Introduction

Kernicterus is a condition where neurological or brain damage has occurred due to very high levels of a byproduct called bilirubin.¹ This usually affects very young children, mostly under the age of 2.² High levels of bilirubin in the blood is known as jaundice, which can typically arise in infants after birth. Early detection, monitoring and intervention are important to prevent the bilirubin levels from rising and causing kernicterus. One effective, non-invasive method of detecting and diagnosing kernicterus is through the use of magnetic resonance imaging (MRI). 

What is neonatal jaundice?

Neonatal jaundice is the term used to describe when bilirubin levels in an infant’s blood are high shortly after birth.³ Bilirubin is a byproduct produced normally from the breakdown of red blood cells when they reach the end of their life cycle. It is usually processed by the liver and excreted as waste in stool or urine.⁴ Because of its yellow pigment, when bilirubin levels build up and tints the skin and whites of the eyes (sclera) yellow. This is what is known as jaundice.

Brief overview of bilirubin synthesis 

When dead red blood cells are broken down by white blood cells, the oxygen-carrying protein haemoglobin is broken down into haem groups and globin.⁴ The haem group is then further broken down into a green pigment known as biliverdin, then further broken down into unconjugated bilirubin (UB). In its unconjugated form, bilirubin is insoluble in water and must be bound to a protein called albumin, which transports UB to the liver where it is conjugated by liver cells (hepatocytes). Conjugation in this context is the addition of glucuronic acid to UB, changing its chemical structure and allowing it to be soluble in water and be transported out of the liver, through the gallbladder and into the intestines for excretion. 

Causes of bilirubin increase in the blood 

Essentially, the buildup of bilirubin occurs either due to an increase in red blood cell breakdown (haemolysis) or prevention of clearance out of the body.³ In the case of neonatal jaundice, approximately 75% is termed as physiological jaundice, meaning that it is not caused by an underlying disease. This occurs because red blood cells are larger in newborns and have a shorter lifespan. In addition, the liver is unable to conjugate UB as efficiently as adult livers, resulting in a buildup of UB in the infant’s blood. 

Pathological jaundice, on the other hand, is when an underlying disease is causing the elevation of bilirubin.³ These can include:¹

• Polycythaemia - a condition where the body produces more red blood cells than usual 
• Birth injury - any injury causing internal bleeding or haemorrhaging, resulting in the death of more red blood cells and elevated UB production as a result 
• Haemolysis - diseases that cause the abnormal destruction of red blood cells 
• Hypoalbuminemia - reduced concentration of albumin in the blood. This means fewer UBs can bind to albumin and be transported to the liver to be conjugated and excreted 
• Breast milk jaundice - an enzyme in breast milk known as glucuronidase deconjugates bilirubin back to UB, elevating the levels in the body 

How does unconjugated bilirubin damage the brain?

As mentioned earlier, UB is insoluble in water; however, this means that it is fat-soluble. The blood vessels in the brain are tightly bound together to prevent harmful substances in the blood from entering the brain.⁵ This is known as the blood-brain barrier (BBB). Despite this, fat-soluble substances such as UB can cross the BBB more easily as they can cross the cell membranes of the cells lining the blood vessels. In the case of neonatal jaundice, the unregulated, high concentrations of UB in the blood cross the BBB and enter the brain.¹ They then preferentially enter certain types of neurons in different parts of the brain. High concentrations of UB are toxic to mitochondria, the organelle responsible for producing energy for cell function. As a result, energy production in these neurons is impaired and signals for neuronal cell death, known as apoptosis. If UB levels remain high, over time, more neurons become damaged or die, resulting in kernicterus. 

Clinical features

Early symptoms

• Weakness¹
• Fatigue 
• Poor feeding 
• Reduced muscle tone 
• Neck dystonia

Late symptoms

• Hearing and vision loss¹
• Delayed developmental milestone achievement 
• Increased reflexes
• Choreoathetoid cerebral palsy 

The role of MRI in kernicterus

Essentially, an MRI machine is a giant magnet that spins around the body to force hydrogen atoms in the body to align.⁶ Radio waves are then pulsed to the body and disrupt this alignment. When the radio waves are turned off, the hydrogen atoms realign and send back radio waves, which are detected and interpreted by the computer to produce a highly detailed image of the brain. Unlike computer tomography (CT) scans and X-rays, MRIs do not use ionising radiation, meaning that they do not cause any cellular damage or increase the risk of cancer.⁷ As a result, it is a safe, non-invasive way to look at the brain and any underlying disease, especially in young children.

MRI findings in kernicterus

MRI can be used to diagnose kernicterus through the identification of hypersensitivity of a structure deep in the brain known as the globus pallidus.⁸ Two types of imaging can be used to efficiently capture this hypersensitivity, depending on the phase of kernicterus: 

T1-weighted MRI - to diagnose kernicterus during the acute phase (first few weeks) 

T2-weighted MRI - to diagnose kernicterus during the chronic phase (after many weeks or months) 

The difference between the two imaging types is that T1 shows higher resolution of fatty tissues in the brain, whereas T2 shows higher resolution of water.⁹ Hypersensitivity is seen as an increased brightness of a segment in the brain, which is better identified in the chronic phases.¹⁰ Along with this, there may be some signs of degeneration as the neuronal damage has progressed.

Diagnostic challenges and limitations

The acute and chronic phases can be further subdivided into 4 phases.⁸ Depending on the phase, diagnosis of kernicterus using MRI can be challenging, as certain diagnostic features may appear diminished or vague. 

• Phase 1 - acute phase globus pallidus intensity observed in T1-weighted images 
• Phase 2 - no obvious abnormalities observed in either T1 or T2 weighted images, this is known as the “blind window” 
• Phase 3 - chronic phase, globus pallidus hyperintensity observed in T2-weighted images 
• Phase 4 - hyperintensity of the globus pallidus can only be seen at the border in T2-weighted images 

Summary 

• Kernicterus is neurological brain damage that occurs in infants with uncontrolled bilirubin levels in the blood 
• The high levels of unconjugated bilirubin cross the blood-brain barrier into the brain and damage the mitochondria in the neurons, which eventually causes them to die 
• MRI is a safe and non-invasive method to diagnose the acute and chronic phases of kernicterus 
• However, diagnosis can be difficult or vague depending on the phase of the disease