Neuromuscular Disorders of the Gastrointestinal Tract
Dhanpat Jain
Introduction
Normal bowel motility depends on smooth muscle, the interstitial cells of Cajal (ICC), the intrinsic and extrinsic nerve supply and supporting cells, and various neuroendocrine peptides. Abnormalities in any of these components may result in bowel dysmotility. In addition, other inflammatory cells such as lymphocytes, eosinophils, and mast cells may act directly or indirectly on the neuromuscular apparatus of the bowel wall. The clinical manifestations of motility disorders depend on the extent and specific site of the abnormality. Some of these disorders manifest with distinct clinical features (e.g., idiopathic hypertrophic pyloric stenosis, Hirschsprung disease, achalasia), whereas others have nonspecific manifestations. Patients with idiopathic hypertrophic pyloric stenosis have projectile vomiting in the first month of life, often associated with an olive-sized abdominal mass. Patients with Hirschsprung disease have delayed passage of meconium. The pathogenesis of many of these conditions is poorly understood. In fact, many disorders have no specific pathologic features and lack standardized diagnostic criteria. This situation has led to marked variability in the approach to diagnostic workups among different laboratories.1
To address these issues, an international working group was formed in 2007. This group published a comprehensive guideline for handling of most specimen, including biopsies and resections, pertaining to gastrointestinal (GI) motility disorders. The classification proposed by this group is recognized as the London Classification of neuromuscular disorders of the GI tract. This classification has placed various primary neuropathies and myopathies into well-delineated categories. However, it includes only a short list of secondary disorders. A modified version of this classification is shown in Table 7.1. It is expected that this modification will lead to an improvement in the understanding of GI motility disorders.
Table 7.1
Classifications of Neuromuscular Disorders
| A. Primary Neuropathy | B. Primary Myopathy |
ICC, Interstitial cells of Cajal.
Muscle Coats of the Bowel Wall
Knowledge of the basic organization of the neuromuscular apparatus of the bowel is essential to understand and diagnose GI motility disorders. The neuromuscular framework of the bowel is similar throughout the tract. However, there are some minor variations.2 The bowel smooth muscle is composed of a thin superficial layer that separates mucosa from submucosa (muscularis mucosae) and a thick outer layer (muscularis propria), which has an inner circular and an outer longitudinal coat. The exception is the esophagus, in which the muscularis propria has only a single longitudinal muscle coat. The proximal part of the muscularis propria of the esophagus is formed entirely of skeletal muscle; the skeletal muscle merges with smooth muscle in the vicinity of the midesophagus (Fig. 7.1). Because of this anatomy, esophageal motility is susceptible to the effects of systemic disorders of both smooth and skeletal muscle. In the stomach, an additional inner oblique muscle layer is also present.
In contrast, the outer longitudinal layer in the colon forms thick localized bands of muscle termed tenia coli. The muscularis mucosae of the colon continues into the anal canal. The inner circular layer of muscularis propria of the rectum becomes thickened distally to form the internal anal sphincter. The external anal sphincter is formed of skeletal muscle and is connected to the skeletal muscle of the pelvic floor. The outer longitudinal muscle layer of the rectum continues between the inner and outer anal sphincters and then separates caudally into multiple septa, which diverge fanwise throughout the subcutaneous part of the external sphincter into the skin. These fibers are responsible for the characteristic corrugated appearance of the perianal skin. In addition, the muscle fibers from the outer longitudinal coat and the internal anal sphincter extend into the submucosa to form a meshwork of fibers surrounding the vascular plexuses (muscularis submucosa ani). The organization of the muscle layers in the appendix is similar to that of the colon, except that the appendix lacks tenia coli.
Neural Network of the Bowel
The organization of the neural network in the bowel is complex. The extrinsic nerve supply of the bowel wall consists of both sympathetic and parasympathetic nerve fibers that penetrate the wall and become the intrinsic neural plexus. The sympathetic fibers originate in the prevertebral ganglia and parallel the superior and inferior mesenteric arteries. The parasympathetic fibers are located alongside the posterior branch of the vagus nerve. The intrinsic neural system of the bowel wall is organized into three plexuses: the submucosal plexus (Meissner plexus), the deep submucosal plexus (Henle plexus), and the myenteric plexus (Auerbach plexus) (Fig. 7.2). The most easily identified and most prominent of these is the myenteric plexus, which is composed of clusters of ganglion cells connected by an intricate network of nerves located in the space between the inner circular and outer longitudinal muscle layers. Although the ganglion cells and nerve bundles are easily identified within these plexuses (Fig. 7.3, A), the intricacy of the neural meshwork of fibers is not easily detectable on hematoxylin and eosin (H&E)-stained tissue sections. Whole-mount specimens, silver stains, and/or immunohistochemical stains are usually needed to visualize the complexity of the neural network (see Fig. 7.3, B).3,4
In addition to muscle fibers and the neural network, a third population of mesenchymal cells, the interstitial cells of Cajal (ICC), are critical for bowel motility. These cells generate a slow wave of depolarization and represent the “pacemaker cells” of bowel peristalsis.5,6 Their function is modulated by both intrinsic and extrinsic neural inputs. Because these cells are difficult to detect on routine tissue sections, most of our knowledge regarding their morphology and structural organization stems from ultrastructural studies.7–9 Ultrastructurally, these cells show a partial basal lamina, many intermediate filaments, darkly staining cytoplasm, abundant rough endoplasmic reticulum, sublamellar caveolae, oval indented nuclei, and lack of myosin filaments. Many of these features overlap with those of smooth muscle cells. ICC express CD117 (KIT), a tyrosine kinase receptor.10 Immunohistochemical stains with antibodies against KIT or ANO1 (formerly DOG1) can be used to visualize these cells.11–13 ICC are part of an intricate neural network and have a close association with smooth muscle cells and nerve endings. They are most easily identified surrounding the myenteric plexus, especially in the small bowel, where the network of cells extends into the inner and outer muscle coats (Fig. 7.4). In addition, there is a distinct ICC plexus in the submucosa. The distribution and organization of ICCs in the appendix is similar to that in the colon. The structural organization of ICC has been described in the various segments of the GI tract, from esophagus to anus. Minor regional differences within each bowel segment do exist, and the reader is referred to a review article by Venderwiden and Rumessen for more details.14
The neuromuscular organization of the appendix is similar to that of the colon and small bowel. However, the ganglia are sometimes embedded deeper into the circular or longitudinal layer (Fig. 7.5, A and B). The neural and ICC networks in the appendix are similar to those in the colon, but with less aggregation of ICC surrounding the myenteric plexus (see Fig. 7.5, B and C). Understanding of the neuromuscular organization of the appendix is helpful, because the appendix is sometimes examined intraoperatively to evaluate the extent of aganglionosis.15
Esophagus
Primary Achalasia
Achalasia is a motor disorder of the esophagus that is characterized by failure of the lower esophageal sphincter (LES) to relax in response to swallowing.16,17 Clinically, achalasia is divided into three subtypes: type I, classic type; type II, achalasia with compression; and type III, spastic achalasia.18 It is uncommon. The overall prevalence rate is less than 10 cases per 105 population.19 Its incidence has been fairly stable during the last 50 years. It is a disease of adults, mainly those older than 60 years of age, and affects both sexes equally. Achalasia is more frequent in North America, northwestern Europe, and Australia than in other regions, and it is more common in whites.
Clinical Features
The major clinical manifestations of achlasia differ between children and adults. A feeding aversion, failure to thrive, choking, recurrent pneumonia, nocturnal cough, aspiration, or nonspecific regurgitation typically develops in younger children (<5 years). Older children and adults often experience vomiting, chest pain, and dysphagia for solids and liquids. Heartburn is a common symptom (50%), even in untreated patients, although only a minority of patients have documented gastroesophageal reflux disease.20
The diagnosis is confirmed with imaging studies and manometry. Barium studies typically reveal reduced peristalsis, a characteristic beaklike deformity of the distal esophagus, and dilatation of the proximal esophagus. Manometry studies reveal abnormal peristalsis, increased intraluminal pressure, and incomplete and delayed relaxation of the LES. Endoscopy and endoscopic ultrasound studies are often performed to rule out coexisting mucosal pathology and to exclude secondary causes of achalasia (“pseudoachalasia”).
Pathogenesis
The most significant feature of achalasia is loss of myenteric ganglion cells. However, the cause of ganglion cell loss is unknown. Current data suggest that myenteric inflammation precedes loss of ganglion cells, but the initial inciting events that cause disease remain unknown.21 Environmental factors, viral infection, autoimmune mechanisms, and genetic predisposition have all been proposed. In addition, some data suggest familial aggregation. Rare familial forms associated with alacrima (absence of tears) and adrenocorticotropic hormone (ACTH) insensitivity have been described (Allgrove syndrome, or triple A syndrome).22,23 Concordance in monozygotic twins and an association with Down syndrome has also been reported. A significant association has been found with the class II human leukocyte antigen (HLA) DQw1 in white patients. The alleles identified, HLA DQB1*0602, DQA1*0101, and DRB1*15, are the same found to be associated with other autoimmune disorders, including multiple sclerosis, Goodpasture syndrome, Graves disease, myasthenia gravis, polymyositis, autoimmune polyglandular syndrome, and Sjögren and sicca syndromes. Antimyenteric neuronal antibodies have been identified in some patients.24–28 It has been demonstrated in an ex vivo model that on exposure to sera from patients with achalasia, gastric corpus mucosa undergoes phenotypic and functional changes that mimic achalasia.29 A factor in the serum, other than an antineuronal antibody, may be responsible for this phenomenon.29 Varicella-zoster viral DNA has been identified in the myenteric plexus in rare cases by in situ hybridization.30 Polypomorphisms in genes such as vasoactive intestinal polypeptide (VIP) receptor 1, KIT/CD117, and interleukin-23 receptor (IL23R) may increase susceptibility to achalasia.31–33 VIP is responsible for relaxation of esophageal smooth muscle, whereas KIT plays an important role in the function of ICC. The IL23 pathway is important in immune activation and plays a vital role in many chronic inflammatory disorders, including inflammatory bowel disease.
As noted previously, the pathogenesis of achalasia is poorly understood. However, progressive inflammatory destruction of myenteric ganglion cells is the most important underlying event. This condition results in failure of the LES to relax in response to swallowing.34 Esophageal peristalsis is decreased or completely absent. This results in esophageal dilatation, chronic stasis, and reactive hypertrophy of the muscularis propria. VIP, which was initially thought to be a major mediator of relaxation of the LES, shows a substantial decrease in VIP-containing neurons in the distal esophagus.35,36 It has been shown that nitric oxide is a primary esophageal inhibitory neurotransmitter. It colocalizes with VIP in ganglion cells. In addition, intrinsic nitrergic ganglion cells are lost, or markedly decreased, in achalasia. In fact, loss of VIP-positive ganglion cells is synonymous with loss of nitrergic ganglion cells.37,38 Although most early studies evaluated specimens only at the time of autopsy or esophagectomy, and therefore showed end-stage disease, study of esophagomyomectomy specimens has now given some insights into the early sequence of events in this condition.35 These studies have revealed that as the disease progresses, the inflammatory infiltrate decreases in intensity, but loss of ganglion cells and degeneration of the myenteric plexus become more prominent features.
Pathologic Features
Grossly, the esophagus in achlasia shows dilation. The extent of dilatation depends on the severity and duration of disease (Fig. 7.6, A). The lumen often contains stagnant and foul-smelling, partially digested food. The distal end is typically narrowed and stenotic.
The main histologic abnormality in achalasia is related to the myenteric plexus, although numerous secondary changes are often present, presumably due to prolonged stasis and reflux. Widespread, often total, loss of myenteric ganglion cells is the cardinal feature of achalasia (Fig. 7.7; see Fig. 7.6, B and C). The ganglion cells may be better preserved in the more proximal portions of the esophagus.16 Some degree of neural hyperplasia may accompany neuronal loss (see Fig. 7.7). A variable amount of chronic inflammation is often admixed with eosinophils and plasma cells. Mast cells may be seen surrounding the myenteric nerves and residual ganglion cells39 (see Figs. 7.6, B and 7.7). In end-stage disease, the degree of inflammation may become minimal or disappear completely. One ultrastructural study showed that numerous mast cells are also present within the inflammatory infiltrate closely associated with the nerve fibers.40 Occasionally, lymphocytes may infiltrate the cytoplasm of ganglion cells (ganglionitis). The majority of chronic inflammatory cells are CD3-positive T cells, most of which are CD8-positive as well (Fig. 7.6, C), although the relative percentage of these cells decreases with progression of disease.34,41,42 A large subset of T cells represent either resting or activated cytotoxic cells.
Other changes frequently present are related to distal esophageal obstruction; they include muscularis propria hypertrophy, muscularis propria eosinophilia, and dystrophic calcification. Hypertrophied muscle may also show degenerative changes, including cytoplasmic vacuolation and liquefactive necrosis. The branches of the vagus nerve within the adventitia are unremarkable in most cases, although degenerative changes in the vagus nerve and in dorsal motor nuclei have been described.17 These changes may be caused by infection with a neurotrophic virus; however, no specific virus has been identified.42,43 The squamous mucosa also shows secondary changes, including diffuse hyperplasia, increased intraepithelial lymphocytes (“lymphocytic esophagitis”), papillomatosis, basal cell hyperplasia, and an increase in nonspecific lamina propria inflammation.44 Some of these changes mimic reflux esophagitis, although sustained lower esophageal pressure does not allow regurgitation of gastric contents in untreated cases.45 After esophagomyotomy, gastroesophageal reflux develops in as many as 50% of patients and can lead to Barrett’s esophagus in some cases.46,47
Differential Diagnosis
Biopsies are not performed to establish a diagnosis of achalasia; pathologists encounter this condition when a resection is performed or at autopsy. The role of biopsy in patients with achalasia is largely to exclude Barrett’s esophagus (after myotomy), dysplasia, and malignancy. The differential diagnosis of achalasia, both clinically and pathologically, is pseudoachalasia, which develops secondary to tumors or paraneoplastic syndrome. These are easily ruled out with esophageal manometry and imaging or with biopsies when a mass is present.
Occasionally, strictures at the gastroesophageal junction resulting from reflux, prior surgery, or trauma can mimic achalasia (Fig. 7.8, A and B). The esophagus may show muscular hypertrophy and neural hyperplasia similar to achalasia. However, on close examination, ganglion cells are easily identified in the neural plexus, and there is a lack of inflammatory or degenerative changes in the ganglion cells. In postinfectious or autoimmune-mediated ganglion cell loss, lymphocytic inflammation may be present in or around ganglion cells. Residual ganglion cells can often be identified (see Fig. 7.8, C).
In paraneoplastic achalasia, the diagnosis of malignancy is often already known, and despite histologic similarity with the idiopathic form, differentiation is seldom a problem clinically.
Chagas disease, which also causes massive dilation of the esophagus with ganglion cell loss, should be suspected in any patient from an endemic area. By the time achalasia-type features develop, the infectious organisms can no longer be demonstrated in the tissues, so one must rely on serologic evidence of infection. Patients with Chagas disease may also show dilatation of other hollow viscera, with ganglion cell loss.
Natural History and Treatment
Achalasia is a chronic disorder, and the treatment is largely palliative. Medications such as anticholinergics, nitrates, and calcium channel blockers are used in some circumstances but result in only partial benefit. Pneumatic dilatation and injection of botulinum toxin into the LES produce an initial response, but the results are usually short lasting. The best results are typically obtained with esophagomyotomy of the LES, with or without pneumatic dilatation. Patients with type II achalasia have the most favorable outcome and better response to treatment. Esophageal resection is usually reserved for end-stage cases. Patients have an increased long-term risk for squamous cell carcinoma of the esophagus.46,48 The risk is approximately 33-fold higher than in the general population.49 Studies show that the risk of adenocarcinoma is also higher, albeit to a lower degree.50
Secondary Achalasia
As discussed earlier, signs and symptoms indistinguishable from primary achalasia may be encountered with other conditions, such as Chagas disease, or in association with a neoplasm that directly invades the myenteric plexus. In some cases, a paraneoplastic phenomenon causes a secondary achalasia, as in paraneoplastic achalasia associated with small cell carcinoma. Rare associations have been described with other tumors, such as leiomyomatosis of the esophagus and sarcoidosis.51–53 In sarcoidosis, inflammation surrounding the myenteric plexus has been described, but without granulomas. One of the reported patients showed resolution of symptoms with steroid treatment.51
Chagas disease results from infection with the protozoan Trypanosoma cruzi.54,55 The infection is acquired from the bite of blood-sucking reduviid bugs. The geographic distribution of the disease is limited to certain parts of the world, including South and Central America and Africa. Chagas disease is uncommon in the United States, occurring almost exclusively among immigrants from endemic countries such as Brazil. Any part of the GI tract may be affected, but the esophagus and the sigmoid colon are the most frequent sites. Infection results in dysmotility and often massive dilatation (e.g., megaesophagus, megacolon) In the esophagus, the symptoms closely resemble idiopathic achalasia. Colonic involvement results in constipation and intestinal pseudo-obstruction. These features are seen in the chronic phase of disease, and by the time symptoms are observed, the organisms usually are no longer present in the myenteric plexus.
Idiopathic Muscular Hypertrophy
Idiopathic muscular hypertrophy of the esophagus is a poorly understood condition of uncertain etiology and clinical significance. Most of the cases reported with pathologic descriptions have been diagnosed at the time of autopsy. The condition can be diagnosed clinically with imaging techniques and esophageal motility studies. New clinical diagnostic criteria have been proposed.56,57 Some patients are symptomatic at presentation, with symptoms such as dysphagia, chest pain, vomiting, and weight loss, whereas others are entirely asymptomatic.58 Gastroesophageal reflux develops in some patients.57 Esophageal spasm and increased intraluminal pressure are believed to be the cause of symptoms. The disorder occurs in adults, with no gender or race predilection. Many patients also have diabetes. Some cases have shown to have autosomal dominant inheritance and association with bilateral cataracts and Alport-like nephropathy.59 Squamous cell carcinoma has also been described in some cases.60 Pathologically, the muscularis propria is markedly thickened, particularly toward the distal end of the esophagus58 (Fig. 7.9). In some cases, there is a mild degree of lymphocytic infiltration in the myenteric plexus. The vast majority lack evidence of muscle fiber degeneration, fibrosis, ganglion cell abnormalities, or neural plexus abnormalities.
Differential Diagnosis
A variable degree of hypertrophy of the esophageal musculature may be seen in patients with distal obstruction of any cause, including achalasia. However, the cause of the obstruction is often obvious clinically (see Fig. 7.8, A). Histologically, the muscle fibers appears normal in idiopathic muscular hypertrophy, and ganglion cells and neural plexus are present. The key is to exclude distal obstruction in the presence of markedly hypertrophic muscularis propria.
Stomach
Idiopathic Hypertrophic Pyloric Stenosis
Idiopathic hypertrophic pyloric stenosis is a disorder characterized by thickened pyloric musculature and features of gastric outlet obstruction. Infantile, late-onset/adolescent, and adult forms of this disorder have been described. The presenting symptom in infants is projectile vomiting, usually within 2 to 4 weeks of birth.61–65
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