Overview

Kernicterus refers to the pathological finding of yellow staining in the deep nuclei of the brain. Specific structures of the brain, such as the globus pallidus and the subthalamic nucleus, are affected.¹ The yellowing of the brain nuclei occurs due to bilirubin exposure. Under normal circumstances, bilirubin is conjugated by binding to a substance called glucuronic acid to make it non-toxic and expelled from the body. When there is excess bilirubin due lack of enzymes responsible for this binding or due to other causes, a person will have high unconjugated bilirubin in the bloodstream, which can cross the blood-brain barrier and cause damage to the brain. This damage, which is a result of high unconjugated bilirubin, is what we call kernicterus. Also, a substance called albumin binds to bilirubin to reduce the circulation of free bilirubin in the bloodstream. When there is too much free bilirubin in the blood, which crosses the blood-brain barrier, kernicterus can occur.

How bilirubin damages the brain

Bilirubin damage to the brain is a selective bilirubin toxicity (that is, its ability to damage specific regions of the brain and not others). The clinical manifestations of classic kernicterus correspond to the selective neuropathology of kernicterus.

The lesion to the basal ganglia, specifically the globus pallidus and the subthalamic nucleus, cerebellum and brainstem nuclei, corresponds to movement disorders seen in kernicterus. Such disorders include dystonia, athetosis and sometimes spasticity.²

The hearing loss and deafness seen in kernicterus are associated with damage to the auditory brainstem nuclei. The vision defect observed in kernicterus corresponds to a lesion in the brainstem ocular nuclei.²

In studies of human autopsies, certain brain areas were more affected by kernicterus. These include the outer and inner parts of the globus pallidus (GPe and GPi), the substantia nigra, the subthalamic nucleus (STN), and sometimes parts of the brainstem involved in hearing and eye movement, the hippocampus, and the cerebellum. Interestingly, the striatum and thalamus were usually not damaged. In most cases, the GPe and GPi showed a moderate to severe loss of nerve cells, damage to the protective covering of nerves (demyelination), and increased support cell activity (gliosis).

Risk factors for kernicterus development

High total serum bilirubin has been linked with the development of kernicterus. This is because the higher the total serum bilirubin, the more we have unconjugated bilirubin. Free bilirubin is available to permeate membranes, including brain cells, and cause neuronal injury. Some conditions that can lead to kernicterus.

Prematurity: In preterm babies, immaturity of their brain cells increases susceptibility to neuronal damage even at lower bilirubin levels. One reason premature babies are more sensitive to bilirubin is that their brain cells are not fully developed enough to process it properly. Also, they have lower levels of a protein called P-glycoprotein (also known as MRP1). This protein is like a pump in the blood-brain barrier that helps push out bilirubin from the brain and keep its levels low, only about 1–2% of what’s in the blood. This pump uses energy to work and has a strong attraction to bilirubin, about 10 times stronger than to other substances like leukotrienes. There is less of this pump in parts of the brain that handle hearing, which might explain why those areas are more likely to be damaged by too much bilirubin.³

Hemolysis: It increases the risk of kernicterus mainly due to a rapid increase in bilirubin production, most notably in the context of delayed treatment. When red blood cells break down too quickly, the level of bilirubin in the blood can rise faster than the body can process or change it after it enters the skin. This can lead to damage to brain cells. As bilirubin levels go up, more of it stays unbound (not attached to albumin), because albumin can only hold so much, like a sponge that gets full. This unbound, or free bilirubin, can more easily enter the brain, which increases the risk of kernicterus.³

Sepsis: Sepsis increases the risk of kernicterus by increasing blood-brain barrier permeability and decreasing the albumin binding capacity.³

Other factors: Hypercarbia increases brain blood flow with resultant increase in entry of bilirubin into the brain. Hyperosmolality (as seen in hyperglycemia, hypernatremia and azotemia), hypoxia and asphyxia affect the integrity of the blood-brain barrier, leading to prolonged exposure of the brain to bilirubin.³

Clinical features and diagnosis of kernicterus

The clinical symptoms observed in kernicterus can occur in stages. In the early stage, there is a decrease in alertness of the child, poor feeding, hypotonia and a weak Moro reflex. In the second stage, there is observed irritability, hypertonia, opisthotonos, a high-pitched cry and retrocollis. In the third stage, there is hypotonia, fever, sun-setting eyes, inability to feed, hearing impairment, apnea, and even coma.³

When diagnosing kernicterus, a history of hyperbilirubinemia needs to be taken into account; hence, taking note of the risk factors that might have led to high bilirubin levels in the bloodstream. Examination is done to note the clinical symptoms of kernicterus. Neuroimaging can be done to properly ascertain the damage that might have occurred to the brain tissues.

Brain imaging findings of kernicterus

Magnetic Resonance Imaging (MRI) is used to ascertain the damage done to the brain tissues in kernicterus. MRIs show changes in a part of the brain called the globus pallidus (GP) and also in the subthalamic nucleus (STN). Even though changes in the STN are not seen often, this might be because it’s harder to see clearly on regular MRI scans.⁴

In brain autopsies, problems have also been found in the hippocampus, putamen, thalamus, certain eye and ear nerve centres (cranial nerves III, IV, VI, and VIII), the dentate nuclei, and the cerebellar flocculi. Some of these are too small to show up on an MRI. Others, like damage in the putamen, may have come from lack of oxygen (hypoxic injury), because these babies lived before breathing machines (respirators) were widely used for newborns with lung problems.⁴

Developmental outcomes of children with kernicterus

Dystonia and athetosis: Children with kernicterus may walk with abnormal gait with or without a walker, and can feed themselves. In severe cases, they are not able to walk or feed themselves. Some may lose the ability to speak.¹

Dystonia means the muscles tighten too much and for too long, even muscles that usually work against each other. At first, this mostly happens when the person tries to move and only affects the muscles they are using. As it gets worse, the tight muscles don’t stop, even in muscles the person is not trying to use. These are called “overflow contractions.” In bad cases, the muscle cramps can be very painful. In the worst cases, the pain is only helped by a strong medicine called intrathecal baclofen, which goes directly into the spine.

There can be problems with swallowing, sucking, and gastrointestinal motility.

Auditory impairment: They often have hearing loss due to the effect on the auditory neurons.¹

Oculomotor pareses: So, oculomotor pareses happen when the third cranial nerve isn’t working properly, leading to symptoms like: drooping eyelid (ptosis), eye turning outward and downward, difficulty moving the eye in certain directions, double vision (diplopia), pupil problems (like being enlarged or not reacting to light).¹

Dental enamel dysplasia of the deciduous teeth: This is a condition where the enamel, the outer protective layer of the teeth, does not develop properly. This can lead to teeth that are thinner than normal, pitted, grooved, or have discoloured spots. 

Sleep disorders: The globus pallidus plays a role in controlling sleep and wakefulness. Therefore, children with kernicterus are noticed to have frequent nighttime awakenings and difficulty in maintaining sleep.⁵

Failure to thrive: This occurs because of trouble speaking and swallowing properly, along with the body needing more energy due to muscle problems (dystonia).

Seizures: Seizures can happen during the early stage of brain damage from high bilirubin, but they usually stop once that stage is over, and the brain wave test, electroencephalogram (EEG) looks normal again.¹

Summary

Kernicterus is brain damage caused by very high levels of unconjugated bilirubin in a baby’s blood. When too much free bilirubin crosses into the brain, it harms specific areas like the globus pallidus, leading to problems such as movement disorders, hearing loss, eye movement issues, and poor feeding. Premature birth, infections, and fast red blood cell breakdown increase the risk. Signs appear in stages, starting with poor feeding and sleepiness, then stiff muscles and high-pitched cries, and later, vision, hearing, and brain function problems. Early diagnosis and treatment are crucial to prevent lasting damage.