Continuing Education Activity

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. This activity reviews the evaluation and management of kernicterus and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Identify the etiology of kernicterus.
• Outline the components of the evaluation of kernicterus.
• Summarize the management options available for kernicterus.
• Identify interprofessional team strategies for improving care coordination and outcomes in neonates with kernicterus.

Introduction

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.[1]

Etiology

Unconjugated hyperbilirubinemia can result from increased production or decreased excretion of bilirubin.

The causes of increased production of unconjugated bilirubin are:

1. Polycythemia - increased number of red blood cells leads to an increase in their turnover.[2]
2. Hemolysis - varied causes such as erythroblastosis fetalis, hemolytic disease of the newborn, and abnormalities of the red cell itself such as hereditary spherocytosis, elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency; and hemoglobinopathies, such as alpha and beta thalassemias.[3]
3. Birth Injuries - cephalohematoma, subgaleal hemorrhage, or peripheral ecchymoses from birth trauma.[4]

The causes of decreased excretion are:

1. Hypoalbuminemia - as the unconjugated bilirubin is lipid-soluble, it is normally bound to albumin; a decrease in the albumin level leads to an increase in free unconjugated bilirubin level.[5]
2. Hereditary Bilirubin Conjugation Defects - Crigler-Najjar syndrome and Gilbert syndrome are due to the deficiency of the enzyme uridine 5'-diphospho-glucuronosyltransferase (UDGPT), which conjugates the bilirubin in the liver cells.[6]
3. Disruption or Obstruction in the Biliary System
4. Breast Milk Jaundice - glucuronidase enzyme in the breast milk deconjugates bilirubin into unconjugated bilirubin.[7]

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.[8]

Epidemiology

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.[9]  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.[10] Kernicterus also occurs in infants with bilirubin levels less than 25 mg/dL, but the population risk of this occurrence is unknown.[11]

Pathophysiology

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.[6]

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.[12]

History and Physical

History

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.[13] 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.

Family History

It is essential to ask about any family history of anemia 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.[14] 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.[3] 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.

Birth History

This should be assessed to rule out any injuries leading to cephalhematoma, subgaleal hemorrhage, or any bleeding manifestations which can cause hyperbilirubinemia.[4]

Postnatal History

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.

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.

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.

Evaluation

The diagnosis and management of kernicterus are based on the following investigations:

Hematologic Studies - most important parameter

• Total and direct bilirubin - indirect bilirubin (bound bilirubin, free bilirubin, and lumirubin in patients receiving phototherapy).[16] Their serial measurements help in keeping track of the disease course.
• Blood type (mother and infant) and Coomb test - helps in the assessment of Rh incompatibility and its treatment with Rho(D) immune globulin to prevent erythroblastosis fetalis (the most fulminant type of hemolytic hyperbilirubinemia).[17]
• Reticulocyte count - can help in the assessment of ongoing hemolysis, anemia, and hematopoiesis. A peripheral blood smear can also help in providing clues to the cause of hemolysis.
• Complete blood count - part of all routine investigations and crucial in ruling out sepsis.
• Serum electrolytes - assessment of serum electrolytes (Na+, K+, Cl-, HCO3-, blood urea nitrogen, and creatinine) is important as they may provide a clue to the cause of the patient's symptoms. An increase in the potassium level may indicate hemolysis; a decreased or increased sodium level by itself can lead to altered mental status changes; alteration in the bicarbonate level may reveal any acidemia or alkalemia.
• Others - additional tests like a lumbar puncture and chest x-ray to rule out sepsis, and transcutaneous bilirubin measurement is helpful in a few cases. If the above results are inconclusive, it might be necessary to check the ammonia levels, lactate levels, heavy metal levels (lead, chromium, nickel, etc.), and serum acetaminophen levels.

Imaging Studies

• 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 impairment.[18]

Treatment / Management

 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:

1. Exchange Transfusion Therapy - the emergent and definitive way to remove the already formed bilirubin from the blood. The method requires extracting the infant's native blood (mainly the plasma) and replacing it with citrate phosphate dextrose (CPD) banked blood that does not contain bilirubin. It is indicated when the signs of acute bilirubin encephalopathy are present, and when serum levels of bilirubin are high despite the attempts to reduce it. Serum bilirubin levels greater than 20-25 mg/dL are usually treated with an exchange transfusion.[19] An ABO-matched and Rh-negative erythrocyte concentrate should be used. Blood product transfusion might carry the risk of contracting infections like hepatitis C, though drastically reduced since the introduction of routine screening. Aberrations, such as hypoglycemia, thrombocytopenia, hyperkalemia (particularly if the banked blood is more than five days old), and hypocalcemia (because of the presence of EDTA in the transfusion products) should be monitored.[20]
2. 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. The infant's eyes should be protected during the procedure as it can damage the retina irreversibly.[21] Oral calcium phosphate, along with phototherapy, may be considered in patients with Crigler-Najjar syndrome type 1. The provider should also keep in mind the adverse effects of phototherapy like the inability to regulate body temperature, tanning, and dehydration. Phototherapy should be initiated when the total serum bilirubin level is:

   • Equal or more than 15 mg/dL in infants 25-48 hours old
   • Equal or more than 18 mg/dL in infants 49-72 hours old
   • Equal or more than 20 mg/dL in infants older than 72 hours[22]
3. 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.[23]

Fluid supplementation in term children presenting with severe hyperbilirubinemia reduces the rate of exchange transfusion and duration of phototherapy.[24]

Differential Diagnosis

Neonatal jaundice contains a wide spectrum of causes.[25] 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:

• Cerebral palsy
• Head trauma
• Neonatal sepsis
• Congenital TORCH infections
• Hypoxic-ischemic brain injury in the newborn
• Fetal alcohol syndrome
• Cretinism/pediatric hypothyroidism

Pertinent Studies and Ongoing Trials

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 less than 0.05 in the difference of the transcutaneous bilirubin levels in the prebiotic group compared to the control group.[26]

Beta-glucuronidase enzyme inhibition by L-aspartic acid and enzymatically-hydrolyzed casein has been shown to reduce enterohepatic circulation in constipated babies.[27]

Sn-mesoporphyrin is an inhibitor of the 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).[28]

Therapies based on gene and cell transfer techniques, although experimental at present, might play an important role in the management of hereditary and metabolic syndromes.[29][30]

Prognosis

The prognosis of kernicterus depends on the severity of the 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.[15][31][32] Kernicterus causes 15% of neonatal deaths in low-middle-income countries.

Complications

 Complications of kernicterus include:

• Hearing loss - most common abnormality[15]
• Extrapyramidal symptoms like athetosis and chorea[31]
• Visual abnormalities including gaze palsies[15]
• Abnormalities in dentition[32]

Deterrence and Patient Education

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.[19] A medical check-up is recommended in all infants discharged within 48 to 72 hours of birth.[19] 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.[33] They should be educated to seek medical attention when any warning signs like decreased activity, altered mental status, and poor suckling reflex are present.

Pearls and Other Issues

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.[34] 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.[13] 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.

Enhancing Healthcare Team Outcomes

Nursing Care

Nursing professionals should report any abnormal development of neonates in the newborn nursery as it can help in the 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 catheter-related complications like displacement of the catheter, infections, etc.

Paraclinical Care

Patients with chronic bilirubin encephalopathy might end up with auditory disabilities, which require speech and hearing rehabilitation.

Diet

Malnutrition is a common sight associated with this neurological impairment.[35] 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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Disclosure: Dinesh Reddy declares no relevant financial relationships with ineligible companies.

Disclosure: Shivlal Pandey declares no relevant financial relationships with ineligible companies.