Kernicterus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdulkerim Yassin, M.B.B.S[2]

Synonyms and keywords: Chronic bilirubin encephalopathy

Overview

Kernicterus is irreversible brain damage due to chronic high levels of unconjugated bilirubin in the baby`s blood which is not treated early. Hyperbilirubinemia frequently occurs in majority of newborn infants but mostly it is benign and in severe cases can progress to kernicterus and developmental abnormalities. The risk of bilirubin induced neurologic damage and kernicterus are more 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 does it for the baby. After birth, some of the baby`s liver enzyme not well developed specially in preterm, bilirubin raises in the baby`s blood and accumulates in the skin and sclera of eyes and cause jaundice. When the jaundice gets severe, The tissues protecting the brain (the blood-brain barrier) are immature in newborns. 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. When the jaundice occurs within (24 hours) of life is always pathological, whereas it happens after 24 hours of life, it can be physiological. Several underlying pathologic processes responsible for hyperbilirubinemia are G6PD deficiency, Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and a decreased ability to conjugate bilirubin in neonates and infants. Newborn babies are often polycythemic, meaning they have too many red blood cells. When they break down the cells, one of the byproducts is bilirubin, which circulates in the blood and causes jaundice. When hyperbilirubinemia occurs in adult and older children, it is frequently due to liver abnormalities. Some medications, such as the antibiotic co-trimoxazole (a combination of trimethoprim/sulfamethoxazole) may induce this disorder in the baby, either when taken by the mother or given directly to the baby, due to displacement of bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the Central Nervous System, because the baby's blood-brain barrier is not fully developed. 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.

In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name].

Classification

• Based on the duration of symptoms, bilirubin encephalopathy may be classified as either acute, subtle or chronic.
  • Acute bilirubin encephalopathy: comprises the cute illness caused by severe hyperbilirubinemia. The sign and symptom includes decreased feeding, lethargy, hypotonia and/or hypertonia, high-pitched cry, retrocollis and opisthotonus, setting-sun sign, fever, seizures, and may be 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.

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 [104 to 291 μmol/l]). 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
        • Sibling with Jaundice
          • Bruising
            • Blood Type

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

The neurologic abnormalities associated with hyperbilirubinemia are known as bilirubin-induced neurologic dysfunction (BIND).[15] They are classified as acute and chronic based on their period of evolution.

Acute bilirubin encephalopathy can be further divided into three phases:[9] Weakness, lethargy, and poor feeding are seen in this phase. These are not specific to this condition and are seen in a variety of diseases, thus making it difficult to identify the condition at this stage. Prompt administration of treatment at this stage will stop the progression of the condition. Extensor hypertonia, retrocollis, opisthotonus are generally seen in this phase. Hypotonia is typically seen in infants aged more than one week. Chronic bilirubin encephalopathy will progress slowly over several years and include:[15] Hypotonia Hyperreflexia Delayed achievement of milestones Visual and auditory defects Choreathetoid cerebral palsy The abdominal examination might show hepatomegaly or splenomegaly indicative of a hemolytic cause.

physical Examination

The physical exam should be comprehensive, with special attention to the neurological exam. The child's level of consciousness should be assessed. The presence of icterus and yellowish discoloration of the body might be evident. The infants are usually not febrile. Vital signs may be significant for tachycardia, dyspnea, and impaired oxygen saturation. The fontanelles should be examined to check for any increase in intracranial pressure. Increased intracranial pressure leads to bulging fontanelles with the separation of suture lines. The setting sun sign is also an indication of increased intracranial pressure. The enlarged third ventricle puts pressure on the upward gaze center in the midbrain, causing a tonic downward eye deviation.

Laboratory Findings

Total and direct bilirubin, Blood type (mother and infant) and Coomb test, Reticulocyte count - can help in the assessment of ongoing hemolysis, anemia, and hematopoiesis, Complete blood count, Serum electrolytes, lumbar puncture and chest x-ray to rule out sepsis, and transcutaneous bilirubin measurement is helpful in a few cases.

ECG

There are no ECG findings associated with Kernicterus.

CT Scan

Head ultrasound, CT, and MRI - not routinely used to diagnose kernicterus. They are indicated only when lab results are inadequate or inconclusive. They may aid in ruling out other causes of encephalopathy. Brainstem evoked auditory response (BEAR) - used to identify the most common sequelae of bilirubin toxicity i.e., hearing impairmen.

Treatment

Medical Therapy

Fluid supplementation in term children presenting with severe hyperbilirubinemia reduces the rate of exchange transfusion and duration of phototherapy. The main objective of the management of kernicterus is to prevent neurotoxicity by reducing bilirubin levels. The three mainstays of therapy to prevent and treat hyperbilirubinemia are: Exchange Transfusion Therapy Phototherapy - refers to the use of light to convert insoluble bilirubin molecules in the body into water-soluble isomers that can be excreted by the body Intravenous Immunoglobulins (IVIG) - is used in cases with immunologically mediated conditions, or in the presence of Rh, ABO, or other blood group incompatibilities that cause significant neonatal jaundice. Administration of IVIG to newborns with significant hyperbilirubinemia due to ABO hemolytic disease with positive direct Coomb test reduces the need for exchange transfusion without producing immediate adverse effects.