Kernicterus

Developmental Pediatrics

Louis Meng, PL2

November 12th 2002

History• Earliest work on jaundice from Baumes-

1785, 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 wasn’t

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

PathophysiologyNewborn 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

PathophysiologyExaggerated Hyperbilirubinemia

• Polycythemia• Hemolysis

– Rh incompatibility– ABO incompatibility– Abnormal RBCs—G6PD, spherocytosis, thalassemia

• Birth Trauma—Bruising, Cephalohematoma• Metabolic Abnormalities—Crigler Najjar, Gilbert

Syndrome, Galactosemia• Medications—Sulfonamides

– 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 ManifestationsBilirubin 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 hypertonia-

Up to years after the first week

Clinical Manifestations:Bilirubin Encephalopathy

• Chronic Encephalopathy: (Perlstein’s 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

babies—UCB 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 baby’s 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

• Equipment—Appropriate 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 CNS—A 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 Jehovah’s Witness Newborns as an Alternative to Exchange Transfusion. Pediatrics 2001; 108(6): 1374-1377.

Sources

• Kernicterus. Nelson’s 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.