Normal gastrointestinal (GI) motility depends on intact neuromuscular functions that consist of both intrinsic and extrinsic innervation. Extrinsic control of peristalsis includes the sympathetic (thoracolumbar) and parasympathetic (vagal) innervation in the ganglionated plexuses. Intrinsic control includes the enteric nervous system (ENS), smooth muscle cells, and interstitial cells of Cajal (ICCs), with the latter serving as both pacemaker cells and as intermediaries of enteric innervation (1,2). Motility disturbances constitute a complex array of clinical and pathologic disorders that result from neural, muscular, neuromuscular, or ICC abnormalities (Tables 10.1, 10.2, 10.3, and 10.4). Intestinal neuropathies appear to be more common than intestinal myopathies. Motility disorders occur at any age and may be primary or may complicate systemic diseases. Primary motility diseases more typically affect children than adults. Conversely, secondary conditions, such as scleroderma-associated myopathy, diabetic neuropathy, drug-induced damage, or viral infections, more frequently affect adults. Primary motility disorders may be familial or sporadic. They may remain limited to the gut, as in Hirschsprung disease (HD), or they may be part of a generalized peripheral autonomic neuropathy, as in familial visceral neuropathy. Familial disorders are inherited as both autosomal recessive and autosomal dominant diseases.

The clinical and/or pathologic findings of gastrointestinal motility disorders may be subtle or dramatic. They can present as dysphagia, nausea, vomiting, diffuse esophageal spasm, gastroparesis, intestinal pseudo-obstruction, constipation, or intestinal diverticulosis. Intestinal pseudoobstruction is defined as a rare, severe disabling disorder characterized by repetitive episodes or continuous symptoms and signs of bowel obstruction, including radiographic documentation of a dilated bowel with air–fluid levels in the absence of a fixed, lumen-occluding lesion (3). In contrast, Ogilvie syndrome is a term used synonymously with acute colonic pseudo-obstruction. The terms megaesophagus, megaduodenum, megajejunum, megacolon, and megarectum describe visceral enlargement of each of these anatomic sites. There is no agreement on the criteria for the minimum diameters of the dilated gastrointestinal segments.

Small intestinal pseudo-obstruction leads to diarrhea, malabsorption, and steatorrhea secondary to bacterial overgrowth. Some patients become malnourished with extreme weight loss.

Extraintestinal manifestations depend on the nature of the underlying disease; some help define specific syndromes. Features suggesting autonomic dysfunction include postural dizziness, difficulties in visual accommodation to bright light, and sweating abnormalities. Recurrent urinary infections and difficulty emptying the urinary bladder suggest a general visceral neuromyopathic disorder. Patients should also be questioned about drug use. Bedridden patients, such as those with dementia, stroke, and spinal cord injuries, are particularly prone to developing megacolon and a chronic pseudo-obstruction.

Motility disorders are clinically diagnosed using specific physiologic measurements of gastrointestinal motor function, including scintigraphy, gastroduodenojejunal manometry, and surface electrogastrography. The clinician will also often seek the pathologist’s assistance to rule out the presence of infiltrative lesions, such as amyloidosis or connective tissue diseases, or to document the presence of neuromuscular abnormalities.

Even though the clinical or gross findings may be dramatic, the histologic features are often inconspicuous, and they may also overlap with nonspecific neural and/or muscular histologic abnormalities accompanying other conditions, such as carcinoma or previous surgery. Additionally, some patients with clinically evident motility disorders may have histologic abnormalities that have not been well described or placed into specific syndromes. In other patients, there may be neurotransmitter alteration that may or may not associate with morphologic abnormalities. These most commonly involve alterations in the nitrergic neural system or changes in vasoactive intestinal polypeptide (VIP) or substance P (SP)-containing nerves. Changes may also be present in the muscle cells or ICCs.

Histologic examination using conventional hematoxylin and eosin (H&E) stains is usually augmented with the use of special stains or ultrastructural examination (Table 10.5). Some histologic changes are so subtle that they require precise neuronal counting to document their presence. However, this is fraught with problems, since the number of
nerves and ganglia vary with age, location, other disease processes, and section thickness. A method for rapidly assessing enteric ICCs and neuronal morphology has been developed using antibodies to c-kit and NF 68. The procedure takes approximately an hour to perform (4). It remains to be seen whether it will be widely adopted.

Treatment of motility disorders ranges from dietary changes or pharmacologic treatment to surgery or intestinal transplantation. Prokinetic drugs such as cisapride, metoclopramide, and octreotide benefit some patients. Patients with acute colonic pseudo-obstruction may benefit from neostigmine treatment (5). Bowel decompression through gastrostomy and jejunostomy may help some patients. Small bowel transplantation is the only definitive cure for patients with chronic pseudo-obstruction. Candidates for transplantation include those receiving total parenteral nutrition with frequent episodes of sepsis, limited intravenous access to nutritional support, or impending liver failure. However, small bowel transplantation tends to be challenging in this clinical setting.

The ENS derives from vagal and sacral regions of the neural crest (10). Crest-derived cells migrate to the gut at a stage when they are morphologically indistinguishable from surrounding mesenchymal cells. Interactions of the neural crest cells with components of the extracellular matrix play a role in specifying where crest-derived cells migrate. Precursors arriving in the gut are multipotential and the enteric microenvironment to which they migrate dictates the phenotypic differentiation of developing enteric ganglion cells.

Enteric neuronal migration and differentiation involves complex interactions of lineage-determined microenvironmental elements, including transcription factors, tyrosine kinase receptor oncogenes and their ligands, the extracellular matrix, and specific adhesion molecules (10,20,21,22). Among some of the more important ligands of the tyrosine kinase receptor ligands are the neurotrophin family of growth factors that promote the differentiation, growth, and survival of various neurons (23). Glial cell line–derived neurotrophic factor (GDNF) and neurturin play an important role in the migration of enteric neuron precursors into and along the small and large intestines and the esophagus, a process that is RET dependent (24,25). GDNF, which acts as a chemoattractant for enteric neural cells, promotes migration of neural crest cells throughout the gastrointestinal tract, attracting them to this site and preventing them from straying out of the gut (26). Analysis of animal models (transgenic and knockout mice) has played an important role in identifying the genes critical for ENS development (21,27,28,29) (Table 10.6).

Vagal nerve trunks can be found in the upper esophagus by the fifth fetal week. Nerve trunks extend on the outer surface of the gut wall and neuroblasts are found along the gastric cardia by the sixth week, the cephalic limb of the midgut by the seventh week, and the entire gut up to the distal half of the colon and rectum by the eighth week. By the 12th week, they have migrated as far as the rectum. The myenteric plexus forms just outside the circular muscle coat, which then develops its longitudinal muscle coat (30). Neuroblasts migrate from the myenteric plexus to form the submucosal plexus; this is completed during the third and fourth months (30). Following neural crest cell migration, the cells proliferate and the neurons
mature (Fig. 10.5), developing processes and synapses that allow for communication within ganglia, between ganglia, and between ganglia and smooth muscle cells. Interruption of this process at different stages produces various myenteric plexus abnormalities ranging from agenesis to incomplete maturation. Interruption of the orderly cranial–caudal migration of nerves and neuroblasts explains the variable length of aganglionic segments in Hirschsprung disease.

At birth, normal enteric ganglia contain both mature and immature neurons. Premature infants have more immature neurons than term infants. Mature neurons are larger than immature neurons and they have a distinct cell membrane, a vesicular nucleus, and a large amount of basophilic cytoplasm. Immature neurons are small cells with dark nuclei, clumped chromatin, and scant cytoplasm (Fig. 10.6). Neural stains highlight immature neurons. The normal mature colon contains 7 ganglion cells/mm of myenteric plexus, 3.6/mm in the jejunum, and 4.3/mm in the ileum in 3 micron sections (31). Ganglion cells lie approximately 1 mm apart; they may occur in clusters of from one to five cells in normal adults (32). Normal neonates often have plentiful, prominent ganglion cells, but they appear small when they are immature (30).

Most patients with congenital myenteric plexus abnormalities fall into one of five categories: (a) aganglionosis, (b) hypoganglionosis, (c) hyperganglionosis, (d) ganglionic immaturity, and (e) poorly classified abnormalities. The pathogenesis of developmental disorders of the ENS results from genetic defects, failed neural crest migration or differentiation, anoxia, or inflammation. Developmental neural diseases occur alone or coexist with systemic disorders such as neurofibromatosis.

Synonyms for Hirschsprung disease include aganglionic megacolon, congenital megacolon, and aganglionosis.

HD is a congenital disorder characterized by intestinal megacolon, neural hyperplasia, and aganglionosis. Several forms of the disease are recognized.

HD affects 1 in every 5,000 to 30,000 live births; 80% of patients are male (34). Approximately 4% to 6% of cases
are familial (34), especially when the megacolon extends to the cecum. Five percent of patients have an affected sibling (35).

IND, another developmental abnormality involving the ENS, occurs in two forms: Type A is characterized by decreased or immature gastrointestinal sympathetic innervation, and type B is characterized by increased numbers of ganglion cells, a dysplastic submucosal plexus, and defective neuronal nerve fiber differentiation (65,66). IND type A is also known as hypoganglionosis. IND type B is also known as hyperganglionosis. The entity known as oligoneuronal disease, which is sometimes called the hypogenetic type of dysganglionosis (67), may also be a form of intestinal neuronal dysplasia type A. These diseases are poorly understood and widely used consensus definitions for each entity are not available.

Patients with hyperganglionosis and diffuse ganglioneuromatosis (Fig. 10.15) almost always have MEN-IIB and a mutation in the RET oncogene. The changes may associate with or be a form of IND type B.

Neuronal immaturity, also known as neuronal maturational arrest syndrome, is characterized by the failure of neural elements to mature properly so that the ganglia appear immature and the patients present with clinical features resembling HD and IND. There may be overlap with IND. The underlying cause of failed neuronal maturation is unknown. Pathogenetic mechanisms may include (a) failure of normal numbers of neural crest cells to migrate into the gut, (b) inadequate neural proliferation in the gut, or (c) lack of growth or death of neuroblasts once they arrive in the gut due to the failure of the local microenvironment to support normal neuronal development during fetal life. There may also be a lack of neurotrophins since the latter are known to be important in neuronal development, differentiation maturation, survival, and maintenance. There may also be absence or delayed maturation of the ICCs, contributing to pseudo-obstruction in neonates.

The histologic features differ depending on the stage at which myenteric plexus development ceased. Patients exhibit several major histologic abnormalities: (a) no myenteric plexus seen in either H&E or specially stained sections, (b) small numbers of neuronal structures (ganglia and nerve trunks), or (c) an apparently normal myenteric plexus seen on H&E-stained sections but a neural deficiency shown by silver or immunohistochemical staining. The immature neurons lack neurofilaments. The ganglion cells may also line up at the periphery of the ganglia (ring-shaped ganglia) as occurs in premature infants (Figs. 10.16 and 10.17). There is no inflammation or neural degeneration. These findings contrast with those seen in patients with HD or IND type B in that there is no neural hyperplasia, but as noted there may be overlap with IND.

Neuronal immaturity often spontaneously improves with conservative therapy and the normal development of the child unless it occurs as part of IND. In other patients the changes persist.

As noted earlier, ICCs are the pacemaker cells of the GI tract that initiate peristalsis in the stomach and the intestines.

They are better known to pathologists as the cells of origin of gastrointestinal stromal tumors (see Chapter 19). These cells may be congenitally hyperplastic, presenting clinically as a pediatric motility disorder. A recent case of a 2-year-old girl was reported who had had scanty stool from birth. Radiographically, the distal colon was rigid and narrowed. The proximal colon was dilated and atonic. She underwent an ileocolectomy and the specimen showed a continuous proliferation of spindle cells located between the layers of the muscularis propria throughout the right colon. The spindle cells were positive for c-kit and CD34 but were negative for neural markers. In addition, the submucosa showed the changes characteristic of IND type B as discussed in an earlier section (77).

The absence of nerves and ganglia from the stomach to the colon characterizes the absent enteric nervous system. This very rare disorder presents as severe perinatal pseudo-obstruction. No nerves or ganglia are present in either the submucosal or myenteric plexus, or in the muscularis propria. S100 and ACE staining confirm the absence of enteric neural structures. Sparse PGP 9.5–positive extrinsic nerve fibers are present in the submucosa. Prominent ICCs are present in the area between the circular and longitudinal muscle layers in a normal distribution in some parts of the gut. In other parts they are absent or in various stages of destruction. The overall prognosis is poor (81).

Damage to the ENS results in enteric neuropathies, the best characterized of which is HD. However, a number of children present clinically with pseudo-obstruction syndromes in the first few weeks, months, or years of life who lack the classic features of either HD or IND (type A or B). These cases are challenging for clinicians to manage and they often look to the pathologist for help in establishing a diagnosis that will guide them into the appropriate therapy for the affected children. Pathologic features are not readily associated with clinical findings and vice versa.

The cases that we see in consultation are challenging in this regard since they often lack features that allow them to be easily categorized (Fig. 10.18). We have seen examples of neuronal immaturity with variable numbers of ganglia and with or without obvious neural disorganization in the bowel wall. Increased, thickened nerve fibers with or without giant ganglia or aganglionosis cases are also encountered. There may be cases with neural degeneration, variable inflammation, and increased apoptosis. We have also seen some cases associated with myenteric plexus loss and cases of hypo- or aganglionosis with shriveled ganglia and dense submucosal fibrosis that may be the equivalent of what has been described as zonal HD. Often in these cases there is a history of intestinal atresia, and we have interpreted such cases as representing prenatal neural injury rather than HD. This injury is likely to be ischemic in nature, complicating the complex series of intestinal twists and turns that associate with fetal intestinal development. Ischemia secondary to malrotational or other events may damage the neuromuscular structures of the gut, especially in the intestines.

The development of the gastrointestinal tract is in some ways more complex than other organ systems with marked lengthenings, rotations, and a cranial–caudal differentiation gradient. Additionally, as noted in earlier sections of this chapter, ENS development is a complex process that is governed by the interactions of numerous proteins that are responsible for neural migration, growth, differentiation, and survival. Alterations in any of these proteins can presumably result in disorders that present clinically like HD but fail to
meet the diagnostic criteria for that disease. Lastly, the developing ENS may be negatively influenced by other fetal events such as intrauterine infections that may lead to ganglionic loss or other neural abnormalities.