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Jiang S, Song CY, Feng MX, Lu YQ. Adult patients with allied disorders of Hirschsprung’s disease in emergency department: An 11-year retrospective study. World J Gastrointest Surg 2022; 14:656-669. [PMID: 36158276 PMCID: PMC9353751 DOI: 10.4240/wjgs.v14.i7.656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/21/2021] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the past years, only a few studies with a limited number of adult patients analyzed clinical features of allied disorders of Hirschsprung’s disease (ADHD), most of which were individual case reports or lacked detailed clinical information. Although many studies have reported patients presenting to the emergency department (ED) with recurrent abdominal symptoms for a number of disorders, there are few data involving ADHD. However, owing to a lack of awareness of the disease, misdiagnoses and mistreatments are common. Severe complications such as perforation, bleeding, malabsorption, and even death in ADHD had been reported by many studies.
AIM To assist ED clinicians in having a more comprehensive understanding of this disease and making an early suspected diagnosis of ADHD more effectively.
METHODS We enrolled 53 patients who visited the ED and were eventually diagnosed with ADHD over the past 11 years in our hospital. Their basic information, clinical manifestations, and imaging findings were analyzed. Blood indices were compared between the ADHD and irritable bowel syndrome (IBS) groups.
RESULTS Adult patients with ADHD had a mean age of 48.8 ± 14.3 years, and 77.4% had been treated before admission. The transverse colon was the most common dilated part (73.6%), and constipation (67.9%) was the most common symptom. ADHD patients can present with uncommon symptoms and false-negative imaging findings. Logistic regression analysis indicated that body mass index (BMI) [odds ratio (OR) = 0.786, P = 0.013], cholinesterase (per 1000 units; OR = 0.693, P = 0.008), and blood chlorine (OR = 0.816, P = 0.022) were determined to be independent related factors between the ADHD and IBS groups. The area under the receiver operating characteristics curve of these three indices combined was 0.812 (P < 0.001).
CONCLUSION Emergency physicians should be vigilant regarding patients with chronic constipation, abdominal pain, or abdominal distension, and consider the possibility of ADHD despite its rarity. Abdominal computed tomography examination is recommended as a useful tool in the suspected diagnosis of ADHD. BMI, cholinesterase, and blood chlorine have good discriminative abilities between ADHD and IBS. The nutritional status of adult patients with ADHD is worthy of further attention. Surgical treatment for adult patients with ADHD is important and inevitable.
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Affiliation(s)
- Shuai Jiang
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Cong-Ying Song
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Xiao Feng
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
| | - Yuan-Qiang Lu
- Department of Emergency Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
- Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou 310003, Zhejiang Province, China
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Terra SA, Gonçalves AC, Lourenção PLTDA, Rodrigues MAM. Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells. World J Gastroenterol 2021; 27:7649-7660. [PMID: 34908804 PMCID: PMC8641051 DOI: 10.3748/wjg.v27.i44.7649] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/26/2021] [Accepted: 11/11/2021] [Indexed: 02/06/2023] Open
Abstract
Intestinal neuronal dysplasia type B (IND-B) is a controversial condition among gastrointestinal neuromuscular disorders. Constipation is its most common clinical manifestation in patients. Despite intense scientific research, there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies. The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system. However, it is very complex to distinguish numerically what is pathological from what is normal, mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms. Thus, a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system. Several of these markers facilitate the identification of other structures of the enteric nervous system, in addition to ganglion cells. These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease, providing a view beyond the number of ganglion cells. This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.
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Affiliation(s)
- Simone Antunes Terra
- Department of Pathology, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618687, São Paulo, Brazil
| | - Anderson Cesar Gonçalves
- Department of Surgery and Orthopedics, Botucatu Medical School - São Paulo State University (UNESP), Botucatu 18618970, São Paulo, Brazil
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Braczynski AK, Gfroerer S, Beschorner R, Harter PN, Baumgarten P, Rolle U, Mittelbronn M. Cholinergic innervation and ganglion cell distribution in Hirschsprung's disease. BMC Pediatr 2020; 20:399. [PMID: 32838761 PMCID: PMC7445925 DOI: 10.1186/s12887-020-02299-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 08/17/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The diagnostic gold standard of Hirschsprung's disease (HD) is based on the histopathological assessment of colorectal biopsies. Although data on cholinergic innervation and ganglion cell (GC) distribution exist, only few studies have examined these two key features together. We assessed the pattern of cholinergic innervation and the amount of GCs in colorectal specimens of 14 HD patients. METHODS We established a semi-quantitative score for cholinergic innervation using acetylcholinesterase (AChE) enzyme histochemistry and quantitatively analyzed the number of GCs via NADH tetrazolium reductase (NADH) enzyme histochemistry. We examined both the entire length of the resected specimens as well as defined areas of the transition zone of both pathological and healthy appearing segment. RESULTS High AChE score values were associated with absence of GCs, and AChE scores were inversely correlated with the number of GCs. Nevertheless, we observed several cases in which one of the two features revealed a normal distribution pattern, whereas the other still displayed pathological features. CONCLUSIONS Our data support the need for transmural colon biopsies, to enable the best evaluation of both cholinergic innervation and GCs for a reliable assessment of HD.
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Affiliation(s)
- Anne K Braczynski
- Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany
- Department of Physical Biology, Heinrich-Heine University, Düsseldorf, Germany
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry, Forschungszentrum Jülich, Jülich, Germany
- Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany
| | - Stefan Gfroerer
- Department of Pediatric Surgery, Helios Hospital Berlin-Buch, Berlin, Germany
| | - Rudi Beschorner
- Institute of Pathology and Neuropathology, Eberhard-Karls University, Tuebingen, Germany
| | - Patrick N Harter
- Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
| | - Peter Baumgarten
- Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany
- Department of Neurosurgery, Goethe University, Frankfurt, Germany
| | - Udo Rolle
- Department of Pediatric Surgery, University of Frankfurt am Main, Frankfurt, Germany
- University Children's Hospital, Goethe University, Frankfurt, Germany
| | - Michel Mittelbronn
- Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany.
- Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Strassen, Luxembourg.
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg City, Luxembourg.
- National Center of Pathology (NCP), Laboratoire national de santé (LNS), 1, Rue Louis Rech, L-3555, Dudelange, Luxembourg.
- Luxembourg Center of Neuropathology (LCNP), 1, Rue Louis Rech, L-3555, Dudelange, Luxembourg.
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Kapur RP, Reyes-Mugica M. Intestinal Neuronal Dysplasia Type B: An Updated Review of a Problematic Diagnosis. Arch Pathol Lab Med 2018; 143:235-243. [DOI: 10.5858/arpa.2017-0524-ra] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context.—
Intestinal neuronal dysplasia type B (IND B) is a controversial histopathologic phenotype that has been associated with intestinal dysmotility, either as an isolated condition or in conjunction with established pathologic disorders (eg, Hirschsprung disease). Many factors contribute to the debate over the existence and/or clinical significance of IND B, including a large body of published data based on inconsistent diagnostic criteria and methods, which have fostered many unwarranted conclusions that lack sufficient scientific basis.
Objective.—
To critically analyze existing published data regarding IND B to provide supporting evidence-based diagnostic practice and to stimulate necessary and scientifically sound research.
Data Sources.—
This update focuses on published literature related to the pathology of IND B because without a reliable pathologic diagnosis, studies of epidemiology, pathogenesis, natural history, management, and outcome are all suspect. Problems with existing data are identified explicitly with suggestions as to how future investigations should be designed and evaluated to better understand this entity.
Conclusions.—
Inconsistencies in diagnostic criteria and methods used to define IND B justifiably encumber the universal acceptance of IND B as a neuropathologic etiology for intestinal dysmotility. IND B will remain a controversial diagnosis until rigorous, well-controlled scientific studies are conducted to establish reproducible and reliable diagnostic criteria that reliably translate from one laboratory to another.
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Affiliation(s)
- Raj P. Kapur
- From the Department of Laboratories, Seattle Children's Hospital, Seattle, Washington (Dr Kapur); the Department of Pathology, University of Washington School of Medicine, Seattle (Dr Kapur); and the Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Reyes-Mugica)
| | - Miguel Reyes-Mugica
- From the Department of Laboratories, Seattle Children's Hospital, Seattle, Washington (Dr Kapur); the Department of Pathology, University of Washington School of Medicine, Seattle (Dr Kapur); and the Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Reyes-Mugica)
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Terra SA, de Arruda Lourenção PL, G Silva M, A Miot H, Rodrigues MAM. A critical appraisal of the morphological criteria for diagnosing intestinal neuronal dysplasia type B. Mod Pathol 2017; 30:978-985. [PMID: 28304401 DOI: 10.1038/modpathol.2017.4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 01/03/2017] [Accepted: 01/03/2017] [Indexed: 01/23/2023]
Abstract
Intestinal neuronal dysplasia type B is a controversial entity expressed by complex changes in the enteric nervous system. Diagnosis depends on rectal biopsy histopathology and diagnostic criteria, both qualitative and quantitative, have changed over time, hindering the diagnostic practice. We analyzed the morphological criteria for the histological diagnosis of intestinal neuronal dysplasia type B in a series of patients with intestinal neuronal dysplasia type B according to the 1990 Frankfurt Consensus criteria and verified the applicability of the numerical criteria proposed by Meier-Ruge et al in 2004 and 2006. Qualitative criteria adopted for the histological diagnosis of intestinal neuronal dysplasia type B included hyperplasia of the submucous plexus with hyperganglionosis and hypertrophy of the nerve trunks. Quantitative criteria considered more than 20% giant ganglia in the submucosa, with more than eight neurons each on 25 ganglia, and children aged over 1 year. Distal colon surgical specimens from 29 patients, aged 0-16 years, diagnosed with intestinal neuronal dysplasia type B were retrospectively analyzed using sections processed for conventional histology (H&E) and calretinin immunohistochemistry. Hyperplasia of the submucosal nerve plexi with hyperganglionosis and hypertrophy of the nerve trunks was observed in all cases. Ganglia with small, immature neurons were detected in the majority of cases. Quantitative analysis confirmed hyperganglionosis (mean number=10.7 neurons per ganglion) and hypertrophy of the nerve trunks (median=44.6 μm thickness). Neurons showed immunostaining for calretinin, but neuron counts in calretinin-stained sections were lower compared with H&E (P<0.01). No significant differences were verified between children aged under and over 1 year regarding hyperganglionosis (P=0.79), neuron counts (P=0.36), and immature ganglia (P=0.66). Only one patient met the numerical criteria proposed by Meier-Ruge et al in 2004 and 2006. In conclusion, the numerical criteria showed limited applicability when transposed to conventional histopathology. Children aged over 1 year presented very similar histological features of neuronal immaturity to younger children, questioning the need for an age criterion when diagnosing intestinal neuronal dysplasia type B.
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Affiliation(s)
- Simone A Terra
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Pedro L de Arruda Lourenção
- Department of Surgery, Division of Pediatric Surgery, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Márcia G Silva
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Hélio A Miot
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Maria A M Rodrigues
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
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Lourenção PLTDA, Ortolan EVP, Rosa LLM, Angelini MC, Terra SA, Rodrigues MAM. Long-term follow-up of patients with intestinal neuronal dysplasia type B: Protocol for an observational, ambispective, and comparative study. Medicine (Baltimore) 2017; 96:e7485. [PMID: 28700491 PMCID: PMC5515763 DOI: 10.1097/md.0000000000007485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Intestinal neuronal dysplasia type B (IND-B) is a pathological entity of the group of gastrointestinal neuromuscular diseases characterized by complex alterations in the enteric nervous system. Patients typically present with intestinal constipation, sometimes complicated by episodes of intestinal obstruction. The 2 therapeutic modalities include conservative clinical treatment and surgical treatment. Nevertheless, the results of the different therapeutic modalities are conflicting, and follow-up studies are scarce and include only a limited number of patients.This is a single-center, ambispective, observational, longitudinal, and comparative follow-up study to compare the results of conservative clinical and surgical treatments in patients with IND-B. Sixty-three patients (<15 years) who received this diagnosis will be included. These patients will be divided into 2 groups according to the type of treatment that they previously received: 29 patients in the surgical treatment group and 34 patients in the conservative treatment group. Previous data will be recovered from the medical records of the study patients, including signs and symptoms present at the time of diagnosis, particularly those related to bowel habits, and treatments undergone. Later, these patients will be invited to participate in a semistructured interview during which aspects related to the long-term functional results of the bowel habit and quality of life will be investigated after a minimum interval of 5 years posttreatment.This project aims to assess the long-term clinical evolution of patients diagnosed with IND-B and compare the results obtained following conservative clinical and surgical treatments.This protocol will provide sufficient data to analyze the long-term clinical outcome obtained through the 2 treatment modalities proposed for patients with IND-B.
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Affiliation(s)
| | | | | | | | - Simone Antunes Terra
- Department of Pathology, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil
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Moore SW. Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease). Pediatr Surg Int 2017; 33:285-298. [PMID: 27988850 DOI: 10.1007/s00383-016-4038-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/05/2016] [Indexed: 12/11/2022]
Abstract
Hirschsprung disease (HSCR) is a fairly well understood congenital, genetically based functional obstruction due to the congenital absence of ganglion cells in the distal bowel. However, although over 90% of Hirschsprung cases conform to the normally accepted histological diagnostic criteria, it has become increasingly clear that in addition to HSCR, there is a group of functional disturbances relating to a number of other congenital neurodysplastic conditions causing some degree of gastrointestinal tract malfunction. Although these represent a variety of possibly separate conditions of the enteric nervous system, this spectrum it would appear to be also influenced by similar developmental processes. The term "variant Hirschsprung" is commonly used to describe these conditions, but ganglion cells are mostly present if abnormal in number and distribution. These conditions are a problem group being amongst the most difficult to diagnose and treat with possible practical and legal consequences. The problem appears to be possibly one of definition which has proven difficult in the relative paucity of normal values, especially when correlated to age and gestation. It is the purpose of this paper to review the current position on these conditions and to explore possible shared common pathogenetic and genetic mechanisms. This article explores those conditions where a similar pathogenetic mechanisms to HSCR can be demonstrated (e.g. hypoganglionosis) as well as other neural features, which appear to represent separate conditions possibly linked to certain syndromes.
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Affiliation(s)
- S W Moore
- Division of Paediatric Surgery, Faculty of Medicine, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, South Africa.
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Toledo de Arruda Lourenção PL, Terra SA, Ortolan EVP, Rodrigues MAM. Intestinal neuronal dysplasia type B: A still little known diagnosis for organic causes of intestinal chronic constipation. World J Gastrointest Pharmacol Ther 2016; 7:397-405. [PMID: 27602240 PMCID: PMC4986395 DOI: 10.4292/wjgpt.v7.i3.397] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 04/14/2016] [Accepted: 05/07/2016] [Indexed: 02/06/2023] Open
Abstract
Intestinal neuronal dysplasia type B (IND-B) is a controversial entity among the gastrointestinal neuromuscular disorders. It may occur alone or associated with other neuropathies, such as Hirschsprung's disease (HD). Chronic constipation is the most common clinical manifestation of patients. IND-B primarily affects young children and mimics HD, but has its own histopathologic features characterized mainly by hyperplasia of the submucosal nerve plexus. Thus, IND-B should be included in the differential diagnoses of organic causes of constipation. In recent years, an increasing number of cases of IND-B in adults have also been described, some presenting severe constipation since childhood and others with the onset of symptoms at adulthood. Despite the intense scientific research in the last decades, there are still knowledge gaps regarding definition, pathogenesis, diagnostic criteria and therapeutic possibilities for IND-B. However, in medical practice, we continue to encounter patients with severe constipation or intestinal obstruction who undergo to diagnostic investigation for HD and their rectal biopsies present hyperganglionosis in the submucosal nerve plexus and other features, consistent with the diagnosis of IND-B. This review critically discusses aspects related to the disease definitions, pathophysiology and genetics, epidemiology distribution, clinical presentation, diagnostic criteria and therapeutic possibilities of this still little-known organic cause of intestinal chronic constipation.
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Goldstein AM, Thapar N, Karunaratne TB, De Giorgio R. Clinical aspects of neurointestinal disease: Pathophysiology, diagnosis, and treatment. Dev Biol 2016; 417:217-28. [PMID: 27059882 DOI: 10.1016/j.ydbio.2016.03.032] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/21/2016] [Accepted: 03/31/2016] [Indexed: 02/07/2023]
Abstract
The enteric nervous system (ENS) is involved in the regulation of virtually all gut functions. Conditions referred to as enteric neuropathies are the result of various mechanisms including abnormal development, degeneration or loss of enteric neurons that affect the structure and functional integrity of the ENS. In the past decade, clinical and molecular research has led to important conceptual advances in our knowledge of the pathogenetic mechanisms of these disorders. In this review we consider ENS disorders from a clinical perspective and highlight the advancing knowledge regarding their pathophysiology. We also review current therapies for these diseases and present potential novel reparative approaches for their treatment.
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Affiliation(s)
- Allan M Goldstein
- Department of Pediatric Surgery, Center for Neurointestinal Health, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Nikhil Thapar
- Division of Neurogastroenterology and Motility, Department of Gastroenterology, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK
| | - Tennekoon Buddhika Karunaratne
- Department of Medical and Surgical Sciences and Gastrointestinal System, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy; Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Roberto De Giorgio
- Department of Medical and Surgical Sciences and Gastrointestinal System, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy; Centro di Ricerca BioMedica Applicata (C.R.B.A.), University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
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Swaminathan M, Oron AP, Chatterjee S, Piper H, Cope-Yokoyama S, Chakravarti A, Kapur RP. Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections. Pediatr Dev Pathol 2015; 18:466-76. [PMID: 26699691 PMCID: PMC4809533 DOI: 10.2350/15-07-1675-oa.1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Intestinal neuronal dysplasia type B (IND) denotes an increased proportion of hyperplastic submucosal ganglia, as resolved histochemically in 15-μm-thick frozen sections. IND has been reported proximal to the aganglionic segment in patients with Hirschsprung disease (HSCR) and is putatively associated with a higher rate of postsurgical dysmotility. We developed and validated histological criteria to diagnose IND-like submucosal ganglion cell hyperplasia (IND-SH) in paraffin sections and used the approach to study the incidence and clinical and/or genetic associations of IND-SH at the proximal margins of HSCR pull-through resection specimens. Full-circumference paraffin sections from the proximal margins of 64 HSCR colonic pull-through specimens and 24 autopsy controls were immunostained for neuron-specific Hu antigen, and nucleated ganglion cells in each submucosal ganglion were counted. In controls, an age-related decline in the relative abundance of "giant" ganglia (≥7 nucleated Hu-positive [Hu+] ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean ± 3× standard deviation) was derived from 15 controls less than 25 weeks of age. No control exceeded this threshold, whereas in the same age range, IND-SH was observed at the proximal margins in 15% (7 of 46) of HSCR resections, up to 15 cm proximal to the aganglionic segment. No significant correlation was observed between IND-SH and length of or distance from the aganglionic segment, sex, trisomy 21, RET or SEMA3C/D polymorphisms, or clinical outcome, but analysis of more patients, with better long-term follow-up will be required to clarify the significance of this histological phenotype.
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Affiliation(s)
| | | | - Sumantra Chatterjee
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine ,Balimore, MD
| | - Hannah Piper
- University of Texas Southwestern, Children's Health, Dallas, TX
| | | | - Aravinda Chakravarti
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine ,Balimore, MD
| | - Raj P. Kapur
- Seattle Children's Research Institute, Seattle, WA,University of Washington, Pathology, Seattle, WA
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Isolated intestinal neuronal dysplasia Type B (IND-B) in Japan: results from a nationwide survey. Pediatr Surg Int 2014; 30:815-22. [PMID: 25052255 DOI: 10.1007/s00383-014-3542-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/18/2014] [Indexed: 12/19/2022]
Abstract
PURPOSE Intestinal neuronal dysplasia Type B (IND-B) has been proposed to be an allied disorder of Hirschsprung's disease (ADHD). The original histological criteria included hyperganglionosis, giant ganglia, ectopic ganglion cells and an increased AChE activity in the lamina propria. The criteria for IND-B have been gradually revised. The present diagnostic criteria are [1] more than 20 % of the submucosal ganglia contain nine or more ganglion cells and [2] the patient is older than 1 year. To clarify the current status of IND-B in Japan, a nationwide retrospective cohort study was performed. METHODS Questionnaires were sent to 161 major institutes of pediatric surgery and gastroenterology in Japan. RESULTS A total of 355 cases of ADHD were collected, including 18 cases of IND-B (5 %). Based on original criteria, 13 out of 18 cases were diagnosed as IND-B. However, only four cases met the current criteria. Three of the four patients (75 %) required pull-through operation. All of the patients exhibited giant ganglia and ganglioneuromatosis-like hyperplasia of the myenteric plexus. CONCLUSIONS IND-B cases matching the current criteria are thought to be quite rare and they are associated with marked hyperplasia of the myenteric plexus. "True" IND-B is a rare and intractable disease.
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Abstract
"Variants of Hirschsprung's disease" are conditions that clinically resemble Hirschsprung's disease (HD), despite the presence of ganglion cells in rectal suction biopsies. The diagnosis and management of these patients can be challenging. Specific histological, immunohistochemical and electron microscopic investigations are required to characterize this heterogeneous group of functional bowel disorders. Variants of HD include intestinal neuronal dysplasia, intestinal ganglioneuromatosis, isolated hypoganglionosis, immature ganglia, absence of the argyrophil plexus, internal anal sphincter achalasia and congenital smooth muscle cell disorders such as megacystis microcolon intestinal hypoperistalsis syndrome. This review article systematically classifies variants of HD based on current diagnostic criteria with an additional focus on pathogenesis, epidemiology, clinical presentation, management and outcome.
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Wu XJ, Zhang HY, Li N, Yan MS, Wei J, Yu DH, Feng JX. A new diagnostic scoring system to differentiate Hirschsprung's disease from Hirschsprung's disease-allied disorders in patients with suspected intestinal dysganglionosis. Int J Colorectal Dis 2013; 28:689-696. [PMID: 23568714 DOI: 10.1007/s00384-013-1691-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/18/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE To create a simple diagnostic scoring system to differentiate Hirschsprung's disease (HD) from Hirschsprung's disease-allied disorders (HAD) in patients with suspected intestinal dysganglionosis (IDs). METHODS Between 1998 and 2008, 967 patients with suspected intestinal dysganglionosis underwent surgical treatment at the pediatric surgery department of Tongji Hospital. The diagnosis of HD or HAD was confirmed by postoperative pathological examination. All patients underwent preoperative work-up including barium enema, anorectal manometry, and histochemical acetylcholinesterase staining of rectal mucosa. Known risk factors for IDs were recorded. The predicting score was calculated by summing the scores of the risk factors and three preoperative tests. The sensitivity, specificity, accuracy, positive predictive values, negative predictive values, positive likelihood ratios, and negative likelihood ratios of the predicting score were calculated. The cutoff score for predicting HD was determined using receiver operating characteristic (ROC) analysis. The accuracy of the predicting score was measured by the area under the ROC curve. RESULTS Failed or delayed passage of meconium, age <3 years and male gender were risk factors associated with HD. The area under the ROC curve of the predicting score was 0.927 (95 % confidence interval, 0.910-0.944). A predicting score of more than 5 was used as a cutoff for predicting HD. The scoring system achieved 83.1 % sensitivity, 89.5 % specificity, and 85.9 % accuracy in predicting HD. CONCLUSION Patients with a predicting score of more than 5 are more likely to be diagnosed with HD, whereas a score less than 5 are mostly indicative of HAD.
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Affiliation(s)
- Xiao-juan Wu
- Department of Pediatric Surgery, Tongji Hospital, 1095 Jiefang Avenue, Wuhan 430030, China
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Obermayr F, Hotta R, Enomoto H, Young HM. Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol 2013; 10:43-57. [PMID: 23229326 DOI: 10.1038/nrgastro.2012.234] [Citation(s) in RCA: 148] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The enteric nervous system (ENS) arises from neural crest-derived cells that migrate into and along the gut, leading to the formation of a complex network of neurons and glial cells that regulates motility, secretion and blood flow. This Review summarizes the progress made in the past 5 years in our understanding of ENS development, including the migratory pathways of neural crest-derived cells as they colonize the gut. The importance of interactions between neural crest-derived cells, between signalling pathways and between developmental processes (such as proliferation and migration) in ensuring the correct development of the ENS is also presented. The signalling pathways involved in ENS development that were determined using animal models are also described, as is the evidence for the involvement of the genes encoding these molecules in Hirschsprung disease-the best characterized paediatric enteric neuropathy. Finally, the aetiology and treatment of Hirschsprung disease in the clinic and the potential involvement of defects in ENS development in other paediatric motility disorders are outlined.
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Affiliation(s)
- Florian Obermayr
- Department of Pediatric Surgery, University Children's Hospital, University of Tübingen, Hoppe-Seyler Straße 3, Tübingen 72076, Germany
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15
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Abstract
PURPOSE The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities. Hirschsprung's disease (HD) is a congenital defect of the ENS, characterised by an absence of ganglia in the distal colon. Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterised by hyperganglionosis, giant and ectopic ganglia, resulting in intestinal dysmotility. Intestinal ganglioneuromatosis is characterised by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudo-obstruction (CIPO). Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a phosphatase that is critical for controlling cell growth, proliferation and cell death. A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS suggesting a role for this protein in ENS development. Ganglioneuromatosis patients have also been shown to have a decreased level of Pten expression in the colon. The aim of our study was to investigate Pten expression in the ENS of HD and IND patients compared to normal controls. METHODS Resected tissue from 10 HD and 10 IND type B patients was fixed and embedded in paraffin wax. Normal control colon tissue was obtained from ten patients who underwent a colostomy closure for imperforate anus. Sections were cut and immunohistochemistry was carried out using a Pten antibody. Results were analysed by light microscopy. RESULTS Staining showed that Pten was strongly expressed in ganglia of both the submucosal and myenteric plexus of normal and HD specimens from the ganglionic colon. Pten expression was significantly reduced in the giant ganglia in IND patients in both the myenteric and submucosal plexuses compared to the normal controls. Specimens from the aganglionic region of HD did not show Pten expression. CONCLUSION To the best of our knowledge, this is the first study demonstrating a marked reduction of Pten expression in the myenteric and submucous plexuses of IND patients. Neuronal Pten deficiency in IND may disrupt the chemical pathway associated with the proliferation and development of neuronal cells forming mature ganglia and thus cause motility dysfunction.
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Affiliation(s)
- Anne-Marie O'Donnell
- National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland
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16
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Knowles CH, Farrugia G. Gastrointestinal neuromuscular pathology in chronic constipation. Best Pract Res Clin Gastroenterol 2011; 25:43-57. [PMID: 21382578 PMCID: PMC4175481 DOI: 10.1016/j.bpg.2010.12.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 12/15/2010] [Indexed: 01/31/2023]
Abstract
Some patients with chronic constipation may undergo colectomy yielding tissue appropriate to diagnosis of underlying neuromuscular pathology. The analysis of such tissue has, over the past 40 years, fueled research that has explored the presence of neuropathy, myopathy and more recently changes in interstitial cells of Cajal (ICC). In this chapter, the data from these studies have been critically reviewed in the context of the significant methodological and interpretative issues that beset the field of gastrointestinal neuromuscular pathology. On this basis, reductions in ICC appear to a consistent finding but one whose role as a primary cause of slow-transit constipation requires further evaluation. Findings indicative of significant neuropathy or myopathy are variable and in many studies subject to considerable methodological bias. Methods with practical diagnostic utility in the individual patient have rarely been employed and require further validation in respect of normative data.
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Affiliation(s)
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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17
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Giri DK, Quist EM, Ambrus A, Gold J, Porter BF, Bratton GR, Storts RW. Enteric dysganglionosis resembling intestinal neuronal dysplasia in a foal with bacterial colitis. Vet Pathol 2010; 47:654-7. [PMID: 20466864 DOI: 10.1177/0300985810370006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A 5-day-old quarter horse colt with a history of hypothermia, agonal breathing, and diarrhea was euthanized. At necropsy, numerous slightly raised, discrete, closely approximated submucosal nodules were observed in the colon and small intestine. Histologically, these nodules were composed of expanded submucosal mesenchyme that contained numerous neurons either individually or in ganglia. Thirty-two percent of these ganglia included 8 or more neurons, in contrast to 6% in an age-matched foal. Some nodules had necrosuppurative inflammation with vasculitis, thrombosis, and bacterial colonization. A few heterotopic neurons were randomly distributed in the mucosa and the muscularis mucosa. Histologic changes were most consistent with intestinal neuronal dysplasia, a disease of the submucosal plexus described in humans.
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Affiliation(s)
- D K Giri
- Integrated Laboratory Systems, 601 Keystone Park Drive, Suite 100, Durham, NC 27713, USA.
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18
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Sutcliffe JR, King S, Hutson JM, Southwell B. What is new in radiology and pathology of motility disorders in children? Semin Pediatr Surg 2010; 19:81-5. [PMID: 20307844 DOI: 10.1053/j.sempedsurg.2009.11.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Disorders affecting colorectal motility lead to significant morbidity in children with surgical conditions. Etiology is frequently unknown, which in turn makes treatment empiric and compromises outcome. A thorough understanding of the normal mechanisms of control and the ability to recognize and manage defects is an important goal for clinicians. This article reviews recent advances made in the investigation of children with colorectal motility disorders, including the role of transit studies (marker studies and scintigraphy), options for assessing anatomy (ultrasound, contrast enema, and sectional imaging) and the use of manometry, both anorectal and colonic. Current concepts in microscopic evaluation are outlined.
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Affiliation(s)
- Jonathan R Sutcliffe
- Department of Paediatric Surgery, Leeds General Infirmary, Leeds LS1 3EX, United Kingdom.
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19
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20
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Bruder E, Meier-Ruge WA. [Hypoganglionosis as a cause of chronic constipation]. DER PATHOLOGE 2008; 28:131-6. [PMID: 17277919 DOI: 10.1007/s00292-007-0892-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Hypoganglionosis comprises 3-5% of gastrointestinal innervation defects which are connected to therapy-resistant chronic constipation in children and adults. Similar to Hirschsprung's disease, hypoganglionosis may be complicated by megacolon formation and must be considered in the differential diagnosis. Three main subtypes may be distinguished: congenital hypoplastic hypoganglionosis occurs predominantly in Hirschsprung's disease proximal to the aganglionic segment and consists of small paucicellular ganglia with increased interganglionic distances. Oligoneuronal dysganglionic hypoganglionosis manifests in childhood. Initially, myenteric ganglia are of normal size and have normal interganglionic spacing and normal neuronal content. However, nerve cells are hypoplastic and ganglia undergo progressive nerve cell loss. This type of hypoganglionosis may progress into atrophic hypoganglionosis, which shows a morphology similar to hypoplastic hypoganglionosis. All subtypes of hypoganglionosis result in decreased acetylcholinesterase activity in the nerve fiber network of the muscularis propria. The pathogenesis of hypoganglionosis is still poorly understood. In Hirschsprung associated hypoganglionosis, mutations in the RET and GDNF-genes have been found. Despite a heterozygote GDNF+/- animal model for hypoganglionosis, no GDNF mutations have so far been demonstrated in human Hirschsprung independent, isolated hypoganglionosis.
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Affiliation(s)
- E Bruder
- Institut für Pathologie, Universitätsspital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
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21
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Abstract
Intestinal neuronal dysplasia type B (IND B) is currently considered to be a subtle malformation of the submucosal plexus, leading to an increased proportion of over-sized ganglia and potentially accompanied by a mild, chronic gastrointestinal motility disturbance. The diagnosis of IND B is morphologically based and involves the demonstration of an increased proportion of giant ganglia in the submucous plexus related to the patient's age. Giant ganglia are physiologically frequent in the neonatal period. Therefore, IND B should not be diagnosed prior to 1 year of age. Morphological features of IND B may occur as an isolated finding or may be observed proximal to an aganglionic segment. IND B and constipation may resolve spontaneously up to the age of 4 years. Treatment of IND B is usually conservative, surgical resection is currently deemed necessary only in a minority of patients. The pathogenesis of IND B is still incompletely understood and the etiology unknown. Future research on the basis of standardized diagnostic conditions is expected to result in a better understanding of this disease, and to reveal the cause of aberrant ganglion development.
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22
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Bruder E, Meier-Ruge WA. [Intestinal neuronal dysplasia type B: how do we understand it today?]. DER PATHOLOGE 2008; 28:137-42. [PMID: 17279410 DOI: 10.1007/s00292-007-0894-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Intestinal neuronal dysplasia type B (IND B) is currently considered to be a subtle malformation of the submucosal plexus, leading to an increased proportion of over-sized ganglia and potentially accompanied by a mild, chronic gastrointestinal motility disturbance. The diagnosis of IND B is morphologically based and involves the demonstration of an increased proportion of giant ganglia in the submucous plexus related to the patient's age. Giant ganglia are physiologically frequent in the neonatal period. Therefore, IND B should not be diagnosed prior to 1 year of age. Morphological features of IND B may occur as an isolated finding or may be observed proximal to an aganglionic segment. IND B and constipation may resolve spontaneously up to the age of 4 years. Treatment of IND B is usually conservative, surgical resection is currently deemed necessary only in a minority of patients. The pathogenesis of IND B is still incompletely understood and the etiology unknown. Future research on the basis of standardized diagnostic conditions is expected to result in a better understanding of this disease, and to reveal the cause of aberrant ganglion development.
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Affiliation(s)
- E Bruder
- Institut für Pathologie, Universitätsspital Basel, Schönbeinstrasse 40, 4031 Basel, Switzerland.
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23
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Meier-Ruge WA, Bruder E, Kapur RP. Intestinal neuronal dysplasia type B: one giant ganglion is not good enough. Pediatr Dev Pathol 2006; 9:444-52. [PMID: 17163795 DOI: 10.2350/06-06-0109.1] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2006] [Accepted: 08/11/2006] [Indexed: 12/20/2022]
Abstract
In this "Current Practice in Pediatric Pathology" article, 2 experts in the field and an associate editor of Pediatric and Developmental Pathology discuss the definition, diagnosis, clinical significance, and management of intestinal neuronal dysplasia type B. Intestinal neuronal dysplasia type B has constituted a diagnostic challenge ever since its first description more than 30 years ago. Intestinal neuronal dysplasia type B is regarded by many as a subtle malformation of the enteric nervous system that is limited to the submucosal plexus of the colon. The precise etiology remains unknown, and, to date, no specific diagnostic test exists other than morphology. Over time, with increasing experience, obligate pathological features have been adapted and refined, leading to contemporary diagnostic criteria that are enunciated in this review and placed into context with prior published data. Rigorous application of these criteria, under standardized laboratory conditions, is crucial for accurate diagnosis and future advances in this field.
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Montedonico S, Sri Paran T, Pirker M, Rolle U, Puri P. Developmental changes in submucosal nitrergic neurons in the porcine distal colon. J Pediatr Surg 2006; 41:1029-1035. [PMID: 16677906 DOI: 10.1016/j.jpedsurg.2005.12.063] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND/PURPOSE As our understanding of the enteric nervous system improves, it becomes clear that it is no longer sufficient to simply determine whether enteric ganglion cells are present but also to determine whether correct number and types of ganglion cells are present. Nitric oxide is recognized as a potent mediator of inhibitory nerves responsible for the relaxation of the smooth muscle of the gastrointestinal tract. The aim of this study was to determine the normal nitrergic neuronal density and morphology in the submucosal plexus of the porcine distal bowel from fetal life to adulthood. METHODS Distal large bowel specimens were obtained from porcine fetuses of gestational age E60 (n = 5), E90 (n = 5), 1-day-old piglets (n = 5), 4-week-old piglets (n = 5), 12-week-old piglets (n = 5), and adult pigs (n = 5). Whole-mount preparations of the submucosal plexus were made and stained with NADPH diaphorase histochemistry. The ganglia density, the number of ganglion cells per ganglia, and nucleus and cytoplasmic area were measured. RESULTS Ganglia density decreased progressively and markedly with age until the adulthood (P < .001). On the contrary, ganglion cells increased their size over time predominantly because of increase in cytoplasm (P < .001). The number of ganglion cells per ganglia increased significantly during the fetal life. However, there was a significant reduction in the number of ganglion cells per ganglia during the period from birth to 4 weeks, remaining constant thereafter (P < .001). CONCLUSIONS The quantitative and qualitative morphometric analysis of the colonic submucous plexus shows that significant developmental changes occur during fetal and postnatal life. These findings indicate that the age of the patient is of utmost importance during histopathologic evaluation of enteric nervous system disorders.
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Affiliation(s)
- Sandra Montedonico
- Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin 12, Ireland
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25
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Goldstein AM. Molecular Basis of Hirschsprung’s Disease and Other Congenital Enteric Neuropathies. SEMINARS IN COLON AND RECTAL SURGERY 2006. [DOI: 10.1053/j.scrs.2006.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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26
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Werner CR, Stoltenburg-Didinger G, Weidemann H, Benckert C, Schmidtmann M, van der Voort IR, Andresen V, Klapp BF, Neuhaus P, Wiedenmann B, Mönnikes H. Megacolon in adulthood after surgical treatment of Hirschsprung’s disease in early childhood. World J Gastroenterol 2005; 11:5742-5. [PMID: 16237779 PMCID: PMC4481502 DOI: 10.3748/wjg.v11.i36.5742] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hirschsprung’s disease (HD) is a disorder associated with congenital malformation of the enteric nervous system with segmental aganglionosis. Prevailing therapy includes a resection of the affected part of the bowel. However, patients often do not obtain complete functional improvement after surgical treatment. We present the case of a 25-year-old woman who had surgical treatment of HD in early childhood. After that procedure she had clinical features of constipation for years in the end, passing of stool once a week, requiring laxatives and enemas. We diagnosed an incomplete resection of the aganglionic bowel via rectal biopsy and resected the remaining aganglionic segment. Two months after surgery the patient’s bowel function improved to a frequency of 1-4 stools per day. We conclude that regular follow-up is required to identify HD patients with persistent alterations of bowel function after surgery. In patients presenting with constipation, recognition of a remaining aganglionic segment or other alterations of the enteric nervous system should be aimed at in an early stage.
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Affiliation(s)
- Christoph R Werner
- Department of Medicine, Division of Hepatology and Gastroenterology, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Augustenburger Platz 1, Germany
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27
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Sutcliffe JR, King SK, Southwell BR, Hutson JM. Paediatric constipation for adult surgeons--article 1: targeting the cause. ANZ J Surg 2005; 74:777-80. [PMID: 15379810 DOI: 10.1111/j.1445-1433.2004.03149.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Constipation is very common in all age groups and can be resistant to standard therapies, producing chronic morbidity. Childhood onset constipation frequently produces symptoms that persist into adulthood. Recent advances have been made in the diagnosis and treatment of childhood constipation that could have application in adult practice. In the first part of the present review, the methods of differentiation of patients with a disorder of colonic motility from those with an anorectal hold-up are discussed. Slow transit constipation, with distinct features on colonic manometry and scintigraphy, has only recently been recognized in children. This diagnosis, together with a novel method of placement of a manometric catheter, is described. While the cause of slow transit constipation remains unclear, clinical features that differ between children and adults may provide an insight into the aetiology. The diagnosis of intestinal neuronal dysplasia is explained and the controversy surrounding the diagnosis outlined. We propose that the traditional histological criteria exclude many other clinically significant forms of dysplasia of the enteric nervous system and should be extended.
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Affiliation(s)
- Jonathan R Sutcliffe
- Department of General Surgery, Royal Children's Hospital, Parkville, Victoria, Australia
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King SK, Sutcliffe JR, Hutson JM, Southwell BR. Paediatric constipation for adult surgeons - article 2: new microscopic abnormalities and therapies. ANZ J Surg 2005; 74:890-4. [PMID: 15456440 DOI: 10.1111/j.1445-1433.2004.03202.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Chronic constipation is a common condition in both adults and children. Children with chronic constipation frequently have symptoms that continue into adulthood. In the second part of the review we describe advances in the identification of abnormalities in the control of motility. The role of neurotransmitters in both paediatric and adult constipation is examined and the radical rethink of colonic dysmotility caused by the re-emergence of interstitial cells of Cajal is discussed. The recognition of chronic constipation as an heterogenous condition has led to the introduction of new therapies. Antegrade washouts through appendix stomas and an exciting new treatment with electrical interferential therapy may, in the future, result in a less invasive approach to the management of chronic constipation. An improved understanding of the assessment and management of chronic constipation in childhood is also likely to reduce the frequency and morbidity of chronic constipation in adults.
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Affiliation(s)
- Sebastian K King
- Department of General Surgery, Royal Children's Hospital, Parkville, Victoria, Australia
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Abstract
Conditions that clinically resemble HD despite the presence of ganglion cells on suction rectal biopsy results, can be diagnosed by providing an adequate biopsy and employing a variety of histological techniques. Intestinal neuronal dysplasia is a distinct clinical entity that can be clearly proven histologically. Patients with IND not only have abnormalities of submucosal and myenteric plexuses but also defective innervation of the muscle. Internal sphincter achalasia, which is histologically characterized by nitrergic nerve depletion, can be diagnosed on anorectal manometry and successfully treated by internal sphincter myectomy. The outcome of smooth muscle disorders is generally fatal. The need for surgical intervention should be weighed carefully and individualized because most explorations have not been helpful and are probably not necessary.
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Affiliation(s)
- Prem Puri
- Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.
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31
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Parisi MA, Baldessari AE, Iida MHK, Clarke CM, Doggett B, Shirasawa S, Kapur RP. Genetic background modifies intestinal pseudo-obstruction and the expression of a reporter gene in Hox11L1-/- mice. Gastroenterology 2003; 125:1428-40. [PMID: 14598259 DOI: 10.1016/j.gastro.2003.08.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS The transcription factor Hox11L1 is expressed by enteric neurons. Two groups mutated murine Hox11L1, and reported lethal intestinal pseudo-obstruction and colonic hyperganglionosis in many, but not all, homozygous null mutants. We investigated the regulation of Hox11L1 and factors that influence the penetrance of pseudo-obstruction in Hox11L1-null mice. METHODS Expression of beta-galactosidase (lacZ), under control of putative Hox11L1 regulatory sequences, was assessed in transgenic mice wild-type, heterozygous, and null for native Hox11L1. Transgene expression and signs of pseudo-obstruction were compared in null mice with different genetic backgrounds. RESULTS In enteric neurons and other parts of the nervous system, the transgene was expressed in a pattern consistent with native Hox11L1. Enteric beta-galactosidase activity initiated in the proximal small intestine and spread cranially and caudally in a subset of postmitotic enteric neurons. Hox11L1-lacZ transgene expression persisted in Hox11L1-null animals, suggesting that Hox11L1 is not required cell autonomously for neuronal survival. Genetic background dramatically affected the phenotypes of Hox11L1-null animals, with complete penetrance of severe proximal colonic distention on a predominantly C57BL/6J (B6) background and very low penetrance of dysmotility on a 129SvJ (129) background. Coincidently, Hox11L1-lacZ expression by most enteric neurons, but not CNS neurons, was lost on a 129 background. CONCLUSIONS Cis-acting, 5' regulatory elements are sufficient to regulate site-specific expression of Hox11L1 in vivo. Expression of the transgene by enteric neurons and penetrance of pseudo-obstruction in Hox11L1-null animals are influenced by one or more modifier genes, counterparts of which may play a similar role in human disease.
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MESH Headings
- Animals
- Animals, Newborn/growth & development
- Cell Line
- Embryonic and Fetal Development
- Enteric Nervous System/embryology
- Enteric Nervous System/metabolism
- Enteric Nervous System/pathology
- Gene Expression
- Genes, Reporter
- Intestinal Pseudo-Obstruction/genetics
- Intestine, Small/embryology
- Intestine, Small/metabolism
- Intestine, Small/pathology
- Mice/embryology
- Mice/genetics
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Inbred Strains
- Mice, Knockout
- Mice, Transgenic
- Mitosis
- Neurons/metabolism
- Penetrance
- Tissue Distribution/genetics
- Umbilical Cord
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Affiliation(s)
- Melissa A Parisi
- Department of Pediatrics, University of Washington School of Medicine, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NW, Seattle, WA 98105, USA
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Abstract
Intestinal neuronal dysplasia (IND) is a clinical condition that resembles Hirschsprung's disease. In the past many years investigators have raised doubts about the existence of IND as a distinct histopathologic entity. One strong piece of evidence that IND is a real entity stems from animal models. Recently, two different HOX11L1 knockout mouse models and a heterozygous endothelin B receptor-deficient rat demonstrated abnormalities of the submucous plexus similar to that observed in human IND. This review describes in detail the diagnostic criteria of IND, staining techniques, correlation between histological findings and clinical symptoms, and management of IND.
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Affiliation(s)
- Prem Puri
- Children's Research Centre, Our Lady's Hospital for Sick Children University College, Dublin, Ireland, UK
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Santos MM, Tannuri U, Maksoud JG. Alterations of enteric nerve plexus in experimental gastroschisis: is there a delay in the maturation? J Pediatr Surg 2003; 38:1506-11. [PMID: 14577076 DOI: 10.1016/s0022-3468(03)00504-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND/PURPOSE After surgical correction of gastroschisis, intestinal transitory hypoperistalsis usually occurs. Long-term parenteral nutrition often is necessary leading to a higher morbidity associated with this malformation. The etiology of this transitory intestinal hypomotility is unknown. It may be caused by a reversible inflammatory process in the intestinal wall or other causes, including an alteration of the maturation of intestinal neural plexus, because the disturbance disappears spontaneously after a variable period. The aim of this work was to study the neuronal cells of the myenteric plexus of the fetal intestine in experimental gastroschisis. The main hypothesis was that the transitory intestinal dismotility seen in gastroschisis could be secondary to alteration in the maturation of the enteric nervous plexus. METHODS Twenty-seven time-mated rabbits, on gestational day 25, were submitted to a midline laparotomy; the gravid bicornuate uterus was exposed and opened, and the more distal fetuses relative to the vaginal opening had the abdominal wall opened by a small incision to produce gastroschisis (n = 29). The fetuses not submitted to gastroschisis were used as controls (n = 12). The amniotic fluid was carefully aspirated from the opened uterus and saved for later repositions. On gestational day 30, the does were again submitted to general anesthesia, and the fetuses were delivered by cesarean section. The fetal intestine was removed, the adjacent mesentery excised, and intestinal specimens were harvested for histologic studies. The specimens were stained for acetyl-cholinesterase activity (AChE) to assess the maturity of the nervous enteric cells and for lactate dehydrogenase (LDH) that identify specifically immature nervous cells. The histologic sections stained by LDH were submitted to histomorphometric analysis of the nervous cells through an image system analysis (Kontron 300). The results were submitted to statistical analyses (P <.05). RESULTS Macroscopic alterations of the fetal gastroschisis intestine are similar to the human findings: shortening of the intestine, intestinal wall thickening, and a hypertrophied muscular layer. In the gastroschisis group, histologic AChE activity was decreased in comparison with control intestines. The histomorphometric assessment in slices stained with LDH, which identify immature nervous cells, showed that the neuronal intestinal cells of the gastroschisis group were significantly smaller and more numerous relative to the control group. CONCLUSIONS There were significant differences in the nervous plexus of the intestine of fetuses with gastroschisis relative to the controls. The observed morphologic changes may be caused by alteration in the maturation of the intestinal neuronal in gastroschisis. This alteration may explain the transitory intestinal hypomotility observed in infants after surgical correction of gastroschisis.
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Affiliation(s)
- Maria Mercês Santos
- Department of Surgery, University of Sao Paulo Medical School, Division of Pediatric Surgery, Pediatric Surgery Laboratory (LIM-30), Sao Paulo, Brazil
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Rolle U, Piotrowska AP, Puri P. Abnormal vasculature in intestinal neuronal dysplasia. Pediatr Surg Int 2003; 19:345-348. [PMID: 12898161 DOI: 10.1007/s00383-003-1008-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2002] [Indexed: 01/17/2023]
Abstract
Intestinal neuronal dysplasia (IND) is an intestinal motility disorder, which clinically resembles Hirschsprung's disease (HD). Adventitial fibromuscular dysplasia (AFMD) consists of proliferation of smooth muscle cells and collagen fibers in the adventitia of blood vessels. The purpose of this study was to investigate vascular abnormalities in large bowel biopsies from patients with isolated HD, IND associated with HD and isolated IND. Large bowel biopsies from patients presenting with isolated HD ( n=23), IND associated with HD ( n=11), isolated IND ( n=16) and normal bowel as controls ( n=6) were investigated using acetylcholinesterase (AChE) histochemistry, van Gieson staining and alpha-smooth muscle actin (alpha-SMA) immunohistochemistry. Increased AChE activity around submucosal vessels was found in 9/16 (56%) cases with isolated IND, 3/11 (27%) cases of IND associated with HD, 5/23 (21%) isolated HD cases and 0/6 controls. AFMD was found in 10/16 (62%) of the isolated IND cases, 4/11 (362) of the cases with IND associated with HD and 4/23 (17%) cases of HD without IND using van Gieson staining. None of the control specimens revealed AFMD. Increased alpha-SMA immunoreactivity filaments were demonstrated in the submucosal vessel wall in 9/16 (56%) of isolated IND and 2/11(18%) of IND associated with HD cases. Normal alpha-SMA immunoreactivity around submucosal vessels was seen in isolated HD and controls. Abnormal submucosal vasculature is a common histological finding in isolated IND and IND associated with HD and may be a useful additional diagnostic feature in these patients.
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Affiliation(s)
- Udo Rolle
- Children's Research Centre, Our Lady's Hospital for Sick Children, University College, Dublin 12, Ireland
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Wilder-Smith CH, Talbot IC, Merki HS, Meier-Ruge WA. Morphometric quantification of normal submucous plexus in the distal rectum of adult healthy volunteers. Eur J Gastroenterol Hepatol 2002; 14:1339-42. [PMID: 12468955 DOI: 10.1097/00042737-200212000-00009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Inadequate morphometric characterization of the normal adult submucous plexus has precluded the diagnosis of colonic dysganglionoses associated with constipation, such as intestinal neuronal dysplasia type B (IND B). The internal submucous plexus (Meissner plexus) was morphometrically quantified in adult healthy volunteers. DESIGN Open, prospective morphometric study in balanced groups of female and male volunteers. PARTICIPANTS Thirty-seven adult healthy male and female volunteers with normal bowel function and no history of gastrointestinal disease. METHODS Four jumbo rectal biopsies (3-5 mm3) were taken 5 and 10 cm above the pectinate line. Two expert gastrointestinal pathologists assessed biopsy sections after specific nerve cell staining for lactic dehydrogenase, nitric oxide synthase and acetylcholinesterase, mainly for characteristics of ganglia and nerve cells in the submucous plexus. RESULTS No healthy individual demonstrated over 20% of submucosal ganglia as giant ganglia or more than four giant ganglia per 30 sections (the morphometric criteria for IND B). Single submucosal nerve cells and ganglion numbers halved between 10 and 5 cm above the pectinate line, but there were no age or gender differences. The biological variability of nerve cell and ganglion density in the submucous plexus was large. CONCLUSIONS Healthy adults show less than 20% of submucosal ganglia as giant ganglia and no more than four giant ganglia per 30 rectal biopsy sections. There is therefore no overlap with the histomorphological criteria of IND B. These data therefore support the specificity of the previously defined criteria for IND B in adults.
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Abstract
This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. In the first part, we describe the critical features of two principal abnormalities of ENS development: Hirschsprung's disease (HSCR) and intestinal neuronal dysplasia type B (INDB) in humans, and the similar abnormalities in animals. These represent the extremes of the diagnostic spectrum: HSCR has agreed and unequivocal diagnostic criteria, whereas the diagnosis and even existence of INDB as a clinical entity is highly controversial. The difficulties in diagnosis and treatment of both these conditions are discussed. We then review the genes now known which, when mutated or deleted, may cause defects of ENS development. Many of these genetic abnormalities in animal models give a phenotype similar or identical to HSCR, and were discovered by studies of humans and of mouse mutants with similar defects. The most important of these genes are those coding for molecules in the GDNF intercellular signaling system, and those coding for molecules in the ET-3 signaling system. However, a range of other genes for different signaling systems and for transcription factors also disturb ENS formation when they are deleted or mutated. In addition, a large proportion of HSCR cases have not been ascribed to the currently known genes, suggesting that additional genes for ENS development await discovery.
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Affiliation(s)
- Donald Newgreen
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, 3052, Victoria, Australia
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Rolle U, Nemeth L, Puri P. Nitrergic innervation of the normal gut and in motility disorders of childhood. J Pediatr Surg 2002; 37:551-567. [PMID: 11912511 DOI: 10.1053/jpsu.2002.31610] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Udo Rolle
- Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland
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Kapur RP. Neuropathology of paediatric chronic intestinal pseudo-obstruction and related animal models. J Pathol 2001; 194:277-88. [PMID: 11439358 DOI: 10.1002/path.885] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic intestinal pseudo-obstruction (CIP) in paediatric patients is due to heterogeneous aetiologies that include primary disorders of the enteric nervous system. These conditions are poorly delineated by contemporary diagnostic approaches, in part because the complex nature of the enteric nervous system may shelter significant physiological defects behind subtle or quantitative anatomical changes. Until recently, relatively few experimental animal models existed for paediatric CIP. However, the availability of rodent models, particularly novel mutants created in the last few years by genetic manipulations, has brought unprecedented opportunities to investigate molecular, cellular, physiological, and histological details of enteric neuropathology. Information gleaned from studies of these animals is likely to change diagnostic and therapeutic approaches to paediatric CIP and related conditions.
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Affiliation(s)
- R P Kapur
- Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
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Imaji R, Kubota Y, Hengel P, Hutson JM, Chow CW. Rectal mucosal biopsy compared with laparoscopic seromuscular biopsy in the diagnosis of intestinal neuronal dysplasia in children with slow-transit constipation. J Pediatr Surg 2000; 35:1724-7. [PMID: 11101723 DOI: 10.1053/jpsu.2000.19228] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND/PURPOSE Intestinal neuronal dysplasia (IND) as a cause for severe chronic constipation remains controversial. The aim of this study is to examine the correlation between a deficiency of substance P (SP) immunoreactive nerve fibers in the colon and enzyme histochemistry of rectal biopsies in children with slow-transit constipation. METHODS Fifty children with intractable constipation have been assessed by rectal biopsies examined with histochemical staining for lactate dehydrogenase, and 32 children among those 50 have been studied by laparoscopic seromuscular biopsy of the colon labelled with antibodies to SP using immunofluorescence methods. RESULTS Four children have evidence of IND. Fifteen children, including all 4 IND cases, showed a deficiency of SP immunoreactivity. There is a significant correlation between giant ganglia and SP deficiency (P <.01). CONCLUSION This study is attempting to propose that a deficiency of SP immunoreactivity in colonic circular muscle nerves may be used as a histologic marker for slow-transit constipation and that IND may be a small subset of patients with SP deficiency.
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Affiliation(s)
- R Imaji
- F. Douglas Stephens Surgical Research Laboratory, Royal Children's Hospital Research Institute, Melbourne, Australia
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Jeng YM, Mao TL, Hsu WM, Huang SF, Hsu HC. Congenital interstitial cell of cajal hyperplasia with neuronal intestinal dysplasia. Am J Surg Pathol 2000; 24:1568-72. [PMID: 11075862 DOI: 10.1097/00000478-200011000-00016] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Interstitial cells of Cajal (ICCs) are intestinal pacemaker cells that initiate peristalsis in the stomach and intestine, and are considered to be precursors of gastrointestinal stromal tumors (GISTs). We report a 2-year-old girl who suffered from scanty stool passage since birth. On barium enema, the distal colon was rigid with narrow lumen, whereas the proximal colon was dilated and atonic. She received right hemicolectomy and ileostomy. Histopathologically, there was continuous proliferation of spindle cells located between the layers of the muscularis propria throughout the right colon. These spindle cells were positive for c-kit and CD34 but negative for myogenic or neurogenic markers, indicating they are ICCs. No germline or somatic mutation of the juxtamembrane domain of c-kit gene was detected. In addition, the changes of the submucosal plexus fulfilled the histologic criteria of neuronal intestinal dysplasia type B. To our knowledge, this is the first reported case of congenital ICC hyperplasia. Further studies of ICC development may contribute to better understanding of the pathogenesis of this congenital malformation and the tumorigenesis of GIST.
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Affiliation(s)
- Y M Jeng
- Department of Pathology, National Taiwan University Hospital
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de Krijger RR, Brooks A, van der Harst E, Hofstra RM, Bruining HA, Molenaar JC, Meijers C. Constipation as the presenting symptom in de novo multiple endocrine neoplasia type 2B. Pediatrics 1998; 102:405-8. [PMID: 9714654 DOI: 10.1542/peds.102.2.405] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Affiliation(s)
- R R de Krijger
- Department of Pathology, University Hospital Dijkzigt, Rotterdam, The Netherlands
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Abstract
Intestinal neuronal dysplasia (IND) is a disorder of the enteric nervous system that was first described by Meier-Ruge in 1971. IND may be associated with Hirschsprung's disease or may occur as an isolated disorder. The incidence of isolated IND varies from 0.3% to 40% of suction rectal biopsies. The uncertainty regarding the incidence of IND has resulted from considerable confusion concerning essential diagnostic criteria. The diagnostic difficulties reflect the wide variability in the literature in terms of diagnostic criteria, biopsy procedures, staining techniques, and patient age. The recent application of histochemical and immunohistochemical techniques indicates that IND is a distinct histopathologic entity. The majority of patients with IND can be treated conservatively with laxatives and enemas. If bowel symptoms persist after at least 6 months of conservative treatment, internal sphincter myectomy should be considered.
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Affiliation(s)
- P Puri
- Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland
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Wester T, O'Briain S, Puri P. Morphometric aspects of the submucous plexus in whole-mount preparations of normal human distal colon. J Pediatr Surg 1998; 33:619-22. [PMID: 9574763 DOI: 10.1016/s0022-3468(98)90328-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE The diagnosis of intestinal neuronal dysplasia (IND) has traditionally been based on the finding of hyperplasia of the submucous plexus and increased acetylcholinesterase activity in parasympathetic nerve fibers in the lamina propria. However, recently it has been suggested that proposed diagnostic criteria relating to nerve cell density may overlap with age-related changes and that the finding of giant ganglia (ganglia containing more than seven ganglion cells) is the most relevant diagnostic parameter of IND. Ganglion cell counting is usually performed on conventional histological sections, whereas the topology of whole ganglia has been poorly studied. The aim of this study was to define the number of ganglion cells per ganglion and the ganglion cell density (the number of ganglion cells per surface area) in submucous whole-mount preparations of normal human colon. METHODS Specimens from distal colon were obtained during postmortem examination from 14 patients who died of nongastrointestinal disease. The submucous layer was prepared as a whole mount and stained for NADPH diaphorase (a nitrergic neurotransmitter marker) and cuprolinic blue (a general neuronal marker). Ganglion cell density was estimated by counting at least 10 mm2. The number of ganglion cells per ganglion was counted in at least 20 ganglia per case. RESULTS Ganglion cell density (NADPH diaphorase) fell markedly during the first 5 to 6 years of life (r = -0.60, P < .05). Most ganglion cells formed ganglia of 3 to 64 cuprolinic blue staining cells. The mean number of ganglion cells per ganglion did not vary with age. CONCLUSIONS The density of NADPH diaphorase-positive ganglion cells in the submucous plexus of human distal colon decreases markedly with age. However, the number of ganglion cells per ganglion remains constant. These findings indicate that the age of the patient has crucial importance for the histolopathologic evaluation of enteric nervous system disorders.
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Affiliation(s)
- T Wester
- Children's Research Center, Our Lady's Hospital for Sick Children, Dublin, Ireland
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Ure BM, Holschneider AM, Schulten D, Meier-Ruge W. Clinical impact of intestinal neuronal malformations: a prospective study in 141 patients. Pediatr Surg Int 1997; 12:377-82. [PMID: 9244104 DOI: 10.1007/bf01076944] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A prospective study of 141 consecutive patients with intestinal neuronal malformations is presented. The single malformation of the autonomic nervous system that always required surgical intervention was aganglionosis. Giant ganglia, reduced parasympathetic tone, immature ganglia, and hypogenetic or heterotopic nerve cells were seen in all forms of malformations. However, the incidence in specific malformations was variable. Multiple giant ganglia were identified in all patients with intestinal neuronal dysplasia (IND) type B, but also in various other malformations. Heterotopic nerve cells in the myenteric plexus were seen in the proximal segment of 15 of 74 patients (20.3%) with aganglionosis and 5 of 9 patients (55.6%) with hypoganglionosis. A significant impact on symptoms was found for IND type B: 34 (45.9%) of 74 children with aganglionosis had associated IND type B, and these children more frequently developed ileus (P < 0.001) and more often needed a second resection (P < 0.05) compared to those with isolated aganglionosis. This indicates an additive effect of both malformations, and therefore, in these patients an extended resection should be carried out. Twelve of 67 patients (17.9%) without aganglionosis needed resection for untreatable constipation. This included 7 of 9 children with hypoganglionosis, both patients with heterotopia of the myenteric plexus, 1 of 20 with isolated IND type B, and 2 of 12 with reduced parasympathetic tone. None of the patients with immaturity, heterotopia of the submucous plexus, or mild dysganglionosis required surgery. Six children (8.9%) without aganglionosis underwent sphincteromyotomy and 2 with IND type B had a temporary colostomy. At follow-up (mean 2.4 +/- 1.4 years), the outcome in patients with resected aganglionosis was better than in patients who had resections for other malformations; 49 (69%) of 71 patients with aganglionosis were asymptomatic compared to 4 (33.3%) of 12 with other malformations (P < 0.05). It is concluded that some intestinal malformations have a relevant clinical impact. However, the severity of symptoms in the individual patient may not be explained by specific histochemical findings from a limited number of mucosal biopsies. The pathognomonic histochemical criteria of isolated IND type B - immaturity, reduced parasympathetic tone, heterotopia of the submucous plexus, and mild dysganglionosis - rarely require surgical therapy and should be treated conservatively.
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Affiliation(s)
- B M Ure
- Department of Pediatric Surgery, The Children's Hospital of Cologne, Amsterdamer Strasse 59, D-50735 Cologne, Germany
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Abstract
There are many clinical conditions that resemble Hirschsprung's disease despite the presence of ganglia cells on rectal biopsy. This group has focused its research interest into delineating variant Hirschsprung's disease based on specific histochemical, immunohistochemical, silver staining and electron microscopic studies. Between 1981 and 1996, full thickness rectal biopsy or resected surgical specimens from 66 patients with clinical symptoms suggesting Hirschsprung's disease were examined. Various functional bowel disorders diagnosed using different histological techniques included, intestinal neuronal dysplasia in 23, hypoganglionosis in 6, immature ganglia in 4, absence of argyrophil plexus in 3, internal sphincter achalasia in 15, and smooth muscle disorders in 15. The findings suggest the following: (1) Clinical conditions resembling Hirschsprung's disease despite the presence of ganglia cells on suction rectal biopsy can be diagnosed by providing an adequate biopsy and employing a variety of histological techniques. (2) Intestinal neuronal dysplasia (IND) is a distinct clinical entity that can be clearly proven histologically. Patients with IND not only have abnormalities of submucosal and myenteric plexuses but also defective innervation of the muscle and neuromuscular junction as well as the internal sphincter. (3) Internal sphincter achalasia, which is histologically characterized by nitregeric nerve depletion, can be diagnosed on anorectal manometry and successfully treated by internal sphincter myectomy. (4) The outcome of smooth muscle disorders is generally fatal. The need for surgical intervention should be weighed carefully and individualized because most operations have not been helpful and are probably not necessary.
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Affiliation(s)
- P Puri
- Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland
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