Anencephaly

INTRODUCTION — Anencephaly is characterized by an open defect in the calvaria and skin such that the cranial neural tube is exposed. It is a severe defect and is not compatible with survival. Nearly all liveborn infants with anencephaly die within the first few hours to days after birth.

The clinical features, diagnosis, and postnatal management of anencephaly are discussed in this topic review.

Anencephaly is one of the three major neural tube defects. The others are encephalocele and myelomeningocele, which are discussed in separate topic reviews:

●Encephalocele is a herniation of the brain and/or meninges through a defect in the skull (cranium bifidum) that is "closed" or covered with skin. (See "Primary (congenital) encephalocele".)

●Myelomeningocele is characterized by a cleft in the vertebral column, with a corresponding defect in the skin so that the meninges and spinal cord are exposed. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications" and "Myelomeningocele (spina bifida): Management and outcome".)

EMBRYOLOGY — The central nervous system appears as a plate of thickened ectoderm called the neural plate at the beginning of the third week of embryonic life. The lateral edges of the neural plate become elevated to form the neural folds and fuse to form the neural tube; the fusion begins in the cervical region and proceeds in both the rostral and caudal directions (figure 1). The rostral neuropore closes on the 25^th day after conception, and the caudal neuropore closes two days later [1]. Neural tube defects (NTDs) result from failure of the neural tube closure between 25 and 27 days after conception. The embryology of the neural tube is discussed in a separate topic review. (See "Closed spinal dysraphism: Pathogenesis and types", section on 'Normal cord development in humans'.)

Anencephaly is a severe defect of development of the neuraxis, in which the developing forebrain and variable amounts of the brainstem are exposed in utero and fail to develop or are destroyed [2,3]. The generally accepted pathologic mechanism of anencephaly is the acrania-exencephaly-anencephaly sequence [4]. Failure of the rostral neuropore to close around postovulatory day 25 causes absence of skull, meninges, and muscles (acrania) [5]. Subsequently, the fetal brain protrudes outward and is exposed to the amniotic fluid (exencephaly). This process causes destruction and degeneration of the brain (anencephaly).

The craniofacial abnormalities in anencephaly are caused by abnormal neural induction from prosencephalic and mesencephalic neural crest tissue [6]. This mechanism is also seen in other anomalies of craniofacial development such as holoprosencephaly.

Craniorachischisis totalis is a related NTD in which anencephaly is accompanied by a contiguous open defect of the spine (spina bifida totalis). It is an extreme example of defective closure of the neural tube during early embryogenesis, around 20 to 22 days gestation [7,8].

INCIDENCE — According to data from birth certificates reported to the National Center for Health Statistics, the prevalence of anencephaly in the United States in 2001 was 9.40 per 100,000 live births [9]. During 1999 to 2004, 2116 cases of anencephaly were reported in the United States [10]. Hispanic infants had the highest prevalence. The malformation is more common in girls than boys, in White than Black infants, and in mothers at the younger and older extremes of age [11]. The rate of anencephaly in live births underestimates the actual rate of occurrence because of unknown numbers of spontaneous abortion or pregnancy termination of affected fetuses.

The birth prevalence of anencephaly decreased 20 percent between the 1999 to 2000 period and the 2003 to 2004 survey periods [10]. This decline is thought to be due to mandatory fortification of foods with folic acid, which began in January 1998.

There is considerable variation in the rates of anencephaly and other neural tube defects worldwide, with particularly high prevalence in Ireland and the British Islands as compared with continental Europe [12]. Rates in Asia and Africa tend to be lower, although there are pockets of higher prevalence in the northern provinces of China and in India, which are not easily explained by geographic or ethnic gradients [13].

RECURRENCE RISK — The risk of recurrence for neural tube defects (NTDs) (spina bifida or anencephaly) is approximately 2 to 4 percent when there is one affected sibling [14-18]. With two affected siblings, the risk is approximately 10 percent [19]. The risk of recurrence appears to be higher in countries such as Ireland where the prevalence of NTDs is high [20]. This familial clustering is due to genetic factors, environmental influences, or a combination of the two [21].

The environmental influences that contribute to anencephaly risk are similar to those of other NTDs. (See 'Prevention' below.)

PRENATAL DIAGNOSIS — Prenatal diagnosis of anencephaly is made with ultrasonography, which shows absence of brain and calvaria superior to the orbits on coronal views of the fetal head (image 1A-B). The sonographic diagnosis of this condition is highly accurate and should be readily apparent on routine second- or third-trimester ultrasound examination. Another sonographic feature is polyhydramnios, which develops in up to 50 percent of the cases during the second and third trimester due to decreased fetal swallowing. Anencephalies are classified into several phenotypic types based on the ultrasound findings [22]. Prenatal ultrasound diagnosis is discussed in greater detail separately. (See "Neural tube defects: Prenatal sonographic diagnosis", section on 'Exencephaly-anencephaly sequence'.)

Prenatal diagnosis is usually followed by discussion of reproductive options (termination or continuation of the pregnancy). (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Anencephaly'.)

CLINICAL FEATURES — In the most common type of anencephaly, the forebrain and variable amounts of upper brainstem are involved [11]. Exposure in utero results in destruction of neural tissue, which appears as a hemorrhagic, fibrotic, nonfunctioning mass (picture 1). Major portions of the central nervous system are absent or malformed. The hypothalamus is typically missing. The cerebellum, brainstem, optic nerves, and spinal cord may be malformed. Underdevelopment or absence of the pituitary, leading to adrenal hypoplasia, is always present [23].

Large portions of the cranium are absent in this disorder. The frontal, parietal, and portions of the occipital bones are most often affected. The absent cranial vault results in the characteristic appearance of bulging eyes and absent neck. The defect in the skull sometimes extends through the level of the foramen magnum and involves the cervical spine. This abnormality is known as holoacrania [11].

Associated malformations — Other congenital malformations frequently accompany anencephaly. In a registry of 456 affected stillborn and liveborn infants in British Columbia, Canada, additional malformations, including cleft lip and/or palate or omphalocele, occurred in 12.7 percent [24]. Craniofacial and ocular anomalies often occur. Cardiac, pulmonary, renal, and skeletal malformations may be associated. Aganglionosis of the intestine is a frequent finding [25].

Neurologic function — Neonates with anencephaly typically have brainstem function, with spontaneous breathing and often with suck, root, and gag responses. However, they are permanently unconscious. Without intensive care, the majority of them die within the first few days after birth [11]. Survival past two weeks has not been reported.

POSTNATAL MANAGEMENT — Nearly all liveborn infants die shortly after birth. There are no neurosurgical management options. Given this poor prognosis, most pregnancies are terminated or induced shortly after diagnosis. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Anencephaly'.)

Management of liveborn anencephalic newborns focuses on comfort measures and providing support for the family. (See "Pediatric palliative care", section on 'End-of-life care'.)

Some affected families may ask whether organ donation is an option. A diagnosis of anencephaly does not preclude consideration for organ donation, particularly donation after circulatory determination of death (DCDD) [26]. However, in many cases, organ donation (either using brain death or DCDD criteria) is not feasible for anencephalic infants because by the time brain or circulatory death occurs, most organs are damaged to an extent that they are no longer suitable for transplantation [27]. Families who wish to pursue organ donation should be informed of this possibility. Clinicians caring for anencephalic newborns should consult with an organ procurement organization to facilitate these discussions. (See "Assessment of the pediatric patient for potential organ donation".)

PREVENTION — Several lines of evidence suggest a link between folic acid deficiency and the development of neural tube defects (NTDs) including anencephaly [28]. Risk factors for NTDs include dietary deficiency of folic acid; administration of valproate or folic acid antagonists such as trimethoprim, carbamazepine, phenytoin, and phenobarbital; and genetic polymorphisms in genes encoding folate-dependent enzymes. Other contributors to NTD risk that are probably not related to folate metabolism include maternal diabetes mellitus with poor glycemic control during the first trimester, hyperthermia, and some genetic syndromes. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Risk factors'.)

Periconceptional folic acid supplementation is recommended for all women who are pregnant or who may become pregnant. Higher doses of folic acid supplements are usually recommended for women who are taking antiseizure medications or who have had a previous pregnancy affected by an NTD. Randomized trials have consistently shown that folic acid supplementation reduces the incidence of NTDs. This issue is discussed in greater detail separately. (See "Preconception and prenatal folic acid supplementation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital malformations of the central nervous system".)

SUMMARY AND RECOMMENDATIONS

●Definition – Anencephaly is a severe defect of development of the neuraxis, in which the developing forebrain and variable amounts of the brainstem are exposed in utero and destroyed or fail to develop (picture 1). Neonates with anencephaly typically have brainstem function but are permanently unconscious. It is a severe defect and is not compatible with survival. Nearly all liveborn infants with anencephaly die within the first few hours to days after birth. (See 'Neurologic function' above.)

●Risk factors – Most isolated open neural tube defects (NTDs), including anencephaly, appear to be caused by folate deficiency, likely in combination with genetic or other environmental risk factors. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Risk factors'.)

●Prenatal diagnosis – Prenatal diagnosis of anencephaly is made with ultrasonography, which shows absence of brain and calvaria superior to the orbits on coronal views of the fetal head (image 1A-B). The sonographic diagnosis of this condition is highly accurate and should be readily apparent on routine second- or third-trimester ultrasound examination. Prenatal diagnosis is usually followed by discussion of reproductive options (termination or continuation of the pregnancy). Prenatal screening and diagnosis of NTDs are reviewed in greater detail separately. (See 'Prenatal diagnosis' above and "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management".)

●Postnatal management – Nearly all liveborn infants with anencephaly die shortly after birth. There are no neurosurgical management options. Given the poor prognosis, most pregnancies are terminated or induced shortly after diagnosis. Management of liveborn anencephalic newborns focuses on comfort measures and providing support for the family. (See 'Postnatal management' above.)

●Prevention – Folic acid supplementation is an effective intervention to decrease the occurrence of NTDs and is recommended for all pregnant individuals, as discussed in a separate topic review. (See "Preconception and prenatal folic acid supplementation".)