Effectiveness of gastric electrical stimulation in gastroparesis: Results from a large prospectively collected database of national gastroparesis registries.

BACKGROUND: Gastric electrical stimulation (GES) for treating gastroparesis symptoms is controversial. METHODS: We studied 319 idiopathic or diabetic gastroparesis symptom patients from the Gastroparesis Clinical Research Consortium (GpCRC) observational studies: 238 without GES and 81 with GES. We assessed the effects of GES using change in GCSI total score and nausea/vomiting subscales between baseline and 48 weeks. We used propensity score methods to control for imbalances in patient characteristics between comparison groups. KEY RESULTS: GES patients were clinically worse (40% severe vs. 18% for non-GES; P < .001); worse PAGI-QOL (2.2. vs. 2.6; P = .003); and worse GCSI total scores (3.5 vs. 2.8; P < .001). We observed improvements in 48-week GCSI total scores for GES vs. non-GES: improvement by ≥ 1-point (RR = 1.63; 95% CI = (1.14, 2.33); P = .01) and change from enrollment (difference = -0.5 (-0.8, -0.3); P < .001). When adjusting for patient characteristics, symptom scores were smaller and not statistically significant: improvement by ≥ 1-point (RR = 1.29 (0.88, 1.90); P = .20) and change from the enrollment (difference = -0.3 (-0.6, 0.0); P = .07). Of the individual items, the nausea improved by ≥ 1 point (RR = 1.31 (1.03, 1.67); P = .04). Patients with GCSI score ≥ 3.0 tended to improve more than those with score < 3.0. (Adjusted P = 0.02). CONCLUSIONS AND INFERENCES: This multicenter study of gastroparesis patients found significant improvements in gastroparesis symptoms among GES patients. Accounting for imbalances in patient characteristics, only nausea remained significant. Patients with greater symptoms at baseline improved more after GES. A much larger sample of patients is needed to fully evaluate symptomatic responses and to identify patients likely to respond to GES.

Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia.

Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body's stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.

NaV1.1 inhibition can reduce visceral hypersensitivity.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis.

BACKGROUND & AIMS: Gastroparesis can lead to food aversion, poor oral intake, and subsequent malnutrition. We characterized dietary intake and nutritional deficiencies in patients with diabetic and idiopathic gastroparesis. METHODS: Patients with gastroparesis on oral intake (N = 305) were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry and completed diet questionnaires at 7 centers. Medical history, gastroparesis symptoms, answers to the Block Food Frequency Questionnaire, and gastric emptying scintigraphy results were analyzed. RESULTS: Caloric intake averaged 1168 ± 801 kcal/day, amounting to 58% ± 39% of daily total energy requirements (TER). A total of 194 patients (64%) reported caloric-deficient diets, defined as <60% of estimated TER. Only 5 patients (2%) followed a diet suggested for patients with gastroparesis. Deficiencies were present in several vitamins and minerals; patients with idiopathic disorders were more likely to have diets with estimated deficiencies in vitamins A, B(6), C, K, iron, potassium, and zinc than diabetic patients. Only one-third of patients were taking multivitamin supplements. More severe symptoms (bloating and constipation) were characteristic of patients who reported an energy-deficient diet. Overall, 32% of patients had nutritional consultation after the onset of gastroparesis; consultation was more likely among patients with longer duration of symptoms and more hospitalizations and patients with diabetes. Multivariable logistic regression analysis indicated that nutritional consultation increased the chances that daily TER were met (odds ratio, 1.51; P = .08). CONCLUSIONS: Many patients with gastroparesis have diets deficient in calories, vitamins, and minerals. Nutritional consultation is obtained infrequently but is suggested for dietary therapy and to address nutritional deficiencies.

Transient gastric irritation in the neonatal rats leads to changes in hypothalamic CRF expression, depression- and anxiety-like behavior as adults.

AIMS: A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them. METHODS: Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured. RESULTS: Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated rats CONCLUSIONS: The present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders.

Gastroparesis and gastroparesis-like syndrome: response to therapy and its predictors.

PURPOSE: The natural history and outcome of patients with gastroparesis is not well known. The aim of this study was to identify the clinical or pathophysiological characteristics, if any, that may be helpful in predicting therapeutic response in this condition. METHODS: This is a retrospective study of a cohort of patients who presented to a tertiary referral center with symptoms suggestive of gastroparesis. All patients were evaluated by scintigraphic measurement of gastric emptying and symptoms were scored using a modification of the Gastroparesis Cardinal Symptom Index (GCSI). Treatment generally included conservative measures such as antiemetics, prokinetics, tricyclic antidepressants, and analgesics as well as various more invasive interventions in selected patients. Response to treatment was defined as a change in the overall GCSI score of two-thirds or more as compared with baseline. RESULTS: Out of a total of 93 patients, 69 patients met the eligibility criteria. Of these, 29 patients had diabetes mellitus and 40 patients had gastroparesis of nondiabetic etiology. Out of 69 patients, 49 were responders (71%) and 20 were nonresponders (29%). The cause (diabetic versus nondiabetic) of gastroparesis or the presence of delayed emptying did not correlate with response. However, the severity of stomach distension, bloating subscale score, and the global GCSI score at baseline presentation were predictive of response by multivariate analysis. CONCLUSION: Higher global GCSI score, bloating subscale score, and severity of stomach distension at baseline presentation correlated with an unfavorable response in gastroparetic patients. On the other hand, neither the etiology of gastroparesis nor associated delay in gastric emptying appeared to be important in the clinical response. Patients with symptoms of typical gastroparesis but without delays in gastric emptying may have a distinct syndrome with a greater proportion of males than classical gastroparesis.

Feasibility of gastric electrical stimulation by use of endoscopically placed electrodes.

BACKGROUND: Gastric electrical stimulation (GES), which has been reported to have therapeutic potentials for gastroparesis and obesity, involves the surgical placement of electrodes with the patient under general anesthesia. New methods are needed for implanting GES electrodes in a safer and more feasible way. OBJECTIVE: Our purpose was to investigate the safety and feasibility of placing electrodes endoscopically for GES. DESIGN AND SETTING: A pilot study. SUBJECTS: Six female hound dogs that weighed 13 to 22 kg. INTERVENTIONS: Endoscopically placed electrodes passed through the abdomen and the stomach wall. MAIN OUTCOME MEASUREMENTS: The study was performed in dogs surgically implanted with gastric serosal electrodes and endoscopically implanted electrodes. The experiment consisted of a 30-minute baseline, a 30-minute GES, and a 30-minute recovery. GES was performed through endoscopically placed electrodes. Gastric slow waves were simultaneously recorded with the serosal electrodes and the endoscopically placed electrodes. RESULTS: (1) The slow wave frequency recorded from the endoscopically placed electrodes was significantly correlated with that from the serosal electrodes (r = 0.97, P < .002). (2) GES through the endoscopically placed electrodes was able to entrain gastric slow waves. (3) No gastric leakage into the abdominal cavity was noted and the dogs were healthy and comfortable. (4) The endoscopically placed electrodes remained for 2 to 3 weeks. LIMITATIONS: The fixation of the electrodes needs to be improved for longer-term uses. CONCLUSIONS: GES may be accomplished without surgery by inserting the electrode wire through the abdomen under endoscopy. The study results indicate that the endoscopically placed electrodes are effective for GES and do not result in any adverse events.

An unusual electrocardiogram artifact: what is its source?

A diabetic female presented with nausea and vomiting. Her electrocardiogram showed sinus rhythm with two artifactual spikes, not synchronized with the cardiac rhythm. The patient had an implanted gastric electrical stimulation system for treating her diabetic gastroparesis. Recent DC shock for ventricular fibrillation during coronary angiography caused malfunction of the gastric pacemaker.

Improvement of gastric motility with gastric electrical stimulation in STZ-induced diabetic rats.

AIMS: The aims of this study were to observe whether gastric motility was impaired in streptozotocin (STZ)-induced diabetic rats and whether gastric electrical stimulation was able to restore the impaired motility. METHODS: Ten control rats and 30 STZ-induced diabetic rats were used in this study. Gastric slow waves were recorded at baseline and 0, 1, 2, 3 and 4 weeks after the injection of STZ or vehicle. Gastric emptying with (long or short pulses) or without gastric electrical stimulation was measured 6 weeks after STZ injection in a group of 10 diabetic rats each. RESULTS: (1) STZ injection resulted in hyperglycemia and weight loss. (2) Gastric motility was impaired in the diabetic rats. The percentage of normal slow waves was progressively reduced 2 weeks after STZ injection. Compared with the control rats, gastric emptying in the diabetic rats was significantly delayed 6 weeks after STZ injection (60 +/- 3 vs. 79 +/- 2%, p < 0.02). (3) Gastric electrical stimulation with either long or short pulses accelerated gastric emptying in the diabetic rats. (4) Gastric electrical stimulation with long but not short pulses was capable of normalizing gastric dysrhythmia in the diabetic rats. CONCLUSION: Our data show that gastric motility is impaired in STZ-induced diabetic rats as reflected by a progressive reduction in the percentage of normal gastric slow waves and delayed gastric emptying. Moreover, here we show that gastric electrical stimulation normalizes delayed gastric emptying in diabetic rats and this normalization is not attributed to the effect of gastric electrical stimulation on gastric slow waves.

Novel surgical approaches to fecal incontinence: neurostimulation and artificial anal sphincter.

Neurostimulation, neosphincters with neurostimulation, and implanted artificial sphincters are recently developed therapeutic options for patients with end-stage fecal incontinence. Of these approaches, sacral nerve electric stimulation appears to be the most promising because of its relative simplicity and low morbidity. However, it is best suited for patients with anatomically intact sphincters. The other procedures target patients with gross structural defects in the sphincter but are still in their infancy. In this article we discuss these techniques and review their rationale, mechanisms of action, indications, outcomes, and complications.

Electroacupuncture accelerates gastric emptying in association with changes in vagal activity.

Gastroparesis is a disorder with a lack of treatment options and this study investigated the effect of electroacupuncture on gastric emptying and involved mechanisms. Dogs implanted with a duodenal cannula and serosal electrodes were fed with Ensure mixed with phenol red, and the gastric effluent was collected. Electroacupuncture was performed from 30 min before until 45 min after the meal. Gastric myoelectrical activity and electrocardiogram were recorded. Gastric emptying was significantly improved with electroacupuncture. Vagal activity assessed from the spectral analysis of heart rate variability was markedly increased with electroacupuncture. Electroacupuncture increased the regularity of gastric slow waves in both the proximal and distal stomach. It also increased the number of spike bursts in the distal but not proximal stomach. Electroacupuncture accelerates gastric emptying of liquid in dogs and its potential for treating gastroparesis may be explored. The effect may be attributed to improvement in gastric slow-wave rhythmicity and antral contractile (spike) activity and may possibly involve the vagal pathway.