Anencephaly

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayesha Javid, MBBS[2]

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Anencephaly
The side view of the head of an anencephalic fetus
ICD-10	Q00.0
ICD-9	740.0
OMIM	206500
DiseasesDB	705
MeSH	C10.500.680.196

Overview

Anencephaly is a cephalic disorder that results from a neural tube defect that occurs when the cephalic (head) end of the neural tube fails to close, usually between the 23rd and 26th day of pregnancy, resulting in the absence of a major portion of the brain, skull, and scalp. Children with this disorder are born without a forebrain, the largest part of the brain consisting mainly of the cerebral hemispheres (which include the isocortex, which is responsible for higher level cognition, i.e., thinking). The remaining brain tissue is often exposed - not covered by bone or skin.

Historical Perspective

• Anencephaly was first recognized in the 16th century. In 1989, Aubrey Milunsky and his colleagues observed a reduction in the cases of neural tube defects in the mothers who took folic acid supplements during pregnancy.
• In 1992, Thresa was born with anencephaly. Her parents knew their daughter is going to die. So, they requested if her organs could be used for transplantation. This initiated a debate on anencephalic infant organ donation.

Classification

Type of Anencephaly	Clinical features
Meroanencephaly	Meroanencephaly is a rare form of anencephaly. Clinical features include malformed cranial bones with a median cranial defect. The fetus also has a cranial protrusion called cerebrovasculosa. It is a spongy vascular tissue mixed with the glial tissue.
Holoanencephaly	It is the most common type of anencephaly. In this condition, the entire fetus brain fails to develop except for the brain stem. Usually, infant survives for only one day after birth.
Craniorachischisis	It is the most severe type of anencephaly. Along with the cranial defect, fetus also has a defect in the vertebral column exposing the underlying neural tissue. Area cerebrovasculosa and area medullovasculosa fill the areas with cranial and spinal defects

Embryology

By the 3rd week of gestation, the embryo has 3 layers, from outer to inner these layers are ectoderm, mesoderm and endoderm. Notochord in the mesoderm sends signal molecule called Sonic Hedgehog protein to the overlying ectoderm forming it a neuroectoderm. Neuroectoderm becomes a neural plate. The neural plate folds and closes to form a tube-like structure called neural tube. It also forms neural crest cells. The neural tube then goes on to form structures of the adult brain.

Pathogenesis

A neural tube defect occurs if the neuropore, opening of the neural tube, fails to close in week 4 of gestation. There are two neuropores, rostral and caudial. Anencephaly results from failure of the rostral neuropore to close anteriorly around day 25.(book reference). The craniofacial abnormalities in anencephaly are caused by abnormal induction by the neural crest cells.

Etiology and Risk factors

Folate deficiency

• Studies show that most of the neural tube defects are caused by folic acid deficiency.
• This inadequate folate could be due to less oral intake, decreased intestinal absorption, or due to abnormal folate metabolism due to gene mutation. Some drugs antagonize the effect of folic acid resulting in folic acid deficiency and hence NTD. Most important ones are anti-epileptic drugs such as valproic acid and carbamazepine. Also, methotrexate, which is an antineoplastic drug also used for the treatment of ectopic pregnancy, has been linked with increased risk of NTD.

Genetics

Neural tube defects do not follow direct patterns of heredity, though there is some indirect evidence of inheritance

, and recent animal models indicating a possible association with deficiencies of the transcription factor TEAD2.

The motivation behind studying the genetic patterns is following:

1. NTDs are consistently prevalent among monozygotic twins as compared to dizygotic twins.
2. There is a high recurrence rate within families. Statistics show the recurrence risk of 1/20 if one previous pregnancy is affected and 1/10 if two pregnancies are affected in a family.
3. Due to predilection towards female fetuses as compared to male.

Syndromes

• Anencephaly is associated with:
  • Trisomy 13 or Trisomy 18
  • Meckel-Gruber syndrome
  • Roberts syndrome
  • Jarcho-Levin syndrome
  • HARD (hydrocephalus, agyria and retinal dysplasia)
  • OEIS complex (omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects)
  • Limb-body wall complex (LBWC)

Fever/hyperthermia

• If pregnant mother’s core body temperature elevates from baseline it could lead to congenital anomalies such neural tube defects, including anencephaly.
• The risk is more profound if this happens during the first trimester as this is the time during which organogenesis takes place. The National Birth Defects Prevention Study (NBDPS) infers that the risk of birth defects due to maternal infection-related fever can be reduced by the usage of acetaminophen.

Amniotic bands

• If a pregnant mother develops amniotic bands, it could effect the normal development and growth of the central nervous system. It could result in neural tube defects including anencephaly

Pregestational diabetes

• If a woman has uncontrolled diabetes mellitus before conception, it could result in neural tube defects including anencephaly.
• Therefore, close monitoring of periconceptional glycemic level is essential to prevent neural tube defects and other congenital anomalies.

Maternal Obesity

• Obesity doubles the risk of neural tube defects. Also, it provides a limitation to fetal imaging.
• Folic acid supplementation does not decrease this risk of NTD, therefore it is mandatory to control weight before conceiving.

Toxins

• Anencephaly and other physical and mental deformities have also been blamed on high exposure to such toxins as lead, chromium, mercury, and nickel.

Differentiating Anencephalopathy from other Disorders

There are many false diagnoses for anencephaly, as it is not a common diagnosis, often confused with exencephaly or microcephaly.

Epidemiology and Demographics

Incidence

In the United States, approximately 1,000 to 2,000 babies are born with anencephaly each year. In 2001, the National Center for Health Statistics reported 9.4 cases among 100,000 live births.

Demographics

The highest prevalence has been seen among the Hispanic population. Female babies, whites and children born to mothers who are at extreme of ages are more likely to be affected by the disorder. Worldwide, Ireland and British Islands has higher prevalence as compared to Asia and Africa which has a lower prevalence rate.

Recurrence rate

Like any other neural tube defect, the recurrence rate of anencephaly is 2-4% if one sibling is affected and 10 percent if two siblings are affected. This familial tendency is due to genetics, environmental factors, or both.

Natural History, Complications, Prognosis

There is no cure or standard treatment for anencephaly and the prognosis for affected individuals is poor. Most anencephalic babies do not survive birth, accounting for 55% of non-aborted cases. If the infant is not stillborn, then he or she will usually die within a few hours or days after birth from cardiorespiratory arrest.

In almost all cases anencephalic infants are not aggressively resuscitated since there is no chance of the infant ever achieving a conscious existence. Instead, the usual clinical practice is to offer hydration, nutrition and comfort measures and to "let nature take its course". Artificial ventilation, surgery (to fix any co-existing congenital defects), and drug therapy (such as antibiotics) are usually regarded as futile efforts. Clinicians and medical ethicists may view the provision of nutrition and hydration as medically futile. Occasionally some may even go one step further to argue that euthanasia is morally and clinically appropriate in such cases.

Prenatal screening

• American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) advocates universal screening of all the pregnant women for the NTD.
• This results in early diagnosis which helps the couple to plan either pregnancy termination or otherwise prepare them for the birth. The maternal serum alpha-fetoprotein (AFP screening) and detailed fetal ultrasound can be useful for screening for neural tube defects such as spina bifida or anencephaly.

Ultrasound

Ultrasound provides a definitive diagnosis of anencephaly before birth. It can often be diagnosed through a transvaginal ultrasound performed at 12th week postmenstrual. The ultrasound findings include open calvaria and characteristic frog-like appearance of the fetus. Also, a large amount of amniotic fluid called polyhydromnios is also seen.

Anencephaly frog like appearance

Alpha-Fetoprotein

• Alpha-fetoprotein (AFP) levels can be measured in maternal serum (MSAFP), amniotic fluid, and fetal plasma.
• Normally, the level rises in early pregnancy, peaks between 10 and 13th week, and then the level declines becoming extremely low near the term.
• For the purpose of prenatal screening, alpha-fetoprotein levels are checked and are found to elevated. This test is non-specific for NTD, as AFP can also be elevated due to other maternal and fetal factors. Therefore, results should always be combined with ultrasound findings and the levels of Acetylcholinesterase (AChE).

Acetylcholinesterase

AChE is an enzyme contained in blood cells, muscle, and nerve tissue. Its levels can be checked from the amniotic fluid via amniocentesis. An elevation of both AFP and AChE values is highly suggestive and accurate for fetal NTD.

Triple screen

Triple screen is a prenatal screening test which includes 3 biomarkers; AFP, hCG and estradiol. It helps to detect certain congenital anomalies, including neural tube defect. The following table shows the triple screening of neural tube defect and how it is differentiated from other anomalies."Triple Screening in Pregnancy--What It Is and What to Expect - American Family Physician".

Anomaly	AFP	hCG	Estradiol
NTD	Increased	Normal	Normal
Trisomy 21	Decreased	Increased	Decreased
Trisomy 18	Decreased	Decreased	Decreased

Diagnosis

Clinical features

• Infants born with anencephaly have the following clinical features:
  • Absence of bony covering over the back of the head.
  • Facial features: Cleft lip, cleft palate.
  • CNS: Absence of bony covering over the back of the head, spina bifida, blindness, deafness.
  • GIT: Absence or underdeveloped organs, gastroschisis, omphalocele
  • Genito-urinary system: Hypospadias, penile hypoplasia, renal agenesis.
  • Skeletal system: Clubbed foot, clubbed hands.
  • Lungs: Diapharagmatic hernia.

Physical Examination

Neurologic

• Reflex actions such as breathing and responses to sound or touch may occur. Although some individuals with anencephaly may be born with a rudimentary brainstem, which controls autonomic and regulatory function, the lack of a functioning cerebrum is usually thought of as ruling out the possibility of ever gaining consciousness, even though it has been disputed specifically.

Cardio-vascular system

• A murmur could be heard due to associated congenital heart disease.

Respiratory system

• Decreased breath sounds if associated diaphragmatic hernia is present.

Gastrointestinal system

• On inspection, abdominal wall is not intact. There could be an abdominal wall defect with organs protruding out in an abdominal swelling, called omphalocele, or without a swelling called gastroschisis can be seen.

Management

So far, prevention is the best management of anencephaly.

Medical Therapy

• There is no known medical therapy available for anencephaly."Anencephaly: Causes, Symptoms, Diagnosis and Treatment for Newborns | St. Louis Childrens Hospital".

Surgery

• At this point in time there are no surgical options available.

Prevention

• Recent studies have shown that the addition of folic acid to the diet of women of child-bearing age may significantly reduce, although not eliminate, the incidence of neural tube defects. Therefore, it is recommended that all women of child-bearing age consume 0.4 mg of folic acid daily, especially those attempting to conceive or who may possibly conceive, as this can reduce the risk to 0.03%.
• It is not advisable to wait until pregnancy has begun, since by the time a woman knows she is pregnant, the critical time for the formation of a neural tube defect has usually already passed. A physician may prescribe even higher dosages of folic acid (4 mg/day) for women who have had a previous pregnancy with a neural tube defect.

Pregnancy management

• Anencephaly has a poor pregnancy outcome. Majority of the fetuses are either stillborn or die soon after birth, however, few infants do manage to live up to 28 days.
• Therefore, mothers are counselled regarding the termination soon after the prenatal diagnosis. Vaginal delivery is the preferred mode unless there are any maternal indications.

References

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