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In some cases, symptoms and physical findings of kernicterus appear two to five days after birth. Within the first few days of life, affected infants develop abnormally high levels of bilirubin in the blood (hyperbilirubinemia) and persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Toxic levels of bilirubin may accumulate in certain areas of the brain (i.e., the basal ganglia and the brainstem), potentially resulting in a variety of symptoms and physical findings that, in some cases, may cause life-threatening complications.

Initial findings associated with kernicterus may vary from case to case, but often include lack of energy (lethargy) or drowsiness, poor feeding habits, fever, a shrill high-pitched cry, and/or absence of certain reflexes (e.g., Moro reflex, etc.). Affected infants may eventually experience respiratory distress, mild to severe muscle spasms including those in which the head and heels are bent backward and the body bows forward (opisthotonus), and/or diminished muscle tone (hypotonia).

As an affected infants ages, other symptoms and physical findings may develop including delayed and/or abnormal motions or motor development; convulsions or seizures; impaired ability to coordinate voluntary movements (ataxia); abnormal muscle rigidity resulting in muscle spasms (dystonia); slow, continuous, involuntary, writhing movements (athetosis) of the arms and legs (limbs) and/or entire body; problems with sensory perception; lack of upward gaze; and/or hearing loss. In some cases, affected infants may exhibit mental retardation and difficulty speaking (dysarthria). In most cases, the syndrome characteristic of kernicterus develops by three to four years of age.

Some cases of kernicterus occur randomly, for no apparent reason (sporadically). According to the medical literature, excess levels of bilirubin (hyperbilirubinemia) alone is not sufficient to produce kernicterus. Potential causes may include Rh disease and/or unknown factors.

Rh Disease, also known as isoimmunization or Erythroblastosis Fetalis, can also cause jaundice during infancy that may lead to kernicterus. In Rh Disease, red blood cells from the fetus may cross the placenta and enter into the mother's bloodstream. This stimulates maternal antibody formation against these "foreign" blood cells. These antibodies eventually reach the fetus via the placenta and cause destruction of fetal red blood cells (hemolysis), resulting in low levels of circulating red blood cells (anemia) in the fetus. In response, the fetal bone marrow releases immature red blood cells (erythroblasts) into the fetal bloodstream. The hemoglobin from the destroyed red blood cells is broken down into bilirubin, a yellow-orange bile pigment. Bilirubin is cleared from the fetal bloodstream by crossing the placenta into the mother's bloodstream. However, after birth abnormally high levels of bilirubin (hyperbilirubinemia) may accumulate in the newborn's bloodstream and brain. This disease is now almost non-existent due to the availability of anti-Rh globulin, which prevents isoimmunization. (For more information on this disorder, choose "Rh Disease" as your search term in the Rare Disease Database.)

In some rare cases, kernicterus may result from a rare disorder known as Crigler-Najjar Syndrome Type I. (For more information on this disorder, choose "Crigler Najjar" as your search term in the Rare Disease Database.)

Kernicterus is a rare neurological disorder that affects newborn infants of both sexes in equal numbers. Kernicterus occurs more often in premature infants than full-term infants.

Diagnosis
Kernicterus may be suspected within the first days of life. The diagnosis may be based upon a thorough clinical evaluation and identification of characteristic physical findings (e.g., jaundice, abnormal cry, loss of Moro reflex, etc.). In most cases, persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice) is apparent within the first few days of life.

Treatment
Treatment for Kernicterus focuses on decreasing the amount of unconjugated bilirubin in the blood. Early treatment is imperative in the attempt to prevent the symptoms and physical findings associated with kernicterus durint the first months of life. Such treatments may include exchange blood transfusions in which small amounts of blood are withdrawn repeatedly and replaced with blood from a donor until most of the blood has been exchanged. In another procedure known as plasmapheresis, unwanted substances (toxins, metabolic substances and plasma parts) are removed from the blood. During this procedure, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individual.

In addition, phototherapy is used for disease management purposes. During this procedure, intense fluorescent light is focused on the bare skin, while the eyes are shielded. This helps to speed up the excretion of bilirubin from the skin and aids in its decomposition. As an affected individual ages, body mass increases and the skin thickens; phototherapy becomes less effective against preventing the symptoms and physical findings associated with kernicterus. Therefore, liver transplantation may be performed. Some researchers believe that liver transplantation should be performed at an early age, before brain damage potentially associated with kernicterus can develop.

Other treatment is symptomatic and supportive.

Research has been conducted as to whether limiting bilirubin production with the use of inhibitors, such as tin-protoporphyrin, may be beneficial in treating infants with kernicterus. More studies are needed to determine the effectiveness and possible side effects of the use of such inhibitors for the treatment this disorder.

The National Institute of Child Health and Human Development (NICHD), in cooperation with investigators at the Rockefeller University, is sponsoring a phase II clinical trial designed to test the effectiveness and safety of administering tin mesoporphyrin to newborns at high risk for hyperbilirubinemia and kernicterus.

For information, contact:

Atallah Kappas, MD
Rockefeller University Hospital
York Avenue
New York, NY 10021-6399
Tel: 212-327-8494

or

Timos Vales, MD
New England Medical Center Hospital
Harrison Avenue
Boston, MA 02111
Tel: 617-636-5322

ID Numbers for this study: 199/12021; RUH-0330795A

The drug being tested bears the trade name of Stanate and has been licensed to InfaCare Pharmaceutical Corp. of Carlsbad, CA. Inquiries may be addressed to:

Ms. Patricia Naffin
WellSpring Pharmaceutical Corp.
1430 State Highway 34
Neptune, NJ 07753-6807
Tel: 732-938-5885
Fax: 732-751-9328

In 1985, the Food and Drug Administration (FDA) designated flumecinol (Zixoryn) manufactured by Farmacon, Inc., of Westport, CT, as an orphan drug for newborn infants with hyperbilirubinemia unresponsive to phototherapy (1985). The results of clinical trials were disappointing and the trials have stopped.

TEXTBOOKS
Behrman RE., ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:496-98.

Menkes JH., au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:611-3.

Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:1026.

JOURNAL ARTICLES
Hansen T, Kernicterus: an international perspective. Semin Neonatol. 2002;7:103.

Bertini G, et al., Prevention of bilirubin encephalopathy. Biol Neonate. 2001;79:219-23.

Ozcelik T, et al., Audiological findings in kernicteric patients. Acta Otorhinolaryngol Belg. 1997;51:31-4.

Maisels MJ, et al., Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics. 1995;96:730-3.

Yokochi K, Magnetic resonance imaging in children with kernicterus. Acta Paediatr. 1995;84:937-9.

Watchko JF, et al., Kernicterus in preterm newborns: past, present, and future. Pediatrics. 1992;90:707-15.