Kernicterus

Developmental Pediatrics Louis Meng, PL2 November 12th 2002

History
Earliest work on jaundice from Baumes1785, and Hervieux-1847 Kernicterus was first described by Johannes Orth, 1875
He postulated that jaundice might have hematologic origins He noted that the brain in jaundiced adults wasnt affected

Christian Schmorl coined the term in 1904

Translated, Kernicterus means jaundice of the kern or nuclear region of the brain

Pathophysiology
RBCs are broken down Bilirubin is an end product of heme metabolism Bilirubin is conjugated in the liver
Enzyme: UDP-Glucuronyl Transferase

Conjugated bili is excreted via the GI tract

Enzyme: Beta-Glucuronidase can unconjugate bili in the small intestine and bili is reabsorbed

Bilirubin Conjugation

Pathophysiology Newborn Hyperbilirubinemia

Relatively high hematocrit; more cells to break down UDP-Glucuronyl Transferase is not fully functional until 3-4 months of life Relative starvation state and slow transit time, especially in breastfeeders Breastmilk contains beta-glucuronidase; enterohepatic circulation is increased

Pathophysiology Exaggerated Hyperbilirubinemia

Polycythemia Hemolysis
Rh incompatibility ABO incompatibility Abnormal RBCsG6PD, spherocytosis, thalassemia

Birth TraumaBruising, Cephalohematoma Metabolic AbnormalitiesCrigler Najjar, Gilbert Syndrome, Galactosemia MedicationsSulfonamides
Displaces bilirubin from albumin; same binding site

Pathophysiology
UCB is lipophilic and crosses the Blood-Brain Barrier
In vitro, free UCB will not precipitate out of solution unless in the presence of a polar lipid membrane In theory, only free UCB crosses, albumin-bound does not. BBB of infants is more permeable than adults, and acidosis causes it to be even more permeable.

UCB has an affinity for the basal ganglia, hippocampus, cranial nerve nuclei
Mechanism is widely studied, but still unknown

UCB interrupts metabolism in glial cells and causes apoptosis of neurons

Exact mechanisms are unknown, but definitely separate pathways. Age of the cell is inversely proportional to susceptibility

MRI of an infant who suffered from severe Erythroblastosis Fetalis

Clinical Manifestations Bilirubin Encephalopathy

Acute Bilirubin Encephalopathy
1st phase: hypotonia, poor suck-present in the first few days 2nd phase: Hypertonia (retrocollis and opisthotonos), fever 3rd phase: Gradual disappearance of the hypertoniaUp to years after the first week

Clinical Manifestations: Bilirubin Encephalopathy

Chronic Encephalopathy:
(Perlsteins Tetrad: Extrapyramidal Abnormalities, Hearing Loss, Gaze abnormality, and Dental Dysplasia)

Extrapyramidal abnormalities: Facial grimacing, drooling, dysarthria, and athetosis--may develop by 18mo or delayed to 8or9 years. Hearing loss is usually due to injury of the cochlear nuclei in the brainstem. It may be the only manifestation Gaze abnormalities: Limitation of upward gaze, palsies Cerebral cortex is relatively spared, so intelligence is often close to normal.

Diagnosis
Kernicterus is a pathologic diagnosis, not clinical. Post-mortem exam of the brain is the definitive diagnosis Clinically, kernicterus is suspected based on the history of hyperbilirubinemia and the clinical manifestations as mentioned above.
The degree of hyperbilirubinemia does not correlate well with the development or severity of kernicterus.

Laboratory Measures
There is currently no lab value that correlates well with the development of kernicterus; there seem to be many factors that lead to its development Guidelines for initiating therapy for hyperbilirubinemia currently include the variables of UCB and age of baby.
There are no good guidelines for preterm infants An unconjugated bilirubin level of 25 or less in TERM, HEALTHY babies has not been correlated with kernicterus Pediatrics 1995; Case reports of Term, Healthy, Breastfed babiesUCB levels associated with clinical Kernicterus were 39-50

It has been hypothesized that measuring UNBOUND UCB can be correlated, but not well supported as of yet

Prevention: Treatment of Hyperbilirubinemia

Phototherapy
Initiate based on UCB level and babys age Isomerizes UCB to Lumirubin, soluble in water and excreted via the kidney

Exchange transfusion
Initiate if phototherapy fails, repeat as needed Incidence of kernicterus has dropped since the advent

Sn-Mesoporphyrin
Inhibits Heme-oxygenase, which is the rate-limiting enzyme in heme catabolism. Only case reports thus far, where exchange transfusion was refused

Incidence and Prognosis

True incidence is not well known
Using pathologic criteria, one-third of all infants with untreated hemolytic diseases that have bilirubin levels >25 will develop Kernicterus

Prognosis depends of severity of effects

Wide spectrum of manifestations, those with early overt neurologic signs usually die.

Treatment
Treatment of clinically suspected kernicterus is centered around early intervention from multiple disciplines
Neurodevelopmental Pediatrics Neurology Physical and Occupational Therapy Audiology Ophthalmology Speech Therapy School, County, EFMP

Follow Up: Spasticity/Dystonia

Botox, Baclofen for severe posturing Physical therapy for training of muscles and teaching stretching techniques Occupational Therapy for independence and activities of daily living Speech Therapy EquipmentAppropriate chairs, braces, etc

Follow Up: Hearing Deficit

Early Diagnosis
Brainstem Auditory Evoked Response

Long-Term follow up by audiology

Sign Language and other alternative means for communication Hearing aids as appropriate Cochlear implants as appropriate

Speech therapy as needed

Follow Up: Gaze Abnormality

Early involvement of ophthalmology
Strabismus surgery as needed Correction/patching as needed

Follow Up: Cognitive Delays

Cerebral cortex is usually relatively spared, but cognitive delays may be present
Neurodevelopmental Pediatrician to continually reassess for these delays Early diagnosis of learning disabilities Early intervention, special schools, IEPs as appropriate

Summary
Kernicterus remains an important topic for discussion
Incidence is down due to advances in recognition and treatment Making a small resurgance due to higher survivial rates from the NICU

Kernicterus is better understood than ever, but still many mysteries remain and research continues Therapy for clinically suspected Kernicterus centers around multidisciplinary early intervention

Sources
Ahlfors, CE: Unbound Bilirubin Associated with Kernicterus: A Historical Approach. Journal of Pediatrics 2000; 137(4): 540-544. Brodersen, R and L. Stern: Deposition of Bilirubin Acid in the CNSA Hypothesis for the Development of Kernicterus: Acta Paediatr Scand 1990; 79: 12-19. Hansen, TR: Pioneers in the Scientific Study of Neonatal Jaundice and Kernicterus. Pediatrics 2000; 106(2): e15. Kappas, A, et al: Sn-Mesoporphyrin Interdiction of Severe Hyperbilirubinemia in Jehovahs Witness Newborns as an Alternative to Exchange Transfusion. Pediatrics 2001; 108(6): 1374-1377.

Sources
Kernicterus. Nelsons Textbook of Pediatrics: Behrman, Ed: pp 517-519. Kim, MH, et al: Lack of Predictive Indices in Kernicterus. Pediatrics 1980; 66(6): 852-858. Maisels, MJ; et al: Kernicterus in Otherwise Healthy, Breast-fed Term Newborns. Pediatrics 1995; 96(4): 730-733. Rodrigues, CM, et al: Aging Confers Different Sensitivity to the Neurotoxic Properties of Unconjugated Bilirubin. Pediatric Research 2002; 51(1): 112-118.

Sources
Rosenbloom, L: Diagnosis and Management of Cerebral Palsy. Archives of Disease in Childhood 1995; 72: 350-354. Rui, FM, et al: Rat Cultured Neuronal and Glial Cells Respond Differently to Toxicity of Unconjugated Bilirubin. Pediatric Research 2002; 51(4): 535-541. Turkel, SB, et al: A Clinical Pathologic Reappraisal of Kernicterus. Pediatrics 1982; 69(3): 267-272.