Development of the Spinal Cord

Ken WS Ashwell , in The Spinal Cord, 2009

From neural plate to neural tube

The central nervous system first appears in the embryo as the neural plate, a tadpole-shaped thickening of the ectoderm rostral to the primitive pit ( Figure 2.1a). This can be seen at approximately 18 to 19 days pc (days post-conception) in the human (Carnegie stages 6 to 7, see Table 2.1 for comparison with mouse and rat) (Kaufman, 1992).

Figure 2.1. Neural plate and neural tube formation

This diagram shows the neural plate and neural tube of human embryos at 19 days pc (a), 20 days pc (b), and 22 days pc (c) showing folding of the neural groove to produce the neural tube. The first point of fusion between the neural folds is at the hindbrain/spinal cord junction.

Table 2.1. Timing of significant events in the development of the spinal cord.

Event Human Days pc/pn Mouse Days pc/pn Rat Days pc/pn
Appearance of neural plate 18-19 pc, C * 6-7 7 pc, T 11 7-7.5 pc, WΩ12
First fusion of neural folds 20 pc, C9 8 pc, T12 8 pc, W15
Closure of anterior neuropore 25 pc, C11 8.5-9 pc, T14 9 pc, W16
Closure of posterior neuropore 27 pc, C12 9.5 to 10 pc, T15 10 pc, W18
Birthdates of motoneurons in brachial (cervical) enlargement 24 to 28 pc?, C11 to C18? 10 to 13 pc, T15 to T21 11 to 14 pc, W20 to W30
Birthdates of motoneurons in lumbosacral enlargement 24 to 28 pc, C11 to C18? 11 to 13 pc, T18 to T21 12 to 14 pc, W22 to W30
Segregation of motoneurons into discrete somatic motor columns 56 to 70 pc 16 to 17 pc, T25 16 to 17 pc, W34
Stretch reflex appears 19 pc
First appearance of Clarke's column ∼ 70 pc 16 pc
Growth of corticospinal tract into cervical spinal cord 98 to 112 pc 0 to 2 pn 0 to 1 pn
Elimination of corticospinal tract axons 3 to ∼ 28 pn 4 to ∼ 28 pn
Myelination of corticospinal tract ∼ 180 pc to ∼ 800 pn 10 to ∼ 28 pn 10 to ∼ 35 pn

See text for references and comments.

*
Carnegie stage
Theiler stage Ω Wistchi stage

Induction of the neural plate appears to be due to an inhibition of epidermis formation due to signals released from the primitive node at the cranial end of the primitive streak (Sadler, 2005). In other words, the default option for the ectoderm in this region is to produce epidermis rather than neurectoderm, and the signal for neurulation involves suppression of bone morphogenetic protein (Bmps) and Wnt signaling pathways (Sadler, 2005). In all vertebrates studied, the notochord underlying the future floor plate and the floor plate itself excrete the molecule Sonic hedgehog (Shh), which may be the signal which induces floor plate formation of the neural groove and tube and effectively ventralizes the neural tube (see Lewis and Eisen, 2003 for review).

Within a day of the appearance of the neural plate in the human, the edges of the neural plate elevate to form the neural folds and a neural groove emerges in the midline (Figure 2.1b). The initial step in elevation of the neural folds depends on proliferation of the underlying mesoderm and production of hyaluronic acid (Solursh and Morriss, 1977), but later stages involve furrowing and folding at three regions of neurectoderm (one median and two lateral hinge points, see Figure 2.2 and Sadler, 2005 for review).

Figure 2.2. Mechanisms involved in the folding of the neural plate to form a neural tube

Most folding occurs at paired lateral and median hinge points where cell division is delayed and nuclei spend more time at the base of the neuroepithelium, thereby narrowing the apical processes of the neuroepithelial cells. Note the aggregation of nuclei at the periphery in these regions and the abundant mitotic figures at non-hinge regions. Glycoprotein on the surface of the adjacent neural folds facilitates adhesion when these points are brought into contact.

Shaping of the neural folds through folding requires apical concentrations of microfilaments and lengthening of the cell cycle at the hinge points. The latter ensures that nuclei of dividing cells remain at the base of the neurectoderm for longer periods of time, thereby widening the bases and narrowing the apices of neural plate cells at these regions (Figure 2.2, Sadler, 2005).

Fusion of the paired neural folds to form a neural tube first occurs at the junction of the hindbrain and spinal cord (level of the 5th somite) at approximately 20 pc in the human (Carnegie stage 9) and 8 days pc in the mouse and rat (Table 2.1) and depends on glue-like coatings of glycoprotein on the opposing surfaces (Sadler, 1978). Fusion of the neural tube extends rostrally and caudally over the next few days (O'Rahilly and Muller, 2002) to effect complete closure of the neural tube (Figure 2.1c). After initial closure, the remaining open ends of the neural tube are known as the neuropores. In humans, the rostral or anterior neuropore closes at about 25 pc, while the caudal or posterior neuropore seals at 27 to 28 pc. After closure of the neuropores, the neural tube expands rostrally to form the brain vesicles, while the caudal tube begins to differentiate into the primitive spinal cord. The process described above is known as primary neurulation and is responsible for generating the brain and spinal cord as far caudally as S4 or S5. More caudal levels of the spinal cord are generated by a mechanism known as secondary neurulation, whereby mesodermal cells coalesce and epithelialize, form a lumen and become continuous with the remainder of the tube (Sadler, 2005).

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780123742476500067

Embryological morphogenesis

Phillip Beach DO DAc OSNZ , in Muscles and Meridians, 2010

Gastrulation and the primitive streak/node/pit

Gastrulation initiates the formation of a trilaminar disc, the notochord, and the onset of organogenesis.

Lewis Wolpert (1986) famously contends 'It is not birth, marriage, or death, but gastrulation, which is truly the most important time in your life.' Wolpert (1991, p. 12) goes on to say 'Excessive perhaps, but the occasion was the attempt to convince the clinician of the importance of studying early development.'

Gastrulation occurs in the development of all animals. As in cleavage, the details of gastrulation vary in pattern across and even within phyla. At 2 weeks, the embryo is termed diploblastic as it consists of two flat layers of cells, the epiblast and the hypoblast. The bilaminar disc is converted to a trilaminar disc via the morphing, called gastrulation. The new layer is called mesoderm, termed an intermediate germ layer as it is spread between the outside layer and the new inside layer. All trilaminar animal groups use the vast, migratory cellular dynamics initiated during gastrulation to bring cells from the outside layer of the embryo to the interior. A form of involution takes place.

Imagine yourself now at that stage in your life. You are entering your third week post conception. You have already established a life-long relationship with your mother. You are shaped like a flattened pear, have two layers, and are surrounded by fluid contained by delicate life-support membranes. Your sense of direction is hazy. Head and tail, left and right have little meaning to you.

Gastrulation gives a left/right laterality by initiating a process that will cleave your epiblastic 'back' in the midline from the caudal toward the cephalic region. During gastrulation, huge numbers of cells are on the move – the whole embryo is heaving, involuting, invaginating in and through itself. The cellular choreography is astoundingly three-dimensionally complex – even a slight aberration will crash the nascent biological system. The Indian tradition talks of 'the kundalini', a powerful coiled energy moving from caudal to rostral that they associate with spiritual illumination. If you could re-experience even a small percentage of the feeling involved in the gastrulation event, your life subsequently would be altered by that physiological tsunami. Wisely, the Indian seers also warn of a great danger if this re-arousal of the serpent power goes awry.

The cleaving running up your middle dorsal surface is like a long fault line into which your epiblastic cells are irresistibly drawn by strong currents – Niagara Falls springs to mind. The cleavage is called the 'primitive streak' and at its cephalic end, it is a midline rounded structure, the 'primitive node' that surrounds the 'primitive pit' (embryology's metaphoric equivalent of a cosmic black hole).

FIG 2.3. The bilaminar disc invaginates (the outside becomes the inside) and in so doing, creates the middle germ layer, the mesoderm.

Adapted from Schoenwolf et al 2008 .

As thousands of cells pour over the lip of the primitive streak they undergo profound, lasting metamorphosis. Cells from the epiblast are transformed into the definitive trilaminar embryo. Epiblastic cells dislodge the hypoblast and form what is now called the definitive endoderm. Endoderm, the deepest of the three germ layers, forms the cells that line your gut tube from mouth to anus. Between the newly forming endoderm and the epiblast a new cell layer is created by the in-pouring epiblastic cells, the mesoderm, forming in time, muscle, bone, blood, and the genito-urinary system. The outside germ layer, the epiblast, is now transformed into a layer called the ectoderm, from which the skin and nervous system are derived. Thus, three definitive germ layers are now present: the endoderm, the mesoderm, and the ectoderm.

FIG 2.4. Where epiblastic cells fall into the primitive streak and node determines the trajectory of their subsequent migration

The oval depicted above the primitive node is the oral membrane – it is a tight pinching of the epiblast and hypoblast – it will be the future mouth region. Likewise, the caudal oval will be the cloacal region (anus).

Adapted from Schoenwolf et al 2008 .

One of the defining characteristics of vertebrates is an embryonic structure called the notochord. All vertebrates have a notochord, if only at this stage of their development. It arises as a cephalic continuation of the primitive pit; in Figure 2.4 it will project forward from the horseshoe-shaped primitive pit. Within the softly structured body of the embryo the notochord is a tough midline rod of cartilage that forms during days 16–31, a rod of spirally bound, fluid-engorged cells that resists being shortened. Dorsal to the notochord will lie the central nervous system; ventral to the notochord will be the gut tube and the heart tubes. Both the gut tube and spinal cord require a notochord for correct development, i.e. the notochord is an inductive agent. Induction is an important concept in embryology that speaks of early affinities and influences across germ layers (Larsen 1993). One group of embryonic cells signals to another group of cells so that the second group is initiated to further develop via a new permission or instruction. For example, the notochord induces mesoderm to materialize.

FIG 2.5. All vertebrates have a notochord for good reason

Without a notochord the locomotion system that is based on side-bending could not have evolved, as muscle contraction one side of the body would have shortened, telescope-like, that side.

Adapted from Kardong 1998 , with permission.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780702031090000079

Spinal Cord Injury

Gregory W.J. Hawryluk , ... Michael G. Fehlings , in Handbook of Clinical Neurology, 2012

Gastrulation and Hensen's node

In the second week gastrulation occurs, which establishes the third germ layer, mesoderm (Fig. 1.2 ). Gastrulation begins with formation of the primitive streak in the caudal region of the epiblast. The cranial end of the primitive streak forms a thickening known variously as the primitive knot, the primitive node, or Hensen's node. The primitive pit forms immediately posterior to the node and cells from the epiblast migrate here, invaginate, and then form intraembryonic endoderm and mesoderm.

Fig. 1.2. Gastrulation and development of the notochord. At the end of the second week of development a thickening of cells forms in the caudal midline of the bilaminar germ disc, referred to as the primitive streak (A). The prechordal plate is visible at the rostral end of the disc and eventually develops into the buccopharyngeal membrane. (B) and (C) show coronal views through the bilaminar disc. Epiblast cells invaginate at the primitive pit and primitive streak creating the cells of the definitive endoderm as well as the mesoderm through the process of gastrulation. Prenotochordal cells invaginate during this process and migrate as far rostral as the prechordal plate. Initially they intercalate with the hypoblast forming the notochordal plate (E). The notochordal plate then detaches from the endoderm, and forms a tube referred to as the definitive notochord (F). (E) and (F) are coronal views looking rostral from planes Ro and Ca shown in (D), which is a mid-sagittal section through the embryo at 17d postfertilization. The neurenteric canal is a temporary communication between the amniotic cavity and yolk sac believed to play a central role in many malformations of the spine and spinal cord.

The primitive node migrates caudally as gastrulation progresses, and although it typically regresses and forms the caudal eminence or end bud after migration to the sacrococcygeal area, it is deserving of some further discussion. Hensen's node secretes morphogens such as fibroblast growth factor (FGF), sonic hedgehog (Shh) and retinoic acid (RA), playing key roles in neural induction and patterning which will be discussed in detail. In this fashion, Hensen's node establishes the longitudinal axis, polarity and right–left sidedness within the embryo. It also participates in rostrocaudal specification along with paraxial mesoderm. Failure of Hensen's node to regress can lead to formation of a sacrococcygeal teratoma.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780444521378000012

Neurenteric Cyst

In Diagnostic Imaging: Pediatrics (Third Edition), 2017

PATHOLOGY

General Features

Etiology

Caused by incomplete separation between primitive endoderm & ectoderm during 3rd embryonic week

Notochord normally separates dorsal ectoderm (skin & spinal cord) from ventral endoderm (foregut)

Failure of separation → split notochord or notochord deviated to side of adhesion

Incomplete separation of notochord layer from endoderm (primitive foregut) layer hinders development of mesoderm → small piece of primitive gut becomes trapped in developing spinal canal

Enteric & spinal structures connected through persistent neurenteric canal (a.k.a. canal of Kovalevsky) in severe cases

Normally this canal transiently connects amniotic cavity & yolk sac through primitive pit from 23-25th day of gestation

Degree of tract persistence predicts severity of abnormality

Associated abnormalities

Other coexisting closed spinal dysraphisms ± cutaneous stigmata

Split cord malformation, lipoma, dermal sinus tract, tethered spinal cord

Klippel-Feil syndrome

Malformations of GI tract

Duplication, fistula, anal atresia

VACTERL association, OEIS, cardiac anomalies, renal malformations

Staging, Grading, & Classification

World Health Organization classification: Other malformative tumors & tumor-like lesions

3 types based on histology (Wilkins & Odum)

Type A: Single layer of pseudostratified cuboidal or columnar epithelium resembling respiratory &/or gastrointestinal epithelium

Type B: Type A + mucous or serous glands, smooth muscle connective tissue, lymphoid tissue or nervous tissue

Type C: Type A + ependymal or other glial elements

Gross Pathologic & Surgical Features

Single smooth unilocular (rarely multilocular) cyst containing clear or proteinaceous fluid (milky, cream-colored, yellowish, xanthochromic)

± cyst connection with spinal cord &/or vertebrae

Dorsal spinal-enteric tract traverses cartilage-lined canal of Kovalevsky through small dysplastic vertebra

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323443067504096

Anatomy and Physiology of Congenital Spinal Lesions

Christopher I. Shaffrey , ... Gregory C. Wiggins , in Spine Surgery (Third Edition), 2005

Neurulation and Neurogenesis

The notochord is formed, at day 16, in the midline at the rostral end of the embryo by mesoblastic cells that migrate cranially from the primitive knot between the ectoderm and endoderm. The rostral ascent of these cells ends at the prochordal plate (a small collection of endodermal cells) that firmly adheres to the overlying ectoderm and is destined to become the oropharyngeal membrane. The notochord runs rostrally to the prochordal plate and caudally to the cloacal membrane. As the notochord develops, the primitive pit extends into it to form the notochordal canal (a lumen). Eventually, when the floor of the notochordal canal disappears, a notochordal plate is formed.

The primitive streak and the notochord are strong inductive tissues and play a critical role in induction and development of future organ systems. During formation, the notochord induces the overlying ectoderm to form the neural plate. Primary neurulation involves the formation and infolding of the neural plate to form the neural tube that eventually becomes the spinal cord down to the level of the lumbosacral junction and occurs days 18 to 27 after ovulation. The neural plate first appears rostral to the primitive knot. On day 18, the neural plate invaginates to form the neural groove with neural folds on both sides (Figure 4.1). By day 21, the neural folds have fused to form the neural tube. The neural tube then separates itself from the overlying ectoderm and the ectoderm fuses to become continuous over the dorsal aspect of the embryo.

The spinal cord distal to the second sacral vertebra develops by secondary neurulation. 115, 157 This secondary neurulation begins by having neural crest cells migrate into the dorsal midline of the mesoderm and become identifiable as ependyma and later evolving into neural cells. 150 These cells then group together to form canals. They eventually fuse into one tubular structure that joins with the distal end of the spinal cord developing from the primary neurulation process.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780443066160500092

Descriptive Overview of Human Embryonic Development

Bruce M Carlson , in Reference Module in Biomedical Sciences, 2015

Carnegie Stages of Early Human Embryonic Development (Weeks 1–8)

Age (days)* External features Carnegie stage Crown-rump length (mm) Pairs of somites
1 ( Figure 1 ) Fertilized oocyte 1 0.1
2–3 ( Figure 2 ) Morula (4–16 cells) 2 0.1
4–5 ( Figure 3 ) Free blastocyst 3 0.1
6 ( Figure 4 ) Attachment of blastocyst to endometrium 4 0.1
7–12 ( Figure 5 ) Implantation, bilaminar embryo with primary yolk sac 5 0.1–0.2
17 ( Figure 6 ) Trilaminar embryo with primitive streak, chorionic villi 6 0.2–0.3
19 ( Figure 7 ) Gastrulation, formation of notochordal process 7 0.4
23 Hensen's node and primitive pit, notochord and neurenteric canal, appearance of neural plate, neural folds, and blood islands 8 1–1.5
25 Appearance of first somites, deep neural groove, elevation of cranial neural folds, early heart tubes 9 1.5–2.5 1–3
28 ( Figure 8 ) Beginning of fusion of neural folds, formation of optic sulci, presence of first two pharyngeal arches, beginning heart beat, curving of embryo 10 2–3.5 4–12
29 ( Figure 9 ) Closure of cranial neuropore, formation of optic vesicles, rupture of oropharyngeal membrane 11 2.5–4.5 13–20
30 ( Figure 10 ) Closure of caudal neuropore, formation of pharyngeal arches 3 and 4, appearance of upper limb buds and tail bud, formation of otic vesicle 12 3–5 21–29
32 ( Figure 11 ) Appearance of lower limb buds, lens placode, separation of otic vesicle from surface ectoderm 13 4–6 30–31
33 ( Figure 12 ) Formation of lens vesicle, optic cup, and nasal pits 14 5–7
36 Development of hand plates, primary urogenital sinus, prominent nasal pits, evidence of cerebral hemispheres 15 7–9
38 ( Figure 13 ) Development of foot plates, visible retinal pigment, development of auricular hillocks, formation of upper lip 16 8–11
41 Appearance of finger rays, rapid head enlargement, six auricular hillocks, formation of nasolacrimal groove 17 11–14
44 ( Figure 14 ) Appearance of toe rays and elbow regions, beginning of formation of eyelids, tip of nose distinct, presence of nipples 18 13–17
46 Elongation and straightening of trunk, beginning of herniation of midgut into umbilical cord 19 16–18
49 Bending of arms at elbows, distinct but webbed fingers, appearance of scalp vascular plexus, degeneration of anal and urogenital membranes 20 18–22
51 Longer and free fingers, distinct but webbed toes, indifferent external genitalia 21 22–24
53 ( Figure 15 ) Longer and free toes, better development of eyelids and external ear 22 23–28
56 More rounded head, fusion of eyelids 23 27–31
*
Based on additional specimen information, the ages of the embryos at specific stages have been updated from those listed in O'Rahilly and Müller in 1987. See O'Rahilly R, Müller F: Human embryology and teratology, ed 3, New York, 2001, Wiley-Liss, p 490.

Data from O'Rahilly R, Müller F: Developmental stages in human embryos, Publication 637, Washington, DC, 1987, Carnegie Institution of Washington.

Figure 1. A newly fertilized human oocyte, with male and female pronuclei in the center and two polar bodies on top of the oocyte.

(From Veeck LL, Zaninovic N: An atlas of human blastocysts, Boca Raton, Fla, 2003, Parthenon.)

Figure 2. Human embryo resulting from in vitro fertilization. Morula, showing the beginning of cavitation.

(From Veeck LL, Zaninovic N: An atlas of blastocysts, Boca Raton, Fla, 2003, Parthenon.)

Figure 3. Human embryo resulting from in vitro fertilization. Blastocyst, showing a well-defined inner cell mass (arrow) and blastocoele. At this stage, the zona pellucida is very thin.

(From Veeck LL, Zaninovic N: An atlas of blastocysts, Boca Raton, Fla, 2003, Parthenon.)

Figure 4. Major stages in implantation of a human embryo. The syncytiotrophoblast is just beginning to invade the endometrial stroma.

Figure 5. Digital photomicrograph of a 12-day human embryo (Carnegie No. 7700) taken just as implantation within the endometrium is completed.

(Courtesy of Dr. Ray Gasser.)

Figure 6. Dorsal view of a 16-day human embryo.

Figure 7. Dorsal view of a 18-day human embryo.

Figure 8. Scanning electron micrograph of a 3-mm human embryo approximately 26 days old. S, Somite.

(From Jirásek JE: Atlas of human prenatal morphogenesis, Amsterdam, 1983, Martinus Nijhoff.)

Figure 9. Gross development of human embryo during the period of early organogenesis. Early in the fourth week.

Figure 10. Scanning electron micrograph of a 4-mm human embryo 30 days old. H, heart. Numbers 1 to 3 indicate pharyngeal arches.

(From Jirásek JE: Atlas of human prenatal morphogenesis, Amsterdam, 1983, Martinus Nijhoff.)

Figure 11. Scanning electron micrograph of a 4-week human embryo (5 mm), with 34 pairs of somites. Toward the lower left, the right arm bud protrudes from the body.

(From Jirásek JE: Atlas of human prenatal morphogenesis, Amsterdam, 1983, Martinus Nijhoff.)

Figure 12. Scanning electron micrograph of a 6-week human embryo showing development of the external ear at an early stage. Pharyngeal arch 2 is beginning to overgrow arches 3 and 4 to form the cervical sinus.

(From Steding G: The anatomy of the human embryo, Basel, 2009, Karger. Courtesy of Dr. J. Männer.)

Figure 13. Scanning electron micrograph of a 5-week human embryo (10 mm). The arm and leg buds (asterisks) are in the flattened paddle stage. H, heart; U, umbilical cord; 1, 2, pharyngeal arches 1 and 2.

(From Jirásek JE: Atlas of human prenatal morphogenesis, Amsterdam, 1983, Martinus Nijhoff.)

Figure 14. A 7-week-old human embryo surrounded by its amnion. The embryo was exposed by cutting open the chorion. The small sphere to the right of the embryo is the yolk sac.

(Carnegie embryo No. 8537A, Courtesy of Chester Reather, Baltimore.)

Figure 15. (a), Head of a human embryo approximately 47 days old. Upper and lower eyelids have begun to form. The external ear is still low set and incompletely formed. (b), A 5 ½ -month-old (crown-rump length 200 mm) human embryo. The upper and lower eyelids are fused, and the external ear is better formed. Note the receding chin.

((a), From Streeter G: Carnegie contributions to embryology, No. 230, 165-196, 1951; (b), EH 1196 from the Patten Embryological Collection at the University of Michigan; courtesy of A. Burdi, Ann Arbor, Mich.)

Figure 16. A 37-mm crown-rump-length human fetus, approximately 9 weeks old.

(Courtesy of A. Burdi, Ann Arbor, Mich.)

Figure 17. A 3 ¾-month-old human fetus (130-mm crown-rump length).

(EH 902 from the Patten Embryological Collection at the University of Michigan. Courtesy of A. Burdi, Ann Arbor, Mich.)

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128012383054647

Human Developmental Genetics

Wen-Hann Tan , ... Hagit N. Baris , in Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), 2013

15.6.3 Gastrulation, Segmentation, and Formation of Body Axes

At approximately day 15, epiblast cells proliferate and migrate to the mid-sagittal plane in what will become the more caudal part of the of the bilaminar embryonic disc to form the primitive streak. The primitive streak then elongates along the sagittal plane and a narrow primitive groove develops within the primitive streak. The cranial end of the primitive streak expands to form the primitive node, within which is a small depression known as the primitive pit. Epiblast cells then migrate toward the primitive streak where epithelial-to-mesenchymal transformation (or transition) (EMT) occurs, a process in which the epiblast cells become less regularly shaped (often "flask-shaped") and less tightly connected with one another, i.e., becoming mesenchymal in nature. These transformed epiblast cells invade and displace the hypoblast, eventually replacing it with a new layer of cells known as the definitive (embryonic) endoderm. Beginning around day 16, the invaginating (or ingressing) mesenchymal epiblast cells enter the space between the epiblast and the hypoblast/endoderm to form the intraembryonic mesoderm (Figure 15-6). Once the definitive endoderm and intraembryonic mesoderm have been formed, the remaining epiblast cells become the ectoderm. The formation of all three germ layers from epiblast cells, resulting in the trilaminar embryonic disc, constitutes gastrulation (18).

FIGURE 15-6. (A) On days 14 and 15, ingressing epiblast cells displace hypoblast and form definitive endoderm. (B) Epiblast that ingresses on day 16 migrates between endoderm and epiblast layers to form intraembryonic mesoderm.

(Schoenwolf, G. C.; Bleyl, S. B.; Brauer, P. R.; Francis-West, P. H. Larsen's Human Embryology, 4th ed., Churchill Livingstone: Philadelphia, 2008.)

In an area just cranial to the primitive streak, the ectoderm forms a mild depression and fuses with the endoderm without the mesoderm to form a bilaminar membrane known as the oropharyngeal membrane, which eventually ruptures during the fourth week of development to form the opening of the mouth; a similar bilaminar membrane––the cloacal membrane, which eventually gives rise to the openings of the anus, the urinary and genital tracts––is formed caudal to the primitive streak. At around day 17, a subpopulation of mesodermal cells migrates cranially from the primitive node to form the hollow notochordal process, which is subsequently transformed into a solid notochord by day 22, as illustrated in Figures 15-7 and 15-8. The notochord is responsible for the induction of vertebral bodies (18).

FIGURE 15-7. Formation of the notochordal process. (A and C) Stages showing hollow notochordal process growing cranially from the primitive node. Note changes in relative length of the notochordal process and primitive streak as the embryo grows. Also note, fusion of ectoderm and endoderm in the oropharyngeal and cloacal membranes. (B) Cross section of the embryonic disc at the level indicated by the dotted lines.

(Schoenwolf, G. C.; Bleyl, S. B.; Brauer, P. R.; Francis-West, P. H. Larsen's Human Embryology, 4th ed., Churchill Livingstone: Philadelphia, 2008.)

FIGURE 15-8. The process by which the hollow notochordal process is transformed into a solid notochord between days 16 and 22. (A and B) First, the ventral wall of the notochordal process fuses with the endoderm and the two layers break down, leaving behind the flattened notochordal plate. As shown in (B), this process commences at the caudal end of the notochordal process and proceeds cranially (the dotted line marks the level of (A)). An open neurenteric canal is briefly created between the amniotic cavity and the yolk sac cavity. (C) Series of events by which the notochordal process becomes the notochordal plate and then the notochord.

(Schoenwolf, G. C.; Bleyl, S. B.; Brauer, P. R.; Francis-West, P. H. Larsen's Human Embryology, 4th ed., Churchill Livingstone: Philadelphia, 2008.)

A subpopulation of mesodermal cells becomes the paraxial mesoderm and flanks the notochord on each side (Figure 15-8). In the region that will eventually become the head, these mesodermal cells form "bands of cells" that remain unsegmented and form the head mesoderm; in the region that will become the trunk, the column of paraxial mesoderm on each side of the notochord, known as the presomitic mesoderm, forms "bands of cells" that segment into blocks known as somites in a cranial–caudal direction, starting at the head–trunk junction on day 20 and lasting through day 30 when about 42–44 pairs of somites are eventually formed. The most caudal somites subsequently regress, leaving about 37 pairs of somites. These somites give rise to the occipital bone of the skull, the spine, and the skeletal muscles of the neck, trunk, and limbs. The first four pairs of somites contribute to the formation of the occipital skull bone, the bones of the mid-face and the inner ear, and the muscles of the tongue. The remaining somites form the vertebrae, skeletal muscles, and dermis of the cervical, thoracic, lumbar, and sacral spine; the three most caudal somites are the coccygeal somites that form the coccyx. Immediately lateral to the somites is the intermediate mesoderm, which also forms segments, and lateral to the intermediate mesoderm is the unsegmented lateral plate mesoderm (18) (Figure 15-9).

FIGURE 15-9. Scanning electron micrograph of the trunk region of a chick embryo with the surface ectoderm partially removed to show the underlying neural tube and mesoderm (cranial is toward the top). Note the somites and, more caudally, the paraxial mesoderm that have not yet segmented. Lateral to the somites, the mesoderm has been subdivided into the intermediate mesoderm and lateral plate mesoderm (somatic mesoderm, the layer just deep to the surface ectoderm, is visible).

(Schoenwolf, G. C.; Bleyl, S. B.; Brauer, P. R.; Francis-West, P. H. Larsen's Human Embryology, 4th ed., Churchill Livingstone: Philadelphia, 2008.)

The formation of the primitive streak establishes the major body axes. Since the primitive node/pit lies at the cranial end of the primitive streak, the primitive streak defines the cranial–caudal axis. With the primitive streak being in the midline (i.e. most medial), the medial–lateral axis is thereby defined. When viewed from within the amniotic cavity, the midline primitive streak divides the embryo into the right and the left sides, hence defining the left–right axis. The early ectoderm–endoderm axis that is established with gastrulation before body folding defines the future dorsal–ventral axis (Figure 15-10).

FIGURE 15-10. Schematic diagram showing the derivation of tissues in human and rhesus monkey embryos. The dashed line indicates a possible dual origin of the extraembryonic mesoderm.

(Gilbert, S. F. Developmental Biology, 9th ed., Sinauer Associates, Inc.: Sunderland, MA, 2010.)

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780123838346000185

Pediatric Neurology Part II

Michel Zerah , Abhaya V. Kulkarni , in Handbook of Clinical Neurology, 2013

Embryology

The term spina bifida was suggested by Nicolas Tulp in his first description of MMC in 1651. It was proposed solely to describe a duplication of the spinous process of the vertebra. This term, as incorrect as it might be, is still used to describe any malformation occurring in the lower spine (Afonso and Catala, 2003).

Gastrulation

After fertilization and approximately five rounds of cell division, the human embryo comprises a spherical blastocele (the future placenta) and an eccentrically placed cluster of cells, the inner cell mass (the future embryo).

By the end of the first embryonic week, it will be composed of two layers, the epiblast and the hypoblast. This establishes a ventrodorsal axis.

During the second week a rostocaudal axis develops and the epiblast cells in the caudal region of the embryo migrate toward the midline to form the primitive streak. At the cranial end of the primitive streak lies the primitive knot or Hensen's node. Cells from the primitive streak and Hensen's node invaginate beneath the epiblast in a process known as gastrulation. This invagination creates a three-layered embryo (endoderm, mesoderm, and ectoderm). The ectodermal cells give rise to the surface ectoderm and the neuroectoderm or neuroepithelium. The regression of the primitive streak, the primitive pit, the notocordal canal, and the notocordal plate has been described in the avian embryo but is still debated in more evolved species (there is no evidence of neurenteric canal in mammals, for example). Some complex dysraphisms (myelomeningocele, split cord malformations) are related to this period of embryogenesis.

Primary neurulation

During the third embryonic week, the ectoderm forms two morphologically distinct tissues: the centrally located neuroectoderm and the more peripherally located cutaneous ectoderm (Catala et al., 1996). The neuroectoderm is visible on embryonic day 16. Between day 16 and day 28, the neuroectoderm undergoes a number of morphological changes, referred to as neurulation, to form the neural tube. A midline neural groove develops. Elevation, growing, and medial convergence of the neural folds brings the neuroectoderm together in the midline to form the neural tube. Fusion of the neural folds and separation from the overlying cutaneous ectoderm completes the process. This process starts at the middle part of the embryo and progresses rostrally to close at day 24–26 at the level of the anterior neuropore (future commissural plate lamina terminalis) and caudally to close 2 days later (caudal neuropore) at the level of the second sacral segment where it joins the process of secondary neurulation.

This entire primary neurulation is finished at the end of the 4th week.

Secondary neurulation

This involves a mechanism entirely different from primary neurulation. The most caudal part of the neural tube develops from a pluripotent group of cells. Secondary neurulation involves the independent formation and canalization of multiple secondary tubules from the caudal cell mass and subsequent fusion of adjacent tubules to form a secondary neural tube. It will eventually fuse with the primary neural tube (Catala, 1999).

Spinal occlusion

This begins at the time of the anterior neuropore closure (D24) and ends a week later. This begins the rapid growth of the neural tube and the dilatation of the ventricular system. Failure to maintain this spinal and spinal cord occlusion may produce myelomeningocele, and mesenchymal and brain anomalies referred to as the Chiari 2 malformation.

Ascent of the conus medularis

By approximately day 45 of gestation, the caudal end of the neural tube extends to the coccygeal spinal level. Thereafter, the caudal end of the neural tube begins to ascend to more cranial spinal levels. This involves two mechanisms: retrogressive differentiation and, more importantly, the differential growth between the spine and the spinal cord during embryonic and fetal life. By 1 or 2 months after birth, the conus medularis lies at its final location, opposite the L1–L2 disk space. Any problems during this relative ascent (i.e., secondary neurulation) can lead to a low and tethered spinal cord.

Embryology of myelomeningocele

Many theories have been discussed (nonclosure, reopening, overgrowth, overdistension) (Till, 1969; Lemire, 1983). The nonclosure theory has gained almost universal acceptance but there is no definitive evidence to refute the other theories. Numerous teratogenic agents and genetic disorders (trisomy 13 or 18, CHILD, Frazer, Waardenburg, Meckel–Gruber syndromes) have been identified that act on specific parts of the neurulation sequence to produce neural tube defects. Folate deficiency has also been identified as one of the main causes of open dysraphism and can be largely prevented by folate supplementation before conception and during the early stages of pregnancy.

Embryology of the occult dysraphisms

While it remains mostly unknown in humans, occult dysraphism involves a mechanism clearly different from that which causes MMC (Till, 1969; Lemire, 1983; Belzberg et al., 1991; Catala, 1998, 2002; Tortori-Donati et al., 2000; Li et al., 2001; Afonso and Catala, 2003; Finn and Walker, 2007; Muthukumar, 2009).

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780444529107000180

Pediatric Spine Surgery (Part I)

Pankaj K. Agarwalla BS , ... Edward R. Smith MD , in Neurosurgery Clinics of North America, 2007

Embryologic considerations

Although a lengthy discussion of embryology is not within the scope of this article (for a more thorough review, see Dias and McLone [23]), understanding the varied clinical manifestations of tethered spinal cord is enhanced by an appreciation of the relevant embryology. A considerable number of developmental errors can result in conditions that functionally tether the spinal cord. These congenital conditions, distinct from acquired causes of tethering (such as infection, tumor, or scar), can present in myriad ways and at different stages of a child's maturation. A working knowledge of the embryologic processes underlying these conditions can aid the neurosurgeon in understanding and avoiding the potential hazards intrinsic to the treatment of these children.

Notochordal development

In the first few weeks of development, neurulation begins with the formation of the notochord arising from the primitive pit [23]. The primitive pit subsequently recedes caudally while the notochord elongates cranially [23]. The notochord then undergoes intercalation, fusing with the underlying endoderm to form the notochordal plate. This plate is continuous with the yolk sac and also is continuous with the amniotic sac [23].

Primary neurulation

The notochord induces formation of the neural tube dorsally from the overlying ectoderm by means of the neural groove from days 18 to 24 after ovulation [24]. This process gives rise to the cervical, thoracic, and lumbar neural tube [25]. Somites develop from the paraxial mesenchyme and represent the majority of the future vertebral column at these levels as well [25]. Most relevant to the tethered cord in primary neurulation is the closure of the neural groove. The level of final closure of the caudal neuropore corresponds to the second sacral vertebral level (S2) [24], suggesting that spinal malformations arising from S2 or above probably result from disordered primary neurulation [23].

Secondary neurulation

During the time of primary neurulation, the primitive streak regresses to form the axial mesenchyme of the caudal eminence (also known as end-bud [24]), which extends from the site of the neurenteric canal to the cloacal membrane [25]. The caudal eminence provides the cells for the formation of the neural tube caudal to somite 31, corresponding to the future S2 level. Once primary closure is complete, secondary neurulation from the caudal eminence begins but not in the form of a folding neural plate as in primary neurulation. Rather, a "neural cord" forms with a central canal continuous with the more rostrally formed primary neural tube; this distinct process of secondary neurulation helps explain the clinically relevant pathophysiologic entity of caudal agenesis [24,26,27].

Ascent of conus and relationship with meninges

Beginning at postovulatory day 43 to 48, the conus medullaris "ascends" relative to the vertebral bodies through two mechanisms: (1) differential growth of bony vertebrae compared with the neural tissue of the spinal cord and (2) retrogressive differentiation during which the caudal cord loses much of its thickness and character [23]. The conus does not ascend throughout childhood and remains at approximately its birth position of L1-2; a cord at L2-3 or above is considered within normal range [28]. Wolf and colleagues [29], using ultrasound, found that the conus is still "ascending" from L2-4 to L1-2 during postmenstrual week 30 to 40 and generally achieves its normal position of L1-2 after postmenstrual week 40. The clinical relevance of these data is that any patient who has a conus found at L3 or below should be considered for evaluation of tethered cord syndrome.

In addition to the formation of the neural tube, the spinal cord must be invested with membranes and a vasculature. These generally are considered to be derived from the mesodermal layer, although there has been debate on their origins [30–32]. In both open and closed spinal dysraphisms, it is clear that the usual meningeal stratification often is abnormal, with the potential for improperly located tissue (eg, subdural extension of adipose tissue in lipomyelomeningocele). In abnormal development, therefore, the surgeon must be aware of unusual meningeal arrangements, both between the dura and the leptomeninges and between the dura and the conus.

This overview of the embryology helps explain the development of the abnormal anatomy that results in a tethered spinal cord. Although this information can be invaluable to understanding and interpreting physical findings and imaging studies, it is important to appreciate a distinction between the anatomic findings of a tethered spinal cord and the functional problems that produce the symptoms of tethered cord syndrome. Some of the symptoms that are part of the clinical presentation of these patients may be caused by intrinsic, congenital defects in the nerves and spinal cord, and, as such, cannot be remedied by surgical intervention. In contrast, some symptoms are secondary to reversible causes that are amenable to surgical treatment. It therefore is important for the treating physician to establish and document a baseline examination before undertaking any potential intervention to help distinguish between pre-existing and recurrent problems.

Read full article

URL:

https://www.sciencedirect.com/science/article/pii/S1042368007000290

Spinal Imaging: Overview and Update

John D. Grimme MD , Mauricio Castillo MD, FACR , in Neuroimaging Clinics of North America, 2007

Embryology

During the first stage of embryologic development (called the "pre-neurulation" stage), the primitive streak forms on approximately day 17 and consists of a longitudinal primitive groove and a primitive node (Hensen's node) with a central pit at the presumptive cranial end (Fig. 1 ). These structures are located on the dorsal (chorionic) surface of the bilaminar embryonic disc. At this time, there is an invagination of cells near the primitive streak between the epiblast (future ectoderm) and the endoderm, forming the mesoderm. This process is called gastrulation. The mesoderm cells that travel through the primitive pit and migrate cranially form the notochordal process (the notochord process initially is a hollow tube called the "notochordal canal"), which parallels the streak. The ventral aspect of the notochordal process fuses to the subjacent endoderm and opens ventrally from the region of the primitive pit, effectively unzipping itself and allowing for a transient communication between the yolk sac and amniotic (ventral surface) cavities. Anomalies at this stage include the so-called "split notochord" anomolies, of which the most common is diastematomyelia. The least common anomolies are intraspinal enteric cysts and fistulas. The open neural tube then flattens and is contiguous with the embryonic endoderm as the notochordal plate. At approximately day 23, the notochordal plate detaches from the neural tube (embryonic ectoderm) and is converted in the process to the definitive solid structure known as the notochord (by obliteration of the notochordal cavity) ( Fig. 2).

Fig. 1. Early development of the neural tube. At day 17, the primitive streak forms distal to the node. Cephalad to these structures is the neural plate; ventral to them the notochordal plate. At day 18 the plates enlarge, and by day 21 they extend from one fetal pole to the other. At this time the neural plate begins to curve dorsally and form the neural folds.

Fig. 2. Diagram illustrating notochordal development. (Top) (1): sagittal view through the embryonic disc shows the dorsal (amniotic) and ventral (yolk sac) surfaces of the disc. Note primitive pit and its extension ventrally. (Bottom) Four images are transverse sections at the level of the dashed line in top drawing. (2) The ventral aspect invaginates into the disc to form the notochordal process. (3) The notochordal process forms the plate. (4) The edges of plate approximate each other to fuse in the midline. (5) When the edges fuse completely, a round tube (notochord) is formed and is located between the amniotic and chorionic surfaces of the embryo.

The notochord does not form elements of the spinal column; however, it plays an important role in the induction of the vertebral bodies (via the para-axial mesoderm) and of the neural tube. Likely in response to induction from the underlying notochordal plate and prechordal plate, a focal area of thickening appears in the surface of the epiblast, called the neural plate. While the cranial portion of the neural plate forms the brain, the caudal portion, overlying the notochord, becomes the spinal cord.

The second stage of development is called "primary neurulation" (from day 17 to about day 28 of life) and is responsible for the formation of nearly 90% of the spinal cord. The caudal portion of the neural plate elongates rapidly from days 22 to 26, and there is a respective elongation of the underlying notochord. During this period, a groove forms along the central portion of the neural plate, and its lateral margins become thickened and raised. These thickened lateral margins are called the "neural crests." At these levels, a group of specialized cells (the neural crest cells) originate and later migrate ventrally to establish peripheral nerves and various mesodermal and vascular structures. The neural crests continue to fold in a concave fashion to meet in the midline and eventually close to form a tube-like structure (the "neural tube"). An increased gradient of bone morphogenic protein establishes the dorsal surface of the neural tube, while an increased gradient of sonic hedgehog gene locates the ventral aspect of the neural tube (therefore establishing the posterior and anterior surfaces of the spinal cord). The spine is established by the presence of repetitive segments called rhombomeres. The organization of these rhombomeres is highly preserved from lesser animals to human beings. These rhombomeres express a variety of genes whose presence aids in the organized development of the spine. Traditionally, the neural tube has been assumed to first fuse in its center and then to extend this closure cephalad and caudally in a zipper-like fashion. This mechanism fails to explain the presence of open spinal dysraphisms in sites other then the extremes of the neural tube. Thus, it is likely that neural tube closure occurs simultaneously at several sites also in a zipper-like manner. From this explanation, it is obvious that failure of primary neurulation results in "open" dysraphisms, which are a group of disorders in which a portion of the neural tube remains exposed and visible (the most common of these disorders is the myelomeningocele).

Once closure of the neural tube commences, it detaches itself from the overlying ectoderm in a process called "disjunction." Disjunction may occur before its appropriate time (so-called "premature disjunction") or late (so-called "incomplete disjunction"). A variety of disorders may arise from either of these two abnormal mechanisms.

The third and last stage in the development of the spine is called "secondary neurulation" and involves the formation of about 10% of the spine, all of it in the caudal-most region. In this process, the most important mechanism is that of "canalization and retrogressive differentiation." The distal-most notochord and neural tube merge inferiorly at the caudal cell mass. The undifferentiated cells in this mass give rise to the bones of the sacrum, coccyx, and probably the fifth lumbar vertebra. They induce cavitation of the distal neural tube until it contains only one central canal (canalization) (Fig. 3). This canalized tube regresses in a cephalad manner (ie, retrogressive differentiation), establishing the nerve roots and the conus medullaris. Complete regression of its cells leaves behind a strand that is made off only pia and ependyma (the filum terminale). Incomplete closure of the central canal in the conus medullaris results in the presence of a terminal ventricle. Exaggerated retrogressive differentiation may be one cause responsible for the caudal regression (or agenesis) syndrome. Maldifferentiation of the caudal cell mass may also contribute to the development of sacro-coccygeal teratomas.

Fig. 3. Secondary neurulation and persistent ventriculus terminus. (A) (1) The primitive cell mass (tiny arrows) begins to be vacuolated (V) and joins the spina cord (small arrows) superiorly but is separated from the cord's central canal (arrowhead). (2) The canalized caudal cell mass joins the central canal (arrowhead) and assumes a more tubular shape. (3) The caudal cell mass undergoes retrogressive differentiation and leaves behind the filum terminal (lower arrowhead). The central canal (superior arrowhead) is contiguous inferiorly with the terminal ventricle (long arrow). (B) Sagittal sonogram shows a prominent terminal ventricle (arrowhead). (C) An axial T2-weighted image (different patient) shows an incidentally found large terminal ventricle.

Read full article

URL:

https://www.sciencedirect.com/science/article/pii/S1052514906001183