Neurulation Case File

Neurulation Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 13

A 38-year-old pregnant woman arrives to the emergency room after her “water breaks.” On questioning, she admits to missing most of her prenatal care appointments, but remembers one of her blood tests was “high,” and believes that she is 4 weeks “early.” Initial examination demonstrates 6 cm of cervical dilation and increasing strength and frequency of contractions. Fetal heart rate monitoring reveals decelerations indicative of fetal distress, prompting delivery via cesarean section. The baby boy was delivered and had reassuring APGAR scores. He is able to move his head and arms, but the lower legs are motionless and contorted. Further examination reveals a 3-cm clear, fluidfilled sac in the mid-lower back.

• Describe the anatomic deformity.
• What is the underlying etiology of the fluid-filled sac?
• Which vitamin may decrease the incidence of this condition?

ANSWERS TO CASE 13: NEURULATION

Summary: A baby boy was delivered with flaccid distal lower extremities. Physical examination demonstrated moderate iliopsoas, hip adductors, quadriceps, and tibialis anterior function with flaccid antagonists resulting in hip adduction-flexion, knee hyperextension, and foot inversion. A thin-walled cystic mass arises from the surrounding skin of the upper lumbar spine. Mild hydrocephalus is noted. The mass is diagnosed as a myelomeningocele, a form of neural tube defect (NTD). The imaging also revealed an associated Chiari malformation and mild hydrocephalus.

• Anatomic deformity: Below the L4 level, the placode of tissue consists of dysplastic neural elements that were unable to form a closed neural tube. This dysfunction extends into the nerve roots emanating from the placode. The exposed neural elements remain covered in meninges, but are not covered by bone, muscle, or skin. Cerebrospinal fluid (CSF) fills the sac as it would normally fill the spinal canal in the nonpathologic state, but because of the paucity of overlying tissue, leakage of fluid is common.
• Underlying etiology: The etiology of NTDs is multifactorial and not clearly understood. NTDs constitute a variety of congenital malformations, as severe as anencephaly (complete absence of telencephalic structures) or as mild as a tethered spinal cord, which have at its core the failure of proper neurulation.
• Vitamin that decreases incidence of NTD: Approximately 400-800 μg of folate per day reduces the risk for both first occurrence of NTDs and recurrent NTDs.

CLINICAL CORRELATIONS

Congenital malformations of the brain occur in approximately 0.5% of live births. Causes are generally ascribed to exogenous and endogenous sources. Exogenous causes include nutritional factors, radiation, infections, chemicals, ischemia, and medications. Endogenous causes are mainly genetic. Defective neurulation, also called neural tube defects (NTDs), spinal dysraphisms or spina bifida (split spine), are among the most common of these congenital CNS malformations. Though the primary defect is a failure of neurulation and of the neuroectoderm, subsequent maldevelopment occurs in the adjacent mesoderm, which, in turn, is responsible for forming the appropriate skeletal and muscular structures surrounding the nervous system. Therefore, NTDs have been classically classified by the severity of this secondary mesodermal disruption: the more severe spina bifida aperta (neural structures communicate with the atmosphere) or the less involved spina bifida occulta (neural elements are skin covered).

Spina bifida aperta or open NTDs are clinically quite obvious, like myelomeningocele; however in spina bifida occulta, the lesion is covered by skin (closed NTD), therefore rendering the underlying neurological involvement occult or hidden. There may be subtle skin changes present: a hairy patch, dermal sinus tract, dimple, hemangioma, or lipoma. Besides cutaneous stigmata, closed NTD can present with: spinal defects (scoliosis or defects in the lamina), orthopedic deformities (clubbed feet or leg length asymmetry), urological problems (neurogenic bladder or incontinence), and/or neurological symptoms (leg pain, weakness, or numbness and sometimes atrophy or hyperreflexia).

Many suspected teratogens have been identified: radiation, infections, hyperthermia, valproic acid, and folate deficiency. Folate is vital during periods of rapid cell growth such as infancy and pregnancy, as it is needed to replicate DNA. Folate deficiency hinders DNA synthesis and cell division, affecting most clinically the bone marrow, a site of rapid cell turnover. Valproic acid is a known folate antagonist and its association with NTD may be through that action. Folic acid is not protective unless ingested during the time surrounding conception. Screening tests have made a significant impact—both serologic markers and imaging studies have proven utility. A blood test for maternal serum alpha-fetoprotein (AFP) between 15 and 20 weeks of gestation can reveal elevated levels, which can be indicative of an open NTD. In addition, the use of fetal ultrasonography can diagnose an NTD with nearly 98% specificity and 95% sensitivity. The prognosis for many forms of NTD is variable: anencephalic babies rarely survive more than a few hours or days and open NTDs like myelomeningocele have many associated anomalies. Hindbrain malformations (Chiari II), hydrocephalus, syringomyelia, as well as brain stem and cranial nerve malformations are all commonly associated with myelomeningoceles. These anomalies conspire to diminish the functional independence of many babies that survive to adulthood. Nevertheless, many individuals with mild NTDs can function independently.

APPROACH TO NEURULATION

Objectives

1. Understand the timing of events during neurulation.
2. Be able to relate the clinical result of developmental failure at various stages in neurulation.
3. Appreciate the role of teratogens in the etiology of NTDs.

Definitions

Neurulation: The developmental process by which the neural plate fuses into the neural tube. The process begins in the cervical region and progresses in both directions, first closing the rostral or cranial neuropore, followed by the caudal neuropore.

Primary neurulation: Refers to the transformation of the neural structures from a plate into a tube, thereby forming the brain and spinal cord. Failure of primary neurulation results in open NTDs.

Secondary neurulation: An independent process from primarily neurulation

that refers to the formation of the lower spinal cord from cells

derived from the embryological tail bud.

Spina bifida: Latin for “split spine,” another term to describe certain NTDs.

Anencephaly: Anencephaly or craniorachischisis is the most severe form of NTD, and refer to a severe deformity in which an extensive defect in the craniovertebral bone causes the brain to be exposed to amniotic fluid. The defect normally occurs after neural fold development at day 16 of gestation but before closure of the anterior neuropore at day 24-26 of gestation.

Encephalocele: An encephalocele represents herniation of the brain through a skull defect. This most commonly occurs in the occipital region in the United States, while in Asian countries, the frontal bone is most involved.

Myelomeningocele: A condition in which the spinal cord and nerve roots herniate into a sac comprised of the meninges. This sac protrudes through a bone and musculocutaneous defect. The splayed open neural structure is called the neural placode.

Meningocele: A meningocele is a herniation of only the meninges through the bony defect (spina bifida). The spinal cord and nerve roots do not herniate into the dural sac, as in a myelomeningocele. These lesions are important to distinguish from myelomeningocele because their treatment and prognosis are different from myelomeningocele. Neonates with a meningocele usually have normal findings upon physical examination and do not have associated neurological malformations such as hydrocephalus or Chiari II malformations.

Diastematomyelia: A split cord malformation in which a bony spur splits the spinal cord in two.

Tethered cord: Tethering of the spinal cord is caused by an abnormal adhesion or thickened filum that can cause traction on the spinal cord with subsequent neurological deficits as the child grows.

Hydrocephalus: Latin for “water head,” it is an abnormal accumulation of CSF within the cerebral ventricles because of physical obstruction (obstructive hydrocephalus) or inability to absorb (nonobstructive hydrocephalus) the circulating fluid.

Chiari malformations: Formerly called Arnold-Chiari malformations, are a series (types I-III) of hindbrain defects. Type I is characterized by the downward herniation of the cerebellar tonsils through the foramen magnum. A type II malformation is herniation of the cerebellar vermis and brainstem below the foramen magnum. The type III malformation is essentially a posterior fossa encephalocele with herniation of the cerebellum through the posterior fossa bone and is a more severe NTD.

Syringomyelia: Syringomyelia is a cavitation of the spinal cord leaving a cystic space within the cord, which can cause progressive neurological dysfunction. This cyst, called a syrinx, can expand and elongate over time and destroy the spinal cord.

DISCUSSION

NTDs include a wide range of clinical malformations: anencephaly, encephalocele, myelomeningocele, meningocele, diastematomyelia, and tethered cord. The lesions often present with associated failure of overlying bony structures to fuse, hence the common term spina bifida, Latin for “split spine.” The multiple descriptive names highlight the fact that these malformations involve not only the ectodermal derivatives (central and peripheral nervous system and skin), but also the other embryonic layers as well, most notably the muscle and bone formed from axial mesoderm.

Timing is critical during development—the earlier the developmental insult, the more devastating the consequences. In relation to NTDs, the first important process is primary neurulation, which refers to the formation of the neural structures into a tube, thereby forming the brain and spinal cord. Secondary neurulation refers to the formation of the lower spinal cord, which gives rise to the lumbar and sacral elements. The neural plate is formed at gestational days 17-19, the neural fold occurs at days 19-21, and the fusion of the neural folds occurs at days 22-23. Any disruption during these early processes (neural plate formation until fusion into a neural tube) can cause craniorachischisis, the most severe form of NTD. Subsequent events include the closure of the rostral neuropore at days 24-26. Failure at this point can result in anencephaly and encephaloceles. A myelomeningocele is a result of disruption occurring around days 26-28, during the closure of the caudal neuropore. After day 28, disruptions are unlikely to be able to cause an open NTD such as myelomeningocele, but may cause more subtle defects, like a closed NTD or tethered cord.

The molecular mechanisms that control neurulation are poorly understood. Experimental evidence suggests that the mechanisms involved in cranial neurulation and closure of the cranial neuropore differs from the closure process at subsequent axial levels. As the flat neural plate physically invaginates and cavitates to form a tube, it is not surprising that aspects of cellular polarity (to direct the movement of cells), cellular cytoskeleton (to dynamically change the shape of cells), and intercellular adhesion (to fuse the neural folds together) are all critical for proper neurulation.

Various studies have provided evidence for abnormal folate metabolism in cell lines from a subset of fetuses affected by NTDs, explaining why prenatal folate is so crucial for decreased incidence of NTDs; however, the specific abnormalities have yet to be elucidated. The recommended daily allowance of folate for women of reproductive age is 400 μg while for pregnant women it is 600-800 μg. Foods that contain folate include leafy vegetables such as spinach and turnip greens, dried beans and peas, fortified cereal products, and sunflower seeds. Normal folate metabolism begins with folate being reduced first to dihydrofolate and then tetrahydrofolate by the enzyme dihydrofolate reductase.

Treatment options

Initial management of an infant with a myelomeningocele with leaking CSF is to avoid trauma to the exposed neural placode and roots. Prolonged exposure increases the risk for CNS infections manifested as meningitis or encephalitis, sometimes leading to systemic sepsis. Surgical closure and repair of the lesion by a pediatric neurosurgeon is required. Additional placement of a ventriculoperitoneal shunt to treat the hydrocephalus and prevent spinal fluid leakage from the repair site can be done contemporaneously. Multiple other developmental anomalies are associated with NTD, which would need to be addressed by a multidisciplinary team to include a geneticist, urologist, orthopedic surgeon, physical medicine specialist, and a pediatric neurosurgeon.

COMPREHENSION QUESTIONS

[13.1] A baby is born to a 17-year-old G1P1 with poor prenatal care who admits to not taking her prenatal vitamin supplements. On examination immediately following birth, the child is noted to have a cystic swelling over the lower back in the midline, but appears to have both motor and sensory modalities intact in both lower extremities. The child is diagnosed with a meningocele. A failure of what neurodevelopmental event results in this defect?

A. Closure of the cranial neuropore

B. Closure of the caudal neuropore

C. Formation of the neural tube

D. Separation of the prosencephalon into paired telencephalons

[13.2] Which of the following decreases the risk for development of NTDs?

A. Decreased maternal AFP

B. Previous history of NTDs

C. Folate deficiency

D. Radiation exposure

E. Maternal valproic acid exposure

[13.3] A myelomeningocele is most likely to be a result of a neurulation defect that occurs during which gestational period?

A. Days 19-21

B. Days 22-23

C. Days 24-26

D. Days 26-28

E. Days 28-30

Answers

[13.1] B. Failure of the neural tube to close results in an NTD. Failure of closure of the cranial neuropore results in anencephaly, in which the brain is not formed, a condition not compatible with life. Failure of closure of the caudal neuropore results in a spectrum of NTDs, ranging from occult spina bifida to meningocele to myelomeningocele. Failure of the entire neural tube to form would result in spontaneous abortion of the developing embryo, and a failure of prosencephalon to separate results in a condition known as holoprosencephaly.

[13.2] A. Increased, not decreased, AFP has been associated with open NTDs. A previous history of a child with an NTD, folate deficiency, radiation exposure, and maternal use of valproic acid are all additional risk factors.

[13.3] D. Disruption of the closure of the caudal neuropore around days 26-28 is responsible for development of a myelomeningocele.

NEUROSCIENCE PEARLS ❖ The process of neurulation involves multiple sequential steps. ❖ NTDs result from failure of proper neurulation. ❖ Central nervous system neurulation is linked with the development of vertebral bone and skeletal muscle, derived from the axial mesoderm.

REFERENCES

Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. NEJM. 1992;327:1832-1835. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 1991. 

MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137. 

Rao MS, Jacobson M, eds. Developmental Neurobiology. 4th ed. New York: Kluwer Academic/Plenum Publishers; 2005. 

Sadler TW, eds. Langman’s Medical Embryology. 7th ed. Baltimore, MD: Williams and Wilkins; 1995. 

Wyszynski DF, ed. Neural Tube Defects: From Origin to Treatment. New York: Oxford University Press; 2006.

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