Dr. Andreas Nickisch and Mrs. Dr. Claudia Massinger, Kinderzentrum München

to

• 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

Zur Kenntnis des Ikterus neonatorum, insbesondere der dabei auftretenden Gehirnveränderungen.

• Zur Kenntnis des Ikterus neonatorum, insbesondere der dabei auftretenden Gehirnveränderungen.

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

MR-findings in a patient with kernicterus

• 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

The term of KERNIKTERUS had been defined at the beginning of the last century by investigations of died newborns.

• 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 pathophysiology of bilirubin

Definition

• 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

Symptoms Part I

• 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. Audiology 2004; 43:516 – 522

Symptoms Part II

• Symptoms Part II

• Shrill crying,feeding problems, lethargy, fever

• Apnoe

• Convulsions

• Auditory neuropathy (one- or both-sided)

Symptoms Part I

• 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

dependent of

• dependent of

• beginning and intensity of bilirubin- increase

• Increase of bilirubin intrauterin

• hemolysis, anemia, hypoxia, acidosis, microcirculationdysfunctions, sepsis etc.

• pregnancy – duration: maturity of organs and brain

• duration of hyperbilirubinemia

• etiology of hyperbilirubinemia

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

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

• 11 patients (ESPED)

• Center for registration of rare diseases in Germany

Reasons

• 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

physiological ikterus

• 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

physiological ikterus: maximum 17 mg/dl

• 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

Risks

• Risks

• refering to outpatient and home-deliveries +

• investigation of newborns under artifical (NEON) - lightsGeburten

Types

• 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.

isoimmunisation/ inkompatibilities

• 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

Hypothyreosis

• Hypothyreosis

• Crigler – Najar

• Lucey – Driscoll

• Galaktosemia

• Cystic fibrosis

• alpha – 1 – antitrypsindeficiency

• Tyrosinosis

• Alagille- Syndrom

• biliare atresia: intra- and extrahepatic

• spherocytosis

intrauterine infections

• intrauterine infections

• sepsis

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

• starvation and thirst

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.

• 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)

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

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

• 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

umbilical cord - bilirubin 6 mg/dl and more

• 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

Phototherapy conditions

• 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

Tim, now 11 years

• Tim, now 11 years

• 4th day of life: 31 mg % Bilirubin

• no exchange transfusion

• symptoms now:

• choreoathetosis, auditory neuropathy, learning disorder

Felix, now 17 years old

• 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

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

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

• ∎ Gyrus dentatus

• ∎ Cornu ammonis

• ∎ Subiculum

∎ conduction of sensoric informations: Consolidation of memory, storage and and transformation of short memory in parts of long-lasting memory

• ∎ conduction of sensoric informations: Consolidation of memory, storage and and transformation of short memory in parts of long-lasting memory

• ∎ orientation – abilities

• 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)

Hyperbilirubinämia in newborns

• 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)

• Which auditory results we find in children with

•  Kernikterus-syndrome and

•  hyperbilirubinemia >20mg% within first days of life

patient - Group

• 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

Bilirubin – Induced Neurologic Dysfunction (BIND)

• Bilirubin – Induced Neurologic Dysfunction (BIND)

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

• Probable or possible Kernicterus*

• Certain Kernikterus*

• *Shapiro (2005)