Embryology and developmental anatomy can be complex topics, but it is important to understand the basics to translate to disease pathology and to do well on neurology exams. This chapter review contains helpful text and diagrams, and a practice quiz.

Authors: Matthew Ginsberg MD, Brian Hanrahan MD

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Neural development

  • All neuronal tissue is derived from the ectoderm germ layer.
  • The notochord (mesoderm) induces the overlying neuroectoderm to differentiate into the neural plate at 18 days gestation.
    • The notochord becomes part of the intervertebral discs in final development
  • During the 3rd-5th weeks of gestation, the neural plate invaginates to form the neural tube (Figure 1).
    • Neurulation occurs in two phases: Primary neurulation (dorsal induction) and secondary neurulation (caudal induction).
      • Defects of primary or secondary neurulation will lead to various cortical and spinal cord malformations.
    • The neural tube develops into the brain, brainstem, spinal cord, and preganglionic sympathetic neurons.
    • During this time the fetus is most at risk for neural tube deficits (NTD).
      • Folate deficiency, valproic acid, and carbamazepine are known to cause NTDs, especially spina bifida.
    • The ventral aspect of the neural tube is the basal plate.
    • The dorsal aspect of the neural tube is the alar plate.
  • By week 10, the basal plate (ventral) of the neural tube becomes motor neurons of the cranial nerve and anterior horn gray matter while the alar plate (dorsal) becomes posterior horn gray matter and sensory neurons.
  • Neural crest cells that border the neural tube lead to the growth of the peripheral nervous system: Schwann cells, neuroglial cells, parasympathetic, and postganglionic sympathetic fibers.
    • Neural crest cells also develop into melanocytes, pia and arachnoid, thyroid, and teeth.

                                                                                  Figure 1: Early Embryonic Development of Nervous System

Diagram of Neuronal Development from the Notochord
Neuronal Development from the Notochord
 

Breakdown of the developing brain

  • There are three primary vesicles of the developing brain at 4 weeks:
    • Forebrain (prosencephalon): Develops into the telencephalon and diencephalon.
    • Midbrain (mesencephalon)
    • Hindbrain (rhombencephalon): Develops into the metencephalon and myelencephalon.
  • By 5 weeks, these develop into five secondary vesicles:
    • Telencephalon: Develops into the cerebral hemispheres, basal ganglia, hippocampus, and amygdala.
    • Diencephalon: Develops into the thalamus, hypothalamus, and retina.
    • Mesencephalon: Develops into the midbrain.
    • Metencephalon: Develops into the pons and cerebellum.
    • Myelencephalon: Develops into the medulla.

Figure 2: Primary and Secondary Vesicle Stages of Development

Diagram of embryologic development of the brain neurology exam review
Embryologic Development of the Brain

Layers of the developed neocortex

  • From superficial to deep:
    1. Molecular layer (most superficial)
    2. External granular layer
    3. External pyramidal layer
    4. Internal granular layer
    5. Internal pyramidal layer
    6. Multiform layer (deepest layer)

Myelination

Central nervous system

  • In utero myelination starts at 14 weeks gestation with the majority occurring in the 3rd trimester.
  • At the time of birth, only components of major sensory and motor systems are well myelinated.
  • Subcortical U fibers start to myelinate around 8 months of life, but are the slowest myelinating fibers, and do not complete myelination until around the second decade of life.
    • U fibers are spared in many congenital leukodystrophies (X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, phenylketonuria, maple syrup urine disease), but can be affected in disorders where direct damage to cells that have already been successfully myelinated occurs (MS, PML, ADEM, Canavan disease, Alexander disease).

Peripheral nervous system

  • Myelination is completed around 3-5 years of age.
    • If a nerve conduction study is performed, action potential conduction velocities will be 50% slower than an adult.
  • Motor roots myelinate before sensory roots.

Developmental malformations of the central nervous system

Congenital dermal sinus

  • A dermal sinus is a tract of squamous epithelium that travels from the skin to the dura of the spinal cord.
    • Lesions are found midline and most often in the lumbar or lumbosacral region.
    • Half of the dermal sinuses are associated with dermoid or epidermoid tumors.
  • Lesions occur due to the failure of differentiation between cutaneous ectoderm and neuroectoderm in the 4th week of development.
  • Patients will present with recurrent meningitis, tethered cord, or cord compression.
  • Complete excision of the tract is required to prevent meningitis or intraspinal abscesses.
    • The sinus acts as a portal for bacteria to enter the central nervous system.

Neural tube disorders (NTD)

  • Neural tube disorders occur during the 4th week of gestation during the closure of the neural tube
  • Causes: Genetic factors, folate/B12 deficiency, valproic acid, and carbamazepine exposure.
  • Craniorachischisis: Complete failure of neural tube formation leading to both anencephaly and extensive spina bifida.

Anencephaly

  • A failure of anterior neural tube closure.
  • Usually incompatible with life.

Encephalocele

  • Defect of cranial mesoderm development which leads to a skull defect with protrusion of both meninges and brain.
  • Associated with Meckel-Gruber syndrome.

Meningocele

  • A pathological opening of the vertebral column in which meninges protrudes through the skeletal defect. No neurologic tissue is herniated outside the spinal cord.

Myelomeningocele (open spina bifida)

  • This occurs due to incomplete closure of the caudal neural tube (Figure 3).
  • Meninges and spinal cord are both herniated through the defect in a covered membrane. The patient will usually present with significant neurologic impairment.
  • If the spinal contents are not covered in a membrane it is called myeloschisis.

Figure 3: Normal spine, meningocele, and myelomeningocele

Spina bifida occulta

  • Abnormality is limited only to incomplete closure of the vertebrae with an overlying tuft of hair or dimple. These lesions tend to be asymptomatic.

Chiari malformations

  • Type I:
    • Imaging will show downward displacement of the cerebellar tonsils at least 5 mm beyond the foramen magnum.

  • Type II:
    • Imaging will also show displacement of the cerebellar tonsils as well as the brainstem. Patients can also have a myelomeningocele and are at risk of developing hydrocephalus.

(Type III and IV are not asked often on the shelf, in-service, or board exams)

  • Both type I and type II Chiari malformations are associated with syringomyelia, which is an enlargement of the central canal of the spinal cord.
    • If symptomatic, patients will complain of loss of pain in a “cape-like” distribution due to damage of the crossing spinothalamic fibers and arm weakness due to damaged anterior horn cells.
Chiari 1 Malformation with Holocord Syrinx
Chiari 1 Malformation with Holocord Syrinx

Malformations of cortical development

Disorders of cell proliferation/apoptosis:

  • Focal cortical dysplasia (FCD) with balloon cells
    • FCD can arise from different mechanisms in early development, based on the type and classification system used. For example, FCD with abnormal radial cortical lamination, without balloon cells (FCD Type Ia) occurs typically due to abnormal cortical organization including neuronal migration, while FCD with balloon cells (FCD-type IIb) occurs secondary to abnormal neuronal and glial proliferation during development.
  • Megalencephaly
  • Microcephaly

Image Gallery of Cell Proliferation/Apoptosis Disorders:

Disorders of cell migration:

Lissencephaly:
  • A complete absence of cortical sulci results in a smooth, cerebral cortex.
  • Most commonly due to a genetic defect (LIS-1 or XLIS genes).

Image Gallery of Cell Migration Disorders:

Disorders of cortical organization:

Polymicrogyria:

  • Often seen as part of a multi-systemic syndrome.
    • Can be seen with Zellweger’s syndrome.
  • Imaging will show excessively small gyri with shallow sulci.
  • Patients will often have developmental delay and seizures.

Schizencephaly:

  • Also known as “cleft brain”.
  • Caused by disruption of the cortical mantle leading to a cleft in the cortex that extends from the lateral ventricle. Possible injuries include prenatal infection, ischemia, or chromosomal abnormalities.
    • Closed-lipped (Type 1) schizencephaly will have a lesion that isn’t open to subarachnoid space.
    • Open-lipped (Type 2) schizencephaly will have lesions where the edges are not fused, leading to cleft exposure to subarachnoid space.

Gallery of Cortical Organization Disorders:

Midline patterning defects

Holoprosencephaly (HPE)

    • Caused by the failure of the prosencephalon to develop midline structures.
    • Severe cases will have a failure of separation of the cerebral hemispheres.
      • Other defects include midline facial anomalies (cyclopia), an absence of the olfactory system, agenesis of the corpus callosum, fused thalamus, and atypical ventricular structure.
    • Known to be caused by gestational diabetes, fetal alcohol syndrome, and genetic abnormalities.
      • Trisomy 13 is the most common genetic cause of HPE (40% – 60% of HPE of all causes and 75% of HPE due to chromosome abnormality).
      • Less common chromosomal causes include trisomy 18 and full triploidy.

Agenesis of the corpus callosum

    • Can occur alone or in the context of other developmental abnormalities such as holoprosencephaly.
    • Imaging will show a lack of callosal white matter and a dilated third ventricle.
Corpus Collosum Dysplasia
Corpus Callosum Dysplasia

Septo-optic dysplasia (DeMorsier syndrome)

  • Patients will present with symptoms secondary to optic nerve hypoplasia, absence of olfactory bulbs and tracts, pituitary gland dysfunction, and absence of the septum pellucidum.
    • Short stature, hypotelorism, endocrine dysfunction, vision deficits, intellectual disability, anosmia, etc.

Image Gallery of Midline Pattern Defects:

Cerebellar-specific malformations

Joubert syndrome

    • A genetic disorder that presents with cerebellar dysfunction, hyperpnea, and intellectual delay.
    • Imaging will show agenesis/underdevelopment of the vermis with the “molar tooth” sign.
Joubert Syndrome
Joubert Syndrome

Dandy-Walker malformation

    • Imaging will show agenesis of the cerebellar vermis, cystic dilation of the fourth ventricle, and elevation of the tentorium.
    • Can be associated with other cerebral malformations.

Other congenital malformations

Arachnoid cyst

    • A space-occupying collection of CSF due to abnormal formation of the leptomeninges.
    • If located in the Sylvian fissure, it can appear “box” shaped.
    • On imaging, the cyst would be isointense to CSF on all sequences.
    • Tend to be clinically silent and only found incidentally.

Porencephalic cyst

    • A cavity in brain tissue due to early intrauterine vascular injury or infection.
    • The cyst is smooth-walled and not lined by cortex, unlike schizencephaly.

Hydranencephaly

    • Imaging will show a large central cyst with a lack of cortical tissue in anterior circulation-supplied areas.
      • The cerebellum, midbrain, and basal ganglia tend to be preserved.
    • Due to a severe hypoxic/ischemic insult early in development.

Hemimegalencephaly

    • Unilateral enlargement of cortex parenchyma with thickened or duplicated grey matter.
    • Patients develop epilepsy, intellectual disability, and hemiparesis. If epilepsy is medically refractory, hemispherectomy can be considered.

Congenital aqueductal stenosis

    • Most commonly due to stenosis of the aqueduct of Sylvius (the narrowest part of the CSF pathway).
    • If symptomatic, patients will present with symptoms secondary to hydrocephalus
      • Headache, nausea, visual disturbances, altered mental status.
      • Enlargement of the circumference of the head if occurs in the first year of life.
    • Imaging will show a narrowing of the aqueduct as well as enlargement of the third ventricle and possibly the lateral ventricles.

  • Treatment: Ventriculo-peritoneal shunt or ventriculostomy.

Many disorders of early childhood development are metabolic and/or genetic. See our Neurogenetics and Toxicology and Metabolic Disease chapters for more!

References

  1. Abdel Razek, A. A. K., et al. (2009). “Disorders of Cortical Formation: MR Imaging Features.” American Journal of Neuroradiology Jan 2009, 30 30(1): 4-11.
  2. Aguilar-Roca, N. Essential Physiology. OpenStax CNX. Jun 14, 2017 Download for free at http://cnx.org/contents/[email protected].
  3. Cinalli, Giuseppe, et al. “Hydrocephalus and Aqueductal Stenosis.” Pediatric Hydrocephalus, 2005, pp. 279–293., doi:10.1007/978-88-470-2121-1_19.
  4. Copp, Andrew J., and Nicholas D. E. Greene. “Neural Tube Defects-Disorders of Neurulation and Related Embryonic Processes.” Wiley Interdisciplinary Reviews: Developmental Biology, vol. 2, no. 2, 2012, pp. 213–227., doi:10.1002/wdev.71.
  5. Fernández, Alfredo Avellaneda, et al. “Malformations of the Craniocervical Junction (Chiari Type I and Syringomyelia: Classification, Diagnosis and Treatment).” BMC Musculoskeletal Disorders, vol. 10, no. Suppl 1, 2009, doi:10.1186/1471-2474-10-s1-s1.
  6. Kang, Peter B. “Pediatric Nerve Conduction Studies and EMG.” The Clinical Neurophysiology Primer, pp. 369–389., doi:10.1007/978-1-59745-271-7_22.
  7. Schacter S. Risks associated with epilepsy and pregnancy. In:  UpToDate,  Post TW (Ed),  UpToDate, Waltham,  MA. (Accessed on 4/14/2018.) https://www.uptodate.com/contents/risks-associated-with-epilepsy-and-pregnancy.
  8. Singh I, Rohilla S, Kumar P, Sharma S. Spinal dorsal dermal sinus tract: An experience of 21 cases. Surg Neurol Int. 2015;6(Suppl 17):S429–S434. Published 2015 Oct 7. doi:10.4103/2152-7806.166752.
  9. Venkataramana NK. Spinal dysraphism. J Pediatr Neurosci. 2011;6(Suppl 1):S31–S40. doi:10.4103/1817-1745.85707
  10. Riley, K. J., O’Neill, D. P., & Kralik, S. F. (2018). Subcortical U-Fibers: Signposts to the Diagnosis of White Matter Disease. Neurographics, 8(4), 234-243.
  11. Solomon, Benjamin D et al. “Holoprosencephaly due to numeric chromosome abnormalities.” American journal of medical genetics. Part C, Seminars in medical genetics vol. 154C,1 (2010): 146-8. doi:10.1002/ajmg.c.30232
  12. Tekendo-Ngongang C, Muenke M, Kruszka P. Holoprosencephaly Overview. 2000 Dec 27 [Updated 2020 Mar 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

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