Anencephaly

# Overview
Anencephaly is a cephalic disorder  in which there is the partial or total absence of the brain. It is an open neural tube defect occurs when the rostral (head) end of the neural tube fails to close resulting in the absence of a major portion of the brain, skull and spinal cord. Children with this disorder are born without a forebrain, the largest part of the brain consisting mainly of the cerebral hemispheres which is responsible for higher cognitive functions and cerebellum which control balance and movement. However, hindbrain is developed. 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

# Pathophysiology
- 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.
- The neural plate folds and closes to form a tube-like structure called neural tube and neural crest cells. The neural tube then goes on to form structures of the adult brain.
- A neural tube defect occurs if the the opening of the neural tube, called neuropore, fails to close in the 4th week of gestation. Neural tube has two neuropores, rostral and caudial. Anencephaly results from failure of the rostral neuropore to close anteriorly around day 25.
- The craniofacial abnormalities in anencephaly are caused by abnormal induction by the neural crest cells.

# Clinical Features
- Infants born with anencephaly have the following clinical features:
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.
- 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.

# Differentiating Anencephalopathy from other Disorders
At times, anencephaly could be misdiagnosed with other similar diagnosis such as;
- exencephaly
- 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. Anually, more than 300,000 babies are born with neural tube defects throughout the world.

## Demographics
In United States, the highest prevalence has been seen among the Hispanic . 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 percent if one sibling is affected and 10 percent if two siblings are affected.  This familial tendency is due to genetics, environmental factors, or both.

# 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. Recent animal models indicate a possible association with deficiencies of the transcription factor TEAD2.
The motivation behind studying genetic patterns is the following:
- NTDs are consistently prevalent among monozygotic twins as compared to dizygotic twins.
- 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.
- There is higher female preponderence as compared to the males. 

## 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)
- 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 a pregnant mothers 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 affect 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. 

# Natural History, Complications, Prognosis
- Prognosis of children born with anencephaly is extremely poor as there is no cure or standard treatment available so far. 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.
- Anencephalic infants are not aggressively resuscitated as there is very little chance of the infant to achieve a full level of consciousness. Instead,  clinicians prefer to provide them with adequate hydration, nutrition and comfort. Artificial ventilation, surgery (to fix any co-existing congenital defects), and medications are not considered an option as they have no role in any improvement. Due to this poor prognosis, couple are discussed about the option of the terminating the pregnancy soon after the prenatal diagnosis is established.

# Diagnosis

## Diagnostic Criteria
- The diagnosis of Anencephaly is made either during a prenatal scan or after the birth.
- In prenatal ultrasound, features like absent calvarium and characteristic frog-like appearance or Micky mouse appearance of the fetus are diagnostic.
- After the birth, clinical features like lack of bony covering over the back of the head and less number of bones around the front and sides of the head are diagnostic.

## Symptoms
- Majority of the infants are stillborn or die soon after birth.
- Symptoms of anencephaly may include the following:
- Decrease or loss of consciousness.
- Blindness
- Deafness
- Inability to feel pain. 

## Physical Examination
- Physical examination may be remarkable for:
- Flattened head
- Absence of the cranial vault
- Positive grasp reflex in both the hands and feet
- Moro reflex could be present or absent depending on the severity of the defect.
- A heart murmur could be present due to associated congenital heart disease.
- cleft lip and/or cleft palate could be present.
- Clubbed foot could be present.
- Gastroschisis, omphalocele, hypospadias could be present in some anencephalic infants.

## Laboratory Findings

### 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.

## Imaging Findings

### 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:
- Absent calvarium.
- No parenchymal tissue above the orbits.
- Reduced crown rump length (CRL)
- A characteristic frog-like appearance or Micky mouse appearance of the fetus due to absent brain and cranial bone and, protruding orbits.
- A large amount of amniotic fluid called polyhydromnios is also seen.

# Management

## Medical Therapy
- There is no known medical therapy available for anencephaly.

## Surgery
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## 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.