Gastroenterology

Gastroenterology

Volume 126, Issue 7, June 2004, Pages 1872-1883
Gastroenterology

Special reports and reviews
Inflammatory neuropathies of the enteric nervous system☆

https://doi.org/10.1053/j.gastro.2004.02.024Get rights and content

Abstract

Inflammatory neuropathy of the enteric nervous system is emerging as an important topic in the field of neurogastroenterology. Enteric ganglionitis can be either primary or secondary to a wide array of diseases (i.e., paraneoplastic, infectious, and neurological disorders) and is characterized by a dense infiltrate of inflammatory/immune cells mainly confined to the neural microenvironment. The clinical picture reflects the involved segment of the gastrointestinal tract (achalasia, gastroparesis, pseudo-obstruction, and megacolon). In these settings, symptoms may develop either acutely (frequently after a flulike episode in otherwise previously healthy individuals) or more slowly (e.g., in paraneoplastic syndromes). The inflammatory/immune response in enteric ganglionitis leads to neuronal dysfunction and degeneration over time and sometimes results in a complete loss of enteric neurons. The diagnosis of enteric ganglionitis is supported by detection of circulating antineuronal antibodies against select molecular targets, including Hu and Yo proteins, neurotransmitter receptors, and ion channels. Potential mechanisms involved in neuronal dysfunction include viral antigen expression in the enteric neural environment, molecular mimicry (onconeural antigens), and the role exerted by cellular and humoral autoimmunity. A short course of steroid or other immunosuppressive therapy has been shown to be helpful in the treatment of these conditions. This feature reinforces the concept of a cause/effect relationship of the immune-mediated insult damaging the enteric innervation. An increased awareness of the clinical features and the immunologic and neurodegenerative mechanisms of these forms of peripheral neuropathy is important to correctly diagnose this problem during the early stages of the disease process and to provide appropriate immunosuppressive therapies.

Section snippets

Clinical features

Enteric ganglionitis refers to an inflammatory neuropathy caused by paraneoplastic (including lung small-cell carcinoma, thymoma, and breast cancer),13, 14, 15, 16 infectious (i.e., Chagas’ disease),17, 18, 19 or neurological (i.e., encephalomyeloneuropathy) means12; connective tissue disorders (i.e., scleroderma)20; and inflammatory bowel diseases (i.e., ulcerative colitis and Crohn’s disease),21 although some cases are idiopathic. In all cases, a histopathologic hallmark of enteric

Irritable bowel syndrome and postinfectious irritable bowel syndrome

IBS, one of the most common functional disorders seen in gastroenterological practice, is characterized by abdominal pain/discomfort associated with bowel habit disturbances, bloating, and other symptoms usually defined as unrelated to any organic abnormality.48 The existence of an inflammatory infiltrate as a morphological basis underlying symptom pathophysiology in functional bowel diseases dates back to the early 1960s, when Hiatt and Katz49 were the first to show an increased number of

Pathologic features

The analysis of tissue specimens obtained from patients affected by an inflammatory neuropathy is characterized by a dense lymphocytic and plasma cell infiltrate that is primarily confined to the myenteric plexus (Figure 2), but submucosal ganglia are sometimes involved as well. These immune/inflammatory changes are associated with progressive neuronal degeneration (Figure 3) that terminates in a complete loss of enteric neurons.40, 41 The dense inflammatory infiltrate is composed of

Antineuronal antibodies

In addition to lymphocyte activation, a significant humoral immune response involving a wide array of circulating antineuronal antibodies has been identified in patients with enteric ganglionitis. In fact, the identification of antineuronal antibodies is recommended as a useful tool to diagnose gut motility disorders related to an underlying enteric ganglionitis.64, 65 Antineuronal antibodies can be detected with a variety of approaches, including classic immunofluorescence techniques (commonly

Infectious forms and experimental models of enteric ganglionitis

Enteric ganglionitis can also occur in the course of an infectious disease (i.e., Trypanosoma cruzi, herpesviruses, or Schistosoma mansoni), with immunologic and histopathologic features that resemble those of the idiopathic forms. T. cruzi is a member of the Trypanosomatidae family; it is transmitted to humans by triatomine insects that are called Reduviidae beetles or “kissing bugs.”17 This parasite is responsible for Chagas’ disease, an endemic disorder of South America (especially Brazil)

Diagnosis

Diagnosis and treatment of patients with dysmotility related to enteric ganglionitis is a challenging task. The general diagnostic workup for severe gut motor abnormalities is beyond the scope of this review, and the reader is referred to extensive reviews.46, 92, 93

Although most acute episodes of gastroenteritis or flulike episodes associated with gastrointestinal symptoms resolve spontaneously in a short period of time, a small proportion may lead to the development of chronic functional

Treatment

Apart from the classic recommendations (maintenance of adequate nutrition and hydration, promotion of gastrointestinal propulsion, and treatment of complications such as bacterial overgrowth and intractable pain) to which the reader is referred,46, 92, 93 the use of immunosuppressive drugs represents the cornerstone of the pharmacological approach for patients with enteric ganglionitis. Once the diagnosis of an inflammatory neuropathy is established, usually steroids such as prednisolone at

Concluding remarks

Although this entity is rarely diagnosed in clinical practice, patients with enteric inflammatory neuropathy, i.e., with enteric ganglionitis, represent a considerable diagnostic and therapeutic challenge—all the more so because the current approach is based mainly on empirical clinical observation rather than controlled studies. Clinical series based on paraneoplastic inflammatory neuropathy14 are paving the way to a better pathophysiological definition of these conditions, which should be

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    ☆

    The original work of the authors was supported by grants from the Italian Ministry of Education, University and Research (COFIN 2002 Project 2002052573; to F.D.P.) and the Italian National Research Council (CNRC0008_02; to V.S. and R.D.G.) and by National Institutes of Health grants NS26995 and DK62267 (to G.M.M.). K.A.S. is an Alberta Heritage Foundation for Medical Research Medical Scientist. Studies in his laboratory are supported by the Canadian Institutes of Health Research and the Crohn’s Colitis Foundation of Canada. V.S. is a recipient of a Janssen Foundation educational grant.

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