Intestinal Neuronal Dysplasia Type Research Articles

Hirschsprung Disease and Intestinal Neuronal Dysplasia Type B: Is There a Difference in the Clinical Presentation of These Two Diseases?

Although the signs and symptoms that comprise the clinical presentation of Hirschsprung disease (HD) and intestinal neuronal dysplasia type B (IND-B) are well established, no studies have specifically compared the clinical characteristics presented by patients with these diseases. We compared the clinical pictures of patients with HD and IND-B at the time of histopathological diagnosis. This was a single-center, retrospective, analytical, and comparative study. We included 119 patients aged 0-15 years diagnosed with HD or IND-B. Information from the medical records of these patients was retrieved to obtain demographic and clinical information at the time of diagnosis. The data were compared statistically according to the characteristics of the variables. Sixty-nine patients (58.0%) were diagnosed with HD, and 50 (42.0%) had IND-B. The HD group had significantly more individuals with symptom onset in the neonatal period (p = 0.001), delayed meconium clearance (p < 0.001), failure to thrive (p = 0.02), and acute complications, such as enterocolitis (p = 0.049) or acute abdominal obstruction (p = 0.031), more commonly requiring emergency surgery (p < 0.001). Patients with IND-B were diagnosed at a significantly older age (p = 0.002). They more commonly had chronic constipation as their main symptom (p = 0.004), with local complications, such as evacuation bleeding (p = 0.007). There were significant differences between the clinical pictures of patients with HD and IND-B. Knowledge of each disease's most common signs and symptoms can help direct diagnostic susception and initial management.

Association between Clinical and Histopathological Findings in Intestinal Neuronal Dysplasia Type B: An Advance towards Its Definition as a Disease.

Intestinal neuronal dysplasia type B (IND-B) is a controversial entity that affects the submucosal nerve plexus of the distal intestine. The lack of definition of the causal relationship between histological findings and clinical symptoms has been identified as the primary point to be elucidated in the scientific investigation related to IND-B, which is essential for it to be considered a disease. To investigate the relationship between histopathological findings and symptoms in a series of patients with IND-B. Twenty-seven patients with histopathological diagnosis of IND-B, according to the Frankfurt Consensus (1990), who underwent surgical treatment through colorectal resections were included. Data from medical records regarding the clinical picture of the patients at the time of diagnosis, including the intestinal symptom index (ISI) and a detailed histopathological analysis of the rectal specimens, were retrieved. Exploratory factor analysis was performed, applying the principal components method for clusters with Varimax rotation. Two factors were determined: the first, determined by histopathological and clinical variables, and the second, composed of the main symptoms presented in patients with IND-B, including ISI. Factorial rotation showed the association between the two factors and, through a graph, demonstrated the proximity between ISI values and histopathological alterations. There was evidence of an association between the clinical features presented by patients with IND-B and the histopathological findings of the rectal samples. These results support the understanding of IND-B as a disease.

Intestinal neuronal dysplasia type B of the duodenum in an adolescent patient

Intestinal neuronal dysplasia type B (IND-B) is a rare neuromuscular, dysmotility disorder that typically affects the lower gastrointestinal tract, commonly presenting as chronic constipation in children. We present the first pediatric case report of successful surgical management of IND-B affecting the duodenum as a likely chronic adaptive sequela to prior obstruction from superior mesenteric artery syndrome.

PTEN Immunohistochemistry.

Intestinal neuronal dysplasia type B (IND B) is a complex entity involving the enteric nervous system, clinically manifested with constipation in infancy. Diagnosis has been established by histopathologic analysis of rectal biopsies. However, the criteria for the diagnosis have been questioned and modified, hindering diagnostic practice. To analyze the applicability of PTEN immunohistochemistry in the diagnosis of IND B and to compare with control cases and cases of Hirschsprung disease (HD). PTEN immunohistochemical expression was analyzed in colorectal samples from 29 cases of IND B and compared with 4 control cases and 6 cases of HD. The pattern of PTEN immunoexpression was analyzed in glial cells of the submucosal and myenteric nerve plexuses and in neural fibrils of the muscularis propria using a scoring system. Marked reduction or absence of PTEN expression was observed in glial cells of the submucosal nerve plexuses in all cases of the IND B group and in the myenteric nerve plexuses in 28 of 29 cases (96.5%). Lack of PTEN expression was detected in neural fibrils within the muscularis propria in 21 of 29 cases (72%) of the IND B group. PTEN expression was positive in the same neural structures of the control and HD groups. PTEN immunohistochemistry may be a valuable tool in the diagnostic evaluation of IND B. Lack of or reduction of PTEN expression in neural fibrils within the muscularis propria suggests that involvement of the neuromuscular junction may be a key event in the pathogenesis of the motility disturbance occurring in IND B.

Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells.

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.

What should be the treatment for intestinal neuronal dysplasia type B? A comparative long-term follow-up study

PurposeTo present the long-term follow-up outcomes of patients with intestinal neuronal dysplasia type B (IND-B) managed either conservatively or surgically. MethodsWe conducted an ambispective, observational, longitudinal, and comparative study. Clinical data were reviewed at the start of treatment. After a minimum period of five years, the patients participated in semi-structured interviews in which the bowel function score (BFS) was applied to assess intestinal function, a proposed intestinal symptom index (ISI) to assess clinical symptoms, and a classification of clinical prognosis to assess treatment success. Comparisons between the two types of treatment were performed by evaluating pre- and post-treatment criteria. ResultsFifty patients diagnosed with IND-B were included in the study. Thirty-eight patients underwent surgical treatment (26 elective surgical treatment for primary colorectal resection and 12 emergency colostomies for intestinal obstruction or enterocolitis). Twelve patients were managed conservatively. With the exception of the patients who required an emergency operation (n = 12), the two groups were composed of patients with severe constipation who had similar clinical and functional characteristics at the time of IND-B diagnosis. A better clinical response was observed in patients submitted to conservative treatment, with a greater increase in the BFS (16.5 [-4/+18] versus 4 [-15/+17]; p = 0.001), indicating better bowel function and a more pronounced drop in ISI (-6 [-7/-4] versus -4 [-6/+1]; p = 0.015), suggesting fewer symptoms. The percentage of patients who had a successful treatment was higher in the group treated conservatively (72.7% versus 42.3%; p = 0.03). ConclusionConservative management showed better long-term outcomes than surgical management in children with IND-B.

Identification of potential molecular pathogenesis mechanisms modulated by microRNAs in patients with Intestinal Neuronal Dysplasia type B

This study proposed to determine global microRNA (miRNA) expression and miRNA-regulated pathways in Intestinal Neuronal Dysplasia type B (IND-B). Fifty patients (0–15 years old) with IND-B were included in the study. Peripheral blood samples were collected from all 50 patients and from 10 healthy asymptomatic children (controls). Rectal biopsies were collected from 29/50 patients; biopsy tissues were needle microdissected to isolate the different intestinal layers, for molecular analysis. Global miRNA expression was determined using TaqMan arrays. Correlation analysis between miRNA expression in plasma and biopsy samples as well as among tissues derived from the distinct intestinal layers was performed. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated genes and enriched pathways biologically relevant to IND-B pathogenesis. miRNAs were statistically significantly deregulated (FC ≥ 2 and p ≤ 0.05) in submucosal and muscular layers: over-expressed (miR-146a and miR-146b) and under-expressed (miR-99a, miR-100, miR-130a, miR-133b, miR-145, miR-365, miR-374-5p, miR-451). Notably, let-7a-5p was highly over-expressed in patient plasma compared to healthy controls (FC = 17.4). In addition, miR-451 was significantly under-expressed in both plasma and all biopsy tissues from the same patients. Enriched pathways (p < 0.01) were axon guidance, nerve growth factor signalling, NCAM signalling for neurite out-growth, neuronal system and apoptosis. miRNA expression is deregulated in the submucosa and muscular layers of the rectum and detected in plasma from patients with IND-B. Biologically enriched pathways regulated by the identified miRNAs may play a role in IND-B disease pathogenesis, due to the activity related to the neurons of the enteric nervous system.

Intestinal Neuronal Dysplasia Type B: Timely Diagnosis and Management

Abstract A 23-year-old female presented to the emergency department with abdominal pain and constipation. She reported an extensive history of constipation. Imaging showed distended bowel without an obstruction. During laparotomy, no obvious mechanical cause was found and a total colectomy was performed. Gross examination of the colectomy specimen showed cobblestoning in a 10-cm portion of the colon. Microscopic examination demonstrated hypoganglionosis of the myenteric plexus, hyperganglionosis of Auerbach’s plexus, and “giant ganglia.” This case met the 2006 Meier-Ruge criteria and diagnosis of intestinal neuronal dysplasia (IND) was established. IND was first described in 1971. The frequency of IND varies widely due to lack of consensus of diagnostic criteria and has a geographic distribution with the highest rates in Europe, which correlates to published research in this region. Diagnostic criteria are controversial and require standardization. Meier-Ruge suggests a quantitative analysis of the number of ganglion cells in the submucosal plexuses and the identification of at least 20% giant ganglia with at least 8 neurons each, in 25 analyzed ganglia. More recent diagnostic criteria are conservative with differences, including (1) elimination of increased AChE-positive nerve fibers around submucosal blood vessels, (2) stipulation that a giant ganglion contains more than 8 ganglion cells, (3) the requirement that more than 20% of at least 25 ganglia be giant ganglia, and (4) diagnostic exclusion of patients &lt;1 year. Clinical management is also controversial. Schimpl et al reported satisfactory results in 80% of 105 patients treated with dietary changes, cisapride, and laxatives with a median 7.2 years follow-up. Since colonic peristalsis is impaired by dysganglionosis, subtotal colectomy procedures have been widely successful. Clinicians should be mindful of IND in patients with a history of chronic constipation with abdominal pain and nonspecific imaging, as timely diagnosis can spare the patient from total colectomy and improve quality of life.

Intestinal Neuronal Dysplasia Type B: An Updated Review of a Problematic Diagnosis.

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. To critically analyze existing published data regarding IND B to provide supporting evidence-based diagnostic practice and to stimulate necessary and scientifically sound research. 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. 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.

A critical appraisal of the morphological criteria for diagnosing intestinal neuronal dysplasia type B.

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.

The clinical pathological analysis of intestinal neuronal dysplasia type B

Objective To investigate the clinicopathological features and diagnosis of intestinal neuronal dysplasia type B. Methods Between January 2004 and August 2014, 9 patients(5 males and 4 females) were treated for constipation and abdominal distention, and in all of them an intestinal neuronal dysplasia type B was confirmed histopathologically.The age of 9 patients ranged from 3 months to 1 year old(mean 7.8 months). The specimen of 9 patients was routinely taken by paraffin-embedded full-circumference sections of lesional bowel, hematoxylin and eosin and immunohistochemical staining were carried out on the specimen.The pathological morphology and quantitative of intestinal neurons and ganglia were retrospectively analyzed. Results Total of the 9 patients, the number and density of myenteric ganglia increased significantly increased in the lesional bowel, the pathological findings included giant nerve plexus, isolated and ectopic ganglia.In the proximal bowel, the number and density of myenteric ganglia were observed abnormal no giant nerve plexus, isolated and ectopic ganglia was observed.Combinated these pathological findings and symptoms, intestinal neuronal dysplasia type B was diagnosed. Conclusion The diagnosis of intestinal neuronal dysplasia type B relies on typical presentations of allied disorders of Hirschsprung's disease, giant ganglia, isolated and ectopic ganglia, and increasing the density of giant submucosal ganglia of pathologic morphology, meanwhile, excluding others primary etiologies. Key words: Intestinal neuronal dysplasia; Allied disorders of hirschsprung disease; Pathology; Diagnosis

Intestinal neuronal dysplasia type B: A still little known diagnosis for organic causes of intestinal chronic constipation.

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.

Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections.

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.

Coexistence of Anal Atresia, Anophthalmia and Intestinal Neuronal Dysplasia Type-A in a Newborn

We report a patient with anal atresia, anophthalmia and intestinal neuronal dysplasia type A.

Mo1185 Clinical Outcome of Patients With Neuronal Intestinal Dysplasia Type B: Results of Different Therapeutic Options

Mo1185 Clinical Outcome of Patients With Neuronal Intestinal Dysplasia Type B: Results of Different Therapeutic Options

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.

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

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

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.&#160; Differential diagnosis may also take into account various anatomical, histological, or other abnormalities that may result in the obstruction of gut.&#160; 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.