Kernicterus
Synonyms and keywords:  Chronic bilirubin encephalopathy

# Overview
Kernicterus is defined as irreversible brain damage due to chronic high levels of unconjugated bilirubin in the baby's blood. It will develop if the high levels of unconjugated bilirrubin are not treated early. Hyperbilirubinemia frequently occurs in newborns, but it is mostly benign. Severe cases can progress to kernicterus and developmental abnormalities. The risk of bilirubin-induced neurologic damage and kernicterus is higher in preterm than term neonates, and the former, suffer adverse effects at lower total bilirubin levels with worse long-term outcomes. Liver metabolizes and excretes bilirubin. During pregnancy, the mother's liver metabolizes it for the baby. After birth, some newborns may have liver enzymes that are still immature, especially if they are preterm. This causes bilirubin to rise in the baby's blood and accumulates in the skin and sclera of eyes, causing jaundice. The tissues protecting the brain (the blood-brain barrier) are immature in newborns, therefore, they are vulnerable to increased levels of unconjugated bilirubin. Bilirubin penetrates the brain and is deposited in the basal ganglia, hippocampus, geniculate bodies, and cranial nerve nuclei causing irreversible damage. Depending on the level of exposure, the effects range from unnoticeable to severe brain damage. Many conditions may cause jaundice, but when it occurs within (24 hours) of life it is always pathological. If it happens after 24 hours of life, it can be physiologic. Some of the several underlying pathologic processes responsible for hyperbilirubinemia are G6PD deficiency, Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and decreased ability to conjugate bilirubin in neonates and infants. Newborn babies are often polycythemic, meaning they have too many red blood cells. When red cells are destroyed, one of the byproducts is bilirubin, which circulates in the blood and causes jaundice. When hyperbilirubinemia occurs in adults and older children, it is frequently due to liver abnormalities. 
Some medications, such as the antibiotic trimethoprim/sulfamethoxazole may induce this disorder in the newborn, either when taken by the mother or given directly to the patient, due to displacement of bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the central nervous system. In the (first 48 hrs of life), a baby should be checked for jaundice and if it is discharged before 72 hrs, the baby should be seen after 2 days. The treatment is phototherapy and exchange transfusion.

# Historical Perspective
- Kernicterus was first discovered by Christrian Georg Schmorl, a German Pathologist, in 1904.
- The association between hyperbilirubinemia and kernicterus was made in 1875.

# Classification
- Based on the duration of symptoms, bilirubin encephalopathy may be classified as either acute, subtle or chronic.
Acute bilirubin encephalopathy: comprises the acute illness caused by severe hyperbilirubinemia. The signs and symptoms includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may cause death.
Subtle bilirubin encephalopathy/Bilirubin induced neurologic dysfunction: defined by the presence of insidious developmental disorders without the classical findings of kernicterus. This may presents with neurodevelopmental disorders such as sensory and sensorimotor integration disorders, hypotonia, ataxia or clumsiness, aphasia, and auditory neuropathy which is impaired auditory brainstem reflexes with normal otoacoustic emissions or cochlear microphonic responses.
Chronic bilirubin encephalopathy: the long-term outcome of acute bilirubin encephalopathy and composed of a tetrad of clinical characteristics that are typically appear after one year of age:
Abnormal motor control, movements, and muscle tone;
An auditory processing disturbance with or without hearing loss;
Oculomotor impairments, especially impairment of the upward vertical gaze; and
Dental enamel hypoplasia/dysplasia of the primary(milk) teeth.
- Acute bilirubin encephalopathy: comprises the acute illness caused by severe hyperbilirubinemia. The signs and symptoms includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may cause death.
- Subtle bilirubin encephalopathy/Bilirubin induced neurologic dysfunction: defined by the presence of insidious developmental disorders without the classical findings of kernicterus. This may presents with neurodevelopmental disorders such as sensory and sensorimotor integration disorders, hypotonia, ataxia or clumsiness, aphasia, and auditory neuropathy which is impaired auditory brainstem reflexes with normal otoacoustic emissions or cochlear microphonic responses.
- Chronic bilirubin encephalopathy: the long-term outcome of acute bilirubin encephalopathy and composed of a tetrad of clinical characteristics that are typically appear after one year of age:
Abnormal motor control, movements, and muscle tone;
An auditory processing disturbance with or without hearing loss;
Oculomotor impairments, especially impairment of the upward vertical gaze; and
Dental enamel hypoplasia/dysplasia of the primary(milk) teeth.
- Abnormal motor control, movements, and muscle tone;
- An auditory processing disturbance with or without hearing loss;
- Oculomotor impairments, especially impairment of the upward vertical gaze; and
- Dental enamel hypoplasia/dysplasia of the primary(milk) teeth.

# Pathophysiology
The neonatal hyperbilirubinemia occurs due to increased production or limited excretion of indirect or unconjugated bilirubin. Newborns baby, especially preterm neonates, have higher rates of bilirubin production than adults, because an increased red cells turnover and a shorter life span. In newborn neonates, unconjugated bilirubin is not easily excreted, and there is limited bilirubin congugation which lead to physiologic jaundice. Excessive physiologic jaundice occurs at values above 7 to 17 mg/dl ). Serum bilirubin concentrations greater than 17 m/dl in full-term infants are no longer considered physiologic and pathologic causes should be identified, of which the most common are Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and a reduced ability to conjugate bilirubin in newborn babies.

# Causes
Bilirubin is a yellow pigment produced by the breakdown of hemoglobin in old or hemolyzed red blood cells. High levels of bilirubin is due to either increased production, decreased hepatic uptake, impaired conjugation, or increased enterohepatic circulation. Kernicterus is caused by very high levels of indirect or unconjugated bilirubin in the blood which crosses blood brain barrier and yellow staining of brain tissues that leads to brain damage and hearing loss.

# Differentiating Kernicterus from other Diseases
Kernicterus must be differentiated from other diseases that cause movement disorder, visual or auditory impairment such as Cerebral palsy, Head trauma, Neonatal sepsis, Congenital TORCH infections, Hypoxic-ischemic brain injury in the newborn, Fetal alcohol syndrome and Cretinism/pediatric hypothyroidism.

# Epidemiology and Demographics
Kernicterus happens in all parts of the world. Geographic areas where glucose-6-phosphate dehydrogenase-deficiency is common, the risk of kernicterus is higher. The incidence rate of kernicterus in Sweden is 1.3 per 100 000 births which is slightly higher than that in other population-based studies in high-resource settings. The incidence rate of kernicterus in Canada, California, and Denmark, has been reported to be 0.5 to 1 per 100 000 births, whereas in Norway, the incidence rate has been estimated to be less than 0.5 per 100 000 births. The risk of kernicterus is higher in male newborns than female. However, the mechanism is unknown.

# Risk Factors
- Preterm babies
- Babies with darker skin color
- East Asian or Mediterranean descent
- Feeding difficulties
- Siblings that presented with jaundice
- Bruising
- Blood type (Rh or ABO incompatibility)

# Screening
There is insufficient evidence to recommend routine screening for kernicterus.

# Natural History, Complications, Prognosis
Kernicterus is a very rare type of brain damage that occurs in a newborn with severe jaundice.The term kernicterus, which refers to yellow staining of the brainstem nuclei (Greek for jaundice of the nuclei). The prognosis of kernicterus depends on the severity and time to intervention. With early intervention, there may be full recovery. However, a late diagnosis can cause Permanent brain damage, enamel dysplasia, paralysis of upward gaze and, intellectual deficits, Hearing loss and Death..

# Diagnosis

## History and Symptoms
- Acute bilirubin encephalopathy presents with;
Weakness 
lethargy
poor feeding 
Extensor hypertonia
retrocollis
-pisthotonus and hypotonia are generally seen in this phase.
- Chronic bilirubin encephalopathy will progress slowly over several years and comprises;
Hypotonia
Hyperreflexia
Delayed achievement of milestones
Visual and auditory defects
Choreathetoid cerebral palsy
Hepatomegaly or splenomegaly on phyical examination are indicative of a hemolytic cause.

## Physical Examination
- Vital signs: afebrile, tachycardia, dyspnea, and impaired oxygen saturation.
- Head and Neck: icteric sclera.
- Skin: yellowish discoloration of the body.
- Neurologic: bulging fontanelles and setting sun sign (upward-gaze paresis).

## Laboratory Findings
Total and direct bilirubin, blood type mother and infant, Coomb test, reticulocyte count and transcutaneous bilirubin measurement is helpful in a few cases.

## ECG
There are no ECG findings associated with Kernicterus.

## x-ray
There are no x-ray findings associated with Kernicterus.

## Echocardiography or Ultrasound
There are no echocardiography findings associated with Kernicterus.

## CT Scan
CT Scan is not routinely indicated to diagnose kernicterus. It may help in ruling out other causes of encephalopathy.

## MRI
MRI is not routinely indicated to diagnose kernicterus. It may help in ruling out other causes of encephalopathy.

## Other Imaging Findings
Advanced MRI including diffusion-weighted imaging, magnetic resonance spectroscopy, and diffusion tensor imaging with tractography may give good understanding of the pathogenesis of bilirubin-induced brain injury and the neural basis of long-term disability in infants and children with chronic bilirubin encephalopathy..

## Other Diagnostic Studies
Brainstem evoked auditory response (BEAR) aid to diagnose the most common complication of bilirubin toxicity i.e., hearing impairmen. Complete blood count, Serum electrolytes and lumbar puncture to rule out sepsis..

# Treatment

## Medical Therapy
Fluid supplementation in term infants presenting with severe hyperbilirubinemia decreases the rate of exchange transfusion and duration of phototherapy. The management of kernicterus is to prevent neurotoxicity by reducing bilirubin levels. The mainstays of therapy to prevent and treat hyperbilirubinemia are:
- Exchange Transfusion Therapy.
- Phototherapy - uses light to convert insoluble bilirubin into water-soluble forms that can be excreted by the body.
- Intravenous Immunoglobulins (IVIG) - Administration of IVIG to newborns with hyperbilirubinemia due to ABO hemolytic disease with positive direct Coomb test decreases the need for exchange transfusion without causing immediate adverse effects.

## Surgery
The mainstay of treatment for kernicterus is medical therapy. Surgery is may be needed to treat the causes of hyperbilirubinemia such as in biliary atresia.

## Primary Prevention
Promote and support breast feeding.

## Secondary Prevention
Identify and evaluat jaundice.
Post delivery, check serum bilirubin levels in all newborns with jaundice in the first 24 hours.
Know that visual estimation of bilirubin levels is inaccurate.
Monitor preterm( i.e less than 37 weeks) newborns closely.
Do a thorough risk assessment for all newborns.
Educate the parents about jaundice and alarm them.
Schedule follow up visit.
Treat jaundiced neonates based on the bilirubin leves with phototherapy or exchange transfusion.