Neural Tube Defects

Introduction

Neural tube defects (NTD) are the consequence of a failure in the closure of the neural tube, and differ depending on their localization and extent.

The term “neural tube defects” includes defects of the cranial vault, including the spectrum of acrania, exencephaly, and anencephaly, and encephaloceles, spinal defects (“spina bifida” or myelomeningocele), and combined cranial and spinal defects such as craniorachischisis. These defects, as well as hemivertebrae, are discussed in this chapter.

Embryology

Neural tube defects (NTDs) arise from the disruption occurring during several different stages of the neurulation process leading to the development of the central nervous system (CNS). The cause is multifactorial, due to the complex interaction between genetic and environmental factors.

Neurulation origins from epiblastic cells migrate toward the primitive streak and form the neuroectodermal tissue of the neural plate as early as postovulatory day 16. At this stage the neural plate is surrounded by paraxial mesodermal cells, which will develop into paired somites. These represent the mesodermal precursors of the vertebral bodies and of the ribs.

Complex interactions involving neural ectodermal cells of the neural plate and nonneural ectoderm, which will develop into the overlying skin layer, are responsible for the induction of the neural plate. The borders of the neural plate elevate into the neural folds, move toward the midline, fuse, and form the neural tube. Although the neural tube was previously thought to close from cranial to caudal in a zipper-like fashion, and starting from the level of the fifth somite, more recent evidence suggests that neurulation proceeds through progressive waves of closure along the craniocaudal neuraxis. After the process of closure has started, the open regions of the neural tube are called the anterior (cranial) and posterior (caudal) neuropores. Once closure is initiated at a site, neuroectodermal cells reorganize to form the roof of the neural tube, while overlying epidermal cells form the ectodermal layer of the skin.

Caudally, the process of closure of the neural tube continues until the posterior neuropore is closed, whereas in the cranial region a second site of temporary closure appears in the forebrain at level of the ninth somite. This process, termed occlusion , is responsible for the spacing of the cranial vesicles and for the prevention of fluid drainage from the vesicles, which remain fluidfilled, forming the neurocele. The cranial neuropore is closed on day 25, whereas the caudal neuropore closes by day 28. At this stage, the neurocele reopens without loss of fluid from the cranial vesicles.

The neurulation process described previously is called primary neurulation, and it is responsible for the development of the brain and of the spinal cord down to the sacral region (probably S4–S5). From this level downward secondary neurulation, which occurs between approximately postovulatory days 23 to 32, forms the caudal end of the cord. Because this process takes place below the surface ectoderm, abnormalities of secondary neurulation produce lesions that are covered by skin and are not involved in the pathogenesis of open spina bifida.

When the cranial neuropore fails to close, the bony tissue covering the brain does not develop, and the unprotected neural tissue is destroyed. This represents the embryologic origin of major brain malformations such as acrania-exencephaly and acrania-anencephaly sequences. Acrania is characterized by the partial or complete absence of the cranial vault. This open defect of the calvaria and the skin results in the exposure of the neural tube, which defines exencephaly. Exencephaly is considered an early stage of anencephaly given that the “external” (intraamniotic) location of the brain tissue results in the abnormal development and regression of the forebrain and the diencephalon, leading to anencephaly. On the other hand, the hindbrain proceeds to develop normally, allowing for the fetus to survive until term.

The development of congenital encephalocele is uncertain, although it seems to depend on defective closure of the anterior wall of the neural tube. The onset of the most severe lesions likely occurs before day 26 (after conception) whereas less severe lesions that primarily involve skull or meninges may occur later. Anterior encephaloceles (sincipital and basal) probably result from defective development of the prosencephalic neural crest tissue; occipital encephaloceles probably arise from abnormal segmentation of the bones of the posterior cranium (supraoccipital, exoccipital, and basioccipital, and the posterior part of the parietal bones).

Myelomeningoceles result either from the failure of closure of the neural tube prior to the reopening of the neurocele, which can also explain the collapse of the cranial vesicles and the development of the Chiari II malformation, or from an overdistension and rupture of a previously normally closed neural tube. More recently it has been hypothesized that in some cases myelomeningoceles may be caused by abnormalities in midline axial integration occurring during the gastrulation process.

Craniorachischisis represents the most extensive NTD characterized by failed closure of both the cranial and the caudal neural tube. The recent hypothesis of “multiple sites of neural tube fusion” explains the pathogenesis of this defect best, in which the calvaria and vertebrae fail to form correctly, exposing the neural tissue to further insult and destruction.

Vertebral defects may arise from the disruption of normally formed anatomic structures, i.e., in the case of amniotic band syndrome, or from failure of the embryologic differentiation or development of a specific anatomic structure. Hemivertebrae, or wedge-shaped vertebrae, are caused by abnormal development or segmentation of somites during osteogenesis, most likely due to insufficient blood supply to the vertebrae. Hemivertebrae and other vertebral abnormalities such as block vertebrae, butterfly vertebrae, transitional vertebrae and spina bifida can cause compression of the spinal cord due to deformation of the vertebral canal, spinal curvature, and alterations of the shape and number of vertebrae.

Acrania, Exencephaly, Anencephaly

Definition

Acrania is the absence of the ossified cranial vault above the orbits, resulting in abnormal brain tissue that is exposed to amniotic fluid.

Because observational ultrasound (US) studies in human embryos indicate a progression from acrania to anencephaly, it was hypothesized that exencephaly is a precursor of anencephaly. The initial defect is the absence of the cranium (acrania), resulting in exposure of brain tissue (exencephaly) with subsequent degeneration. Ossification of the skull vault as a continuous process ( Fig. 41.1 ) is complete at 12 + 0 weeks. By 12 weeks, the sonographic diagnosis of deficient ossification is based on the absence of the bony part of the neurocranium (calvarium) with the orbits ( Fig. 41.2 ) visible as the most cranial bony structure ( Fig. 41.3 ).

In exencephaly, the area cerebrovasculosa (i.e, the abnormal disorganized central nervous tissue that replaces the cerebral hemispheres) is prominent as outwardly extruding brain tissue ( Figs. 41.4A,B ). The absence of the cranial bone and the abnormal shape of the exposed brain help distinguish between a normal immature brain and exencephaly.

Anencephaly

Etiology and Pathophysiology

Closure of the cranial neuropore normally occurs between 23 and 28 days. A failure in this process eventually leads to anencephaly, with incomplete development of the brain and lack of formation of the cranial bones above the orbits. Some consider anencephaly as an extreme form or end-stage of acrania, with the cerebral hemispheres having been destroyed by direct exposure to the amniotic cavity and constant trauma from fetal movements, bringing the brain tissue into contact with the uterine walls.

Clinical Presentation

Anencephaly is characterized by the absence of the cerebral hemispheres and the cranial vault. A layer of angiomatous stroma, but no skin, covers the defect. Brain development is incomplete: the brainstem and part of the midbrain are present. A part of the cerebral hemispheres may sometimes be observed in the first trimester; this condition is usually called exencephaly. Anencephaly may be associated with spina bifida, urinary tract abnormalities, cleft lip and palate, gastrointestinal, and cardiac abnormalities.

The majority of neonates with anencephaly die within hours or a few days of birth. The mortality in utero is 23%, and approximately 35% during labor; neonatal survival up to 8 days has been reported. An observational study of the natural history of anencephaly showed that about 25% of ongoing pregnancies are complicated by polyhydramnios, and nearly 20% of deliveries are complicated by shoulder dystocia. Furthermore, this study reported an increased rate of other complications including prolonged induction and delay in the second stage of labor.

Imaging Technique and Findings

Anencephaly was the first fetal anomaly diagnosed by antenatal US in 1972. Nowadays, exencephaly is often diagnosed in the first trimester, by demonstrating the irregularity of the cephalic pole with protrusion of the brain mass and irregular shape of the cranial pole, resulting in a characteristic image in the coronal plane that has been called the “Mickey Mouse sign” ( Figs. 41.5 and 41.6 ).

In the second trimester, the absence of the calvarium is easily recognized above the orbits, which look prominent ( Figs. 41.7A,B ). There is little or no brain remaining above the base of the skull.

Classic Signs

“Mickey Mouse” face in the first trimester. Absence of the calvarium above the bony orbits in the second trimester.

Differential Diagnosis From Imaging Findings

Extreme microcrania or large encephaloceles can be confused with anencephaly, but in microcrania the calvarium is present and not interrupted. Amniotic band syndrome may cause destruction of the cranial vault, but usually this is accompanied by other abnormalities, such as limb amputation. Acrania, exencephaly, and anencephaly may be part of the same spectrum of abnormalities.

Synopsis of Treatment Options

Termination of pregnancy should be offered.

In monochorionic twins, selective termination of the anencephalic fetus may be more harmful to the unaffected twin than expectant management due to complications, such as preterm labor and preterm ruptured membranes, although radiofrequency or microwave interruption of circulation to the affected fetus can be considered, especially in the setting of severe polyhydramnios.

Encephalocele