Normal Development

During the first two weeks, postfertilization embry­onic development involves repeated cell division and organization, resulting in a blastocyst, an embryo with two layers: the epiblast and the hypoblast.

The development of the primitive streak is fol­lowed by invagination of epiblast cells, forming a trough along the midline. Subsequent movement of different populations of epiblast cells remodels the embryo (ie, gastrulation) into a three-layered structure comprised of ectoderm, mesoderm, and endoderm, the precursors of all tissue types and body structures. As the primitive streak regresses, presumptive notochord cells migrate through a structure at the rostral end known as Hensen's node. These cells align themselves along the midline of the embryo between the underly­ing endoderm and the overlying ectoderm (presump­tive neuroderm and overlying surface ectoderm). The exact process by which this occurs varies among dif­ferent species, and it has not been clearly defined in humans.

In humans, the formation of the neural tube begins around Day 16, when the neuroectoderm and the later­ally adjacent cutaneous ectoderm can be seen overly­ing the notochord in a “platelike” structure along the midline groove of the embryo. Direct cell-cell contact by the notochord is required for neural plate induction as well as the production of diffusible factors. By about day 21, the plate bends as the groove deepens, and its walls and their adjacent cutaneous epithelium begin to oppose one another.

The eventual closure of the neural tube proceeds over a period of four to six days and typically involves primary closure of the cutaneous ectoderm. This is first followed by the neuroectoderm, which subse­quently separates from the overlying cutaneous ecto­derm, resulting in a closed tube. Closure begins at a point just caudal to the developing rhombencephalon and proceeds via several waves rostrally rather than in the continuous “zipperlike” fashion previously envi­sioned. Spinal closure appears to proceed in a con­tinuous fashion from the initial rostral closure point caudally to the end of the neural tube. There is, how­ever, an alternative view proposed by Van Allen and colleagues that describes several closure initiation sites over the same period of time (7,8). Regardless, closure of the primary neural tube is typically com­plete around developmental day 27. This process, pri­mary neurulation, completes the presumptive spinal cord down to the lower lumbar and/or upper sacral levels.

A secondary wave of neurulation begins around day 25 from a collection of remaining primitive streak cells and mesoderm located along the midline axis from the caudal end of the primary neural tube to the cloaca. These collections of cells form cavities that coalesce to form a tube that eventually becomes con­tinuous with the primary neural tube. This process completes the formation of the sacral levels of the spi­nal cord and terminal filum, and is species-specific. The specific process by which secondary neurulation occurs and merges with the primary neural tube is uncertain in humans.

Understanding the process of primary and sec­ondary neurulation is of paramount importance in comprehending the pathogenesis of spina bifida. The process of neurulation is completed by the end of the first month of embryonic development.

Expansion of the cranial brain structures via devel­opment of a primitive ventricular system is thought to be accomplished by temporary occlusion of the cau­dal (spinal) neural tube (days 23-27), which creates a rostral-enclosed fluid-filled space, thus providing pressure to expand the cranial lumen, providing the impetus for brain enlargement. Theory suggests that, in part, failure of this expansion pressure is a cause for Chiari malformation (9).

Neural crest cells, precursors to cell types such as melanocytes, Schwann cells, dura matter, and dorsal root, as well as autonomic ganglion, are thought to arise during this same time from the neural tube near the junction between neuroectoderm and cutaneous ectoderm.