Transcript Kernikterus – ein altes oder doch noch aktuelles Problem in Europa

Hyperbilirubinemia-IntoxicationEncephalopathy-Syndrome
Hubertus von Voss, Munich
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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
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History of
Kernikterus
Christian Georg Schmorl
* 2. Mai 1861 in Mügeln; † 14. August 1932 in Dresden
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Christian Georg Schmorl
Zur Kenntnis des Ikterus neonatorum,
insbesondere der dabei auftretenden
Gehirnveränderungen.
Verh Dtsch Pathol Ges 6, 109-115 (1904)
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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
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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
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Part I
Physiology and pathophysiology
of bilirubin
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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
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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: 558 - 565
**Int. J. AudiologyCopyright
2004;H von
43:516
– 522
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Kernikterus
Symptoms Part II
Shrill crying,feeding problems, lethargy,
fever
• Apnoe
• Convulsions
• Auditory neuropathy (one- or bothsided)
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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
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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
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Kernikterus
Incidence 1. 7. 2003 bis 31. 12. 2004
11 patients (ESPED)
Center for registration of rare diseases in
Germany
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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
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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
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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
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Hyperbilirubinemia - Kernikterus
Risks
refering to outpatient and home-deliveries +
investigation of newborns under artifical
(NEON) - lightsGeburten
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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.
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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
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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
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Causes for Hyperbilirubinämie
Part III
intrauterine infections
sepsis
toxoplasmosís,rubeola, cytomegaly,
herpes, syphilis (lues)
starvation and thirst
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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)
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Hyperbilirubinemia and preterms
Phototherapy with blue light (460 nm):
These lights can be used only time –
limited
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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
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Therapy recommendations (American Academy of Ped.)
for hyperbilirubinemia – mg/ dl ; ()= µMol/ Liter)
age (hours
after birth)
photo –
therapy
phototherapy
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)
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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
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Hyperbilirubinemia and
phototherapy
Phototherapy conditions
• intensive care of newborns
• increased fluid offer: plus 20 ml/kg bodyweight/ 24 Stunden
• Aluminiumfolia over inkubator
• temperatur-control: incubator and on ,
child (rectal - measuring)
• Covering of eyes
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Part II
Hyperbilirubinemia-IntoxicationEncephalopathy-Syndrome
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Casus I
Tim, now 11 years
4th day of life: 31 mg % Bilirubin
no exchange transfusion
symptoms now:
choreoathetosis, auditory neuropathy,
learning disorder
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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
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Casus I
Prof. Dr. B. Ertl – Wagner, Radiological Institute Munich, Klinkum Grosshadern, LMU
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Casus II
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HIPPOCAMPUS
aus WIKIPEDIA 2005
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HIPPOCAMPUS
• Zum Hippocampus (= Teil des
Telencephalons (Großhirn) gehören:
∎ Gyrus dentatus
∎ Cornu ammonis
∎ Subiculum
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HIPPOCAMPUS
aus WIKIPEDIA 2005
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Hippocampus - functions
∎ conduction of sensoric informations:
Consolidation of memory, storage
and and transformation of short
memory in parts of long-lasting
memory
∎ orientation – abilities
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Pedaudiological findings in children with
Kernikterus- syndroA. Nickisch, C. Massinger, H. von
Voss
Kinderzentrum München, Abteilung für Phoniatrie und Audiologie,
Institut für Soziale Pädiatrie und Jugendmedizin der Ludwig-Maximilians-Universität München
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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)
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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)
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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)
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Results and recommendations
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Which auditory results we find in children with
 Kernikterus-syndrome and
 hyperbilirubinemia >20mg% within first
days of life
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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
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Maximum Bilirubinvalues (mg/dl)
in both groups
7
6
5
Anzahl
4
Bili >20mg%
3
Kontrollen
2
1
0
12,515
1517,5
17,519,5
2024,9
2529,9
max. Bilirubin (mg/dl)
3034,9
3539,9
40-46
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T-Test zur Mittelwertgleichheit (max. Biliwert): signifikante Gruppendifferenz (t=6.01, p<0.0001)
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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
ø
BERA = SA
1
1****
< SA
4*
0
+
Ø
3
0
+
+
2**
13
1x no OAE
Hearing problems
Hearing loss with AN
ø or
+
Subjective normal hearing but
with AN
Subjective normal hearing
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*** Frühgeburt 33.SSW ****Bili 19mg%+Colisepsis
** Bili 25-27mg%
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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
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Normogramm für die Risikoeinschätzung von 2840 normalen Neugeboren mit einem Gestationsalter von 36
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Monaten und mehr, Geburtsgewicht von
>2000g
basierend
den Serumbilirubinwerten (aus: 1).
* Frühgeburten, ** schwere hämolytische Anämien 2011
bei RH-/AB0-Inkompatibilität
Kernikterus – Hyperbilirubinämie –
Toxizitäts – Enzephalopathie – Syndrom
(v.Voss)
Fig. From Shapiro S. M. J.Perinat. 2005, 54 - 59
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Synonymes for
KERNIKTERUS - Syndrom
• Bilirubin – Induced Neurologic
Dysfunction (BIND)
• Kernikterus – Hyperbilirubinämie –
Toxizitäts – Enzephalopathie –
Syndrom (v. Voss)
• Probable or possible Kernicterus*
• Certain Kernikterus*
*Shapiro (2005)
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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) , eyemovement dysfunctions, NMR
–positive, dental anomaly
Subtile – mild Kernikterus
Learning disorder, path. hearing tests e. g.
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Thank you for
invitation and your
interest
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