Kernicterus is a

bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...

-induced

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

when its

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'', ...

in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

is too high, a condition known as hyperbilirubinemia. Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, potentially causing irreversible neurological damage. Depending on the level of exposure, the effects range from clinically unnoticeable to severe

brain damage Brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage. A common ...

and even death. When hyperbilirubinemia increases past a mild level, it leads to jaundice, raising the risk of progressing to kernicterus. When this happens in adults, it is usually because of liver problems. Newborns are especially vulnerable to hyperbilirubinemia-induced neurological damage, because in the earliest days of life, the still-developing

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

is heavily exercised by the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

is not as developed. Mildly elevated serum bilirubin levels are common in newborns, and neonatal jaundice is not unusual, but bilirubin levels must be carefully monitored in case they start to climb, in which case more aggressive

therapy A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications a ...

is needed, usually via light therapy but sometimes even via exchange transfusion.

Classification

Acute bilirubin encephalopathy (ABE)

ABE is an acute state of elevated

in the central nervous system. Clinically, it encompasses a wide range of symptoms. These include lethargy, decreased feeding,

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...

or hypertonia, a high-pitched cry, spasmodic torticollis, opisthotonus, setting sun sign, fever, seizures, and even death. If the bilirubin is not rapidly reduced, ABE quickly progresses to chronic bilirubin encephalopathy.

Chronic bilirubin encephalopathy (CBE)

CBE is a chronic state of severe bilirubin-induced neurological lesions. Reduction of bilirubin in this state will not reverse the sequelae. Clinically, manifestations of CBE include: # movement disorders – dyskinetic CP with often spasticity. 60% have severe motor disability (unable to walk). # auditory dysfunction – auditory neuropathy (ANSD) # visual/oculomotor impairments ( nystagmus,

strabismus Strabismus is an eye disorder in which the eyes do not properly align with each other when looking at an object. The eye that is pointed at an object can alternate. The condition may be present occasionally or constantly. If present during a ...

, impaired upward or downward gaze, and/or cortical visual impairment). In rare cases, decreased visual acuity(blindness) can occur. # dental enamel

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.dysplasia of the

deciduous teeth Deciduous teeth or primary teeth, also informally known as baby teeth, milk teeth, or temporary teeth,Fehrenbach, MJ and Popowics, T. (2026). ''Illustrated Dental Embryology, Histology, and Anatomy'', 6th edition, Elsevier, page 287–296. are ...

, # gastroesophageal reflux, # impaired digestive function. # slightly decreased intellectual function: Although most individuals (approximately 85%) with kernicterus fall in normal or dull-normal range. #

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

is uncommon. These impairments are associated with lesions in the

basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...

, auditory nuclei of the

brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...

, and oculomotor nuclei of the brain stem. Cortex and white matter are subtly involved. Cerebellum may be involved. Severe cortical involvement is uncommon.

Subtle bilirubin encephalopathy (SBE)

SBE is a chronic state of mild bilirubin-induced neurological dysfunction (BIND). Clinically, this may result in neurological, learning and movement disorders, isolated

hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...

and auditory dysfunction. * In the past it was thought that kernicterus (KI) often causes an intellectual disability. This was assumed due to difficulty with hearing which is typically not detected in a normal audiogram, accompanied by impairments of speech with choreoathetosis. With advances in technology this has proven to not be the case, as those living with KI have repeatedly demonstrated their intelligence using Augmentative Communication devices. Although most individuals with kernicteric cerebral palsy have normal intelligence, some children with mild choreoathetosis develop dull normal intelligence or mild intellectual disability even without auditory dysfunction.

Causes

In the vast majority of cases, kernicterus is associated with unconjugated hyperbilirubinemia during the neonatal period. The

is not fully functional in neonates and therefore bilirubin is able to cross into the central nervous system. Moreover, neonates have much higher levels of bilirubin in their blood due to: # Rapid breakdown of fetal red blood cells immediately prior to birth, with subsequent replacement by normal adult human red blood cells. This breakdown of fetal red blood cells releases large amounts of bilirubin. # Severe

hemolytic disease of the newborn Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...

. Many children who survive exhibit permanent mental impairment or damage to motor areas of the brain because of precipitation of bilirubin in neurons. # Neonates have a limited ability to metabolize and excrete bilirubin. The sole pathway for bilirubin elimination is through the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) enzyme, which performs a reaction called "glucuronidation". This reaction adds a large sugar to the bilirubin, which makes the compound more water-soluble, so it can be more readily excreted via the urine and/or the feces. The UGT1A1 enzyme is not active in appreciable amounts until several months after birth. Apparently, this is a developmental compromise since the maternal liver and placenta perform glucuronidation for the fetus. # Administration of

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

to neonates and infants. Aspirin displaces bilirubin from serum albumin, thus generating an increased level of free bilirubin which can cross the developing blood brain barrier. This can be life-threatening. Bilirubin is known to accumulate in the gray matter of neurological tissue where it exerts direct neurotoxic effects. It appears that its neurotoxicity is due to mass-destruction of neurons by apoptosis and necrosis.

Risk factors

Premature birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...

* Rh incompatibility *

Polycythemia Polycythemia (also known as polycythaemia) is a laboratory finding in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythr ...

– often present in neonates *

Sulfonamides In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the Chemical structure, structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this gro ...

(e.g. co-trimoxazole) – displaces bilirubin from serum albumin * Crigler–Najjar syndrome, type I * G6PD deficiency * Bruising Gilbert's syndrome and G6PD deficiency occurring together especially increases the risk for kernicterus.

Diagnosis

Naturally all neonates are prone to jaundice development due to immaturity of the liver that cannot filter the vast amount of fetal hemoglobin that is rapidly changing to Adult hemoglobin. Therefore it is recommended to assess all newborns for jaundice. Kernicterus presents as jaundice and neurological symptoms such as Cerebral paresis, gaze palsy and hearing loss. Bilirubin tests needs to be done on Newborns as Indirect bilirubin level above 25mg/dl, is diagnostic for Kernicterus. If Newborn's Rh is differ from mothers Rh then there is Rh incompatibility, which increases the risk of developing Kernicterus.

Prevention

Measuring the serum bilirubin is helpful in evaluating a baby's risk for developing kernicterus. These numbers can then be plotted on the Bhutani nomogram. In neonates with hyperbilirubinemia, light therapy may be effective in reducing the serum bilirubin level. More severe cases may require the use of exchange transfusion.

Treatment

Currently, no effective treatment exists for kernicterus. Future therapies may include neuroregeneration. A handful of patients have undergone deep brain stimulation and experienced some benefit. Drugs such as baclofen, clonazepam, gabapentin, and artane are often used to manage movement disorders associated with kernicterus.

Proton pump inhibitors Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of gastric acid, stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase, H+/K+ ATPase proton pump. The body ...

are also used to help with reflux. Cochlear implants and hearing aids have also been known to improve the hearing loss that can come with kernicterus (auditory neuropathy – ANSD).

References

External links

{{Certain conditions originating in the perinatal period Neurological disorders Haemorrhagic and haematological disorders of fetus and newborn Cerebral palsy and other paralytic syndromes Neonatology Rare diseases