copyright h von voss, munich 2011 hyperbilirubinemia-intoxication- encephalopathy-syndrome hubertus...

Copyright H von Voss, Munich 2011

Hyperbilirubinemia-Intoxication-Encephalopathy-Syndrome Hubertus von Voss, Munich


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 2010 2

History of

Kernikterus


Christian Georg Schmorl * 2. Mai 1861 in Mügeln; † 14. August 1932 in Dresden


http://de.wikipedia.org/wiki/2._Mai

http://de.wikipedia.org/wiki/1861

http://de.wikipedia.org/wiki/M%C3%BCgeln

http://de.wikipedia.org/wiki/14._August

http://de.wikipedia.org/wiki/1932

http://de.wikipedia.org/wiki/Dresden


Christian Georg Schmorl

Zur Kenntnis des Ikterus neonatorum, insbesondere der dabei auftretenden

Gehirnveränderungen.

Verh Dtsch Pathol Ges 6, 109-115 (1904)



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 – 15

2. Pedaudiolgic findings after severe neonatal hyperbilirubinemia

Nickisch A, Massinger C, Ertl – Wagner B, von Voss H

Eur Arch Otorhinolaryngol. 2009, 266, 207 - 212



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



Part I

Physiology and pathophysiologyof bilirubin


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


Kernikterus*

Symptoms Part IHypotonie, 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: 558 - 565**Int. J. Audiology 2004; 43:516 – 522


Kernikterus

Symptoms Part II

Shrill crying,feeding problems, lethargy, fever

• Apnoe

• Convulsions

• Auditory neuropathy (one- or both-sided)


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: 558 - 565**Int. J. Audiology 2004; 43:516 – 522

12von Voss Copyright 2010


Kernikterus - Intensity

dependent of

1. beginning and intensity of bilirubinincrease

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



Kernikterus

Incidence 1. 7. 2003 bis 31. 12. 2004

11 patients (ESPED)

Center for registration of rare diseases in Germany


Kernikterus

Reasons

late detection of hyperbilirubinemia and late dectection of risks along pregnancy

American Academy of Pediatrics

Pediatrics Vol 94, 4. Oktober 1994, Seite 558 - 565


Hyperbilirubinemia

physiological ikterusprevalence: 60% in all newborns

physiological ikterusbeginning 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


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-hoursIkterus gravis ►20 mg/dlIkterus prolongatus

►14 TageEmergency case !!

►6mg/dl in umbilical cord

directly after birth


Hyperbilirubinemia - Kernikterus

Risks

refering to outpatient and home-deliveries +

investigation of newborns under artifical (NEON) - lightsGeburten


BILIRUBIN

Typeslipophile 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.


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


Causes for hyperbilirubinemia Part II

HypothyreosisCrigler – NajarLucey – DriscollGalaktosemiaCystic fibrosisalpha – 1 – antitrypsindeficiencyTyrosinosisAlagille- Syndrombiliare atresia: intra- and extrahepaticspherocytosis


Causes for Hyperbilirubinämie Part III

intrauterine infections

sepsis

toxoplasmosís,rubeola, cytomegaly, herpes, syphilis (lues)

starvation and thirst


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)


Hyperbilirubinemia and preterms

Phototherapy with blue light (460 nm): These lights can be used only time – limited


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


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

25 - 48 ≥ 12

(170)

≥ 15

(260)

≥ 20

(340)

≥ 25

(430)

49 - 72 ≥ 15

(260)

≥ 18

(310)

≥ 25

(430)

≥ 30

(510)

►72 ≥ 17

(290)

≥ 20

(340)

≥ 25

(430)

≥ 30

(510)26

von Voss Copyright 2010


Early exchange blood transfusionconditions 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



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


Part II

Hyperbilirubinemia-Intoxication-Encephalopathy-Syndrome


Casus I

Tim, now 11 years

4th day of life: 31 mg % Bilirubin

no exchange transfusion

symptoms now:

choreoathetosis, auditory neuropathy, learning disorder


Casus II

Felix, now 17 years oldalong pregancy non identified rhesus - incomaptibilityBIRTH: hemoglobin 6 g%, bilirubin 9,8 mg/dl acidosis pH 6,9; base – excess minus 19, Reanimation: hydrops congenitussymptoms nowhigh intelligence (IQ ~130=, musician (guitarr),one siedes auditory neuropathy, epilepsia, loss of short-memory, severe orientation - disorder

Casus I

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


Casus II


HIPPOCAMPUSaus WIKIPEDIA 2005


http://upload.wikimedia.org/wikipedia/commons/d/db/Hippocampus.png


HIPPOCAMPUS

• Zum Hippocampus (= Teil des Telencephalons (Großhirn) gehören:

∎ Gyrus dentatus

∎ Cornu ammonis

∎ Subiculum



HIPPOCAMPUSaus WIKIPEDIA 2005


http://upload.wikimedia.org/wikipedia/de/a/aa/Hippokampus_korr.jpg


Hippocampus - functions

∎ conduction of sensoric informations: Consolidation of memory,

storage and and transformation of short memory in parts of long-lasting memory

∎ orientation – abilities



Pedaudiological findings in children with Pedaudiological findings in children with Kernikterus- syndroKernikterus- syndroA. Nickisch, C. Massinger, H. von A. Nickisch, C. Massinger, H. von

VossVoss Kinderzentrum München, Abteilung für Phoniatrie und Audiologie, Kinderzentrum München, Abteilung für Phoniatrie und Audiologie,

Institut für Soziale Pädiatrie und Jugendmedizin der Ludwig-Maximilians-Universität Institut für Soziale Pädiatrie und Jugendmedizin der Ludwig-Maximilians-Universität MünchenMünchen



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


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)



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. 20-21mg% (5) bzw. Bilir. von 12-15mg% (8, 15, 16, 17)



Results and recommendations


Which auditory results we find in children with

Kernikterus-syndrome and

hyperbilirubinemia >20mg% within first days of life



patient - Groupn = 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 - duration53von Voss Copyright 2010


Maximum Bilirubinvalues (mg/dl)in both groups

0

1

2

3

4

5

6

7

12,5-15

15-17,5

17,5-19,5

20-24,9

25-29,9

30-34,9

35-39,9

40-46

Bili >20mg%

Kontrollen

max. Bilirubin (mg/dl)

Anz

ahl

T-Test zur Mittelwertgleichheit (max. Biliwert): signifikante Gruppendifferenz (t=6.01, p<0.0001) 54von Voss Copyright 2010


subjective audiometry (SA)

TOAE BERA Gruppe 1 Gruppe 2

Max. Bilirubin postnatal

>20 mg% 12,5-19,5 mg%

deafness ø ø 3 1***

Deafness with auditor. Neuropathy (AN)

+ ø 1* 0

One – sided neuropathy ø ø 1 0

Hearing problemsø BERA = SA 1 1****

Hearing loss with AN ø or +

< SA 4* 0

Subjective normal hearing but with AN

+ Ø 3 0

Subjective normal hearing + + 2**13

1x no OAE

* Je 1x TOAE anfangs +, später erloschen! *** Frühgeburt 33.SSW ****Bili 19mg%+Colisepsis ** Bili 25-27mg%



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



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



Kernikterus – Hyperbilirubinämie – Toxizitäts – Enzephalopathie – Syndrom

(v.Voss) Fig. From Shapiro S. M. J.Perinat. 2005, 54 - 59



Synonymes for KERNIKTERUS - Syndrom

• Bilirubin – Induced Neurologic Dysfunction (BIND)

• Kernikterus – Hyperbilirubinämie – Toxizitäts – Enzephalopathie – Syndrom (v. Voss)

• Probable or possible Kernicterus*

• Certain Kernikterus*

*Shapiro (2005)



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 KernikterusLearning disorder, path. hearing tests e. g.


Thank you for invitation and your interest


copyright h von voss, munich 2011 hyperbilirubinemia-intoxication- encephalopathy-syndrome hubertus...

Documents

voss copyright

copyright h

munich slide

history of kernikterus

cerebellum slide

birth slide

sided slide

molliter slide