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New perspectives in the diagnosis and management of enteric neuropathies

Nature Reviews Gastroenterology & Hepatology volume 10, pages 206–218 (2013)Cite this article

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Abstract

Chronic disturbances of gastrointestinal function encompass a wide spectrum of clinical disorders that range from common conditions with mild-to-moderate symptoms to rare diseases characterized by a severe impairment of digestive function, including chronic pain, vomiting, bloating and severe constipation. Patients at the clinically severe end of the spectrum can have profound changes in gut transit and motility. In a subset of these patients, histopathological analyses have revealed abnormalities of the gut innervation, including the enteric nervous system, termed enteric neuropathies. This Review discusses advances in the diagnosis and management of the main clinical entities—achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation—that result from enteric neuropathies, including both primary and secondary forms. We focus on the various evident neuropathologies (degenerative and inflammatory) of these disorders and, where possible, present the specific implications of histological diagnosis to contemporary treatment. This knowledge could enable the future development of novel targeted therapeutic approaches.

Key Points

  • A wide spectrum of clinical phenotypes are characterized by degrees of gut sensorimotor dysfunction; at the clinically severe end, patients can have profound changes of gut transit and motility, with or without chronic visceral dilatation

  • When histologically studied (and accepting some methodological limitations), a subset of patients with demonstrable gastrointestinal motor disturbances have evidence of disease to nerves of the enteric nervous system termed enteric neuropathies

  • Several disorders, for example, oesophageal achalasia, gastroparesis, enteric dysmotility, intestinal pseudo-obstruction and chronic constipation, can result from enteric neuropathies, including both primary and secondary forms

  • Inflammatory and degenerative cellular mechanisms can contribute to neural changes in primary and secondary neuropathies; understanding these mechanisms could promote the development of new therapeutic approaches for enteric neuropathies

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Figure 1: The relative prevalence of disorders that are characterized by unexplained abdominal pain and dysmotility.
Figure 2: Representative microphotographs illustrating noninflammatory (degenerative) and inflammatory enteric neuropathies.

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References

  1. Thompson, W. G. et al. Functional bowel disorders and functional abdominal pain. Gut 45 (Suppl. 2), 43–47 (1999).

    Google Scholar 

  2. Mann, S. D., Debinski, H. S. & Kamm, M. A. Clinical characteristics of chronic idiopathic intestinal pseudo-obstruction in adults. Gut 41, 675–681 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Heneyke, S., Smith, V. V., Spitz, L. & Milla, P. J. Chronic intestinal pseudo-obstruction: treatment and long term follow up of 44 patients. Arch. Dis. Child. 81, 21–27 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stanghellini, V. et al. Chronic intestinal pseudo-obstruction: manifestations, natural history and management. Neurogastroenterol. Motil. 19, 440–452 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. De Giorgio, R., Cogliandro, R. F., Barbara, G., Corinaldesi, R. & Stanghellini, V. Chronic intestinal pseudo-obstruction: clinical features, diagnosis, and therapy. Gastroenterol. Clin. North Am. 40, 787–807 (2011).

    Article  PubMed  Google Scholar 

  6. Furness, J. B. The enteric nervous system and neurogastroenterology. Nat. Rev. Gastroenterol. Hepatol. 9, 286–294 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Knowles, C. H. et al. Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol. 118, 271–301 (2009).

    Article  PubMed  Google Scholar 

  8. Knowles, C. H. et al. The London Classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group. Gut 59, 882–887 (2010).

    Article  PubMed  Google Scholar 

  9. Knowles, C. H. & Martin, J. E. Enteric neuromuscular pathology update. Gastroenterol.Clin. North Am. 40, 695–713 (2011).

    Article  PubMed  Google Scholar 

  10. Chitkara, D. K. & Di Lorenzo, C. From the bench to the 'crib'-side: implications of scientific advances to paediatric neurogastroenterology and motility. Neurogastroenterol. Motil. 18, 251–262 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Laranjeira, C. & Pachnis, V. Enteric nervous system development: recent progress and future challenges. Auton. Neurosci. 151, 61–69 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Panza, E. et al. Genetics of human enteric neuropathies. Prog. Neurobiol. 96, 176–189 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Csendes, A. et al. Histological studies of Auerbach's plexuses of the oesophagus, stomach, jejunum, and colon in patients with achalasia of the oesophagus: correlation with gastric acid secretion, presence of parietal cells and gastric emptying of solids. Gut 33, 150–154 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goldblum, J. R., Rice, T. W. & Richter, J. E. Histopathologic features in esophagomyotomy specimens from patients with achalasia. Gastroenterology 111, 648–654 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Goldblum, J. R., Whyte, R. I., Orringer, M. B. & Appelman, H. D. Achalasia. A morphologic study of 42 resected specimens. Am. J. Surg. Pathol. 18, 327–337 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Gockel, I., Bohl, J. R., Eckardt, V. F. & Junginger, T. Reduction of interstitial cells of Cajal (ICC) associated with neuronal nitric oxide synthase (n-NOS) in patients with achalasia. Am. J. Gastroenterol. 103, 856–864 (2008).

    Article  PubMed  Google Scholar 

  17. De Giorgio, R. et al. Esophageal and gastric nitric oxide synthesizing innervation in primary achalasia. Am. J. Gastroenterol. 94, 2357–2362 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Clark, S. B., Rice, T. W., Tubbs, R. R., Richter, J. E. & Goldblum, J. R. The nature of the myenteric infiltrate in achalasia: an immunohistochemical analysis. Am. J. Surg. Pathol. 24, 1153–1158 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Di Nardo, G. et al. Review article: molecular, pathological and therapeutic features of human enteric neuropathies. Aliment. Pharmacol. Ther. 28, 25–42 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Boeckxstaens, G. E. et al. Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia. N. Engl. J. Med. 364, 1807–1816 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Grover, M. et al. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology 140, 1575–1585 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Hirst, G. D. & Edwards, F. R. Role of interstitial cells of Cajal in the control of gastric motility. J. Pharmacol. Sci. 96, 1–10 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Liu, M. T., Kuan, Y. H., Wang, J., Hen, R. & Gershon, M. D. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29, 9683–9699 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Knowles, C. H. & Aziz, Q. Basic and clinical aspects of gastrointestinal pain. Pain 141, 191–209 (2009).

    Article  PubMed  Google Scholar 

  25. Rohrmann, C. A. Jr, Ricci, M. T., Krishnamurthy, S. & Schuffler, M. D. Radiologic and histologic differentiation of neuromuscular disorders of the gastrointestinal tract: visceral myopathies, visceral neuropathies, and progressive systemic sclerosis. Am. J. Roentgenol. 143, 933–941 (1984).

    Article  Google Scholar 

  26. Stanghellini, V., Camilleri, M. & Malagelada, J. R. Chronic idiopathic intestinal pseudo-obstruction: clinical and intestinal manometric findings. Gut 28, 5–12 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lindberg, G. et al. Full-thickness biopsy findings in chronic intestinal pseudo-obstruction and enteric dysmotility. Gut 58, 1084–1090 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Knowles, C. H. et al. Deranged smooth muscle α-actin as a biomarker of intestinal pseudo-obstruction: a controlled multinational case series. Gut 53, 1583–1589 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cogliandro, R. F. et al. Patient-reported outcomes and gut dysmotility in functional gastrointestinal disorders. Neurogastroenterol. Motil. 23, 1084–1091 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Wingate, D., Hongo, M., Kellow, J., Lindberg, G. & Smout, A. Disorders of gastrointestinal motility: towards a new classification. J. Gastroenterol. Hepatol. 17 (Suppl.), S1–S14 (2002).

    Article  PubMed  Google Scholar 

  31. Drossman, D. A. & Dumitrascu, D. L. Rome III: New standard for functional gastrointestinal disorders. J. Gastrointest. Liver Dis. 15, 237–241 (2006).

    Google Scholar 

  32. Tornblom, H., Lindberg, G., Nyberg, B. & Veress, B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology 123, 1972–1979 (2002).

    Article  PubMed  Google Scholar 

  33. Moayyedi, P. et al. The American College of Gastroenterology irritable bowel syndrome monograph: translating systematic review data to clinical practice. Gastroenterology 138, 789–791 (2010).

    Article  PubMed  Google Scholar 

  34. Tack, J. et al. Functional gastroduodenal disorders. Gastroenterology 130, 1466–1479 (2006).

    Article  PubMed  Google Scholar 

  35. Stanghellini, V. et al. Natural history of chronic idiopathic intestinal pseudo-obstruction in adults: a single center study. Clin. Gastroenterol. Hepatol. 3, 449–458 (2005).

    Article  PubMed  Google Scholar 

  36. Knowles, C. H. et al. Quantitation of cellular components of the enteric nervous system in the normal human gastrointestinal tract--report on behalf of the Gastro 2009 International Working Group. Neurogastroenterol. Motil. 23, 115–124 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Mousa, H., Hyman, P. E., Cocjin, J., Flores, A. F. & Di Lorenzo, C. Long-term outcome of congenital intestinal pseudoobstruction. Dig. Dis. Sci. 47, 2298–2305 (2002).

    Article  PubMed  Google Scholar 

  38. Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes affecting the nervous system. Semin. Oncol. 33, 270–298 (2006).

    Article  PubMed  Google Scholar 

  39. De Giorgio, R. & Camilleri, M. Human enteric neuropathies: morphology and molecular pathology. Neurogastroenterol. Motil. 16, 515–531 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. De Giorgio, R. et al. Inflammatory neuropathies of the enteric nervous system. Gastroenterology 126, 1872–1883 (2004).

    Article  PubMed  Google Scholar 

  41. Thapar, N. Future horizons in the treatment of enteric neuropathies. J. Pediatr. Gastroenterol. Nutr. 45 (Suppl. 2), S110–S114 (2007).

    Article  PubMed  Google Scholar 

  42. Patel, M. & Yang, S. Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell. Rev. 6, 367–380 (2010).

    Article  CAS  PubMed Central  Google Scholar 

  43. Drossman, D. A. et al. What determines severity among patients with painful functional bowel disorders? Am. J. Gastroenterol. 95, 974–980 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Wingate, D. & Grundy, D. Neurogastroenterology and motility: at last, an equal partnership. Neurogastroenterol. Motil. 12, 1 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Hiatt, R. B. & Katz, L. Mast cells in inflammatory conditions of the gastrointestinal tract. Am. J. Gastroenterol. 37, 541–545 (1962).

    CAS  PubMed  Google Scholar 

  46. Chadwick, V. S. et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 122, 1778–1783 (2002).

    Article  PubMed  Google Scholar 

  47. Barbara, G. et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126, 693–702 (2004).

    Article  PubMed  Google Scholar 

  48. Veress, B., Nyberg, B., Tornblom, H. & Lindberg, G. Intestinal lymphocytic epithelioganglionitis: a unique combination of inflammation in bowel dysmotility: a histopathological and immunohistochemical analysis of 28 cases. Histopathology 54, 539–549 (2009).

    Article  PubMed  Google Scholar 

  49. Selgrad, M. et al. JC virus infects the enteric glia of patients with chronic idiopathic intestinal pseudo-obstruction. Gut 58, 25–32 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. De Giorgio, R. et al. Chronic intestinal pseudo-obstruction related to viral infections. Transplant. Proc. 42, 9–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Zuliani, L., Graus, F., Giometto, B., Bien, C. & Vincent, A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J. Neurol. Neurosurg. Psychiatry 83, 638–645 (2012).

    Article  PubMed  Google Scholar 

  52. Blackshaw, L. A., Brookes, S. J., Grundy, D. & Schemann, M. Sensory transmission in the gastrointestinal tract. Neurogastroenterol. Motil. 19, 1–19 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Sandgren, J. E., McPhee, M. S. & Greenberger, N. J. Narcotic bowel syndrome treated with clonidine. Resolution of abdominal pain and intestinal pseudo-obstruction. Ann. Intern. Med. 101, 331–334 (1984).

    Article  CAS  PubMed  Google Scholar 

  54. Grover, C. A., Wiele, E. D. & Close, R. J. Narcotic bowel syndrome. J. Emerg. Med. 43, 992–995 (2012).

    Article  PubMed  Google Scholar 

  55. Gosselin, R. D., Suter, M. R., Ji, R. R. & Decosterd, I. Glial cells and chronic pain. Neuroscientist 16, 519–531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Agostini, S. et al. Evidence of central and peripheral sensitization in a rat model of narcotic bowel-like syndrome. Gastroenterology 139, 553–563 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Brint, E. K., MacSharry, J., Fanning, A., Shanahan, F. & Quigley, E. M. Differential expression of toll-like receptors in patients with irritable bowel syndrome. Am. J. Gastroenterol. 106, 329–336 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Hutchinson, M. R. et al. Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. Scientific World Journal 7, 98–111 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Holzer, P. Opioid antagonists for prevention and treatment of opioid-induced gastrointestinal effects. Curr. Opin. Anaesthesiol. 23, 616–622 (2010).

    Article  Google Scholar 

  60. Squires, J. E. & Squires, R. H. Jr. Munchausen syndrome by proxy: ongoing clinical challenges. J. Pediatr. Gastroenterol. Nutr. 51, 248–253 (2010).

    PubMed  Google Scholar 

  61. Preston, D. M., Hawley, P. R., Lennard-Jones, J. E. & Todd, I. P. Results of colectomy for severe idiopathic constipation in women (Arbuthnot Lane's disease). Br. J. Surg. 71, 547–552 (1984).

    Article  CAS  PubMed  Google Scholar 

  62. Hutson, J. M., Chow, C. W. & Borg, J. Intractable constipation with a decrease in substance P-immunoreactive fibres: is it a variant of intestinal neuronal dysplasia? J. Pediatr. Surg. 31, 580–583 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Knowles, C. H. & Farrugia, G. Gastrointestinal neuromuscular pathology in chronic constipation. Best Pract. Res. Clin. Gastroenterol. 25, 43–57 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Smith, B., Grace, R. H. & Todd, I. P. Organic constipation in adults. Br. J. Surg. 64, 313–314 (1977).

    Article  CAS  PubMed  Google Scholar 

  65. Krishnamurthy, S., Schuffler, M. D., Rohrmann, C. A. & Pope, C. E. 2nd. Severe idiopathic constipation is associated with a distinctive abnormality of the colonic myenteric plexus. Gastroenterology 88, 26–34 (1985).

    Article  CAS  PubMed  Google Scholar 

  66. Porter, A. J., Wattchow, D. A., Hunter, A. & Costa, M. Abnormalities of nerve fibers in the circular muscle of patients with slow transit constipation. Int. J. Colorectal Dis. 13, 208–216 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Wattchow, D. et al. Regional variation in the neurochemical coding of the myenteric plexus of the human colon and changes in patients with slow transit constipation. Neurogastroenterol. Motil. 20, 1298–3105 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Knowles, C. H. et al. Smooth muscle inclusion bodies in slow transit constipation. J. Pathol. 193, 390–397 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Wedel, T. et al. Oligoneuronal hypoganglionosis in patients with idiopathic slow-transit constipation. Dis. Colon Rectum 45, 54–62 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Mitolo-Chieppa, D. et al. Cholinergic stimulation and nonadrenergic, noncholinergic relaxation of human colonic circular muscle in idiopathic chronic constipation. Dig. Dis. Sci. 43, 2719–2726 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Camilleri, M., Kerstens, R., Rykx, A. & Vandeplassche, L. A placebo-controlled trial of prucalopride for severe chronic constipation. N. Engl. J. Med. 358, 2344–2354 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Scharli, A. F. & Meier-Ruge, W. Localized and disseminated forms of neuronal intestinal dysplasia mimicking Hirschsprung's disease. J. Pediatr. Surg. 16, 164–170 (1981).

    Article  CAS  PubMed  Google Scholar 

  73. Koletzko, S. et al. Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective multicentre study on interobserver variation and clinical outcome. Gut 44, 853–861 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Knowles, C. H., Scott, M. & Lunniss, P. J. Outcome of colectomy for slow transit constipation. Ann. Surg. 230, 627–638 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hutson, J. M. Intestinal neuronal dysplasia. Defining a new cause for chronic constipation. Aust. Fam. Physician 25, 1357 (1996).

    CAS  PubMed  Google Scholar 

  76. Van den Berg, M. M. et al. Morphological changes of the enteric nervous system, interstitial cells of cajal, and smooth muscle in children with colonic motility disorders. J. Pediatr. Gastroenterol. Nutr. 48, 22–29 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Di Lorenzo, C., Solzi, G. F., Flores, A. F., Schwankovsky, L. & Hyman, P. E. Colonic motility after surgery for Hirschsprung's disease. Am. J. Gastroenterol. 95, 1759–1764 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Pensabene, L., Youssef, N. N., Griffiths, J. M. & Di Lorenzo, C. Colonic manometry in children with defecatory disorders. role in diagnosis and management. Am. J. Gastroenterol. 98, 1052–1057 (2003).

    PubMed  Google Scholar 

  79. Bassotti, G., Imbimbo, B. P., Betti, C., Dozzini, G. & Morelli, A. Impaired colonic motor response to eating in patients with slow-transit constipation. Am. J. Gastroenterol. 87, 504–508 (1992).

    CAS  PubMed  Google Scholar 

  80. Rao, S. S. Diagnosis and management of fecal incontinence. American College of Gastroenterology Practice Parameters Committee. Am. J. Gastroenterol. 99, 1585–1604 (2004).

    Article  PubMed  Google Scholar 

  81. Bytzer, P. et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch. Intern. Med. 161, 1989–1996 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Kassander, P. Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum). Ann. Intern. Med. 48, 797–812 (1958).

    Article  CAS  PubMed  Google Scholar 

  83. Harberson, J., Thomas, R. M., Harbison, S. P. & Parkman, H. P. Gastric neuromuscular pathology in gastroparesis: analysis of full-thickness antral biopsies. Dig. Dis. Sci. 55, 359–370 (2010).

    Article  PubMed  Google Scholar 

  84. Mashimo, H., Kjellin, A. & Goyal, R. K. Gastric stasis in neuronal nitric oxide synthase-deficient knockout mice. Gastroenterology 119, 766–773 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Plourde, V., Quintero, E., Suto, G., Coimbra, C. & Tache, Y. Delayed gastric emptying induced by inhibitors of nitric oxide synthase in rats. Eur. J. Pharmacol. 256, 125–129 (1994).

    Article  CAS  PubMed  Google Scholar 

  86. Orihata, M. & Sarna, S. K. Inhibition of nitric oxide synthase delays gastric emptying of solid meals. J. Pharmacol. Exp. Ther. 271, 660–670 (1994).

    CAS  PubMed  Google Scholar 

  87. Anvari, M., Paterson, C. A. & Daniel, E. E. Role of nitric oxide mechanisms in control of pyloric motility and transpyloric flow of liquids in conscious dogs. Dig. Dis. Sci. 43, 506–512 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Takahashi, T., Nakamura, K., Itoh, H., Sima, A. A. & Owyang, C. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology 113, 1535–1544 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Wrzos, H. F., Cruz, A., Polavarapu, R., Shearer, D. & Ouyang, A. Nitric oxide synthase (NOS) expression in the myenteric plexus of streptozotocin-diabetic rats. Dig. Dis. Sci. 42, 2106–2110 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Chandrasekharan, B. & Srinivasan, S. Diabetes and the enteric nervous system. Neurogastroenterol. Motil. 19, 951–960 (2007).

    CAS  Google Scholar 

  91. Ordog, T. Interstitial cells of Cajal in diabetic gastroenteropathy. Neurogastroenterol. Motil. 20, 8–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. He, C. L. et al. Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 121, 427–434 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Chandrasekharan, B. et al. Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol. Motil. 23, 131–138 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Nakahara, M. et al. Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus. J. Gastroenterol. Hepatol. 17, 666–670 (2002).

    Article  Google Scholar 

  95. Bagyanszki, M. & Bodi, N. Diabetes-related alterations in the enteric nervous system and its microenvironment. World J. Diabetes 3, 80–93 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Pereira, E. C. et al. Biomarkers of oxidative stress and endothelial dysfunction in glucose intolerance and diabetes mellitus. Clin. Biochem. 41, 1454–1460 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Pereira, R. V. et al. L-glutamine supplementation prevents myenteric neuron loss and has gliatrophic effects in the ileum of diabetic rats. Dig. Dis. Sci. 56, 3507–3516 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Choi, K. M. et al. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology 135, 2055–2064 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Negi, G., Kumar, A., Joshi, R. P. & Sharma, S. S. Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: old perspective with a new angle. Biochem. Biophys. Res. Commun. 408, 1–5 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Lin, Z., Forster, J., Sarosiek, I. & McCallum, R. W. Treatment of diabetic gastroparesis by high-frequency gastric electrical stimulation. Diabetes Care 27, 1071–1076 (2004).

    Article  PubMed  Google Scholar 

  101. Van der Voort, I. R. et al. Gastric electrical stimulation results in improved metabolic control in diabetic patients suffering from gastroparesis. Exp. Clin. Endocrinol. Diabetes 113, 38–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Abell, T. et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 125, 421–428 (2003).

    Article  PubMed  Google Scholar 

  103. Forno, L. S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, 259–272 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Wakabayashi, K. & Takahashi, H. Neuropathology of autonomic nervous system in Parkinson's disease. Eur. Neurol. 38 (Suppl. 2), 2–7 (1997).

    Article  PubMed  Google Scholar 

  105. Beach, T. G. et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 119, 689–702 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wakabayashi, K., Takahashi, H., Takeda, S., Ohama, E. & Ikuta, F. Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses. Acta Neuropathol. 76, 217–221 (1988).

    Article  CAS  PubMed  Google Scholar 

  107. Annerino, D. M. et al. Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol. 124, 665–680 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Lebouvier, T. et al. Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PLoS ONE 14, e12728 (2010).

    Article  CAS  Google Scholar 

  109. Salat-Foix, D. & Suchowersky, O. The management of gastrointestinal symptoms in Parkinson's disease. Expert Rev. Neurother. 12, 239–248 (2012).

    Article  PubMed  Google Scholar 

  110. Goetze, O. et al. Predictors of gastric emptying in Parkinson's disease. Neurogastroenterol. Motil. 18, 369–375 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Soykan, I., Sarosiek, I. & McCallum, R. W. The effect of chronic oral domperidone therapy on gastrointestinal symptoms, gastric emptying, and quality of life in patients with gastroparesis. Am. J. Gastroenterol. 92, 976–980 (1997).

    CAS  PubMed  Google Scholar 

  112. Djaldetti, R., Koren, M., Ziv, I., Achiron, A. & Melamed, E. Effect of cisapride on response fluctuations in Parkinson's disease. Mov. Disord. 10, 81–84 (1995).

    Article  CAS  PubMed  Google Scholar 

  113. Asai, H. et al. Increased gastric motility during 5-HT4 agonist therapy reduces response fluctuations in Parkinson's disease. Parkinsonism Relat. Disord. 11, 499–502 (2005).

    Article  PubMed  Google Scholar 

  114. Pfeiffer, R. F. Autonomic dysfunction in Parkinson's disease. Expert Rev. Neurother. 12, 697–706 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Zangaglia, R. et al. Macrogol for the treatment of constipation in Parkinson's disease. A randomized placebo-controlled study. Mov. Disord. 22, 1239–1244 (2007).

    Article  PubMed  Google Scholar 

  116. Cassani, E. et al. Use of probiotics for the treatment of constipation in Parkinson's disease patients. Minerva Gastroenterol. Dietol. 57, 117–121 (2011).

    CAS  PubMed  Google Scholar 

  117. Nguyen-tat, M. et al. Severe paraneoplastic gastroparesis associated with anti-Hu antibodies preceding the manifestation of small-cell lung cancer. Z. Gastroenterol. 46, 274–278 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Lennon, V. A. et al. Enteric neuronal autoantibodies in pseudoobstruction with small-cell lung carcinoma. Gastroenterology 100, 137–142 (1991).

    Article  CAS  PubMed  Google Scholar 

  119. Lucchinetti, C. F., Kimmel, D. W. & Lennon, V. A. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 50, 652–657 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Lee, H. R., Lennon, V. A., Camilleri, M. & Prather, C. M. Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics. Am. J. Gastroenterol. 96, 373–379 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Pardi, D. S. et al. Paraneoplastic dysmotility: loss of interstitial cells of Cajal. Am. J. Gastroenterol. 97, 1828–1833 (2002).

    Article  PubMed  Google Scholar 

  122. Vernino, S. et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N. Engl. J. Med. 343, 847–855 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Hubball, A., Martin, J. E., Lang, B., De Giorgio, R. & Knowles, C. H. The role of humoral autoimmunity in gastrointestinal neuromuscular diseases. Prog. Neurobiol. 87, 10–20 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Sodhi, N. et al. Autonomic function and motility in intestinal pseudoobstruction caused by paraneoplastic syndrome. Dig. Dis. Sci. 34, 1937–1942 (1989).

    Article  CAS  PubMed  Google Scholar 

  125. Gerl, A. et al. Paraneoplastic chronic intestinal pseudoobstruction as a rare complication of bronchial carcinoid. Gut 33, 1000–1003 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pande, R. & Leis, A. A. Myasthenia gravis, thymoma, intestinal pseudo-obstruction, and neuronal nicotinic acetylcholine receptor antibody. Muscle Nerve 22, 1600–1602 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Martin, A. et al. A case of paraneoplastic inflammatory neuropathy of the gastrointestinal tract related to an underlying neuroblastoma: successful management with immunosuppressive therapy. J. Pediatr. Gastroenterol. Nutr. 46, 457–460 (2008).

    Article  PubMed  Google Scholar 

  128. Schobinger-Clement, S., Gerber, H. A. & Stallmach, T. Autoaggressive inflammation of the myenteric plexus resulting in intestinal pseudoobstruction. Am. J. Surg. Pathol. 23, 602–606 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Badari, A., Farolino, D., Nasser, E., Mehboob, S. & Crossland, D. A novel approach to paraneoplastic intestinal pseudo-obstruction. Support Care Cancer 20, 425–428 (2012).

    Article  PubMed  Google Scholar 

  130. Drukker, C. A., Heij, H. A., Wijnaendts, L. C., Verbeke, J. I. & Kaspers, G. J. Paraneoplastic gastro-intestinal anti-Hu syndrome in neuroblastoma. Pediatr. Blood Cancer 52, 396–398 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Da Silveira, A. B. et al. Glial fibrillary acidic protein and S-100 colocalization in the enteroglial cells in dilated and nondilated portions of colon from chagasic patients. Hum. Pathol. 40, 244–251 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Jabari, S. et al. Selective survival of calretinin- and vasoactive-intestinal-peptide-containing nerve elements in human chagasic submucosa and mucosa. Cell Tissue Res. 349, 473–481 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Kierszenbaum, F. Chagas' disease and the autoimmunity hypothesis. Clin. Microbiol. Rev. 12, 210–223 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Da Silveira, A. B. et al. Enteroglial cells act as antigen-presenting cells in chagasic megacolon. Hum. Pathol. 42, 522–532 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Higuchi, M. D. et al. Association of an increase in CD8+ T cells with the presence of Trypanosoma cruzi antigens in chronic, human, chagasic myocarditis. Am. J. Trop. Med. Hyg. 56, 485–489 (1997).

    Article  CAS  PubMed  Google Scholar 

  136. Kierszenbaum, F. Where do we stand on the autoimmunity hypothesis of Chagas disease? Trends Parasitol. 21, 513–516 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Goin, J. C. et al. Functional implications of circulating muscarinic cholinergic receptor autoantibodies in chagasic patients with achalasia. Gastroenterology 117, 798–805 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Teixeira, A. R., Nitz, N., Guimaro, M. C., Gomes, C. & Santos-Buch, C. A. Chagas disease. Postgrad. Med. J. 82, 788–798 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Rodriques Coura, J. & de Castro, S. L. A critical review on Chagas disease chemotherapy. Mem. Inst. Oswaldo Cruz. 97, 3–24 (2002).

    Article  PubMed  Google Scholar 

  140. Crema, E., Ribeiro, L. B., Terra, J. A. Jr & Silva, A. A. Laparoscopic transhiatal subtotal esophagectomy for the treatment of advanced megaesophagus. Ann. Thorac. Surg. 80, 1196–1201 (2005).

    Article  PubMed  Google Scholar 

  141. Gama, A. H. et al. Volvulus of the sigmoid colon in Brazil: a report of 230 cases. Dis. Colon Rectum 19, 314–320 (1976).

    Article  CAS  PubMed  Google Scholar 

  142. Perlemuter, G. et al. Chronic intestinal pseudo-obstruction in systemic lupus erythematosus. Gut 43, 117–122 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ebert, E. C. & Hagspiel, K. D. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J. Clin. Gastroenterol. 45, 436–441 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Ferrante, M. et al. The value of myenteric plexitis to predict early postoperative Crohn's disease recurrence. Gastroenterology 130, 1595–1606 (2006).

    Article  PubMed  Google Scholar 

  145. Sokol, H. & Beaugerie, L. Inflammatory bowel disease and lymphoproliferative disorders: the dust is starting to settle. Gut 58, 1427–1436 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Smith, V. V. et al. Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement. Gastroenterology 112, 1366–1371 (1997).

    Article  CAS  PubMed  Google Scholar 

  147. Hanemann, C. O., Hayward, C. & Hilton, D. A. Neurofibromatosis type 1 with involvement of the enteric nerves. J. Neurol. Neurosurg. Psychiatry 78, 1163–1164 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Moline, J. & Eng, C. Multiple endocrine neoplasia type 2: an overview. Genet. Med. 13, 755–764 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Iantorno, G. et al. The enteric nervous system in chagasic and idiopathic megacolon. Am. J. Surg. Pathol. 31, 460–468 (2007).

    Article  PubMed  Google Scholar 

  150. Schuffler, M. D., Lowe, M. C. & Bill, A. H. Studies of idiopathic intestinal pseudoobstruction. I. Hereditary hollow visceral myopathy: clinical and pathological studies. Gastroenterology 73, 327–338 (1977).

    Article  CAS  PubMed  Google Scholar 

  151. McDonald, G. B., Schuffler, M. D., Kadin, M. E. & Tytgat, G. N. Intestinal pseudoobstruction caused by diffuse lymphoid infiltration of the small intestine. Gastroenterology 89, 882–889 (1985).

    Article  CAS  PubMed  Google Scholar 

  152. De Giorgio, R. et al. Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult. Eur. J. Gastroenterol. Hepatol. 12, 613–616 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. De Giorgio, R. et al. Clinical and morphofunctional features of idiopathic myenteric ganglionitis underlying severe intestinal motor dysfunction: a study of three cases. Am. J. Gastroenterol. 97, 2454–2459 (2002).

    Article  PubMed  Google Scholar 

  154. Schappi, M. G., Smith, V. V., Milla, P. J. & Lindley, K. J. Eosinophilic myenteric ganglionitis is associated with functional intestinal obstruction. Gut 52, 752–755 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Ooms, A. H. et al. Eosinophilic myenteric ganglionitis as a cause of chronic intestinal pseudo-obstruction. Virchows. Arch. 460, 123–127 (2012).

    Article  PubMed  Google Scholar 

  156. Messing, B. & Joly, F. Guidelines for management of home parenteral support in adult chronic intestinal failure patients. Gastroenterology 130 (Suppl. 1), S43–S51 (2006).

    Article  PubMed  Google Scholar 

  157. Joly, F., Amiot, A. & Messing, B. Nutritional support in the severely compromised motility patient: when and how? Gastroenterol. Clin. North Am. 40, 845–851 (2011).

    Article  PubMed  Google Scholar 

  158. Davis, M. P. Drug management of visceral pain: concepts from basic research. Pain Res. Treat. http://dx.doi.org/10.1155/2012/265605.

  159. Emmanuel, A. V., Kamm, M. A., Roy, A. J., Kerstens, R. & Vandeplassche, L. Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction--a double-blind, placebo-controlled, cross-over, multiple n = 1 study. Aliment. Pharmacol. Ther. 35, 48–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Andersson, S. et al. Gastric electrical stimulation for intractable vomiting in patients with chronic intestinal pseudoobstruction. Neurogastroenterol. Motil. 18, 823–830 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Abu-Elmagd, K. M. et al. Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation. Ann. Surg. 256, 494–508 (2012).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors of this Review are supported by grants PRIN and COFIN from the Italian Ministry of University, Research and Education 2008 and 2010 and Ricerca Fondamentale Orientata funds from the University of Bologna to R. De Giorgio. He is also the recipient of research grants from Fondazione Del Monte di Bologna e Ravenna. C. Knowles is funded by the Higher Education Funding Committee of England (HEFCE).

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Authors and Affiliations

  1. Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London, E1 2AD, UK

    Charles H. Knowles

  2. Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Hälsovägen, Stockholm, SE-141 86, Flemingsberg, Sweden

    Greger Lindberg

  3. Department of Human Genetics, Howard Hughes Medical Institute, University of Utah, 2030 East 15 North, Salt Lake City, 84112, UT, USA

    Emanuele Panza

  4. Department of Medical and Surgical Sciences, Centro di Ricerca Biomedica Applicata and Centro Interdipartimentale di Ricerca sull'Alimentazione Umana, University of Bologna, Via Massarenti 9, Bologna, 40138, Italy

    Roberto De Giorgio

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Knowles, C., Lindberg, G., Panza, E. et al. New perspectives in the diagnosis and management of enteric neuropathies. Nat Rev Gastroenterol Hepatol 10, 206–218 (2013). https://doi.org/10.1038/nrgastro.2013.18

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