Electrogastrography: a document prepared by the gastric section of the American Motility Society Clinical GI Motility Testing Task Force.

The objective of this document is to present the consensus opinion of the American Motility Society Clinical GI Motility Testing Task Force on the performance and clinical utility of electrogastrography (EGG). EGG is a non-invasive means of recording human gastric myoelectrical activity or slow waves from cutaneous leads placed over the stomach. In healthy volunteers, EGG tracings exhibit sinusoidal waveforms with a predominant frequency of 3 cycles per minute (cpm). Clinical studies have shown good correlation of these cutaneous recordings with those acquired from serosally implanted electrodes. The amplitude of the EGG waveform increases with ingestion of caloric or non-caloric meals. Some patients with nausea, vomiting, or other dyspeptic symptoms exhibit EGG rhythm disturbances or blunting of meal-evoked EGG signal amplitude increases. These abnormalities correlate to some degree with delayed gastric emptying of solids. In selected patients, EGG may be complementary to gastric emptying testing. To date, no therapies have convincingly demonstrated in controlled studies that correcting abnormalities detected by EGG improves upper gastrointestinal symptoms. Proposed clinical indications for performance of EGG in patients with unexplained nausea, vomiting and dyspeptic symptoms must be validated by prospective controlled investigations.

Update on acute colonic pseudo-obstruction.

Acute colonic pseudo-obstruction is characterized by distention of the colon in the absence of mechanical obstruction. This presentation is typically related to recent surgery, severe illness, or medication. Nasogastric and rectal tube decompression and correction of electrolyte abnormalities are the standard of care. Colonoscopic decompression, performed in a number of these cases, was felt to be unwarranted in many situations and is associated with a high recurrence rate. Medical management beyond conservative measures has been limited. Medical therapy with pharmacologic agents such as erythromycin, metoclopromide, and cisapride was of limited use. Recent findings confirm that an older agent, neostigmine, provides excellent results, including colonic decompression and clinical improvement after administration. This suggests a new standard of care.

Assessment of gastric emptying using a low fat meal: establishment of international control values.

OBJECTIVE: The diagnosis of gastroparesis implies delayed gastric emptying. The diagnostic gold standard is scintigraphy, but techniques and measured endpoints vary widely among institutions. In this study, a simplified scintigraphic measurement of gastric emptying was compared to conventional gastric scintigraphic techniques and normal gastric emptying values defined in healthy subjects. METHODS: In 123 volunteers (aged 19-73 yr, 60 women and 63 men) from 11 centers, scintigraphy was used to assess gastric emptying of a 99Tc-labeled low fat meal (egg substitute) and percent intragastric residual contents 60, 120, and 240 min after completion of the meal. In 42 subjects, additional measurements were taken every 10 min for 1 h. In 20 subjects, gastric emptying of a 99Tc-labeled liver meal was compared with that of the 99Tc-labeled low fat meal. RESULTS: Median values (95th percentile) for percent gastric retention at 60, 120, and 240 min were 69% (90%), 24% (60%) and 1.2% (10%) respectively. A power exponential model yielded similar emptying curves and estimated T50 when using images only taken at 1, 2 and 4 h, or with imaging taken every 10 min. Gastric emptying was initially more rapid in men but was comparable in men and women at 4 h; it was faster in older subjects (p < 0.05) but was independent of body mass index. CONCLUSIONS: This multicenter study provides gastric emptying values in healthy subjects based on data obtained using a large sample size and consistent meal and methodology. Gastric retention of >10% at 4 h is indicative of delayed emptying, a value comparable to those provided by more intensive scanning approaches. Gastric emptying of a low fat meal is initially faster in men but is comparable in women at 4 h; it is also faster in older individuals but is independent of body mass.

Gastric myoelectrical activity and gastric emptying in patients with functional dyspepsia.

OBJECTIVES: The aims of this study were to investigate gastric myoelectrical activity and gastric emptying (GE) and their relationship in patients with functional dyspepsia. METHODS: The study was conducted in 15 healthy volunteers (six women, nine men, mean age: 42 yr) and 15 patients (13 women, two men, mean age: 43 yr) with functional dyspepsia. Gastric myoelectrical activity was recorded using cutaneous electrogastrography (EGG) for 30 min in the fasting state and for 120 min simultaneously with GE monitoring after an isotope-labeled solid meal. The anterior/posterior images of the stomach were taken using a technetium scanner immediately after eating, and then at 1, 2, and 4 h to determine the percentage of gastric retention. The dominant frequency of the EGG, the change of the postprandial EGG peak power (deltaP), and the percentage of normal 2-4 cycles/min (cpm) slow waves during each recording session were calculated and compared between the patients and healthy subjects. RESULTS: The patients had a significantly lower mean percentage of 2-4 cpm slow waves, both in the fed state and in the fasting state, than did healthy subjects. Compared to the EGG in the fasting state, a significant increase of the EGG dominant frequency in the fed state was observed in healthy subjects but not in the patients. The mean postprandial EGG power increase in the patients was substantially less than in the healthy subjects during the first postprandial hour but similar during the second postprandial hour. The mean percentage of gastric retention in patients is substantially higher than in the healthy subjects, both at 2 h after eating and at 4 h after eating. Of 15 patients, nine (60%) had delayed GE (gastric retention at 2 h >50%) and 10 (66%) had abnormal EGGs (percentage of 2-4 cpm <70% and/or deltaP < 0). Eight of these 10 patients (80%) with abnormal EGGs had delayed GE. CONCLUSIONS: A high proportion of adult patients (60%) with functional dyspepsia have abnormally slow GE and abnormalities in gastric myoelectrical activity.

Myenteric neuronal antibodies in scleroderma: passive transfer evokes alterations in intestinal myoelectric activity in a rat model.

Although the mechanism for neuropathic gastrointestinal motility disturbances in scleroderma is unknown, we have previously described anti-myenteric antibodies in some patients with scleroderma. The aim of this study was to screen patients with scleroderma who had gastrointestinal symptoms for the presence of anti-myenteric neuronal antibodies and then purify the immunoglobulin G (IgG) fraction from serum samples for passive immunization into a rat model and observe for intestinal motility effects. Patients with scleroderma were screened, a serum sample from a patient with high titer anti-myenteric neuronal antibodies was obtained, and IgG was purified. Using a rat model with chronic indwelling intestinal electrodes to measure intestinal myoelectric activity, we passively transferred the IgG from either control subjects or this patient with scleroderma. We immunosuppressed the rats and intraperitoneally injected IgG from control subjects and this patient with scleroderma daily for 7 days. Recordings of myoelectric activity in control injected rats revealed no difference from baseline, but a prolongation in the activity front duration and interval and a disruption were seen after scleroderma IgG injections. IgG from a patient with scleroderma with antimyenteric neuronal antibodies, when passively immunized into a rat model, evokes intestinal myoelectric activity alterations. We hypothesize that these antibodies could account for the gastrointestinal neuropathic motility disturbances seen in scleroderma.

Myenteric plexus neurons in culture: developmental changes in neurofilament and related proteins.

Myenteric plexus neurons appear to have unique features in their expression of cytoskeletal proteins. In particular, neurofilaments have been shown to be present in a subset of neurons, and the medium molecular weight subunit of neurofilament is modified during the first week of development. We utilized cultured myenteric plexus neurons to examine if these changes could be reproduced outside of the intestinal wall. Myenteric neurons from neonate rat small intestine were cultured using a dissection and enzymatic dispersion technique previously described, and cells were fixed after one day or seven days in culture. Antibodies to the neurofilament proteins, peripherin, alpha-internexin, nestin, and microtubule-associated proteins tau and tubulin were studied. Similar to what was seen in tissues, cultured cells initially stained and then lost staining for antibodies to one area of the carboxy terminal region of neurofilament during the first week in culture. Peripherin and alpha-internexin showed good staining both initially and after 7 days in culture (differing from intact tissues). Developmental modifications in immunoreactivity to neurofilament proteins in myenteric neurons occur both in culture and in intact tissues. However, the intermediate filament proteins peripherin and alpha-internexin immunolocalized in cultured neuron cells differently than in intact tissues. Thus, factors other than the intact intestinal wall appear to be responsible for these unique cytoskeletal characteristics in myenteric plexus neurons.

Prospective study of esophageal botulinum toxin injection in high-risk achalasia patients.

OBJECTIVES: Intrasphincteric injection of botulinum toxin has been reported as a safer treatment alternative to balloon dilation or myotomy in achalasia. We studied botulinum toxin injection in achalasia patients who are at high surgical risk because of age or concomitant medical problems. METHODS: Consecutive patients who were elderly (age > 60 yr) or who had significant medical problems or both were enrolled after confirming achalasia by history, manometry, and esophageal scintigraphy. Patients underwent esophagogastroduodenoscopy, and 20 units of botulinum toxin were injected into each of four quadrants of the lower esophageal sphincter. Patients were interviewed at 1, 3, 5, and 6 months, and esophageal scintigraphy was repeated at 1 month. RESULTS: Sixteen patients with increased surgical risks were studied: many had serious coronary heart disease, diabetes, or obstructive lung disease. At 1 month, 12 of 16 patients had a clinical response but 5 developed recurrent symptoms within 6 months. One developed reflux, and two were found to have esophageal wall inflammation, loss of tissue planes, and mediastinal adhesions at subsequent myotomy. CONCLUSIONS: Intrasphincteric botulinum toxin injection may be appropriate in those achalasia patients who are elderly or have concomitant medical problems but concern persists regarding the length of the response and untoward side effects.

Neurofilament and intermediate filament immunoreactivity in human intestinal myenteric neurons.

It has been reported previously that rat myenteric neurons have neurofilament (NF) immunoreactivity that differs from the brain. Now the result of a study of neurofilaments and intermediate filament immunoreactivity in human colon and ileum using a panel of antibodies and indirect immunofluorescence techniques is reported here. Results with polyclonal neurofilament antisera showed positive immunoreactivity in subsets of myenteric neurons. Results with peripherin and alpha-internexin showed immunoreactivity in some neurons that contained neurofilaments and in many that were neurofilament negative, similar to our observations in rat. Some monoclonal antibodies to epitopes on NF-M and NF-H demonstrated weak or negative immunoreactivity in human myenteric neurons yet showed positive immunoreactivity in brain. Some of these antibodies are phosphorylation dependent, suggesting NF-M and NF-H epitopes in myenteric neurons are not as phosphorylated as in brain; other antibodies are phosphorylation independent, suggesting other differences or masking of epitopes. In summary, neurofilaments are present in a subset of myenteric neurons. In those human myenteric neurons that contain them, the neurofilaments appear immunologically distinct from those in the brain.

Colchicine is an effective treatment for patients with chronic constipation: an open-label trial.

Chronic constipation is a common clinical condition that frequently does not respond to routine therapeutic measures. We hypothesized that colchicine would be effective in this condition because we reported that it stimulates intestinal motility in rats and commonly causes diarrhea in patients taking the drug for either gouty arthritis or Familial Mediterranean fever. We prospectively studied seven patients with chronic constipation who were refractory to medical therapy and treated them with oral colchicine 0.6 mg per os three times a day for eight weeks in an open-label pilot study. During the study, the mean number of spontaneous bowel movements significantly increased (P < 0.05) from 1.7 +/- 0.5 noted during routine therapy of constipation with laxatives and enemas to 6.4 +/- 0.7 per week; mean colonic transit time significantly (P < 0.05) decreased from 58.1 +/- 2.5 to 47.1 +/- 5.0 hr; and symptoms of abdominal pain, nausea, and bloating significantly (P < 0.05) improved during therapy with colchicine. Oral colchicine (0.6 mg three times a day) therapy appears to be an a promising treatment for chronic constipation and a placebo-controlled trial is indicated to confirm these findings.

Regulation of superoxide dismutase in primary cultures of rat colonic smooth muscle cells.

We have observed a rapid induction of manganese superoxide dismutase (MnSOD) in epithelial, neuronal, and smooth muscle cells (SMC) after acetic acid-induced colitis. To examine the regulation of MnSOD in the SMC more specifically, primary cultures of colonic SMC were developed by enzymatic digestion of the circular muscle layer from an adult rat. SMC were treated for 2-72 h with 0.5 microgram/ml Escherichia coli endotoxin [lipopolysaccharide (LPS)], 10 ng/ml tumor necrosis factor (TNF)-alpha, or 2 ng/ml interleukin-1 beta (IL-1 beta). Cotreatments were performed with IL-1 beta and 4 microM actinomycin or 50 microM cycloheximide. Northern analysis demonstrated 23-fold, 8-fold, and 6-fold inductions of MnSOD mRNA by IL-1 beta, LPS, and TNF-alpha, respectively. Induction of MnSOD by IL-1 beta was eliminated by actinomycin but not by cycloheximide, implicating a requirement for de novo transcription. Western analysis resulted in a 23.7-fold induction of MnSOD protein after 48-h treatment with IL-1 beta. Induction of MnSOD by IL-1 beta and other inflammatory mediators may serve as a protective mechanism to reduce oxygen free radical- and nitric oxide-mediated cell damage during inflammation.

Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study.

Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies. We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining. Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.

Colitis and interleukin 1beta up-regulate inducible nitric oxide synthase and superoxide dismutase in rat myenteric neurons.

BACKGROUND & AIMS: Manganese superoxide dismutase (MnSOD) is rapidly induced in myenteric plexus neurons (MPNs) in acute colitis and may protect cells from nitric oxide toxicity. Inducible nitric oxide synthase (iNOS) regulation was examined in acute colitis, and MnSOD and iNOS were examined in primary cultures of MPNs. METHODS: Acute colitis in rats was induced with 5% acetic acid. iNOS messenger RNA (mRNA) was analyzed by Northern analysis, and reduced nicotinamide adenine dinucleotide phosphate diaphorase was used to identify potential NO synthase activity. MnSOD and iNOS mRNA levels were evaluated in cultured MPNs after treatment with tumor necrosis factor alpha, interleukin (IL) 1beta, or IL-6. iNOS and MnSOD protein expression in control and IL-1beta-treated neurons was evaluated by immunofluorescence microscopy. RESULTS: iNOS mRNA was detected in the mucosal and muscularis layers after the initiation of colitis. Reduced nicotinamide adenine dinucleotide phosphate diaphorase localized NO synthase activity to MPNs in controls and in epithelial cells and MPNs in the inflamed colon. In MPN cultures, tumor necrosis factor alpha and IL-1beta treatment resulted in induction of MnSOD, but only IL-1beta induced iNOS. Immunolocalization confirmed that the neurons were the primary source of iNOS and MnSOD. CONCLUSIONS: Induction of MnSOD and iNOS are coordinated and may limit NO cytotoxicity. The function of iNOS in gut neurons remains to be delineated.

Presence of gonadotropin-releasing hormone (GnRH) receptor mRNA in rat myenteric plexus cells.

Idiopathic neuromuscular disease of the gastrointestinal tract (functional bowel disease) is thought to result from the malfunction of neurons within the enteric nervous system. Gonadotropin-releasing hormone (GnRH) analogs have recently been shown to organize the disordered motility patterns typical in these patients and to produce significant, long-term symptomatic improvement. To determine whether GnRH analogs might bind to an endogenous enteric nervous system GnRH receptor, reverse transcription-polymerase chain reaction (RT-PCR) was performed using cultured neonatal rat enteric neuron RNA and rat GnRH receptor primers. A PCR product of the predicted size was cloned and nucleotide sequence analysis demonstrated that the myenteric plexus PCR product encoded a portion of the GnRH receptor sequence previously identified in rat pituitary. These results suggest that cells in the myenteric plexus express GnRH receptors that may bind exogenously administered GnRH analogs. The expression of GnRH receptors in enteric neurons would provide an explanation for the effectiveness of GnRH analogs in treatment of idiopathic neuromuscular disease of the gastrointestinal tract.

Differential increase in neuropeptide Y-like levels and myenteric neuronal staining in diabetic rat intestine.

Neuropeptide Y is a regulatory peptide found in adrenergic and non-adrenergic neurons. Diabetes, which may cause autonomic neuropathy, induces an increase in hypothalamic neuropeptide Y (NPY) levels; thereby we measured the effects of chronic diabetes on neuropeptide Y in the intestine. Rats were injected with streptozotocin (65 mg/kg) and maintained for up to 20 weeks. Another group of rats was injected with 6-hydroxydopamine (50 mg/kg) x 2 to induce sympathectomy. Ileum and colon were harvested and both whole and microdissected intestine were (1) stained with antibodies to neuropeptide Y, vasoactive intestine polypeptide, and neurofilaments or (2) extracted for neuropeptide Y radioimmunoassay. Neuropeptide Y levels were similar under all conditions in the colon, but there was a trend toward an increase in the diabetic whole ileum. NPY levels were significantly increased in the dissected myenteric plexus ileal layer in diabetics. We noted an increase in the number of neuropeptide Y and vasoactive intestine polypeptide immunoreactive myenteric neurons in diabetics and after 6-hydroxydopamine-induced sympathectomy. Diabetes, and to a lesser extent sympathectomy, induced an increase in ileal neuropeptide Y levels and neuropeptide Y-staining myenteric but not submucosal neurons. Altered tissue levels of neuropeptide Y may account for certain of the gastrointestinal disturbances commonly seen in diabetes.

Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction.

Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20-33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2 +/- 0.3 AFs/4 hr, 2.7 +/- 0.7 min, and 85 +/- 23 min mm Hg to 4.1 +/- 0.8 AFs/4 hr, 5.5 +/- 0.7 min, and 152 +/- 24 min mm Hg, respectively (P < 0.05). Antral activity was decreased from 63 +/- 14 to 23 +/- 8% by octreotide (P < 0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy.

We studied the effect of erythromycin on gastric emptying in nine patients with gastroparesis following truncal vagotomy and antrectomy, and assessed their clinical response to chronic oral erythromycin. Gastric emptying was evaluated using a solid-phase radio-labeled meal. Patients were studied after erythromycin 200 mg intravenously (N = 9) and after an oral suspension of erythromycin 200 mg (N = 7) each given 15 min after ingestion of the meal. Three parameters of gastric emptying were analyzed: half-emptying time (T1/2), area under the curve, and percent gastric residual at 2 hr. Nine patients were subsequently placed on oral suspension erythromycin 150 mg three times a day before meals (range 125-250 mg three times a day) and symptoms of nausea, vomiting, postprandial fullness, and abdominal pain were assessed before and after erythromycin. Intravenous erythromycin markedly accelerated the gastric emptying (all three parameters studied) of solids (P < 0.01) in seven of nine patients with postsurgical gastroparesis [baseline T1/2 154 +/- 15 min; after intravenous erythromycin, T1/2 56 +/- 17 min (mean +/- SEM)]. Oral erythromycin enhanced (P < 0.05) the gastric emptying rate (T1/2, area under the curve) in five of seven patients (baseline T1/2 146 +/- 16 min; after oral erythromycin, T1/2 87 +/- 20 min). Of the nine patients who were placed on oral maintenance erythromycin, three showed clinical improvement after two weeks. In summary, erythromycin significantly enhances gastric emptying in many patients with vagotomy and antrectomy-induced gastroparesis; however, only a small subset of patients respond clinically to chronic oral erythromycin.