Intestinal pseudoobstruction caused by a new form of visceral neuropathy: palliation by radical small bowel resection

We report a case of chronic intestinal pseudoobstruction caused by a newly recognized type of degenerative neuropathy of the myenteric plexus. Failure to improve despite aggressive medical management led to radical resection of the clinically involved small intestine. At follow-up 10 mo later, the patient is doing well without the need for parenteral nutrition. Radical resection of the small intestine may be necessary for palliation in rare patients with intractable pseudoobstruction.     

Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction

The purpose of this study was to define the cause of severe gastrointestinal motor dysfunction in 7 patients with lung cancer. Six patients had small cell carcinoma and 1 patient had pulmonary carcinoid. Their ages ranged from 58 to 74 yr. All had intestinal pseudoobstruction and obstipation/constipation; 6 of 7 patients had gastroparesis; 4 of 4 patients had esophageal peristaltic abnormalities; and 2 patients had neurogenic bladders, autonomic insufficiency, and peripheral neuropathy. Five of 7 patients had dilated small bowel with 4 of them showing slow transit of barium; 2 of 7 patients had dilated colons; and 3 of 7 patients had slow colonic transit. Five patients died 4-9 mo after onset of gastrointestinal symptoms, and 2 survived. Post-mortem or surgical samples of the esophagus, stomach, small bowel, and colon showed neuron and axon degeneration and dropout, lymphoplasmacytic infiltration, and glial cell proliferation within the myenteric plexus of 6 patients. The antrum from the seventh patient had inflammatory cells within the myenteric plexus but without neuron dropout. Neuron numbers were significantly less than normal in each area of the gastrointestinal tract. Thus, we conclude that lung cancer may be complicated by severe gastrointestinal motor dysfunction resulting from visceral neuropathy of the myenteric plexus, a paraneoplastic effect of the cancer.     

A familial neuronal disease presenting as intestinal pseudoobstruction.

The purpose of this paper is to describe 2 siblings who had a generalized neurological disease which presented as intestinal pseudoobstruction. The siblings had 40-year histories of abdominal pain, distention, and vomiting as well as gait ataxia, small, irregular, poorly reactive pupils, dysarthria, absent deep tendon reflexes, and impaired vibratory and position senses. Compared with age-matched controls, they had inappropriate blood pressure responses to phenylephrine, the Valsalva maneuver, and upright posture, lack of sweating on warming, and pupillary denervation hypersensitivity. Radiographs revealed hyperactive, nonpropulsive contractions of a dilated esophagus and small intestine and extensive colonic diverticulosis. Esophageal manometry recorded repetitive, spontaneous, nonperistaltic waves and positive Mechyolyl tests. Postmortem examinations showed degeneration of the myenteric plexuses of the esophagus, small intestine, and colon of both patients. Myenteric plexus neurons were significantly reduced in number compared with 7 controls. About one-third of the siblings' neurons contained round, eosinophilic intranuclear inclusions, which, by histochemistry, were composed of protein by lacked RNA, DNA, carbohydrate, and fat. By electron microscopy the inclusions consisted of an irregular array of nonviral, nonmembrane-bounded filaments. Neurons and glial cells of the brain, spinal cord, dorsal root, and celiac plexus ganglia contained identical intranuclear inclusions. Intestinal smooth muscle was normal. These 2 siblings represent a unique disease in which degeneration of the myenteric plexus resulted in hyperactive but uncoordinated smooth muscle activity and the clinical syndrome of intestinal pseudoobstruction, the presenting manifestation of their neurological disease.     

Chronic Intestinal Pseudoobstruction as a Possible Sequel to Encephalitis

A patient is reported who presented with a typical intestinal pseudoobstruction syndrome. Before this illness, the patient had suffered from measles encephalitis at the age of 15 months. A postencephalitic syndrome was present which included severe mental retardation, parkinsonism, and epilepsy. There were no relatives with a similar disease. Clinically, there was a frank recurrent pseudoobstruction syndrome with occasional diarrhea. Radiographic barium studies showed delayed transit, hypomotility of the intestines, and gross distension of the esophagus, stomach, small intestine, and colon. Histological examination of the gastrointestinal tract revealed a normal appearance of the mucosa; however, there was a hypertrophic muscle layer with abnormalities of the plexuses. Both the submucosal and the myenteric plexuses were reduced in number and size. They showed a decreased number of ganglion cells, proliferation of Schwann cells and infiltration by lymphocytes. The abnormalities were most strikingly present in the esophagus and the small intestine. The intestinal neuropathy resulting in clinical pseudoobstruction is proposed to be part of the generalised neurological pathology as a late sequel to the measles encephalitis.     

An inflammatory axonopathy of the myenteric plexus producing a rapidly progressive intestinal pseudoobstruction

A previously well 39-yr-old man presented with a 4-wk history of abdominal pain, nausea, vomiting, and weight loss. An upper gastrointestinal examination showed retained food in the stomach and duodenal dilatation. A radioisotope meal showed little gastric emptying; esophageal manometry was normal. Because of persistent symptoms, a duodenojejunostomy was done. However, the patient remained symptomatic and after an episode of profuse vomiting, aspirated and died 10 wk after initial presentation. At autopsy, no tumor was found. Hematoxylin and eosin stains throughout the gastrointestinal tract showed many lymphocytes and plasma cells within the myenteric plexus. Silver stains showed the argyrophilic and argyrophobic neurons to be normal, but axons showed beading, fragmentation, and dropout in all areas. We therefore concluded the following: intestinal pseudoobstruction can be caused by an inflammatory neuropathy of the myenteric plexus, not associated with a distant carcinoma, and this process produced an axonopathy while sparing neuron bodies.     

Familial Visceral Neuropathy as Part of a Diffuse Neuronal Syndrome: Four Fatal Cases in One Sibship

Familial visceral neuropathy is a rare cause of chronic intestinal pseudo-obstruction. It is characterized by progressive destruction of the gastrointestinal myenteric plexus resulting in dysmotility and associated early satiety, post-prandial bloating, recurrent nausea and vomiting, abdominal distension, chronic diarrhea, Height loss, and malnutrition. In its varying forms, there may be neuronal destruction in other parts of the peripheral and central nervous system. We report on four siblings who presented in their third or fourth decades with initial clinical features of chronic intestinal pseudoobstruction and eventual progressive diffuse neuronal disease, characterized by leukoencephalopathy and peripheral neuropathy. Within 5 yr of presentation, all four patients died from inanition and sepsis, despite aggressive nutritional support. Their clinical and pathological features are characteristic of familial visceral neuropathy of the autosomal recessive form. This presentation may represent a unique syndrome characterized by a tetrad of polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction.     

The colon in the pseudoobstructive syndrome

Colonic pseudoobstruction can occur as part of a generalized chronic intestinal pseudoobstruction syndrome or as an isolated entity. Isolated colonic pseudoobstruction can occur in two unrelated forms: the acute and chronic forms. Acute colonic pseudoobstruction is frequently a hospital-acquired disease that arises as a complication of other illnesses. The syndrome must be recognized and treated with early colonoscopic decompression to prevent cecal or colonic perforation. Chronic colonic pseudoobstruction is a syndrome of many causes. The prognosis of patients with chronic colonic pseudoobstruction is much better than that of generalized chronic intestinal pseudoobstruction, because the patients become asymptomatic with appropriate operations. The pathogenesis of acute colonic pseudoobstruction and several types of chronic colonic pseudoobstruction is not known. Further investigations should include bacteriologic study, histopathologic studies (examinations of smooth muscle and myenteric plexus), and examination of extrinsic nerves of the colon. With these approaches, a better understanding of the pathogenesis of these syndromes will be achieved.     

Intestinal pseudo-obstruction in patients with amyloidosis: clinicopathologic differences between chemical types of amyloid protein.

A clinicopathologic study was made of 16 patients with amyloidosis and with clinical signs of intestinal pseudo-obstruction. amyloid deposits in the small intestine were proved in all cases by endoscopic or intra-operative biopsies, and immunohistochemical study identified the chemical types of amyloid protein: amyloid A protein (AA) in 13 cases, light chain protein (AL) in two, and beta 2-microglobulin (AH) in one. Clinically, an acute self limiting obstructive condition was evident in 13 cases with AA, and 12 of them returned to normal bowel function after receiving total parenteral nutrition. Two cases with AL and one with AH presented chronic, intermittent, obstructive symptoms, and medical treatment, including total parenteral nutrition, was ineffective with no recovery of intestinal propulsion. Pathological examination of the necropsy specimens in seven cases showed considerable differences in the preferential sites of gastrointestinal deposits between the chemical types of amyloid; extensive infiltration and replacement of the muscularis propria by amyloid deposits throughout the gastrointestinal tract, especially the small intestine, were found in the AL and the AH cases, while amyloid deposits in the myenteric plexus without appreciable muscle infiltration were shown in the AA cases. These results show that intestinal pseudo-obstruction in patients with amyloidosis is caused by either myopathy or neuropathy, and that chemical types of amyloid may determine which of the two factors has the dominant affect on the bowel function.     

Chronic idiopathic intestinal pseudo-obstruction caused by a degenerative disorder of the myenteric plexus: the use of Smith's method to define the neuropathology

In this paper we report the pathologic basis of chronic idiopathic intestinal pseudo-obstruction in a patient who had a subtotal colectomy and ileorectal anastomosis for severe obstipation. Conventional light microscopy of the resected intestine showed an increased thickness of the longitudinal muscle, minimal amounts of smooth muscle fibrosis, and normal smooth muscle cells. The morphology of the myenteric plexus was difficult to interpret with this technique, but quantification of colonic neurons revealed a significantly decreased number compared with controls. Silver stains of the myenteric plexus by Smith's method showed: (a) patchy loss of nerve tracts with replacement by Schwann cells, (b) degeneration and decreased numbers of both argryophilic and argyrophobic neurons, (c) fragmentation and dropout of many axons, and (d) increased thickness and disorganized spatial arrangement of other axons. The pathology of this intestinal neuropathy could be missed by conventional light microscopy and may be apparent only when a silver technique is used to visualize the myenteric plexus.     

Intestinal pseudo-obstruction as the presenting manifestation of small-cell carcinoma of the lung. A paraneoplastic neuropathy of the gastrointestinal tract

A 58-year-old woman who had presented with intestinal pseudo-obstruction died 9 months later from rapidly progressive neurologic symptoms and autonomic insufficiency. Her gastric emptying had been markedly delayed and transit of markers had been slowed throughout the small bowel. A 5-hour manometric recording of the antrum and duodenum had shown absence of the normal interdigestive motor complex, which was replaced by irregular contractile activity of reduced amplitude. A small-cell carcinoma of the lung was found at autopsy. Pathologic study of the gut showed widespread degeneration of the myenteric plexus, which was infiltrated by plasma cells and lymphocytes and contained significantly reduced numbers of neurons. The extra-intestinal nervous system had neuronal loss and lymphocytic infiltrates in dorsal root ganglia. Thus, a gastrointestinal neuropathy causing intestinal pseudo-obstruction may be the presenting manifestation of a paraneoplastic syndrome associated with small-cell carcinoma.     

Notable postnatal alterations in the myenteric plexus of normal human bowel

BACKGROUND: Nitric oxide is the most important transmitter in non-adrenergic non-cholinergic nerves in the human gastrointestinal tract. Impaired nitrergic innervation has been described in Hirschsprung's disease, hypertrophic pyloric stenosis, and intestinal neuronal dysplasia (IND). Recent findings indicate that hyperganglionosis, one of the major criteria of IND, is age dependent. However, information is scanty regarding the neurone density in normal human bowel in the paediatric age group. AIMS: To determine neurone density, morphology, and nitric oxide synthase distribution of the normal myenteric plexus at different ages during infancy and childhood. METHODS: Specimens were obtained from small bowel and colon in 20 children, aged one day to 15 years, at postmortem examination. Whole mount preparations were made of the myenteric plexus, which were subsequently stained using NADPH diaphorase histochemistry (identical to nitric oxide synthase) and cuprolinic blue (a general neuronal marker). The morphology of the myenteric plexus was described and the neurone density estimated. RESULTS: The myenteric plexus meshwork becomes less dense during the first years of life. The density of ganglion cells in the myenteric plexus decreases significantly with age during the first three to four years of life. The NADPH diaphorase positive (nitrergic) subpopulation represents about 34% of all neurones in the myenteric plexus. CONCLUSIONS: The notable decrease in neurone density in the myenteric plexus during the first years of life indicates that development is still an ongoing process in the postnatal enteric nervous system. Applied to the clinical situation, this implies that interpretation of enteric nervous system pathology is dependent on the age of the patient.     

Enteric neuropathology of congenital intestinal obstruction： A case report

Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system (ENS),although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations: the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second (2 years later) was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third (9 years after the hyperganglionosis was identified) disclosed a Ladd's band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd's band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital (partial) mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudoobstruction.     

Familial visceral neuropathy with autosomal dominant transmission

This report describes a family with a visceral neuropathy without extraintestinal manifestations transmitted over at least four generations in an autosomal dominant manner. Four of 7 living patients underwent extensive evaluation including histology, radiography, gastric emptying and secretory studies, esophageal and jejunal manometry, and measurements of plasma levels of gastrointestinal hormones. The only characteristic radiologic abnormality in 7 patients was dilatation of jejunum and ileum. Gastric emptying studies were normal in 2 patients, whereas 2 others showed accelerated emptying of liquids either alone or in combination with grossly delayed solid emptying. Manometry of the esophagus and proximal small intestine and gastric secretory studies were normal. Histologic studies showed hypertrophy of the smooth muscle, a markedly reduced number of argyrophilic neurons, and degenerative changes of argyrophilic neurons and nerve fibers but without Schwann cell proliferation, intranuclear inclusions, or inflammatory cells. This appears to be a familial visceral neuropathy characterized by distinct involvement of the jejunum and ileum as defined radiographically, histology different from that of two previously described forms of familial visceral neuropathy, autosomal dominant transmission, and no evidence for extraintestinal neurologic manifestations.     

Direct spread of reovirus from the intestinal lumen to the central nervous system through vagal autonomic nerve fibers.

A crucial event in the pathogenesis of systemic enteric virus infections is entry of virus into the nervous system. Whether enteric virus spreads from the intestinal tract to the central nervous system through nerves or through the bloodstream was examined using a serotype 3 reovirus strain. After peroral inoculation of newborn mice with reovirus, serial histologic sections of small intestine, brain and spinal cord were prepared and stained by immunoperoxidase to detect viral antigen. Three days after inoculation, viral antigen was observed in mononuclear cells of ileal Peyer's patches and in neurons of the adjacent myenteric plexus. Infection first appeared in the central nervous system 1-2 days later in neurons of the dorsal motor nucleus of the vagus nerve. Endothelial cells, meninges, choroid plexus, hypothalamus, and area postrema were not infected, indicating neural rather than bloodborne spread from the intestine. Staining of neurons in the dorsal motor nucleus of the vagus nerve depended on the route of virus inoculation and was independent of the amount of virus in the bloodstream. These results demonstrate that an enteric virus entering a host from the intestinal lumen can spread to the central nervous system through nerve fiber innervating the intestine.     

Development of interstitial cells of Cajal in a full-term infant without an enteric nervous system

The relationship between the development of the enteric nervous system and interstitial cells of Cajal (ICC) in the human small intestine was investigated in a full-term infant who presented with intestinal pseudo-obstruction. Immunohistochemistry revealed absence of enteric nerves and ganglia but abundant c-Kit immunoreactivity associated with Auerbach's plexus (ICC-AP). However, c-Kit immunoreactivity associated with the deep muscular plexus (ICC-DMP) and intermuscular ICC was absent. Electron microscopy showed ICC-AP with a normal ultrastructure; ICC-DMP were seen but were severely injured, suggesting degeneration. In vitro recording of intestinal muscle showed slow wave activity as well as response to cholinergic stimulation. Fluoroscopic examination of the small bowel showed a variety of motor patterns, including rhythmic, propagating contractions. In conclusion, total absence of enteric nerves was associated with absence of normal ICC-DMP. However, a normal musculature, including a network of ICC-AP, allowed for generation of rhythmic, propagating contractile activity, suggesting the presence of functional motor activity.     

Gastric antral dysrhythmias in children with chronic idiopathic intestinal pseudoobstruction.

Chronic idiopathic intestinal pseudoobstruction is a serious disorder of intestinal neuromuscular function resulting in recurrent episodes of intestinal obstruction, and is caused by primary disease of the enteric nerves or enteric smooth muscle. Gastric electrical control activity detected by the non-invasive technique of surface electrogastrography was investigated in 11 children (0.1-16 years) with proven chronic idiopathic intestinal pseudoobstruction (four with known disease of the enteric nerves, three with disease of smooth muscle cells, and four without defined pathology), to determine whether abnormalities were present and whether these were useful in detecting the underlying pathology. Abnormalities were present in eight of 11 patients. Persistent tachygastria (electrical control activity frequency > 5 cycles/minute) was found in three patients, all with a proven neuropathy. A continuously irregular frequency was found in five patients, three with a proven myopathy and two with undefined pathology. A normal electrical control activity frequency was present in three patients, one with a proven neuropathy and two with undefined pathology. It is suggested that this non-invasive technique may provide a useful screening test of the pathophysiological basis of the functional obstruction in children with chronic idiopathic intestinal pseudoobstruction.     

Origins of peptide and norepinephrine nerves in the mucosa of the guinea pig small intestine

Norepinephrine, acetylcholine, and certain peptides are contained in mucosal nerves and have potent effects on transepithelial water and electrolyte fluxes. It is difficult to ascribe roles for these nerves as their sources are unknown. The present studies were undertaken to determine the origins of nerve fibers that are found in the mucosa of the guinea pig small intestine and which contain one of the following substances: vasoactive intestinal peptide, substance P, somatostatin, neuropeptide Y, cholecystokinin, or norepinephrine. Nerve fiber origins were ascertained by making lesions to sever pathways through which the nerves could reach the mucosa. The lesioning operations were homotopic autotransplants of short (2 cm) segments of intestine; myectomies, in which a 5-10-mm length of intestine was stripped of longitudinal muscle and myenteric plexus; and extrinsic denervation, in which nerves reaching the intestine through the mesentery were severed. The results of these studies, considered along with previously published work, led to the upcoming conclusions. Nerve fibers in the mucosa showing immunoreactivity for vasoactive intestinal peptide, somatostatin, cholecystokinin, and neuropeptide Y arise from cell bodies in the overlying submucous plexus. Substance P fibers arise in part from the overlying submucous plexus and in part from the overlying myenteric plexus. Mucosal norepinephrine fibers arise from extrinsic sympathetic ganglia. Enkephalin, gastrin-releasing peptide, and 5-hydroxytryptamine, which are in some enteric nerves, are not found in submucous nerve cells and few, if any, fibers containing these substances supply the mucosa. Thus, the mucosa receives a dense nerve supply, much of which arises locally from submucous ganglia.     

DNA viruses in the pathogenesis of sporadic chronic idiopathic intestinal pseudo-obstruction.

BACKGROUND: Hereditary forms of chronic idiopathic intestinal pseudo-obstruction (CIIP) are well described but the aetiology of most cases of sporadic CIIP is unknown. AIM: To determines whether herpes viruses can persist in the gastrointestinal tract, thereby implicating them in the pathogenesis of CIIP. METHODS: Twenty one specimens of small and large intestine from 13 patients with CIIP (eight visceral myopathy, three visceral neuropathy, two undifferentiated), and 12 patients operated on for colorectal cancer (controls) were examined for evidence of Herpesvirus DNA (cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex virus type 1, and varicella zoster virus) by nested polymerase chain reaction (PCR) and in situ DNA hybridisation (ISH) to localise signal to the muscularis propria or myenteric plexus. RESULTS: Screening with nested PCR produced three patients with positive results. One patient with an inflammatory visceral neuropathy had EBV detected in the small intestine by PCR, and ISH demonstrated localisation to neurones in the myenteric plexus. A patient with a visceral myopathy had EBV DNA in both the small and large intestine; and one patient with a visceral neuropathy had small intestine positive for CMV DNA (both negative by ISH). No control tissue was positive for any virus. CONCLUSIONS: In individual patients there appears to be evidence linking a viral aetiology to sporadic CIIP. The role of neurotropic viruses in acute and chronic motility disturbances needs further study.     

Familial intestinal pseudoobstruction dominated by a progressive neurologic disease at a young age

Chronic neuropathic intestinal pseudoobstruction is a rare entity, characterized by recurrent episodes of bowel obstruction without a mechanical obstructive cause. We report five members of two Jewish-Iranian families in whom chronic neuropathic intestinal pseudoobstruction was associated with an identical and unique progressive severe neuronal disease. It appeared within the first two decades of life. The disease consisted of external ophthalmoplegia, ptosis, and severe sensory and motor peripheral neuropathy. Three patients also had neuronal hearing loss. There was no evidence of central nervous system involvement and all patients were mentally intact. The combined disease was confirmed by radiologic, electrophysiologic, and histologic studies. Specific nutritional deficiencies, toxic elements, and systemic diseases affecting both the gastrointestinal tract and the nervous system were ruled out. It seems that these patients suffer from an autosomal recessive, presently unrecognized variant, of chronic neuropathic intestinal pseudoobstruction. In a patient with severe peripheral neuropathy of unknown etiology associated with symptoms suggestive of intestinal obstruction, the possibility of chronic neuropathic intestinal pseudoobstruction has to be considered.     

Familial visceral neuropathy with neuronal intranuclear inclusions: diagnosis by rectal biopsy.

A family with a visceral neuropathy manifested as chronic idiopathic intestinal pseudo-obstruction is reported. Diagnoses were made histologically by simple rectal biopsy. Discrete eosinophilic intranuclear inclusions, diagnostic of a disease known as neuronal intranuclear inclusion disease, were found in the submucosal ganglion cells. Abnormalities of the autonomic nervous system were identified by pupillary examination and electroretinography. In this family, three of four siblings were affected by the disease, which is apparently transmitted from the paternal side. This pedigree was unique for several reasons: (a) diagnosis in multiple members of two generations indicates that this familial visceral neuropathy was expressed in an autosomal dominant manner, (b) central autonomic nervous system abnormalities were detected by eye examination, and (c) the definitive pathological diagnosis was established antemortem by rectal biopsy in all cases.