both groups max. Bilirubin (mg/dl) Anzahl T-Test zur Mittelwertgleichheit (max. Biliwert): signifikante Gruppendifferenz (t=6.01, p<0.0001) 54von Voss Copyright 2010

55 Copyright H von Voss, Munich 2011 subjective audiometry (SA) TOAE BERAGruppe 1Gruppe 2 Max. Bilirubin postnatal >20 mg%12,5-19,5 mg% deafness øø31*** Deafness with auditor. Neuropathy (AN) +ø1*0 One – sided neuropathy øø10 Hearing problems øBERA = SA11**** Hearing loss with AN ø or + < SA4*0 Subjective normal hearing but with AN +Ø30 Subjective normal hearing ++2** 13 1x no OAE * Je 1x TOAE anfangs +, später erloschen! *** Frühgeburt 33.SSW ****Bili 19mg%+Colisepsis ** Bili 25-27mg% 55von Voss Copyright 2010

56 Copyright H von Voss, Munich 2011 Folgerungen bei Biliwerten >20mg% All children with hyperbilirubinemia >19 mg% must be investigated for their hearing All preterms must be investigated with bilirubin >12mg% during first days of life Normal OAE – results don´t exclude central hearing problems. So all children with hyperbilirubinemia need subjective hearing tests + OAE + BERA 56von Voss Copyright 2010

57 Copyright H von Voss, Munich 2011 Normogramm für die Risikoeinschätzung von 2840 normalen Neugeboren mit einem Gestationsalter von 36 Monaten und mehr, Geburtsgewicht von >2000g basierend auf den Serumbilirubinwerten (aus: 1). * Frühgeburten, ** schwere hämolytische Anämien bei RH-/AB0-Inkompatibilität 57von Voss Copyright 2010

58 Copyright H von Voss, Munich 2011 Kernikterus – Hyperbilirubinämie – Toxizitäts – Enzephalopathie – Syndrom (v.Voss) Fig. From Shapiro S. M. J.Perinat. 2005, von Voss Copyright

59 Copyright H von Voss, Munich 2011 Synonymes for KERNIKTERUS - Syndrom Bilirubin – Induced Neurologic Dysfunction (BIND) Kernikterus – Hyperbilirubinämie – Toxizitäts – Enzephalopathie – Syndrom (v. Voss) Probable or possible Kernicterus* Certain Kernikterus* *Shapiro (2005) von Voss Copyright

60 Copyright H von Voss, Munich 2011 Acute Bilirubinenzephalopathy Lethargy,feeding dysfunctions,muscletonus dysfunctions, shrill cry, Opisthotonus,convulsions, fever, death chronical Bilriubinenzephalopathie Athetosis, Dystonia, spasticity,hypotonia, auditoriy dysfunktion (neuropathy =´hearing loss or deafnessErtaubung), eye- movement dysfunctions, NMR –positive, dental anomaly Subtile – mild Kernikterus Learning disorder, path. hearing tests e. g.

61 Copyright H von Voss, Munich 2011 Thank you for invitation and your interest 61von Voss Copyright 2010


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