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.     

Etiology and pathogenesis of achalasia: the current understanding

Idiopathic achalasia is an inflammatory disease of unknown etiology characterized by esophageal aperistalsis and failure of LES relaxation due to loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Proposed causes of achalasia include gastroesophageal junction obstruction, neuronal degeneration, viral infection, genetic inheritance, and autoimmune disease. Current evidence suggests that the initial insult to the esophagus, perhaps a viral infection or some other environmental factor, results in myenteric plexus inflammation. The inflammation then leads to an autoimmune response in a susceptible population who may be genetically predisposed. Subsequently, chronic inflammation leads to destruction of the inhibitory myenteric ganglion cells resulting in the clinical syndrome of idiopathic achalasia. Further studies are needed to better understand the etiology and pathogenesis of achalasia-such an understanding will be important in developing safe, effective, and possibly curative therapy for achalasia.     

Clinical and morphofunctional features of idiopathic myenteric ganglionitis underlying severe intestinal motor dysfunction: a study of three cases

Ganglionitis, i.e., the inflammatory neuropathy characterized by a marked lymphoplasmacellular infiltrate in the myenteric plexus, may underlie a variety of paraneoplastic, infectious, or neurological disorders, although occasional cases are idiopathic in origin. We report clinical, manometric, morphofunctional, and immunological features of three cases of idiopathic ganglionitis. All patients had megacolon and underwent surgery for repeated episodes of intestinal subocclusion. Esophageal, GI, and colonic manometry performed in one patient showed dysmotility of the whole gut. Histological examination of colonic and ileum specimens identified a prominent lymphoplasmacellular infiltrate within the myenteric plexus along with a marked decrease of a wide array of neuronal peptides/transmitters. In one patient, tissue analysis revealed progressive neuronal changes up to marked myenteric neuron damage. The inflammatory infiltrate in all patients comprised CD4+ and CD8+ T lymphocytes. Abundance of both subclasses of lymphocytes suggests that immune-mediated mechanisms were responsible for neuronal degeneration. In one patient, systemic steroid therapy brought a significant clinical improvement. The immunosuppressive approach deserves further investigation in patients with severe gut motor abnormalities attributable to idiopathic myenteric ganglionitis.     

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.     

Chronic primary intestinal pseudo-obstruction from visceral myopathy.

Chronic intestinal pseudo-obstruction is an uncommon syndrome characterized by relapsing episodes suggesting intestinal obstruction during which no mechanical causes are identified to account for symptoms. Etiologic factors may be manifold. Among them a number of neurologic conditions, gastrointestinal smooth muscle myopathies, endocrino-metabolic and autoimmune diseases, and the use of selected drugs stand out. We report a case of chronic intestinal pseudo-obstruction originating in a sporadic, primary intestinal myopathy that corresponds to no type thus far described. A histological study of the intestinal wall showed disrupted muscle bundles and the presence of interstitial edema. Myocytes had severe degenerative changes, and no alterations were seen in submucosal and myenteric plexus neurons. The activity of enzyme complexes in the mitochondrial respiratory chain, and of thymidine phosphorylase was normal. No mitochondrial DNA changes were seen.     

Severe paraneoplastic gastroparesis associated with anti-Hu antibodies preceding the manifestation of small-cell lung cancer

Gastroparesis is a common but challenging disorder which can be idiopathic or induced by a variety of underlying diseases, most frequently by diabetes, or post-surgical conditions of the upper abdomen. Clinicians must also consider rare causes of gastric motor dysfunction, such as collagen vascular disorders and paraneoplastic syndromes. Here we present the case of a patient with severe gastroparesis, who was admitted to our hospital for vomiting and weight loss of 25 kg within four months. Endoscopy showed a dilated fluid-filled stomach without peristalsis but no obstruction. High titres of anti-Hu antibodies were detected in patient's serum, supporting the diagnosis of severe paraneoplastic gastroparesis with chronic intestinal pseudo-obstruction. Fine-needle aspiration of suspicious mediastinal lymph nodes guided by endoscopic ultrasound revealed lymphatic metastases of a small-cell lung carcinoma. Jejunal tube feeding and chemotherapy with carboplatin and etoposide were initiated. Paraneoplastic gastrointestinal dysmotility is rare, however, clinicians should consider this differential diagnosis in otherwise unexplained gastrointestinal motor dysfunction. The pathophysiology of paraneoplastic gastroparesis, the diagnostic relevance of anti-Hu antibodies as well as therapeutic options are discussed.     

Nitric oxide synthase and VIP distribution in enteric nervous system in idiopathic chronic constipation

Idiopathic chronic constipation has been correlated to neural abnormalities that consist of a reduced number of myenteric plexus neurons and a decreased concentration of VIP-positive nerve fibers within the circular muscle. Recent studies hypothesized the involvement of nitric oxide in motility disorders of the human gut. To date, no information is available on nitric oxide involvement in idiopathic chronic constipation. The density of VIP- and nitric oxide-producing neurons was evaluated by immunocytochemistry using anti-VIP and anti-nitric oxide synthase antibodies in five patients with idiopathic chronic constipation. A low total neuron density was found at the myenteric plexus. The density of VIP-positive neurons was low while that of nitric oxide synthase-positive neurons was high at both plexuses. Our data confirm that idiopathic slow-transit chronic constipation is due to abnormal neurogenic factors. The presence of numerous nitric oxide synthase-positive neurons, all along the colon and at both plexuses, supports the hypothesis that an excessive production of nitric oxide may cause the persistent inhibition of contractions.Supported by MURST University Funds.     

Neuropathy in the brain-in-the-gut

* The enteric nervous system has sensory neurons, interneurons and motor neurons and functions as a brain-in-the-gut. * Smooth muscles of the digestive tract are autogenic in the absence of neural control. * Enteric inhibitory motor neurons control excitability of the autogenic musculature. * The neuropathic form of chronic intestinal pseudo-obstruction is a form of disinhibitory motor disease linked with neuropathic degeneration in the enteric nervous system. * Patients with inflammatory degenerative neuropathy may progress from irritable bowel syndrome (IBS)-like symptoms to chronic pseudo-obstruction. * Detection of anti-enteric neuronal antibodies may be a useful diagnostic test for early stages of inflammatory degenerative neuropathy in patients with symptoms of a functional gastrointestinal disorder. Awareness is increasing that autoimmune attack targeted to neuronal elements of the enteric nervous system may underlie irritable bowel-like symptoms that progress to chronic pseudo-obstruction. The inflammatory neuropathy disrupts the integrative functions of the brain-in-the-gut, including reduction in the population of inhibitory motor neurons to the musculature. Extreme loss of inhibitory motor neurons is manifest as disinhibitory motor disease characterized by achalasia in smooth muscle sphincters and hyperactive, disorganized contractile behaviour of intestinal circular muscle which results in pseudo-obstruction. Detection of anti-enteric neuronal antibodies in the serum of patients with early symptoms of a functional gastrointestinal motility disorder may prove to be a useful diagnostic test for inflammatory enteric neuropathy.     

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.     

Small cell lung cancer with positive anti-Hu antibodies presenting as gastroparesis.

Lung cancer is the most common cancer in North America. Small cell lung cancer (SCLC) represents 15% to 25% of lung cancers. SCLC commonly relapses, resulting in a 3% to 8% five- year survival rate. The poor prognosis associated with SCLC is partly due to late diagnosis of the disease. Paraneoplastic syndromes can be early manifestations of SCLC. The potential benefit of early diagnosis has prompted investigations into markers of this disease. Some patients may present with predominantly gastrointestinal dysmotility symptoms that have no obvious explanation. Testing for anti-Hu antibodies, as a valuable marker of SCLC, should be considered in the investigation. A case of SCLC with positive anti-Hu antibodies presenting with intestinal pseudo-obstruction is presented. Gastrointestinal dysmotility as a manifestation of paraneoplastic syndrome is reviewed.     

Jejunal water and sodium secretion occurs in chronic idiopathic intestinal pseudo-obstruction

We observed jejunal water and sodium secretion in two patients with chronic idiopathic intestinal pseudo-obstruction by standard perfusion techniques. The ability of glucose to reverse this secretory state was impaired. These observations suggest that a jejunal secretory state may contribute to the diarrhea in chronic idiopathic intestinal pseudo-obstruction.     

Unclassified rhabdomyosarcoma in a patient with anti-Hu syndrome

Anti-Hu syndrome is a paraneoplastic neurological syndrome, most frequently associated with small cell carcinoma of the lung. Subacute sensory neuronopathy is thought to be the most frequent presentation of the anti-Hu syndrome, but it seems that sensory-motor neuropathy is the most common form in the anti-Hu neuropathy. Neurological symptoms often appear before the associated cancer has been identified. Sometimes the tumor is discovered months or even a few years after the appearance of the neurological syndrome. FDG-PET scan seems a better method for finding the tumor in patients with paraneoplastic neurological syndrome and anti-Hu antibodies who had negative test results after an initial workup using radiological methods. In this case report we present a patient with the anti-Hu syndrome associated with an unclassified rhabdomyosarcoma with epitheloid cellular morphology and neuroendocrine differentiation.     

The striking effect of hyperbaric oxygenation therapy in the management of chronic idiopathic intestinal pseudo-obstruction

Chronic idiopathic intestinal pseudo-obstruction is one of the disorders that is most refractory to medical and surgical treatment. Even when patients are given nutritional support, including total parenteral nutrition, obstructive symptoms seldom disappear. We report a case of chronic idiopathic intestinal pseudo-obstruction, due to myopathy, in which hyperbaric oxygenation therapy was strikingly effective. The presence of myopathy was histologically confirmed on the surgically resected jejunal specimen. Hyperbaric oxygenation resulted not only in relief of the patient's obstructive symptoms but also in a rapid decrease of abnormally accumulated intestinal gas. At last, he could resume oral intake without any critical adverse effects. These observations strongly suggest that hyperbaric oxygenation can be an effective therapy in the management of chronic idiopathic intestinal pseudo-obstruction.     

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.     

Eosinophilic myenteric ganglionitis: a case of intestinal pseudo-obstruction in a 93-year-old female

Eosinophilic myenteric ganglionitis is a disorder characterized by infiltration of the Auerbach plexus by eosinophils. It can be associated with a bowel dysmotility and a few cases of intestinal pseudo-obstructive syndrome have been described in children. In this case report, we present an elderly 93-year-old woman who presented with episodes of functional bowel obstruction of unknown etiology. After several admissions for recurrent obstipation requiring fecal disimpaction, she had a Hartmann procedure performed with a resection of the sigmoid colon. The sigmoid colon was markedly dilated and the only significant finding on histology was infiltration of the Auerbach plexus by eosinophils. The mucosa and the muscular layers appeared unremarkable. Her symptoms resolved after the resection and the patient is currently well after 5 months. Recurrent gastrointestinal pseudo-obstruction can arise secondary to eosinophilic myenteric ganglionitis even in adults. Clinical improvement is likely if this disease entity is promptly recognized and treated.     

Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult

Inflammatory infiltration of intestinal myenteric plexuses (i.e. myenteric ganglionitis), along with severe intestinal motor abnormalities, may accompany paraneoplastic syndromes, neurological disorders and gastrointestinal infections, although rare cases can be idiopathic. In this report, we describe the case of a patient who presented with chronic intractable vomiting and weight loss associated with idiopathic myenteric ganglionitis mainly involving the stomach. Tissue analysis showed that the inflammatory infiltrate comprised T lymphocytes (CD4+ and CD8+), and peptide immunolabelling revealed a marked decrease of substance P/tachykinin immunoreactive staining in nerve fibres and myenteric neurones. Following systemic steroid therapy, the patient's symptoms dramatically improved, and after one year of follow-up his general condition remains satisfactory. The possible mechanisms leading to symptom generation and gastric dysmotility in the context of an idiopathic myenteric ganglionitis are discussed.     

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.     

Aerobilia and hypomotility of the sphincter of Oddi in a patient with chronic intestinal pseudo-obstruction.

A 50-year-old woman with a typical history of chronic idiopathic intestinal pseudo-obstruction was admitted to hospital because of an acute episode of abdominal cramps, nausea, and vomiting. The diagnosis of chronic idiopathic intestinal pseudo-obstruction had been established in this patient who had malnutrition and extreme weight loss as a result of severe malabsorption syndrome. The abdominal roentgenogram showed a typical hypotonic intestine with an enlarged stomach and distended intestinal loops with the radiological signs of an ileus. In addition to former episodes, there was also a transient aerobilia. The patient had not undergone biliary surgery or endoscopic sphincterotomy. To investigate the cause of the findings, endoscopic retrograde cholangiopancreatography and endoscopic manometry of the sphincter of Oddi were performed. The endoscopy showed the stomach and duodenum with a wide and dilated lumen and no spontaneous motility. Endoscopic manometry of the biliary tract and the sphincter of Oddi showed several abnormalities compared with a group of normal volunteers or patients who were examined via biliary manometry for other reasons. There was a low basal pressure (3.5 mm Hg) in the sphincter of Oddi together with low-amplitude phasic contractions (25-30 mm Hg), but the contraction frequency was in the normal range. Further investigations of the motility of the gastrointestinal tract in this patient showed diffuse esophageal spasms and a markedly delayed gastric emptying. The findings of biliary manometry in this patient suggest involvement of the sphincter of Oddi and the biliary system in chronic idiopathic pseudo-obstruction.     

Hereditary visceral myopathy: an entity in idiopathic intestinal pseudo-obstruction

A 17 year-old girl with chronic idiopathic intestinal pseudo-obstruction is reported. Abnormalities of smooth intestinal muscle were shown on light and electron microscopic studies of the excised small intestine and led to the diagnosis of visceral myopathy based on the following features: vacuolar degeneration of intestinal smooth muscle cells with replacement by fibrous preferential involvement of the external longitudinal muscle layer normal myenteric plexus. For the first time similar ultrastructural changes were found on histological study of the colon. Manometric studies revealed a diffuse disease involving the esophagus, small bowel, and bladder. Anorectal abnormalities, never described before, were reported. Family involvement was shown by abnormal esophageal and anorectal manometries in the patient's brother and by paternal history of fatal small intestine occlusion without mechanical obstruction. The prognosis of severe forms of visceral myopathy is generally poor because of the inefficiency of drugs. In this case, after a long period of parenteral nutrition with maintenance of a good nutritional status, a terminal ileostomy (with a special procedure to avoid evagination) associated with a second stage total colectomy allowed to stop parenteral nutrition.     

Abnormal distribution of the interstitial cells of cajal in an adult patient with pseudo-obstruction and megaduodenum

Interstitial cells of Cajal (ICC) are fundamental regulators of GI motility. Here, we report the manometrical abnormalities and abnormalities of ICC distribution and ultrastructure encountered in a 30-yr-old patient with megaduodenum and pseudo-obstruction. Full thickness biopsies taken during laparoscopic placement of a jejunostomy showed vacuolated myocytes and fibrosis predominantly in the outer third of the circular muscle layer of the duodenum, suggestive for visceral myopathy. The distribution of ICC was also strikingly abnormal: by light microscopy, ICC surrounding the myenteric plexus were lacking in the megaduodenum, whereas ICC were normally present in the duodenal circular muscle and in the jejunum. By electron microscopy, very few ICC were identified around the duodenal myenteric plexus. These findings suggest that abnormalities in ICC may contribute to the disturbed motility in some myopathic forms of intestinal pseudo-obstruction.