Kernicterus, or bilirubin encephalopathy, is bilirubin-induced neurological damage, which is most commonly seen in infants. It occurs when the unconjugated bilirubin (indirect bilirubin) levels cross 25 mg/dL in the blood from any event leading to decreased elimination and increased production of bilirubin. The unconjugated bilirubin can cross the blood-brain barrier as it is lipid-soluble, unlike the water-soluble conjugated bilirubin. It gets deposited in the brain tissue, mainly the basal ganglia. The neurotoxicity of unconjugated bilirubin leads to various neurologic sequelae.
Unconjugated hyperbilirubinemia can result from increased production or decreased excretion of bilirubin.
The causes of increased production of unconjugated bilirubin are:
The causes of decreased excretion are:
In the United States kernicterus registry, 56% had abnormalities known to increase the bilirubin concentration in the blood. Glucose-6-phosphate dehydrogenase deficiency was diagnosed in 21.3%, severe hemolytic processes were recognized in 20.5%, birth trauma was identified in 15%, and other causes such as galactosemia, Crigler-Najjar syndrome, and sepsis were diagnosed in 7%. However, no etiology was identified in 43.4% of the infants.
The condition occurs primarily in children, mostly African Americans and South Asians, and is slightly more common in males than females.
The incidence of kernicterus is not exactly known in the United States. Asian, Hispanic, Native American, and Eskimo infants have a higher production of bilirubin than white infants. Black infants, on the other hand, have lower production levels. Preterm infants are at a higher risk of kernicterus than term infants.
Male infants have a higher level of serum bilirubin than female infants.
The prevailing risk of chronic kernicterus is about one in seven in infants with total serum bilirubin greater than 30 mg/dL.
Kernicterus also occurs in infants with bilirubin levels less than 25 mg/dL, but the population risk of this occurrence is unknown.
The pathophysiology is dependent upon the underlying condition causing a buildup of unconjugated bilirubin. Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and decreased ability to conjugate bilirubin in neonates are the most common conditions.
The circulating unconjugated bilirubin, which is lipid-soluble, passes the blood-brain barrier and enters neuronal and glial membranes. In the brain, bilirubin has a special affinity for the globus pallidus, the hippocampus, and the subthalamic nucleus. Many other structures, including the striatum, thalamus, cranial nerve nuclei, inferior olives, and dentate nuclei of the cerebellum, are less frequently affected. Bilirubin attaches to cell membranes and is toxic to neurons and oligodendroglia. It damages the mitochondria, inhibits oxidative phosphorylation, and causes calcium release promoting apoptosis. It also affects axonal and dendritic growth in the central nervous system.
Onset and duration
The case history should begin by asking about the onset and duration of jaundice. The onset of jaundice within 24 hours of life is always pathological, whereas it can be physiological after 24 hours of life. The presence of neurologic symptoms like altered mental status, hypotonia, and decreased reflexes, especially in a preterm infant, should arouse the suspicion of kernicterus. The infants can also present with non-specific symptoms like reduced feeding from the inability to suck efficiently. The onset and duration of the symptoms should also be noted to assess the reversibility of neurologic damage. The risk factors for hemolytic diseases are one of the most important clues for determining the underlying cause of kernicterus.
It is essential to ask about any family history of anemia and/or jaundice since birth or in adulthood. This history gives an idea about conditions like Gilbert syndrome, Crigler-Najjar syndrome, G6PD deficiency, sickle cell disease, and spherocytosis. A family history of metabolic disorders like urea cycle disorders and fatty acid metabolism disorders should be ruled out as these disorders can also have a similar presentation. The mother should be asked about any similar presentations in a previously born child to rule out Rh incompatibility. It may also indicate that the mother might have 20% to 40% more beta-glucuronidase enzyme, leading to hyperbilirubinemia in babies.
Social history - A detailed social history should be asked, outlining any harmful practices in the mother, such as alcoholism or drug use. Antenatal history should be noted down to determine any pre-existing conditions in the mother, like TORCH infections or diabetes mellitus.
This should be assessed to rule out any injuries leading to cephalhematoma, subgaleal hemorrhage, or any bleeding manifestations which can cause hyperbilirubinemia.
Congenital infections in infants can present with jaundice due to decreased glucuronidation or increased hemolysis. A baby born to a mother with diabetes is usually large for gestational age, which indicates a higher number of red blood cells with an increased rate of turnover leading to jaundice.
A detailed history is a stepping stone to diagnosing the etiology of kernicterus as it aids in eliminating the cause of hyperbilirubinemia, thus alleviating the symptoms and the resulting neurologic damage.
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 O2 saturation. The fontanelles should be examined to check for any increase in intracranial pressure. Increased intracranial pressure leads to bulging fontanelles with 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.
The neurologic abnormalities associated with hyperbilirubinemia are known as bilirubin induced neurologic dysfunction (BIND). They are classified as acute and chronic based on their period of evolution.
The abdominal examination might show hepatomegaly or splenomegaly indicative of a hemolytic cause.
The diagnosis and management of kernicterus are based on the following investigations:
Hematologic Studies - most important parameter
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:
Fluid supplementation in term children presenting with severe hyperbilirubinemia reduces the rate of exchange transfusion and duration of phototherapy.
Neonatal jaundice contains a wide spectrum of causes. The neonates are naturally prone to developing jaundice due to the replacement of fetal hemoglobin with adult hemoglobin, and the inability of the immature liver to keep up. However, physiologic jaundice should be a diagnosis of exclusion. It is of utmost importance to rule out other serious diseases as they can have disabling sequelae. As kernicterus presents with jaundice and neurologic symptoms, other diseases that cause either of the symptoms should also be considered and evaluated. A few differential diagnoses to keep in mind are:
Constipation (and inability to pass meconium in neonates) can lead to the increased enterohepatic circulation of bilirubin, causing hyperbilirubinemia and jaundice. Accelerated meconium evacuation through glycerin suppositories has been proposed in the management of hyperbilirubinemia. However, there was no effect on the total bilirubin levels in the patients, though it helped in an earlier passage of meconium.
An increased amount of oligosaccharides, like fructose and galactose, are being added to the formulations due to their prebiotic role in increasing the frequency of stool passage. In a randomized controlled study, 76 newborns were assigned to two groups: one with the formulation containing oligosaccharides (prebiotics) and the other with no oligosaccharides. The study showed a statistical significance of p<0.05 in the difference of the transcutaneous bilirubin levels in the prebiotic group compared to the control group.
Beta-glucuronidase enzyme inhibition by L-aspartic acid and enzymatically-hydrolyzed casein has been shown to reduce enterohepatic circulation in constipated babies.
Sn-mesoporphyrin is an inhibitor of heme oxygenase enzyme involved in the catabolic pathway of hemoglobin metabolism. This therapy is still undergoing clinical trials and has not been approved for use by the Food and Drug Administration (FDA).
The prognosis of kernicterus depends on the severity of disease at presentation and the treatment provided. If caught early, there may be full recovery provided adequate treatment is given upon diagnosis. However, a late diagnosis can cause permanent neurological damage, leading to involuntary movements like chorea, visual and auditory disabilities, and cerebral palsy. Kernicterus causes 15% of neonatal deaths in low-middle-income countries.
The involvement of neurologic complications makes it necessary to concentrate on preventive measures of kernicterus. Optimal antenatal care can help healthcare professionals and the mother to prepare for any kind of complications that can predispose the newborn to hyperbilirubinemia.
American Academy of Pediatrics (AAP) has published an hour-of-age-specific guideline linking bilirubin levels and degree of risk and further management.
A medical check-up is recommended in all infants discharged within 48 to 72 hours of birth. Any infant with a family history of hyperbilirubinemia, prematurity, birth injuries like cephalhematoma, or any other complications should be closely monitored with additional vigilance.
The parents should be counseled on proper feeding methods and the importance of breastfeeding. They should be educated to seek for medical attention when any warning signs like decreased activity, altered mental status, and poor suckling reflex are present.
Traditionally, kernicterus is defined by neurologic damage due to excessive unconjugated bilirubin deposition in the brain tissue. However, there are cases where an infant has neurologic abnormalities with normal or mildly elevated bilirubin levels. A normal bilirubin level or a level within the reference range should not rule out kernicterus as this can lead to permanent disability from neurologic damage. Other causes like neonatal sepsis, acidotic states, and metabolic disorders should be identified to alleviate the symptoms.
Conversely, infants with dangerously high levels of unconjugated hyperbilirubinemia have been diagnosed as physiologic jaundice after ruling out other causes. These infants have recovered without any neurologic complications. All these uncertainties challenge the causal relationship of hyperbilirubinemia and kernicterus, though bilirubin has been demonstrated to be toxic to neural tissue at the cellular level. This calls for a holistic approach to kernicterus in neonates with or without known risk factors rather than strictly abiding by the definition.
Nursing professionals should report any abnormal development of neonates in the newborn nursery as it can help in early diagnosis of a disease and provide timely intervention. In some cases, the placement of a central venous catheter for exchange transfusion might be indicated. The team responsible for the placement should also be vigilant about the catheter-related complications like displacement of the catheter, infections, etc.
Patients with chronic bilirubin encephalopathy might end up with auditory disabilities, which require speech and hearing rehabilitation.
Malnutrition is a common sight associated with this neurological impairment. Based on the severity of the condition, the ability to eat is affected accordingly. This might necessitate intervention by a dietician and a nutritionist.
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