Holoprosencephaly

Definition

Congenital brain defects are a group of disorders of brain development.

Description

Brain development begins shortly after conception and continues throughout the growth of a fetus. A complex genetic program coordinates the formation, growth, and migration of billions of neurons, or nerve cells, and their development into discrete, interacting brain regions. Interruption of this program, especially early in development, can cause structural defects in the brain. In addition, normal brain formation requires proper development of the surrounding skull, and skull defects may lead to brain malformation. Congenital brain defects may be caused by inherited genetic defects, spontaneous mutations within the genes of the embryo, or effects on the embryo due to the mother's infection, trauma, or drug use.

Early on in development, a flat strip of tissue along the back of the fetus rolls up to form a tube. This so-called "neural tube" develops into the spinal cord, and at one end, the brain. Closure of the tube is required for subsequent development of the tissue within. Anencephaly (literally "without brain"), results when the topmost portion of the tube fails to close. Anencephaly is the most common severe malformation seen in stillborn births. It is about four times more common in females than males. Anencephaly is sometimes seen to run in families, and for parents who have conceived one anencephalic fetus, the risk of a second is as high as 5%. Fewer than half of babies with anencephaly are born alive, and survival beyond the first month is rare.

Encephalocele is a protrusion of part of the brain through a defect in the skull. The most common site for encephalocele is along the front-to-back midline of the skull, usually at the rear, although frontal encephaloceles are more common among Asians. Pressure within the skull pushes out cranial tissue. The protective layer over the brain, the meninges, grows to cover the protrusion, as does skin in some cases. Defects in skull closure are thought to cause some cases of encephalocele, while defects in neural tube closure may cause others. Encephaloceles may be small and contain little or no brain tissue, or may be quite large and contain a significant fraction of the brain.

Failure of neural-tube closure below the level of the brain prevents full development of the surrounding vertebral bones and leads to spina bifida, or a divided spinal column. Incomplete closure causes protrusion of the spinal cord and meninges, called meningomyelocele. Some cases of spina bifida are accompanied by another defect at the base of the brain, known as the Arnold-Chiari malformation or Chiari II malformation. Part of the cerebellum is displaced downward into the spinal column, for reasons that are unclear. Symptoms may be present at birth or delayed until early childhood.

The Dandy-Walker malformation is marked by incomplete formation, or absence of, the central section of the cerebellum, and the growth of cysts within the lowest of the brain's ventricles. The ventricles are fluid-filled cavities within the brain, through which cerebrospinal fluid (CSF) normally circulates. The cysts may block the exit of the fluid, causing hydrocephalus. Symptoms may be present at birth or delayed until early childhood.

Soon after closure of the neural tube, the brain divides into two halves, or hemispheres. Failure of division is termed holoprosencephaly (literally "whole forebrain"). Holoprosencephaly is almost always accompanied by facial and cranial deformities along the midline, including cleft lip, cleft palate, fused eye sockets and a single eye (cyclopia), and deformities of the limbs, heart, gastrointestinal tract, and other internal organs. Most infants are either stillborn or die soon after birth. Survivors suffer from severe neurological impairments.

The normal ridges and valleys of the mature brain are formed after cells from the inside of the developing brain migrate to the outside and multiply. When these cells fail to migrate, the surface remains smooth, a condition called lissencephaly ("smooth brain"). Lissencephaly is often associated with facial abnormalities including a small jaw, a high forehead, a short nose, and low-set ears.

If damaged during growth, especially within the first 20 weeks, brain tissue may stop growing, while tissue around it continues to form. This causes an abnormal cleft or groove to appear on the surface of the brain, called schizencephaly (literally "split brain"). This cleft should not be confused with the normal wrinkled brain surface, nor should the name be mistaken for schizophrenia, a mental disorder. Generalized destruction of tissue or lack of brain development may lead to hydranencephaly, in which cerebrospinal fluid fills much of the space normally occupied by the brain. Hydranencephaly is distinct from hydrocephalus, in which CSF accumulates within a normally-formed brain, putting pressure on it and possibly causing skull expansion.

Excessive brain size is termed megalencephaly (literally "big brain"). Megalencephaly is defined as any brain size above the 98th percentile within the population. Some cases are familial, and may be entirely benign. Others are due to metabolic or neurologic disease. The opposite condition, microcephaly, may be caused by failure of the brain to develop, or by intrauterine infection, drug toxicity, or brain trauma.

Causes & symptoms

Causes

Congenital brain defects may have genetic, infectious, toxic, or traumatic causes. In most cases, no certain cause can be identified.

Some brain defects are caused by trisomy, the inclusion of a third copy of a chromosome normally occurring in pairs. Most trisomies occur because of improper division of the chromosomes during formation of eggs or sperm. Trisomy of chromosome 9 can cause some cases of Dandy-Walker and Chiari II malformation. Some cases of holoprosencephaly are caused by trisomy of chromosome 13, while others are due to abnormalities in chromosomes 7 or 18. Individual gene defects, either inherited or spontaneous, are responsible for other cases of congenital brain malformations.

Drugs known to cause congenital brain defects when used by the mother during critical developmental periods include:

• Anticonvulsant drugs
• Retinoic acid and tretinoin
• Warfarin
• Alcohol
• Cocaine.

Other causes of congenital brain defects include:

• Intrauterine infections, including cytomegalovirus, rubella, herpes simplex, and varicella zoster
• Maternal diabetes mellitus
• Maternal phenylketonuria
• Fetal trauma.

Symptoms

Besides the features listed above, symptoms of congenital brain defects may include:

• Chiari II malformation: impaired swallowing and gag reflex, loss of the breathing reflex, facial paralysis, uncontrolled eye movements (nystagmus), impaired balance and gait.
• Dandy-Walker malformation: symptoms of hydrocephalus, lack of muscle tone or "floppiness," seizures, spasticity, deafness, irritability, visual impairment, deterioration of consciousness, paralysis.
• Lissencephaly: lack of muscle tone, seizures, developmental delay, spasticity, cerebral palsy.
• Hydranencephaly: irritability, spasticity, seizures, temperature oscillations.
• Megalencephaly due to neurological or metabolic disease: mental retardation, seizures.

Diagnosis

Congenital brain defects are diagnosed either from direct physical examination or imaging studies including computed tomography scans (CT) andmagnetic resonance imaging (MRI) scans. Electroencephalography (EEG) may be used to reveal characteristic abnormalities.

Prenatal diagnosis of neural tube defects causing anencephaly or meningomyelocele is possible through ultrasound examination and maternal blood testing for alpha-fetoprotein, which is almost always elevated. Ultrasound can also be used to diagnose Dandy-Walker and Chiari II malformations. Amniocentesis may reveal trisomies or other chromosomal abnormalities.

Treatment

Meningomyelocele may be treated with surgery to close the open portion of the spinal cord. Surgery for encephalocele is possible only if there is a minimal amount of brain tissue protruding. Malformations associated with hydrocephalus (Dandy-Walker, Chiari II, and some cases of hydranencephaly) may be treated by installation of a drainage shunt for cerebrospinal fluid. Drugs may be used to treat some symptoms of brain defects, including seizures and spasticity.

Prognosis

Most congenital brain defects carry a very poor prognosis. Surgical treatment of meningomyelocele and encephalocele may be successful, with lasting neurological deficiencies, which vary in severity. Early treatment of hydrocephalus may prevent more severe brain damage.

Prevention

Some cases of congenital brain defects can be prevented with good maternal nutrition, including folic acid supplements. Folic acid is a vitamin which has been shown to reduce the incidence of neural tube defects. Pregnant women should avoid exposure to infection, especially during the first trimester. Abstention from drugs and alcohol during pregnancy may reduce risk. Genetic counseling is advisable for parents who have had one child with anencephaly, since the likelihood of having another is increased.

Key Terms

Amniocentesis

Removal of fluid from the sac surrounding a fetus for purposes of diagnosis.

Cerebrospinal fluid

Fluid produced within the brain for nutrient transport and structural purposes. CSF circulates through the ventricles, open spaces within the brain, and drains through the membranes surrounding the brain.

Congenital

Defect present at birth.

Fetus

The unborn human, developing in a woman's uterus, from the eighth week after fertilization to birth.

Further Reading

For Your Information

Books

• Bradley, et al. Neurology in Clinical Practice, 2nd ed. Butterworth-Heinemann, 1996.
• Fenichel, G.M. Clinical Pediatric Neurology, 3rd ed. W.B. Saunders, 1997.
• Norman, M.G., et al. Congenital Malformations of the Brain. Oxford University Press, 1995.

Gale Encyclopedia of Medicine. Gale Research, 1999.