Peripheral Nervous System Case File

Peripheral Nervous System Case File

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

CASE 12

A 32-year-old mother brings in her 5-day-old newborn boy for his first postnatal checkup. The pregnancy was uneventful—all the screening tests were normal, he was born after a full-term gestation via vaginal delivery without complication, and height, weight, and head circumference were of average size. The mother remarked that her son has been increasingly difficult over the last 2 days. He has been breast-feeding well, but has started to spit up more of his feedings. She is also concerned about his lack of bowel movements. He averages 10 wet diapers a day, but has only had one small watery soiled diaper since he left the hospital. Initial physical examination revealed a crying, but normal-appearing infant with a moderately distended abdomen. Rectal examination revealed an empty rectal vault and abnormal muscle tone. An abdominal x-ray was obtained that demonstrated a distended colon up to the transverse colon with gas and feces present. The diagnosis is determined to be Hirschsprung disease, which results from the absence of parasympathetic ganglion neurons in the myenteric and submucosal plexus of the rectum and/or distal colon. Without these neurons, the gut musculature remains tonically contracted, unable to distend.

• What is the cause of the patient’s symptoms?
• What is the underlying mechanism causing the symptoms?

ANSWERS TO CASE 12: PERIPHERAL NERVOUS SYSTEM

Summary: A baby boy presents with a progressive history of constipation, vomiting, and abdominal distention. Initial plain radiograph imaging confirms large bowel obstruction with proximal dilation with gas/feces. Further radiographic images taken during a barium enema study confirm obstruction at the mid-transverse colon. A diagnosis of congenital aganglionic megacolon or Hirschsprung disease is made. A rectal biopsy is performed that demonstrates a lack of ganglion neurons in the myenteric plexus and increased acetylcholinesterase staining—pathognomonic for Hirschsprung disease.

• Cause of the patient’s symptoms: The abdominal obstruction is caused by a lack of nervous system control of the intestinal musculature. Normal gut function requires motility that is mediated by the peripheral nervous system (PNS).
• Underlying mechanism: The neurons that are fated to innervate the distal gut travel along the vagus nerve (cranial nerve X) to populate the enteric gut plexus. It is failure of neurons to successfully navigate this distant trip that results in Hirschsprung disease.

CLINICAL CORRELATIONS

Congenital aganglionic megacolon or Hirschsprung disease was first recognized in 1886 as a cause of constipation in early infancy. The ganglion cells that innervate the enteric nervous system are derived from neural crest cells. These cells are of ectodermal origin and form along the lateral “crest” as the neural plate undergoes neurulation. They have multiple fates, with some forming the autonomic ganglia in the PNS. A subset of these cells travels with the vagus nerve along the intestinal tract to populate the enteric plexus. These ganglion cells arrive in the proximal colon by 8 weeks of gestational age and in the rectum by 12 weeks of gestational age. Arrest in this migration leads to an aganglionic segment and Hirschsprung disease. Hirschsprung disease occurs in around 1 in 5000 live births in the United States. It is associated with enterocolitis in about one-third of cases, which represents the majority of the mortality. More severe cases are diagnosed in neonates with signs and symptoms of bowel obstruction and inability to pass meconium or stool. Milder cases are diagnosed at later ages with chronic constipation, abdominal swelling, and malnutrition (decreased growth). Most cases are sporadic in nature, though a family history of a similar condition is present in up to 30% of cases. Male cases outnumber female cases four to one. A strong association exists with Down syndrome—5%–15% of patients with Hirschsprung disease also have trisomy 21. Mutations in a variety of genes have been associated with Hirschsprung disease: the Ret proto-oncogene, glial cell-derived neurotropic factor (GDNF), the endothelin-signaling system, and Sox10 (sex determining region Y-box).

APPROACH TO PNS DEVELOPMENT

Objectives

1. Relate the various PNS developmental structures.
2. Understand the sequence of steps involved in PNS formation.
3. Understand the tissue-specific signals involved.

Definitions

PNS: The part of the nervous system that is not a part of the CNS, that is, everything except the brain and spinal cord. It can be subdivided into somatic and autonomic components.

Somatic nervous system: Composed of efferent nerves that control skeletal muscle and external sensory receptors, as well as afferent nerves that convey sensory information from skin and muscle receptors.

Autonomic nervous system (ANS): Composed of efferent and afferent nerves that control/regulate homeostatic processes and internal organ physiology. The ANS can be further subdivided into the sympathetic and parasympathetic systems.

Neural crest cell (NCC): An ectodermal-derived cell originating at the lateral edge of the neural plate. As the neural folds rise up and fuse to form the neural tube, the NCCs are brought together along the dorsal “crest” of the tube. These cells then dissociate from the neuroepithelium, allowing them to migrate throughout the organism to form the PNS.

Ectodermal placode: These placodes are discrete areas of thickened ectoderm that appear on the heads of all embryos and develop into the peripheral sensory nervous system. Along with NCC, these placode cells form the PNS.

Epithelio-mesenchymal transformation: A critical step in the differentiation of neural crest cells as they separate from the neuroepithelium. This delamination process is mediated by changes in the cell–cell and cell–intracellular matrix interactions.

DISCUSSION

The entire PNS of vertebrates is descended from two embryonic cell populations: the neural crest and the cranial ectodermal placodes. Both cell populations form at the lateral border of the neural plate, with the placodes occupying the most rostral end of the neuraxis while the neural crest start at the level of the diencephalon and descend caudally. They both give rise to a vast assortment of cell types. Neural crest cells form a tremendous array of different cell types: bone and cartilage in the head, teeth, endocrine cells (adrenal medulla), peripheral sensory neurons (including the dorsal root ganglia neurons), all peripheral autonomic neurons (enteric, postganglionic sympathetic, and parasympathetic neurons), all peripheral glial cells, and all melanocytes. Cranial ectodermal placodes are mainly responsible for the numerous peripheral sensory organs in the head, including olfaction, mechanosensory hair cells, trigeminal sensation to the head, taste, as well as all the endocrine cells in the anterior pituitary.

The neural crest development into the PNS is characterized by a complex program of events that can be summarized into three stages: induction, migration, and differentiation. The neural plate is defined by early BMP signaling from axial mesoderm (see Chapter 11), and in much the same way, neural crests are induced by signals from paraxial mesoderm. These signals appear to involve intermediate levels of the BMP inhibitors, noggin and follistatin. Additional factors involving fibroblast growth factor (FGF) and the Wnt gene family continue the process of forming neural crest. The epithelial-mesenchymal transition is the last step in defining a neural crest cell, without which the cell is not a bona fide neural crest cell. Multiple signals and genes contribute to this transformation; however, it appears again that BMP signaling is implicated. This delamination process proceeds in a rostral to caudal direction.

Neural crest cells now must migrate to their target tissues. Cranial neural crest cells are observed to travel in characteristic streams associated with the branchial arches as coherent populations. The paraxial mesoderm again plays a vital role in providing the cues (mainly repulsive) to guide the traveling cells. The extracellular matrix plays an important role by providing a permissive pathway for migration. In the rest of the body, the paraxial mesoderm develops into repeating units, called somites. Somites are masses of mesoderm distributed along the two sides of the neural tube that will eventually become dermis, skeletal muscle, and vertebrae. These segmented somites define levels along the rostrocaudal axis. Approximately 44 somites form and give rise to the bones of the face, vertebral column, associated muscles, and overlying dermis.

For the final step in development, the neural crest must assume its final identity through differentiation. There are two main theories to explain the lineage segregation of neural crest cells: instruction and selection. The first theory (instruction) posits that the neural crest is a homogenous group of multipotent cells whose differentiation is instructed by environmental signals. The second theory (selection) holds that the neural crest is a heterogeneous population of predetermined cells, which are selected to survive in permissive environments, and eliminated from inappropriate ones. The experimental evidence suggests that both multipotent and fate-restricted neural crest cells exist. Most of the signals the cells respond to, not surprisingly, are from the tissues which they migrate past and that surround their postmigration destination.

Initial therapy consists of gastrointestinal decompression to avoid perforation and enterocolitis. Nasogastric suctioning combined with frequent digital rectal stimulation or irrigation is sufficient. Intravenous antibiotics or hydration is sometimes necessary to treat enterocolitis or dehydration, respectively. Definitive treatment is surgical removal of the dysfunctional bowel and reanastomosis. Other therapeutics, often reserved for recurrent or intractable cases include: rectal dilation or myotomy (physical dilation), application of topical nitric oxide (chemical dilation), or injection of botulinum toxin to block muscular contraction (neurotransmitter blockade).

COMPREHENSION QUESTIONS

[12.1] A 32-year-old woman presents with recurrent, episodic headaches, palpitations, sweating, and hypertension. After appropriate workup, she is diagnosed with a pheochromocytoma, a catecholaminesecreting tumor of the adrenal medulla. From what embryologic structure do the cells that make up this tumor arise?

A. Neural tube

B. Neural crest

C. Epidermal placodes

D. Mesoderm

[12.2] A 35-year-old man comes into the office complaining of lower back pain that radiates down the back of his left leg, as well as weakness of foot plantarflexion on the same side. You suspect that this man has a herniated vertebral disk, which is confirmed by MRI which shows herniation of L5-S1 disk and compression of the S1 nerve root. The muscles innervated by this nerve root are derived from a segmental unit of mesoderm known as what?

A. Branchial arch

B. Somite

C. Motor unit

D. Spinal segment

[12.3] Which of the following best describes the mesoderm’s effect on the migration and differentiation of neural crest cells?

A. Mesoderm guides migration and neural crest cell differentiation.

B. Mesoderm guides migration of neural crest cells but does not affect differentiation.

C. Mesoderm guides neural crest differentiation but does not affect migration.

D. Mesoderm has no effect on either migration or differentiation of neural crest cells.

Answers

[12.1] B. The chromaffin (catecholamine secreting) cells of the adrenal medulla arise from the neural crest, which also gives rise to ganglion cells of the PNS, and melanocytes, among other structures. Neural tube cells become the cells of the CNS. Epidermal placode cells become PNS structures in the head and neck, and mesoderm gives rise to the cells of the adrenal cortex.

[12.2] B. In the developing nervous system, each spinal segment is paired with a segment of mesoderm known as a somite. Each spinal segment gives rise to paired dorsal sensory and ventral motor nerve roots. These nerve roots innervate the sensory organs and muscles that derive from the corresponding somite. Dermatomes and myotomes are a result of this segmental development and innervation. Branchial arches are related structures that occur in the developing head and neck. A motor unit comprises a motor nerve and the muscles that it innervates, there are multiple motor units in each spinal segment/somite pair.

[12.3] A. Mesoderm plays a key role in generating signals that affect both the migration of neural crest cells and their differentiation into their final identities. Migration of cells is mostly guided by repulsive signals generated by mesoderm not in the proper location for the specific neural crest cells. The final identity of a neural crest cell is determined in large part by signaling molecules secreted by the cells of the surrounding tissue.

NEUROSCIENCE PEARLS ❖ The PNS develops from two populations of cells formed on the lateral border of the neural plate: neural crest cells and ectodermal placodes. ❖ Neural crest cells undergo a three-stage process to form the PNS: (1) induction, (2) migration, and (3) differentiation. ❖ The paraxial mesoderm is a critical source of signaling in the establishment of the PNS.

REFERENCES

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

Kessmann J. Hirschsprung’s disease: diagnosis and management. Am Fam Physician. 2006 Oct 15;74(8):1319-1322. 

Paran TS, Rolle U, Puri P. Enteric nervous system and developmental abnormalities in childhood. Pediatr Surg Int. 2006;22:945-959. 

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

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

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