Intestinal Neuronal Dysplasia Research Articles

Пороки развития кишечника у недоношенных, протекающие под маской некротического энтероколита

Some congenital malformations of the gastrointestinal tract in premature infants are difficult to diagnose due to a lack of specific clinical picture. As a rule, they are masked under necrotizing enterocolitis resulting in the improper management of such patients. The article describes two clinical cases of Hirschsprung's disease and neuronal intestinal dysplasia in newborns. Both cases were regarded as necrotizing enterocolitis of newborns resulting in tactical treatment errors. We made a conclusion that the surgical tactics for patients with congenital disorders of both the enteric nervous system and muscular intestinal wall tissue, which manifest themselves as enterocolitis or perforation, should be determined only when you are fully confident in the functional usefulness of all parts of the intestine.

A comment on difficulties in diagnosis and treatment of Hirschsprung's disease allied disorders

Enteric nervous system abnormalities are the main cause of severe chronic constipation in children.These abnormalities are collectively known as intestinal dysganglionosis, including Hirschsprung's disease(HD), and Hirschsprung's disease allied disorders(HAD) such as immature ganglion, hypoganglionosis(HG) and intestinal neuronal dysplasia(IND). HD and HAD have similar clinical manifestations, and accurate diagnosis is challenging.In this paper, difficulties in diagnosis and treatment of HAD are introduced. Key words: Hirschsprung's disease; Hirschsprung's disease allied disorders; Hypoganglionosis; Intestinal neuronal dysplasia

Intestinal Neuronal Dysplasia in a Patient With Chronic Colonic Pseudo-Obstruction

La pseudoobstruccion intestinal se relaciona con anomalias de inervacion ganglionica enterica. La displasia neuronal intestinal es una disganglionosis y se diferencia de la enfermedad de Hirschprung por ser una hiperplasia del plexo mienterico y submucoso, con hipertrofia de celulas ganglionares. Presentamos el caso de un paciente varon de 47 anos, con cuadro de insuficiencia respiratoria progresiva y distension abdominal severa por un megacolon masivo, con compresion diafragmatica (fig. 1). Tras una colonoscopia fallida, se realizo laparotomia y descompresion con colostomia. Dos meses despues se realizo una colectomia subtotal con anastomosis ileo-rectal (fig. 2), con evolucion favorable. La anatomia patologica diagnostico una displasia neuronal intestinal. c i r e s p . 2 0 1 4 ; 9 2 ( 1 0 ) : e 5 9

Isolated intestinal neuronal dysplasia Type B (IND-B) in Japan: results from a nationwide survey.

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. Questionnaires were sent to 161 major institutes of pediatric surgery and gastroenterology in Japan. 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. 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.

Chronic intestinal pseudo-obstruction: systematic histopathological approach can clinch vital clues

The histopathological approach of chronic intestinal pseudo-obstruction (CIP) is critical, and the findings are often missed by the histopathologists for lack of awareness and nonavailability of standard criteria. We aimed to describe a detailed histopathological approach for working-up cases of CIP by citing our experience. Eight suspected cases of CIP were included in the study to determine and describe an approach for reaching the histopathological diagnosis collected over a period of the last 1.5 years. The Hirschsprung's disease was put apart from the scope of this study. A detailed light microscopic analysis was performed along with special and immunohistochemical stains. Transmission electron microscopy was carried out on tissue retrieved from paraffin embedded tissue blocks. Among the eight cases, three were neonates, one in the pediatric age group, two adolescent, and two adults. After following the described critical approach, we achieved the histological diagnoses in all the cases. The causes of CIP noted were primary intestinal neuronal dysplasia (IND) type B (in 4), mesenchymopathy (in 2), lymphocytic myenteric ganglionitis (in 1), and duplication of myenteric plexus with leiomyopathy (in 1). Desmosis was noted in all of them along with other primary pathologies. One of the IND patients also had visceral myopathy, type IV. Histopathologists need to follow a systematic approach comprising of diligent histological examination and use of immunohistochemistry, immunocytochemistry, and electron microscopy in CIP workup. Therapy and prognosis vary depending on lesions identified by pathologists. These lesions can be seen in isolation or in combinations.

A Practical Guide for the Diagnosis of Primary Enteric Nervous System Disorders

Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

Classification and diagnostic criteria of variants of Hirschsprung’s disease

"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.

State's pull-through for total colonic aganglionosis and GI dismotility.

Total colonic aganglionosis (TCA) is present in 4% - 5% of the patients with Hirschsprung's disease and has a high surgical mortality rate between 13% - 23%. Diagnosis and treatment of TCA is still a major challenge for pediatric surgeons. Many techniques with several advantages and disadvantages were established for its treatment. We have performed State's pull-through as total colectomy and ileo-proctostomy with long posterior rectal myotomy in TCA and severe dysmotility disorders. In this retrospective study, 13 patients with TCA were evaluated from 1992 through 2012 in two pediatric surgery centers, which consisted of 10 TCA, one intestinal neuronal dysplasia (IND), and two chronic intestinal pseudo- obstruction syndrome (CIP). All patients underwent total colectomy, resection of part of the involved small intestine, and rectal anastomosis in one layer with 4/0 vicryl with long posterior rectal myotomy. All patients had preoperative barium enema and rectal biopsy for diagnosis. Leveling ileostomy was performed in 12 patients and mid-jejunostomy in one patient. In two of 13 children, proximal diverting loop ileostomy was established after definitive operation. In three patients, trans-rectal myotomy was needed two weeks after the initial operation. All patients were females with the age ranging from six months to six years. State's pull-through was carried out for all (the mean age of definitive procedure was 5.1 months). Rectal biopsy of 10 patients reported no ganglion cells of which one had extended aganglionosis to mid- jejunum, one had IND, and two had ganglionicbowel bowel with clinical presentation of CIP. The follow- up period was from six months to 10 years (the mean follow- up period was 10 months). There were no significant complications in 12 patients except episodes of diarrhea and severe dehydration which needed hospitalization. One patient with mid- jejunum aganglionosis had severe failure to thrive and needed repeated hospitalization for parenteral nutrition. All patients had acceptable bowel function following operation (two to six times a day). Now, five of the 13 patients are above the age of toilet training, having voluntary bowel movement with little or no medication (Leopromid). State's pull-through is recommended in all cases of TCA and severe dysmotility problems of the colon. This technique is less difficult to perform, and avoids the complications and disadvantages of removal of the rectum and has satisfactory results.

Immunohistochemical study of enteric nervous system in hirschsprung's disease and intestinal neuronal dysplasia.

Hirschsprung's disease (HD) is one of the most common motility disorders in pediatric age groups and it is very important that it be differentiated from other types of motility disorders, especially intestinal neuronal dysplasia B (IND B). Although many studies regarding the differences between the two disorders by immunohistochemical studies exist, there is as yet no consistent result. The purpose of this research was to study the immunohistochemical findings of enteric nervous system in these two motility disorders in comparison with colectomies without motility disorder. Full wall thickness specimens of three groups of patients (HD, IND B and non motility disorders) were included in the study to be evaluated by immunohistochemistry (IHC). Markers were specific for neuronal cells and pace maker cells composed of PGP 9.5, c-kit, synaptophysin, S100 and CD56. The number of cells was evaluated in the muscularis properia, and myenteric plexus. The number of all the IHC markers i.e. PGP9.5, c-kit, synaptophysin, S100 and CD56 was completely different in HD from the two other groups, while IND B was quite similar to control group. Our finding suggests that there is a marked and significant difference between HD and IND B by IHC markers, which can be used as an additional test for the diagnosis of HD with more accuracy. Further multicenter studies with a greater number of cases would be necessary to find a cut-off point for every IHC marker to differentiate HD and IND B.

Sigmoid volvulus as a presentation of neuronal intestinal dysplasia type B in an adolescent

Sigmoid volvulus as a presentation of neuronal intestinal dysplasia type B in an adolescent

Mast Cells Connections with Nerve Fibers in Hirschsprung’s Disease

Introduction: Hirschsprung’s disease (HD) is rare (1/5000 newborns) congenital condition of the bowel nervous system, clinically characterized by dilatation and hypertrophy of colon. There are an increased number of mast cells (MC) in aganglionic bowel segments and in those with intestinal neuronal dysplasia (IND). The exact role of MC in HD is still not known. The aim of this study was to examine the colonic distribution of mast cells (MC) and the relationship between MC and nerve fibers and to estimate connections of these cells with gut nervous system. Material and Methods: Distal colon wall specimens were harvested from patients with normal bowel function and with normal ganglion cells, patients with constipations and with normal ganglion cells and a group of patients with Hirschsprung’s disease. The age of the patients ranged from 2nd day of live to 12 years. The density of the mast cells was calculated using a light microscope with digital camera. The connections of localization of a MC with nerve fibers and ganglions were taken under consideration and observed under light microscope. Test for the significance of differences between groups were performed using the Kruskal-Wallis test. Results: We revealed that there is a greater number of the MC in mucosa, lamina propria, submucosa and muscle layer of large bowel in patients with HD. There was no difference in density of the MC in serosa. Some of the colon MC in HD was located near or they were even attached to the hypertrophic nerve trunks. We found a correlation of MC number with the number of nerve fibers in HD patients. Conclusions: Higher number of MC and their localization in close connection with hypertrophied nerve trunks in patients with HD than in patients with constipation or normal bowel function, is a proof of the influence of MC on defected nervous system in aganglionic bowel. MC probably affect hypertrophied nerve trunks. Mobilization and activation of the mast cells which produce and store NGF can be directed to repair defective nervous system. Obviously, MC repairing reaction is not effective in restoring nervous system function of the gut.

Subtotal colectomy with a single-incision laparoscopic surgery technique in children with long-segment Hirschsprung disease and allied disorders

Over the last 15years, the laparoscopic-assisted endorectal pull-through procedure has become the standard treatment for Hirschsprung disease in many centers around the world. Recently, single-incision laparoscopic techniques have drawn more attention. We describe a single-incision laparoscopic surgery (SILS) subtotal colectomy to treat long-segment Hirschsprung disease (LSHD) and Hirschsprung disease allied disorder (HAD) in children. A total of 22 patients who underwent SILS subtotal colectomy, including three patients with a failed first surgery, were included in this retrospective study. For SILS, a 1-cm skin incision was first made below the umbilical margin and a 5-mm trocar was placed into the abdomen after incising the peritoneum. Two 5-mm trocars were then placed on both sides of the umbilicus. Subsequently, based upon preoperative examination and biopsy results, we performed subtotal colectomy. The affected colon was mobilized successively beyond the peritoneum using high-frequency cutting and sealing devices, followed by a pull-through procedure and colon-anal anastomosis. The average operative time was 206.39min. No case needed conversion from SILS to either conventional laparoscopy or open surgery. Of the 22 patients, 15 were diagnosed as LSHD, while 6 cases were diagnosed with intestinal neuronal dysplasia and one was diagnosed with hypoganglionosis. There were no intra-operative complications. One child had incision dehiscence on postoperative day three. During the follow-up over 12months, all patients were noted to have excellent cosmetic outcomes, and enterocolitis was observed in four children. Subtotal colectomy with the SILS technique can be safely performed in LSHD or HAD patients in the pediatric population without major complications.

Anorectal malformation associated with small and large bowel atresias: a rare association.

Anorectal malformation (ARM) is one of frequent neonatal surgical problem managed in pediatric surgical units. Gastrointestinal malformations are associated in approximately 5% cases of ARM. Some of the common associations are oesophageal atresia and trachea oesophageal fistula, duodenal atresia, hirschsprung`s disease, pouch colon and neuronal intestinal dysplasia [1]. Association of ARM with either colonic atresia or jejuno-ileal atresia has rarely been reported in literature [2-5]. Here we report a case of ARM associated with both colonic and multiple jejuno-ileal atresias.

Variants of Hirschsprung disease

Variants of Hirschsprung disease are conditions that clinically resemble Hirschsprung disease, despite the presence of ganglion cells in rectal suction biopsies. The characterization and differentiation of various entities are mainly based on histologic, immunohistochemical, and electron microscopy findings of biopsies from patients with functional intestinal obstruction. Intestinal neuronal dysplasia is histologically characterized by hyperganglionosis, giant ganglia, and ectopic ganglion cells. In most intestinal neuronal dysplasia cases, conservative treatments such as laxatives and enema are sufficient. Some patients may require internal sphincter myectomy. Patients with the diagnosis of isolated hypoganglionosis show decreased numbers of nerve cells, decreased plexus area, as well as increased distance between ganglia in rectal biopsies, and resection of the affected segment has been the treatment of choice. The diagnosis of internal anal sphincter achalasia is based on abnormal rectal manometry findings, whereas rectal suction biopsies display presence of ganglion cells as well as normal acetylcholinesterase activity. Internal anal sphincter achalasia is either treated by internal sphincter myectomy or botulinum toxin injection. Megacystis microcolon intestinal hypoperistalsis is a rare condition, and the most severe form of functional intestinal obstruction in the newborn. Megacystis microcolon intestinal hypoperistalsis is characterized by massive abdominal distension caused by a largely dilated nonobstructed bladder, microcolon, and decreased or absent intestinal peristalsis. Although the outcome has improved in recent years, survivors have to be either maintained by total parenteral nutrition or have undergone multivisceral transplant. This review article summarizes the current knowledge of the aforementioned entities of variant HD.

P24.15: Antenatal sonographic features of intestinal neuronal dysplasia type A associated with polydactyly and micromelia

P24.15: Antenatal sonographic features of intestinal neuronal dysplasia type A associated with polydactyly and micromelia

Connective Tissue in Gut Development: A Key Player in Motility and in Intestinal Desmosis

Efficient intestinal peristalsis is a function of intact enteric nervous system, muscle, and connective muscularis propria tissue. Malfunction of any component results in impaired peristalsis. Hirschsprung disease (HD) as prototypic enteric neural migration disorder is increasingly well characterized. More recently, intestinal myopathies and particularly defects of myenteric collagenization have entered the focus of attention. However, detailed development of muscularis propria connective tissue is not well known. The aim of this study was to morphologically characterize intestinal connective tissue in fetal and postnatal development and intestinal pseudo-obstruction. In this study, 130 archival specimens of fetal autopsies, intestinal resections, and biopsies were analyzed. Patients' age was 10th gestational week (gw) to 70 years. Muscularis mucosae, muscle layers, collagen tissue, and enteric plexus were analyzed. Picrosirius red stains, enzyme histochemistry, and immunohistochemistry for collagens I, III, and IV were performed. Total 89 normal intestinal specimens were from fetal autopsies or intestinal resections; 41 patients showed a primary structural colon wall defect (HD, desmosis). Our results showed a constant increase in tunica muscularis propria thickness with age. Separation into circular and longitudinal muscle layer first occurred in the 11th gw. A tendinous collagen plexus layer first arose in the 10th gw and showed a steady caliber increase. Muscularis mucosae first appeared in the 10th gw and grew independent of any primary gastrointestinal disease. In the 11th gw, enteric ganglia were fully developed. In desmosis, a collagen plexus layer was absent. In contrast, in HD, muscularis mucosae showed hypertrophy, but the collagen plexus layer was intact in the aganglionic segment. In intestinal neuronal dysplasia and hypoganglionosis, nerve cell development was disturbed; connective tissue and muscle layers were well developed. Our comprehensive study of intestinal connective tissue development in comparison to neural intestinal wall components in normal and pathological conditions showed that tendinous tissue develops parallel to muscularis propria and arises early in embryogenesis. In enteric nervous system disorders, ganglionic lesions develop independently of impaired collagen network, whereas mucosal biopsies serve for diagnosis of HD, seromuscular biopsies are required to prove desmosis in gastrointestinal dysmotility disorders.

Unusual cause of neonatal intestinal obstruction

There are many causes of intestinal obstruction in the neonatal age. The most common types are mechanical and result from congenital malformations of the gastrointestinal tract. However, functional disorders also occur. In some cases, diagnosis can be made prenatally but in others manifestation occurs after birth. The aim of this article is to present the case of a newborn with intestinal obstruction characterized by microcolon, dilated small bowel and megacystis known as Megacystis-Microcolon-Intestinal Hypoperistalsis syndrome, a very rare cause of intestinal obstruction. So far, less than three hundred cases have been reported in the literature. The prognosis of this syndrome is generally poor with most affected children dying in the neonatal period or infancy. Intestinal obstruction is a serious and life threatening condition. It may be explained by gross anatomical, histological or other abnormalities affecting the gut of the fetus.  Differential diagnosis may also take into account various anatomical, histological, or other abnormalities that may result in the obstruction of gut.  The incidence of intestinal obstruction is estimated at about one in 1500 live births.2 The cause of obstruction can be extrinsic or intrinsic. Atresia is quite common in the anorectal region, while atresia of the stomach occurs rarely. Colonic atresia is a rare condition of bowel obstruction in neonates. Membranous or complete obstruction may be present in the small intestine and may affect multiple sites. Stenosis may result from extrinsic or intrinsic factors. It arises from the failure of physiological rotation or fixation of the intestine in utero. Malrotation is one of the most serious cases, when there is incomplete rotation of the intestine into flexura duodenojejunalis or incomplete rotation of the caecum. Duodenal obstruction may also result when adhesion bands of Ladd straps down the second part of the duodenum. The second group of causes of bowel obstruction in the newborn consists of functional intestinal obstructions. It develops due to defects of bowel inervation and differentiation of ganglion cells. It includes small left colon syndrome or neuronal intestinal dysplasia type A and neuronal intestinal dysplasia type B.

Antenatal sonographic features of intestinal neuronal dysplasia type A associated with polydactyly and micromelia

Type A intestinal neuronal dysplasia is a congenital abnormality that is a very rare disease. Here, we report on a patient who had intestinal dilatation with serial changes and polydactyly, as shown on prenatal ultrasound. Bowel obstruction symptoms were shown at 16 days of life. An open abdominal surgery was performed. Malrotation of the bowel and narrowing of the area from 15 cm above the ileocecal valve were noted. Therefore, a right hemicolectomy, including lesions was performed. The patient was diagnosed with type A intestinal neuronal dysplasia by pathology.

Role of rectal myomectomy in refractory chronic constipation

To assess the role of diagnostic and therapeutic value of anorectal myectomy in cases of chronic refractory constipation. Twenty-eight patients 11 months to 9 years of age presenting with chronic constipation, with contrast enema showing dilated rectum and sigmoid colon were included in the study. Anorectal myectomy under general anaesthesia was carried out in these selected patients and were followed-up for up to 6 months to 5 years. Clinical improvement was measured by post-operative bowel habits and relief of symptoms. Twenty-two patients improved clinically; partial response in 4 patients, no response in 2 patients. Two patient required further pull through surgery and was found to have transition zone at the recto-sigmoid level. Ten patients had aganglionosis (of which 5 had ganglion cells present in the proximal part of speciment), 7 had normal histology, 7 had hypoganglionosis, 2 had intestinal neuronal dysplasia, one had nerve hypertrophy and one had immature ganglia. Anorectal myectomy is an effective and technically simple procedure in selected patients with chronic refractory constipation, for both diagnostic and therapeutic purpose. Because apart from confirming Hirschsprung's disease, it also therapeutically relieves symptoms in 93% of patients with chronic refractory constipation.

Favorable surgical treatment outcomes for chronic constipation with features of colonic pseudo-obstruction

To determine long-term outcomes of surgical treatments for patients with constipation and features of colonic pseudo-obstruction. Consecutive 42 patients who underwent surgery for chronic constipation within the last 13 years were prospectively collected. We identified a subgroup with colonic pseudo-obstruction (CPO) features, with dilatation of the colon proximal to the narrowed transitional zone, in contrast to typical slow-transit constipation (STC), without any dilated colonic segments. The outcomes of surgical treatments for chronic constipation with features of CPO were analyzed and compared with outcomes for STC. Of the 42 patients who underwent surgery for constipation, 33 patients had CPO with dilatation of the colon proximal to the narrowed transitional zone. There were 16 males and 17 females with a mean age of 51.2 ± 16.1 years. All had symptoms of chronic intestinal obstruction, including abdominal distension, pain, nausea, or vomiting, and the mean duration of symptoms was 67 mo (range: 6-252 mo). Preoperative defecation frequency was 1.5 ± 0.6 times/wk (range: 1-2 times/wk). Thirty-two patients underwent total colectomy, and one patient underwent diverting transverse colostomy. There was no surgery-related mortality. Postoperative histologic examination showed hypoganglionosis or agangliosis in 23 patients and hypoganglionosis combined with visceral neuropathy or myopathy in 10 patients. In contrast, histology of STC group revealed intestinal neuronal dysplasia type B (n = 6) and visceral myopathy (n = 3). Early postoperative complications developed in six patients with CPO; wound infection (n = 3), paralytic ileus (n = 2), and intraabdominal abscess (n = 1). Defecation frequencies 3 mo after surgery improved to 4.2 ± 3.2 times/d (range: 1-15 times/d). Long-term follow-up (median: 39.7 mo) was available in 32 patients; all patients had improvements in constipation symptoms, but two patients needed intermittent medication for management of diarrhea. All 32 patients had distinct improvements in constipation symptoms (with a mean bowel frequency of 3.3 ± 1.3 times/d), social activities, and body mass index (20.5 kg/m(2) to 22.1 kg/m(2)) and were satisfied with the results of their surgical treatment. In comparison with nine patients who underwent colectomy for STC without colon dilatation, those in the CPO group had a lower incidence of small bowel obstructions (0% vs 55.6%, P < 0.01) and less difficulty with long-distance travel (6.7% vs 66.7%, P = 0.007) on long-term follow-up. Chronic constipation patients with features of CPO caused by narrowed transitional zone in the left colon had favorable outcomes after total colectomy.