Embryology, Central Nervous System

Development

Embryogenesis: Weeks 2 to 8

Beginning with the trilaminar germ disc, which refers to the epiblast and hypoblast, the epiblast cells undergo an epithelial-mesenchymal transition that replaces the hypoblast. They also proliferate in the middle layer to form the mesoderm, where they remain mesenchymal and differentiate into connective tissue. The primitive streak then appears superiorly from the thickened region of the ectoderm. It grows caudal to the cranial and induces notochord formation. The ectoderm then invaginates as cells migrate to form the primitive node and primitive pit, where the notochordal process is formed.

1. The primitive pit is a depression at the center of the primitive node, which is an opening in the notochordal canal.
2. Neurulation refers to the folding of the neural plate. The neural plate folds, via induction from the notochord, into the neural tube, which then becomes the neuroectoderm, which finally forms the CNS, namely the brain and spinal cord; the brain from the cranial two-thirds of the segment and spinal cord from the caudal one-third of the segment.
3. Neural Crest cells form dorsal root ganglia and connective tissue in the head and neck.
4. The notochord defines the longitudinal axis of the embryo and contributes to parts of the intervertebral discs, but it does not form the spinal cord or vertebrae. The notochordal process develops above the primitive node and elongates caudally, extending toward the cranial end of the embryo.

The CNS is derived from the neuroectoderm: the notochord induces the formation of the neural plate (thickening of the ectodermal layer), which further differentiates into neural folds with a neural groove between them, leading to the formation of the neural tube (via neurulation).

Spinal Cord

The spinal cord is formed from the neural plate and now contains 3 layers:

1. The ventricular layer that lines the central canal.
2. The mantle layer contains neuronal bodies, which eventually form the gray matter.
3. Marginal layer that contains axons and eventually forms the white matter.[3][4]

While this topic summarizes the embryological changes that occur within the CNS, the peripheral nervous system (PNS) is formed from neuroepithelial cells. These cells travel from the pia mater to the ventricular layer of the spinal cord, where they differentiate and migrate to form glioblasts (support cells, Schwann cells), neurons, and ependymal cells. As this information is often tested on boards, the myelin sheath, composed of support cells, wraps around axons and insulates neurons, increasing the speed of neuronal conduction.

1. Myelination of peripheral axons occurs via the neurolemma, which arises from Schwann cells (derived from neural crest cells).
2. Myelination of CNS axons occurs via oligodendrocytes, which are neuroepithelium derivatives.

Three membranous layers cover the whole CNS:

1. Dura mater: derived from surrounding mesenchyme and is tough and durable.
2. Arachnoid mater: derived from neural crest; forms as a single layer with Pia mater.
3. Pia mater: derived from neural crest; intimately covers the CNS.

Brain

During brain formation, there are 3 primary brain vesicles that differentiate into 5 secondary brain vesicles (see Image. Brain Vesicles).

1. Prosencephalon, which becomes the forebrain: This later develops into the cerebral hemispheres, which contain structures underneath, such as the epithalamus, thalamus, and hypothalamus. This section of the brain is responsible for consciousness, sensorimotor transformation, and sensory integration.
2. Mesencephalon, which becomes the midbrain: This part of the brain undergoes little structure reorganization compared to the spinal cord and other brain vesicles.
3. Rhombencephalon, which becomes the hindbrain: This part can be further divided into 3 segments:

1. Metencephalon: The dorsal growth of the cerebellum (integrates sensory information to fine-tune output)
2. Caudal myelencephalon: Similar to the structure of the spinal cord with a “closed” central canal of Medulla
3. Rostral myelencephalon: “Open part” of medulla; cerebrospinal fluid is produced via choroid plexus and leaks into the subarachnoid space.

Finally, the hypophysis gives rise to the pituitary gland, which has 2 origins. The posterior pituitary is an outgrowth of the hypothalamus and, therefore, has a direct connection. On the other hand, the anterior pituitary is an ectodermal growth from the mouth. It depends on a dense capillary network and communicates with the brain via the vascular system.[5][6]

Testing

Non-invasive prenatal testing can be performed as early as 10 weeks of gestation and analyzes cell-free DNA in maternal plasma to help identify certain fetal anomalies or genetic conditions. Amniocentesis, typically performed between 14 and 20 weeks, involves sampling amniotic fluid and serves as a diagnostic test to screen for fetal anomalies. First-trimester testing assesses the risk of trisomy 21, trisomy 18, trisomy 13, and other neural tube defects. Alpha-fetoprotein levels in amniotic fluid are elevated in central nervous system and ventral abdominal wall anomalies and decreased in fetuses with trisomy 21, trisomy 18, or other chromosomal defects. Anatomy sonography can be performed throughout pregnancy, with particular emphasis between 16 and 22 weeks, to estimate fetal weight and gestational age using measurements of head circumference, biparietal diameter, femur length (from epiphysis to epiphysis), and abdominal circumference. Although beyond the scope of this topic, a Quad-screen test can also be performed in the second trimester. The components of this screening test include alpha-fetoprotein, hCG, Estriol, and Inhibin-A.[7]

Pathophysiology

Embryogenesis can be complex and may result in mild or severe defects (pathophysiological changes). Teratogenesis is defined as any external factor that can influence the growth of the embryo. Embryos are highly susceptible and critical between weeks 3 and 8, when organ systems develop. Dysraphism is the failure of fusion between the symmetric halves of an anatomical structure. These include, and are not limited to, spina bifida malformations.

1. Spina bifida occulta occurs when the vertebral column fails to fuse, but other layers develop normally. It is the least severe form of dysraphism and usually affects the lumbosacral region (S1 to S2 most commonly). It can be associated with moles, angiomas, lipomas, and abnormal hair growth in the affected area.
2. Spina bifida aperta occurs when there is an incomplete fusion of the skin with or without a cyst. The spinal cord is still covered by the arachnoid mater, thus preserving the subarachnoid space and preventing leakage of the cerebrospinal fluid.
3. Spina bifida cystica is the most severe form of dysraphism. Patients may develop urinary or fecal incontinence. 80% of these lesions occur in the lumbosacral region.

Dysraphism in the cranium causes malformations analogous to spina bifida:

1. Encephalocele: Protrusion of the brain into the subarachnoid space. It can be associated with Chiari III malformation, in which part of the cerebellum protrudes, and the spinal cord becomes twisted. This is commonly associated with cleft lip and palate.
2. Anencephaly is characterized by the absence of the cerebral cortex and thalamic structures, with the cerebellum, brainstem, and spinal cord present (though they may be deformed). This can occur due to failure of notochord signaling, which is necessary for median hinge point formation or for the induction of neural crest cell maturation.
3. Holoprosencephaly: Failure of features to form along the midline of the face. Features include a single central incisor, cyclopia, or an unpaired cerebral hemisphere.
4. Craniorachischisis totalis is when the entire neural plate fails to fold, and the CNS is open to the amniotic cavity. These are often associated with stillborn fetuses.[8]

Clinical Significance

Pathophysiological processes that can occur during embryogenesis are rare and do not occur very often; when they do, the newborn is alive rather than stillborn. However, the newborn may require certain surgeries to correct the craniofacial anomalies before significant damage occurs.[9] Furthermore, those babies born with spina bifida require further evaluation with an ultrasound and surgical correction of the spinal cord to prevent herniation or other complications. Clinically, to avoid abnormal embryonic development, the mother should avoid teratogens or any external factors that can influence the baby's growth, especially during weeks 3 through 8 of embryogenesis. Significant teratogens include alcohol, tobacco use, certain prescription drugs, and illicit drugs. Most importantly, women seeking to get pregnant or who are pregnant take multivitamins, especially folic acid supplements to aid with neurodevelopment.[10]