Embryology, Anencephaly


Article Author:
Sean Tafuri


Article Editor:
Forshing Lui


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
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James Hughes
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Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/5/2019 10:02:45 AM

Introduction

Anencephaly is a pathology of development characterized by a fetus that has no calvarium, with a lack of most or all of the fetus' brain tissue.[1] Anencephaly belongs to a collective group known as neural tube defects (NTD) and is a result of the neural tube failing to close in its rostral end during fetal development.[2] While the central nervous system (CNS) is developing in a fetus, the neural plate becomes folded and fused, creating the neural tube. Any disturbance to the process of neural tube closure can result in structural abnormalities collectively called neural tube defects. Anencephaly is one of the two main types resulting from the failure of closure of the rostral end of the neural tube.[3] The other primary type is due to failure of closure of the caudal end called spina bifida. The development of anencephaly is not believed to have one single origin but can be a result of many factors, including environmental and nutritional factors.[2] 

Mechanism

Neural tube defects emerge when there is a disturbance during neurulation.[4] Neurulation is a mechanical process that occurs during the early embryogenesis of a fetus. The main goal of the neurulation is to form the neural tube, which is a hollow structure that provides the basis for the central nervous system.[5]

Primary neurulation:

Neurulation is a series of systematic, morphologic, structural changes. The process begins with the Hensen node and the nascent ectoderm signaling to one another, which induces the neural plate to begin neurulation.[5] The neural plate is a flat, open neural epithelium that bends to form neural folds on each end.[4] The two neural folds begin to elevate and start to bend towards one another, both ends growing in the direction of the midline, forming the neural groove. The two bends continue elongating, meet in the middle, and fusing. The fusion creates the neural tube and marks the end of primary neurulation.[6][5] During the third week of gestation, the neural tube is developing from the neural plate. The fourth week is the time when the neural tube closes. Failure of the closure of the rostral end will result in anencephaly which occurs between days 23rd and 26th of gestation. Any insult to the fetus during the fourth gestational week may result in anencephaly in the developing fetus.

Secondary neurulation:

At the sacral and coccygeal level, the neural tube is referred to as the tailbud.[5] The tail bud gives rise to the neural tube and other non-epidermal tissues.[7] The tailbud cells begin to aggregate together and proliferate,[7] forming the medullary cord.[6] While the medullary cord is forming, intercellular junctions arise and join lateral cell surfaces.[5] Epithelization of the medullary cord results in the formation of many lumina.[6][5] The process of cavitation takes place and results in the creation of a central lumen. This singular lumen is the secondary neural tube, which eventually merges with the primary neural tube, forming one continuous structure. Regardless of successful anterior neural tube formation during primary neurulation, secondary neurulation can still be successful.[5]

Testing

PRENATAL

Ultrasound

The presence of anencephaly can be detected as early as the first trimester through fetal ultrasound. However, since some organ systems are still developing through the first trimester, screening for structural abnormalities is used to be delayed until the second trimester. Ultrasound remains the gold standard for diagnostic imaging in pregnant women due to its increased efficacy from technological advances and its safety for the fetus.[8] Upon ultrasound imaging, there is an absence of the superior portion of the cranial vault. In addition, there is an absence of brain tissue at the location of the cerebral hemispheres.[9]

Alpha-fetoprotein

Alpha-fetoprotein (AFP) is a protein normally found in human serum. During pregnancy, AFP concentrations rise quickly, reaching peak levels at the end of the first trimester. After the first trimester, AFP is continuously synthesized, but its presence becomes diluted due to increases in fetal blood volume.[10] In about 90-percent of Anencephaly cases, there is a substantial elevation in serum alpha-fetoprotein levels in the mother. Also, almost all cases are found to have a notable increase in the alpha-fetoprotein levels in the amniotic fluid, accompanied by a presence of acetylcholinesterase.[9]

POSTNATAL

In the postnatal period, diagnosis is by physical examination. All of the following criteria are requisite for a positive diagnosis[9]:

  1. No calvarium present
  2. Absence of scalp
  3. External presence of a hemorrhagic, fibrous mass or tissue 
  4. Lack of cerebral hemispheres

Pathophysiology

The pathogenesis and etiology of anencephaly remain poorly understood but is believed to have a multifactorial origin comprised of both nutritional and environmental risk factors.[2]

NUTRITIONAL FACTORS

Folate is a coenzyme that facilitates the transfer of one-carbon units, which are then in various reactions, such as purine and pyrimidine synthesis, as well as methylation reactions.[11] Folate deficiency is an important nutritional risk factor known to contribute to the development of the disease.[12] A deficiency in folate can result from a variety of causes:

  1. Medications that block folate absorption
  2. Malabsorption of folate
  3. Increased bodily demand for folate
  4. Insufficient intake of dietary folate

Folate is involved in the process of methylating homocysteine and cytosine. It also contributes to the synthesis of purines and pyrimidines. Consequently, a lack of folate leads to an inability to properly build proteins and DNA and also alters the expression of some genes.[11] Although the role folate plays in reducing the risk of NTD is not well known, women of reproductive age are encouraged to incorporate a folate supplement into their diet.[11][13]

ENVIRONMENTAL FACTORS

Anti-epileptic drugs (AEDs) are a known cause of NTDs. Use of AEDs, such as valproate, carbamazepine, and phenytoin, alters folate absorption, leading to decreased levels of folate in the blood. Of note, valproate is considered the most teratogenic AEDs, especially when combined with lamotrigine.[12] Other folic acid antagonists include trimethoprim (an antibiotic used to treat infections, such as malaria), triamterene (a potassium-sparing diuretic), and aspirin (an over-the-counter anti-coagulant).[12][14]

Diabetes complicates pregnancies by increasing the risk the fetus developing congenital birth defects (diabetic embryopathy).[15] This complication is because high blood sugar causes dysfunction during organogenesis.[16][17] The mechanism behind this is that hyperglycemia causes a disturbance in protein folding and promotes apoptosis in embryonic cells. The misfolded proteins aggregate and are unable to be degraded properly. The aggregates then accumulate in the cytosol and disrupt organelle function, leading to the creation of reactive oxygen species (ROS). Oxidative stress causes intracellular signaling to become disrupted, and cells are unable to function properly.[15]

Hyperthermia during the first trimester can alter anterior neural tube closure and correlates with anencephaly. Possible causes of hyperthermia in the mother include use of saunas or hot tubs, exercising in an environment with increased temperatures and febrile illness.[18]

Excess Vitamin A has shown to be teratogenic in pregnant rats due to decreased protein synthesis.[12] Increases in Vitamin A prevent the anterior neural tube from closing, leading to the development of anencephaly or other NTDs.[19]

Clinical Significance

Anencephaly is not compatible with life. The most important aspect of the management of this condition is prevention. The simplest way to reduce the incidence of anencephaly is to advise women of childbearing age to take a supplement of folic acid. Any dose at or more than 0.4 mg a day is effective; this is especially important for any woman taking anticonvulsants. For a young female patient with epilepsy, counseling is essential about the risk of seizures during pregnancy to the developing fetus and the risk of teratogenicity. The patient and provider should develop a plan before she starts a family. The seizures should best be under optimal control with at all possible a single anti-epileptic agent at the lowest possible dose. Valproate should be avoided. The anticonvulsant with the best track record concerning teratogenicity is lamotrigine.

Maternal serum and fetal ultrasonography are diagnostic procedures during pregnancy for in utero diagnosis of any neural tube defect, including anencephaly. Early termination of pregnancy may be an option upon the diagnosis of anencephaly.


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Embryology, Anencephaly - Questions

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Failure of the anterior neuropore to close causes which of the following?



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A 35-year-old woman who is 20 weeks pregnant undergoes a transabdominal ultrasound. The technician notes the presence of a lemon sign and feels that there is a neural tube defect present. What is the most common type of neural tube defect?



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During a 20-week gestational ultrasound, the technician notes the absence of parenchymal tissues above the orbits and the calvarium is missing. However, he does visualize the mid-brain and occipital bone. Prior bloodwork had shown elevated levels of maternal alpha-fetoprotein. What has the fetus most likely developed?



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A 26-year-old woman delivered her first baby with anencephaly recently. She was extremely nervous that her next baby may have the same problem. She is counseled about a healthy lifestyle and the avoidance of alcohol, smoking, and exposure to chemicals. What is the supplement that can prevent subsequent anencephaly in this patient?



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A 25-year-old woman is exposed to a known teratogen during her pregnancy at 3-4 weeks of gestation. What will be the most likely outcome in the fetus?



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Embryology, Anencephaly - References

References

Padmanabhan R, Etiology, pathogenesis and prevention of neural tube defects. Congenital anomalies. 2006 Jun     [PubMed]
Yamaguchi Y,Miyazawa H,Miura M, Neural tube closure and embryonic metabolism. Congenital anomalies. 2017 Sep;     [PubMed]
Edwards L,Hui L, First and second trimester screening for fetal structural anomalies. Seminars in fetal     [PubMed]
Naidich TP,Altman NR,Braffman BH,McLone DG,Zimmerman RA, Cephaloceles and related malformations. AJNR. American journal of neuroradiology. 1992 Mar-Apr;     [PubMed]
Nikolopoulou E,Galea GL,Rolo A,Greene ND,Copp AJ, Neural tube closure: cellular, molecular and biomechanical mechanisms. Development (Cambridge, England). 2017 Feb 15;     [PubMed]
Copp AJ,Greene ND, Neural tube defects--disorders of neurulation and related embryonic processes. Wiley interdisciplinary reviews. Developmental biology. 2013 Mar-Apr;     [PubMed]
The infant with anencephaly. The New England journal of medicine. 1990 Mar 8;     [PubMed]
Brock JH, Alphafetoprotein and neural tube defects. Journal of clinical pathology. Supplement (Royal College of Pathologists). 1976;     [PubMed]
Ebara S, Nutritional role of folate. Congenital anomalies. 2017 Sep;     [PubMed]
Kondo A,Matsuo T,Morota N,Kondo AS,Okai I,Fukuda H, Neural tube defects: Risk factors and preventive measures. Congenital anomalies. 2017 Sep     [PubMed]
Doležálková E,Unzeitig V, [Folic acid and prevention of the neural tube defects]. Ceska gynekologie. 2014 Apr;     [PubMed]
Hernández-Díaz S,Werler MM,Walker AM,Mitchell AA, Folic acid antagonists during pregnancy and the risk of birth defects. The New England journal of medicine. 2000 Nov 30;     [PubMed]
Miller P,Smith DW,Shepard TH, Maternal hyperthermia as a possible cause of anencephaly. Lancet (London, England). 1978 Mar 11;     [PubMed]
Langman J,Welch GW, Effect of vitamin a on development of the central nervous system. The Journal of comparative neurology. 1966 Sep;     [PubMed]
Correa A,Gilboa SM,Botto LD,Moore CA,Hobbs CA,Cleves MA,Riehle-Colarusso TJ,Waller DK,Reece EA, Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects. American journal of obstetrics and gynecology. 2012 Mar;     [PubMed]
Nasri HZ,Houde Ng K,Westgate MN,Hunt AT,Holmes LB, Malformations among infants of mothers with insulin-dependent diabetes: Is there a recognizable pattern of abnormalities? Birth defects research. 2018 Jan;     [PubMed]
Zhao Z,Cao L,Reece EA, Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects. Proceedings of the National Academy of Sciences of the United States of America. 2017 Apr 25;     [PubMed]
Vijayraghavan DS,Davidson LA, Mechanics of neurulation: From classical to current perspectives on the physical mechanics that shape, fold, and form the neural tube. Birth defects research. 2017 Jan 30;     [PubMed]
Colas JF,Schoenwolf GC, Towards a cellular and molecular understanding of neurulation. Developmental dynamics : an official publication of the American Association of Anatomists. 2001 Jun;     [PubMed]

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