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Intestinal Neuronal Dysplasis/NID
Congenital
malformations and perinatal morbidity associated with intestinal
neuronal dysplasia
Are giant ganglia a reliable marker of intestinal neuronal dysplasia type B (IND B)?
Notable postnatal alterations in the myenteric plexus of normal human bowel
Pediatric Surgery International
ISSN: 0179-0358 (printed version) ISSN: pending (electronic version)
Table of Contents Abstract Volume 13 Issue 7 (1998) pp 474-479 main topic:
Congenital malformations and perinatal morbidity associated with intestinal neuronal dysplasia
S. Berger, P. Ziebell, M. Kessler, S. Hofmann-von Kap-herr Department of Pediatric Surgery, Johannes-Gutenberg-University, Langenbeckstrasse, D-55131 Mainz, Germany
Abstract A close relation between different forms of dysganglionosis such as intestinal neuronal dysplasia (IND) type B and aganglionosis has been established. No systematic analysis of other malformations and diseases accompanying IND has been made as yet. Congenital malformations and perinatal morbidity were analyzed in 109 patients with IND seen at the Department of Pediatric Surgery in Mainz from 1977 to 1996. IND was associated with Hirschsprung's disease in 47 cases; 22 children with IND had other abdominal malformations, including anal atresia, rectal stenosis, sigmoidal stenosis, ileal atresia, pyloric stenosis, and esophageal atresia. A cystic bowel duplication, a choledochal cyst, and a persisting urachus were also found. Extra-abdominal malformations such as Down's syndrome, congenital diaphragmatic hernia, aortic stenosis, and malformations of vertebral bodies were seen. Twin siblings of children with IND were either healthy (n=3) or died in utero (n=1). Seventeen children with IND developed severe intra-abdominal complications during the perinatal period such as necrotizing enterocolitis (NEC), meconium ileus, or bowel perforations. NEC was frequently associated with preterm birth. Bowel perforations were seen in mature and preterm newborns with IND. Taken together, IND is found in a variety of obstructive bowel diseases. This may support the hypothesis that IND is a secondary phenomenon or that congenital atresias and stenoses of the digestive tract have a pathogenesis similar to that of intestinal innervation disturbances. IND may also be a part of complex malformation patterns since it occurs with a number of extraintestinal and non-obstructive intestinal malformations.
Abstract Volume 432 Issue 2 (1998) pp 103-106
Are giant ganglia a reliable marker of intestinal neuronal dysplasia type B (IND B)?
P. D. Lumb, L. Moore Department of Histo/Cytopathology, Central Manchester Healtheare Trust, Clinical Sciences Building, Oxford Road, Manchester, M13 9WL, UK Tel.: (+44)1612768811, Fax: (+44)1612766348, e-mail:lmoore@fs1.cmht.nwest.nhs.uk
Received: 3 September 1997/Accepted: 3 November 1997
Abstract It has been suggested that giant ganglia are a marker for a developmental bowel disorder, intestinal neuronal dysplasia of the submucosal plexus (IND B), diagnosed in a proportion of patients with severe intractable constipation. Diagnosis of this condition, however, remains controversial with a wide variation in the frequency of diagnosis in different centres. Our aim was to assess the frequency with which giant ganglia could be found in the bowel of individuals who did not give a history of life-long constipation. We also aimed to assess the reproducibility of giant ganglia counts. For this two pathologists independently assessed pieces of normal bowel taken away from the site of the lesion in patients who had undergone surgery for colorectal carcinoma. Giant ganglia containing seven or more ganglion cells were found in 76 and 78% of subjects by each of the two pathologists. There was 1 giant ganglion per 10 ganglia counted in those patients in whom they were identified and 1 giant ganglion per 10.9 ganglia overall. Sections from eight patients in whom there was a history of constipation and/or melanosis coli did not show a greater number of giant ganglia. We conclude therefore that so-called "giant ganglia" are a common feature in the submucosa of normal bowel and that the presence of occasional giant ganglia cannot be considered diagnostic uf IND B.
Publisher: BMJ Publishing Group
Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective multicentre study on interobserver variation and clinical outcome
Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective multicentre study on interobserver variation and clinical outcome
GUT, June 1999, vol. 44, no. 6, pp. 853-861(9)
Nützenadel W.[1]; Koletzko S.[2]; Schmittenbecher P.[3]; Jesch I.[2]; Holschneider A.[4]; Faus-Keßler T.[5]; Sacher P.[6]; Briner J.[7]; Meier-Ruge W.[8]; Müntefering H.[9]; Coerdt W.[9]; Wessel L.[10]; Keller K.M.[11]
[1] Kinderklinik der Universität Heidelberg, Germany
[10] Kinderchirurgische Klinik der Universität Mannheim, Germany
[11] Kinderklinik der Universität Bonn, Germany
[2] Kinderpoliklinik der Ludwig-Maximilians-Universität, München, Germany [3] Kinderchirurgische Klinik der Ludwig-Maximilians-Universität, München, Germany
[4] Kinderchirurgische Klinik der Stadt, Köln, Germany
[5] GSF-Forschungszentrum für Umwelt und Gesundheit, München, Germany
[6] Chirurgische Klinik des Universitäts-Kinderspital, Zürich, Switzerland
[7] Pathologisches Institut der Universität Zürich, Switzerland
[8] Pathologisches Institut der Universität Basel, Switzerland
[9] Pathologisches Institut der Universität Mainz, Germany
[*]Dr S Koletzko, Kinderklinik und Kinderpoliklinik im Dr v Haunerschen Kinderspital, Ludwig-Maximilians-Universität, Pettenkoferstr 8a, D-80336 München, Germany.
Abstract:
Background Intestinal neuronal dysplasia (IND) of the colonic submucous plexus is considered to be a congenital malformation of the enteric nervous system causing symptoms resembling those of Hirschsprung's disease. In contrast with the established diagnosis of aganglionosis using enzyme histochemistry, controversy exists over the diagnostic criteria of IND on rectal biopsies previously defined by a consensus report and the causal relation between morphological findings and clinical symptoms. Aims The interobserver variability was prospectively investigated with respect to final diagnoses and several histological features in rectal biopsy specimens from children suspected of having colonic motility disturbances. Methods 377 biopsy specimens from 108 children aged 4 days to 15 years were independently coded without knowledge of clinical symptoms by three experienced pathologists for 20 histological features, and a final diagnosis was given for every case. Interobserver variation for the different items and the final diagnosis were analysed using Cohen's statistic. Clinical data at biopsy and outcome after 12 months were related to morphological findings. Results The three pathologists agreed completely with respect to the diagnosis Hirschsprung's disease ( = 1), but in only 14% of the children without aganglionosis. In 15 (17%) of the 87 children without aganglionosis, at least one pathologist judged the case as normal, while another diagnosed IND. values were close to the zero value expected by chance for the diagnoses normal and IND. Young age was related to the presence of several morphological features-for example, acetylcholine esterase staining and presence of giant ganglia. Children with chronic constipation diagnosed as having IND, given no other specific diagnosis by any of the pathologists, were significantly younger (median 8.8 months) and had a higher cure rate after one year (60%) than constipated patients considered by all observers to have no histological abnormalities (median 6.1 years, cure rate 23%). Conclusions In contrast with Hirschsprung's disease, there is a high interobserver variation with regard to the different morphological features and final diagnosis of IND, based on the criteria and conditions of the previous consensus report. The high frequency of histological "abnormalities" in young infants suggests that some of the features may represent a normal variant of postnatal development rather than a pathological process. Investigations using more refined and morphometric methods in rectal specimens from infants and children without bowel disease are needed to define the normal range of morphological appearance at different ages. These preliminary data indicate that, with current knowledge, rectal biopsy for diagnostic purposes should only be performed in constipated children for diagnosis of Hirschsprung's disease.
Keywords: intestinal neuronal dysplasia; Hirschsprung's disease; constipation; enzyme histochemistry
Language: English Document Type: Original article ISSN: 0017-5749
Publisher: BMJ Publishing Group
Notable postnatal alterations in the myenteric plexus of normal human bowel
GUT, May 1999, vol. 44, no. 5, pp. 666-674(9)
Wester T.[1]; O'Briain D.S.[1]; Puri P.[1]
[1] Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland
[*]Mr P Puri, Director of Research, Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.
Abstract:
Background Nitric oxide is the most important transmitter in non-adrenergic non-cholinergic nerves in the human gastrointestinal tract. Impaired nitrergic innervation has been described in Hirschsprung's disease, hypertrophic pyloric stenosis, and intestinal neuronal dysplasia (IND). Recent findings indicate that hyperganglionosis, one of the major criteria of IND, is age dependent. However, information is scanty regarding the neurone density in normal human bowel in the paediatric age group. Aims To determine neurone density, morphology, and nitric oxide synthase distribution of the normal myenteric plexus at different ages during infancy and childhood. Methods Specimens were obtained from small bowel and colon in 20 children, aged one day to 15 years, at postmortem examination. Whole mount preparations were made of the myenteric plexus, which were subsequently stained using NADPH diaphorase histochemistry (identical to nitric oxide synthase) and cuprolinic blue (a general neuronal marker). The morphology of the myenteric plexus was described and the neurone density estimated. Results The myenteric plexus meshwork becomes less dense during the first years of life. The density of ganglion cells in the myenteric plexus decreases significantly with age during the first three to four years of life. The NADPH diaphorase positive (nitrergic) subpopulation represents about 34% of all neurones in the myenteric plexus. Conclusions The notable decrease in neurone density in the myenteric plexus during the first years of life indicates that development is still an ongoing process in the postnatal enteric nervous system. Applied to the clinical situation, this implies that interpretation of enteric nervous system pathology is dependent on the age of the patient.
Keywords: whole mount preparation; myenteric plexus; nitric oxide; neurone density; development; human
Language: English Document Type: Original article ISSN: 0017-5749
BMJ 1996;312:261-262 (3 February)
Editorials
Small bowel transplantation
Unique problems but now standard treatment for small bowel insufficiency
Intestinal transplantation is the logical alternative to definitiveparenteral nutrition in patients with chronic intestinal failureafter conditions such as necrotising enterocolitis or midgutvolvulus. Long term parenteral nutrition is associated withcomplications such as liver impairment and local and systemicinfections. But since its introduction in the late 1960s, parenteralnutrition has improved greatly, especially with the developmentof long term home parenteral nutrition, and, as a result, interestin small bowel transplantation has waned. The evolution of theprocedure, first reported in experimental animals by AlexisCarrel in 1902, has therefore taken longer than that of othersolid organ transplants. However, recent advances in immunosuppressionand the monitoring of rejection have brought small bowel transplantationinto the realms of standard treatment for certain conditions.
Several features of the small bowel make it unique among transplantableorgans: the large amount of lymphoid tissue contained in themesenteric lymph nodes, Peyer's patches, and lamina propria;its heavy colonisation with microorganisms; and the expressionof great quantities of class II antigens on the surface of epithelialcells. These features may contribute respectively to graft versushost disease, graft rejection, and sepsis.
Difficulties in transplanting small bowel in humans were firstperceived in the 1960s. Seven adults who had undergone massivesmall bowel resection and subsequent small bowel transplantationwere treated with antilymphoglobulins, corticosteroids, andazathioprine, but none survived more than 76 days after theoperation. The limitations of parenteral nutrition and reportsof long term survival in animals treated with the new immunosuppressivedrug cyclosporin have revived interest in the procedure. However,among the 20 recipients treated with cyclosporin after smallbowel transplantation between 1985 and 1990, only two patients,one adult and one child, were able to resume normal oral nutrition;most of the grafts failed because of rejection or infectionbut surprisingly not as the result of graft versus host disease.
Data on long term patient and graft survival are now availablefrom the intestinal transplant registry (D Grant, IVth InternationalSymposium on Small Bowel Transplantation, Pittsburgh, October1995). Currently more than 170 patients have received smallbowel transplants; 38% of them isolated, 46% combined with livertransplantation, and 16% as part of a multivisceral transplantation.Two thirds of the recipients were children or adolescents. Withthe immunosuppressive drug tacrolimus, actuarial graft survivalrates at one year and three years were 65% and 29% for isolatedsmall bowel transplantation, 64% and 38% for the combined procedure,and 51% and 37% for multivisceral transplantation. Eighty percent of the 86 survivors no longer require parenteral nutritionand are totally orally fed.
Two recent advances have made small bowel transplantation apromising option for the treatment of end stage intestinal failure:combination with liver transplantation, and the developmentof tacrolimus. In 1990 Grant et al reported the successful outcomeafter combined small bowel and liver transplantation in an adulttreated with cyclosporin. This result has opened the procedureto patients who have developed end stage liver disease as acomplication of parenteral nutrition and has raised the possibilitythat liver transplantation from the same donor may induce toleranceto the small bowel graft. With regard to this last possibility,experimental models and clinical results (D Grant, IVth InternationalSymposium on Small Bowel Transplantation) have given conflictingevidence. A large series showed no advantage in long term survivalof small bowel grafts when the procedure was combined with livertransplantation. Currently there is no indication to transplantthe liver unless the patient has end stage cirrhosis.
Early diagnosis of rejection is essential
The second advance has been the introduction by Starzl et alof a new macrolide immunosuppressive drug, tacrolimus (FK506).This drug has produced two year graft survival rates after isolatedsmall bowel transplantation of 40% compared with 11% with cyclosporin(D Grant, IVth International Symposium on Small Bowel Transplantation),and it may prove as useful in small bowel transplantation ascyclosporin has been in liver and heart transplantation.
Monitoring for intestinal rejection is vital after small boweltransplantation since graft rejection is the main complicationof the procedure and early diagnosis and treatment of graftrejection is an absolute necessity. Macroscopic changes of mucosalinjury and clinical symptoms of graft rejection appear lateafter the first signs of histological damage. It seems thatthe combination of conventional histology with haematein eosinstaining and immunohistochemistry on repeated mucosal biopsiesprovides not only early and rapid diagnosis but informationon mechanisms of mucosal injury. Patients receive a majorhistocompatibility class incompatible small bowel cadavericallograft. The distal part of this is left as an enterostomyfor at least the first three months, allowing close histologicaland immunohistochemical follow up by sequential biopsy.
Human allograft rejection is the consequence of a successionof non-specific events, amplifying the immune reaction triggeredby allogenic T cells. This is probably due to the abundant lymphoidpopulation within the intestine and explains the main difficultyof controlling the rejection process once it has started. Thedestructive effect of the cytokines released by this inflammatorycascade emphasises the importance of prevention by active immunosuppressionand early detection of rejection with appropriate immunohistochemicalmonitoring. Other complications of intestinal transplantationinclude rare cases of graft versus host disease, cases of lymphoproliferativedisorders related to small bowel transplantation, and the usualcomplications of immunosuppression such as viral and fungalinfections.
Finally, despite dramatic improvements in clinical outcome,indications for small bowel transplantation will always be rarerthan for other solid organ transplants such as kidney, heart,or liver. In Britain an estimated two patients per million population,with an equal number of adults and children, are estimated torequire small bowel transplantation each year. The procedureshould be offered to patients with small intestine insufficiencydue to anatomical abnormalities (short bowel syndrome) or functionaldisorders (intractable diarrhoea of infancy or chronic intestinalpseudo-obstruction syndrome). In the treatment of intestinalfailure, however, small bowel transplantation can only becomestandard when it can offer greater safety and better qualityof life than long term home parenteral nutrition.
Professor of pathology Professor of paediatrics Department ofPathology and Gastroenterology and Nutrition (Pr C.Ricour),Hopital Necker-Enfants Malades, 75743 Paris, Cedex 15, France
Nicole Brousse, Olivier Goulet
- Carrel A. La technique operatoire des anastomoses vasculaires et le transplantation des visceres. Lyon: MEO, 1902;98:859-65.
- Fortner JG, Sichuk G, Litwin SD, Beattie EJ. Immunological response to an intestinal allograft with HLA identical donor-recipient. Transplantation 1972;14:531-5.
- Schroeder P, Goulet O, Lear P. Small bowel transplantation: European experience. Lancet 1990;336:110-1.
- Grant D, Wall W, Mimerault R, Zhong R, Ghent C, Garcia B, et al. Successful small bowel-liver transplantation. Lancet 1990;335:181-4.
- Sarnacki S, Revillon Y, Cerf-Bensussan N, Calise D, Goulet O, Brousse N. Long-term small bowel survival induced by spontaneously tolerated liver allograft in inbred rat strains. Transplantation 1992;54:383-5.
- Murase N, Demetris AJ, Kim DG, Todo S, Fung JJ, Starzl TE. Rejection of multivisceral allografts in rats: a sequential comparison to isolated orthotopic small-bowel and liver graft. Surgery 1990;108:880-9.
- Abu-Elmagd K, Todo S, Tzakis A, Reyes J, Nour B, Furukawa H, et al. Three years clinical experience with intestinal transplantation. J Am Coll Surg 1994;179:385-400.
- Gruessner RWG, Fryer JP, Fasola C, Nakhleh RE, Gruessner AC, Kim S, et al. A prospective study of FK506 versus CsA and Pig ATG in a porcine model of small bowel transplantation. Transplantation 1995;59:164-71.
- Fromont G, Peuchmaur M, Devergne O, Jan D, Emilie D, Goulet O, et al. In situ expression of cytokines and serine esterase B in small-bowel allograft rejection. Histopathology 1993;22:503-5.
- Fromont G, Cerf-Bensussan N, Patey N, Canioni, Rambaud C, Goulet O, et al. Small bowel transplantation in children: an immunohistochemical study of intestinal grafts. Gut 1995;37:783-90.
- Ingham Clarke CL, Lear PA, Wood S, Lennard-Jones JE, Wood RF. Potential candidates for small bowel transplantation. Br J Surg 1992;79:676-9.