Disorders of the enteric nervous system

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The enteric nervous system is arranged in the form of two major plexuses: the myenteric plexus, which is located between the longitudinal and circular muscle layers and primarily provides motor innervation to the muscle coats; and the submucous plexus, which lies in the submucosa between the circular muscle layer and the muscu-laris mucosae.26 The submucous plexus is important in regulating secretion by the mucosa and providing sensory innervation of the mucosa. As a whole it is a collection of neurons derived from neural crest cells and has been referred to as the 'brain of the gut' or the 'little brain'. Whilst there is a two-way flow of information between the central nervous system and the enteric nervous system, often referred to as the 'big brain' and 'little brain', respectively, the little brain can function independently of the big brain.27 The neurons of the enteric nervous system are grouped into small ganglia that are connected by bundles of nerve processes forming the two major nerve plexuses. Ganglia consist of tightly packed neurons, terminal bundles of nerve fibers and glial cells, which usually outnumber the enteric neurons.26 Normally, there are between five and seven neurons in a ganglion. There are numerous interneurons between the two plexuses and within the plexuses. Both are connected to the central autonomic neural network by parasympathetic and sympathetic nerves. Throughout the gastrointestinal tract there are also non-neural cells derived from the mesenchyme, the interstitial cells of Cajal, that generate and propagate slow waves.28 The interstitial cells are important modulators of communication between nerves and muscle. The enteric nervous system is particularly concerned with the propulsion of the gut contents in an ordered physiologically effective fashion, and the control of secretion by the gut. Both quantitative and qualitative changes in the enteric nervous system have been identified and these are described below.

Primary visceral neuropathies

Primary visceral neuropathies can be subdivided into familial neuropathies, where a distinct pattern of inheritance is known, and sporadic cases, in which there are distinctive clinical and morphological findings. In this chapter, Hirschsprung's disease, which is clearly a primary visceral neuropathy, will not be discussed. A number of neuropathic motility disorders, including those that present with slow-transit constipation, remain unclassified, although most frequently degenerative changes are found in the enteric neurons.

Familial visceral neuropathy without extraintestinal manifestations

In this disorder it is mainly the colon and distal small intestine that are affected, and it is inherited as an autosomal dominant trait.39 The age of onset may differ within the same family, but in general symptoms develop after infancy. Most patients present with severe slow-transit constipation associated with abdominal distension and colicky pain. In about half of the patients severe episodes of functional obstruction have occurred which have required decompression. To date, there have been no descriptions of any associated abnormalities, such as extrinsic autonomic dysfunction. Full-thickness biopsies of the affected parts of the bowel have shown evidence of degeneration, both on silver staining and on routine hematoxylin-and-eosin staining. No other abnormalities have been observed.

Familial visceral neuropathy with pyloric stenosis, a short small intestine and malrotation

This syndrome has been described in several families. An extended kindred from Sicily and Southern Italy has shown that it is inherited as an X-linked recessive trait through four generations. Linkage analysis assigns the genetic defect to a locus at XQ28. To date, the gene involved has not been identified. Affected infant boys usually present with functional obstruction in the neonatal period and most have died during the first year of life. Histology of the nerve plexuses has shown the presence of shrunken neurons with particular loss of argyrophilic neurons. However, apparent loss of argyrophilic neurons may be a normal finding at this age, as the acquisition of argy-rophilia is associated with changes in the neurofil-amentous content of the neuron and this occurs progressively during the first year of life.

Familial visceral neuropathy with neuronal intranuclear inclusions

This condition may be inherited as an autosomal dominant trait, as it was described in three siblings (two female, one male) and their father.30 The patients developed symptoms during childhood and, in addition to pseud-obstruction, suffered from dysphagia, diarrhea and constipation. They became developmentally delayed, had autonomic dysfunction and ataxia, and developed dementia. A characteristic feature of the condition is the presence of eosinophilic intranuclear inclusions in the neurons of the myenteric plexus and in the central nervous system.3 In some of the patients the intranuclear inclusions could be seen within the ganglion cells of the submucous plexus on suction rectal biopsy. This appears to be a progressive degenerative condition affecting a widespread class of neurons in both the enteric and the central nervous systems.

Familial visceral neuropathy with neurological involvement

A number of families have been described in which there are least two affected siblings. The condition is probably inherited as an autosomal recessive disorder. The symptoms start in early childhood, with neuropathic dysmotility of the gut and involvement of the central nervous system. The central nervous system disorder appears to consist of progressive sensory and motor peripheral neuropathies, ophthalmoplegia and hearing loss.31 It seems highly likely that this is a mitochondrial disorder. On full-thickness biopsy, neurons in the myenteric plexus appear normal on conventional staining, but there is evidence of degeneration of argyrophobic C cells.

Familial visceral neuropathy associated with multiple endocrine neoplasia

The multiple endocrine neoplasia type 2 syndromes may be associated with involvement of the gastrointestinal tract. These include multiple endocrine neoplasia (MEN) 2A, MEN 2B and isolated medullary thyroid carcinoma. These conditions are inherited as autosomal dominant traits and are as a consequence of mutation of the gene encoding the RET tyrosine kinase receptor. It is extremely important in the development of the enteric nervous system as RET null knockout mice do not develop neurons within the gut.32 There is now good evidence to show that RET is important not only for colonization of the primitive gastrointestinal tract by neural crest cells but also for their migration down the length of the gut and their further differentiation. In MEN 2A and isolated medullary thyroid carcinoma, there is an abnormality of the RET gene between codons 619 and 638, the cysteine-rich region of the gene, which results in the development of medullary thyroid carcinoma with or without pheochromocytoma. In about 5% of patients with MEN 2A, Hirschsprung's disease is also present with pheochromocytoma.33

In MEN 2B there is always involvement of the gastrointestinal tract, with transmural intestinal ganglioneuromatosis. In most patients, disorders of gastrointestinal motility are the first manifestations of the disease, but the presentation is variable both in severity and in time. Some patients present in early infancy, similarly to Hirschsprung's disease, but others not until adult life.34 There is nearly always colonic dysfunction present and the most usual presentations are either with chronic constipation, episodes of functional obstruction or as if this were Hirschsprung's disease. In all the patients that the author has studied, evidence of medullary thyroid carcinoma has been present from very early on, either as clumps of malignant cells in situ within the thyroid gland or as an overt tumor. Frequently in those patients in whom there are only collections of cells in situ within the gland, screening investigations such as CT scanning of the thyroid and calcitonin determinations have not been helpful. It is only when there is a considerable mass of C cells present that the normal screening investigations become positive. It is for this reason, together with the fact that there is no satisfactory radiotherapeu-tic or chemotherapeutic treatment available, that prophylactic thyroidectomy is recommended.35

The characteristic histopathological findings are an increased density of nerve fibers and possibly ganglion cells in the submucosa and myenteric plexus with penetration of the hyperplastic nerve fibers into the mucosal area. The hyperplastic nerve fibers are accompanied by large ganglionic nodes containing numerous glial cells, with a normal to increased quantity of neurons. This abnormality of the enteric nervous system is present along the entire gastrointestinal tract and the hyperplastic neurons may be seen within the mouth or anal canal.35

Sporadic visceral neuropathies

Neuropathic dysmotility may also be produced by having too few neurons within the enteric nervous systems (hypoganglionosis) as well too many (hyperganglionosis) or none at all (aganglionosis). The conditions that cause these states are nearly always congenital, although both hypogangliono-sis and aganglionosis may result from acquired disorders in which there is destruction of neurons. As these conditions are defined by the numbers of neurons present, it is clear that a reliable means of assessing neuronal density is required.36 Neuronal density is affected by the age of the patient, tissue freshness and intestinal dilatation as well as by the disease process. It is therefore important that a standardized technique for assessing neuronal density be used. A full-thickness sample of intestine at an appropriate site, needing to be greater than 1 cm in length, is required. Preferably neurons should be counted in sections cut longitudinally along the long axis of the bowel rather than transversely.36 If sections are cut transversely they should be at least 30 |im apart to avoid counting each neuron more than once. There are few published studies, especially in children, but Smith reported a mean neuronal density of 3.6 neurons/mm for the jejunum, 4.3/mm for the ileum and 7.7/mm for the colon, with no significant difference between transverse and longitudinal sections.36


A reduced number of neurons in the myenteric plexus, so-called hypoganglionosis, is perhaps the most frequent diagnosis in children who present with functional obstruction due to a visceral neuropathy. Hypoganglionosis also occurs commonly in children with severe slow-transit constipation. Navarro et al3 reported hypogan-glionosis of the myenteric plexus in 13 of 26 patients who presented with functional obstruction. Most commonly the hypoganglionosis was confined to the distal segment of the colon, and diffuse disease was uncommon. Histologically the ganglia were smaller than normal, often infiltrated with collagen, and there was a paucity of neurons within the ganglia. Between the ganglia there were numerous thickened nerve fibers that stained strongly with acetylcholinesterase. Krishnamurthy et al described a further series of patients with hypoganglionosis37 in four of 26 children, but unlike those described by Navarro et al the nerve tracts did not strongly stain with cholinesterase. As in both of these series the majority of the children presented as infants, care must be taken in the interpretation of silver staining as during the first year of life there may be absence of silver staining. In the Krishnamurthy group37 there were 19 children with a deficiency of argyrophilic neurons. When argyrophilic neurons were present, they were small and had few processes. It was suggested that these patients suffered from a defect in differentiation and maturation of neurons from primitive neuroblasts. As these processes continue after birth, this would explain why some infants during the first year of life may have apparent abnormalities of the myenteric plexus which are not the case.38

The problem of the diagnosis of hypoganglionosis is emphasized by the marked variability of the clinical course of such patients. Most will present in the newborn period with symptoms suggestive of Hirschsprung's disease, but others become symptomatic only during their preschool years. In those in which the disorder is restricted to the colon, ileostomy or colonic resection and the pull-through procedure relieves their symptoms, but those in whom the disease is diffuse remain dependent on parenteral nutrition for their survival.


Hyperganglionosis is characterized by an excess of intestinal neurons in the myenteric plexus with or without hyperplasia of nerve fibers. The condition may also affect the submucous plexus, but in some, the submucous plexus will be normal. Hyperganglionosis requires the presence of large ganglia containing more than seven ganglion cells at a greater density than the normal range for the region. There is also some evidence that infants, especially those during the neonatal period, have a higher neuronal density than that in older children.38,39 Therefore, the finding of hypergan-glionosis in a very small infant with dysmotility requires caution in its interpretation.

Marked hyperganglionosis is the hallmark of intestinal ganglioneuromatosis and MEN 2B. This is dealt with above and will not be considered further here. In view of the implications of MEN 2B in those with severe hyperganglionosis and ganglioneuromatosis, mutations of the RET gene should be sought in all patients who have severe hyperganglionosis even if only the submucous plexus is involved.

Intestinal neuronal dysplasia

Those with mild submucous hyperganglionosis have sometimes been reported to suffer from intestinal neuronal dysplasia, a term that has been used over the past 30 years to describe quantitative and qualitative abnormalities of enteric ganglia. The term was originally used to describe abnormalities of both the myenteric and submucous plexus.40 However, over the past 20 years, diagnosis has largely been dependent on suction rectal biopsy and thus on changes in the submucous plexus and the mucosal innervation. The term has raised confusion and controversy among clinicians and pathologists. It appears to affect all age groups, although it is mostly seen in infants with chronic constipation and was first considered to be a developmental defect of the submucous plexus.41 Part of the problem has been the lack of agreed criteria, and the confusion has been further compounded by the use of the histological description as a clinical diagnosis. No studies have shown a correlation between morphological features of intestinal neuronal dysplasia and symptoms or long-term outcome.42,43 Nevertheless, surgical procedures have been recommended on the basis of the histological diagnosis. In one prospective study of rectal biopsies, the interobserver variation between centers was enormous and close to that which that might occur by chance. In this study,43 377 biopsies from 108 children aged 4-15 years were assessed by three experienced pathologists for a number of agreed histological features and a final diagnosis. Complete concordance was obtained for the diagnosis of Hirschsprung's disease, but in only 14% of the remainder was there concordance. Assessment of the clinical symptoms 1 year after biopsy, demonstrated that the diagnosis of intestinal neuronal dysplasia had no prognostic value for the outcome in these individuals. It seems, therefore, that intestinal neuronal dysplasia describes neither a specific histological nor a clinical entity, and remains controversial. This author can see very little use for the term until it is better defined. It should at the present time be avoided and certainly not used as a criterion for individual treatments.

Acquired visceral neuropathies

Damage to the enteric nervous system may occur from a variety of agents as well as being secondary to a systemic disease. Secondary visceral neuropathies may occur at any age, before or after birth, but most often occur in adults compared to children.

Infectious agents

Infectious agents may damage enteric neurons either by direct invasion of the neuron or by involvement in an inflammatory process, often autoimmune, that the infectious agent provokes. The best example of this is Chagas' disease, caused by infection with Trypanosoma cruzi, in which the inflammatory response to the parasite results in an autoimmune response in which antibodies to the muscarinic receptors on neurons is produced. Whilst the most common clinical presentation following such an infection is achalasia, other areas of the bowel may be affected, including the small and large intestines.

Functional obstructive episodes have also been observed with a variety of other infectious agents, including acute Lyme disease and the neurotrophic viruses from the herpes virus family, including cytomegalovirus, varicella zoster virus, Epstein-Barr virus and herpes simplex virus type

1 44-46

Chronic inflammation and autoimmune disease

A number of patients have been reported with different non-infectious inflammatory diseases. Clearly, classical mucosal inflammatory conditions such as Crohn's disease and necrotizing enterocolitis may result in damage to both enteric nerves and muscular structures of the bowel. However, other autoimmune diseases affecting the gut, such as celiac disease and ulcerative colitis, may also result in severe dysmotility. It is becoming apparent that the neuromusculature of the bowel may become involved in the inflammatory process.

Lymphocytic ganglionitis associated with the presence of circulating enteric neuronal antibodies has been described both in association with small round cell carcinoma as a paraneoplastic syndrome and in isolation.47 In both settings acquired progressive aganglionosis occurs as a result of a severe T-cell-mediated inflammatory ganglionitis of both enteric plexuses. In the isolated form of the disease the antibody produced is similar to the Hu-protein antibody found in the paraneoplastic syndrome, but instead of antibody staining being restricted to the nucleus, it is present in the cytoplasm. In both forms of the disease, episodes of functional obstruction are responsive to immunosuppressive treatment, with a consequent fall in the titers of antibodies produced.

The enteric neuromusculature may also become involved in a variety of connective tissues disorders including systemic sclerosis, systemic lupus erythematosus and dermatomyositis.

Miscellaneous conditions

The enteric neuromusculature can be affected by a wide variety of other conditions or affected by toxic agents, drugs and irradiation. These are listed in Table 18.1.

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