Methods of gastric electrical stimulation and pacing: a review of their benefits and mechanisms of action in gastroparesis and obesity

Abstract  Development of gastric electrical stimulation techniques for treatment of gastric dysmotility syndromes and obesity has been a long-standing goal of investigators and clinicians. Depending on stimulus parameters and sites of stimulation, such methods have a range of theoretical benefits including entrainment of intrinsic gastric electrical activity, eliciting propagating contractions and reducing symptomatology in patients with gastroparesis and reducing appetite and food intake in individuals with morbid obesity. Additionally, gastric stimulation parameters have extragastrointestinal effects including alteration of systemic hormonal and autonomic neural activity and modulation of afferent nerve pathways projecting to the central nervous system that may represent important mechanisms of action. Numerous case series and smaller numbers of controlled trials suggest clinical benefits in these two conditions, however better controlled trials are mandated to confirm their efficacy. Current research is focusing on novel stimulation methods to better control symptoms in gastroparesis and promote weight reduction in morbid obesity.     

Variable abnormal physiological motility in the proximal upper gastrointestinal tract in gastroparesis

Background Traditional testing for gastroparesis with gastric emptying scintigraphy (GES) likely misses a subset of patients because of the heterogeneous nature of the disease. The primary aim of this study is to determine the prevalence of simultaneously measured transit and pressure abnormalities in patients with gastroparesis. The secondary aim is to assess diagnostic gain realized by measuring antroduodenal pressure and gastric transit with wireless motility capsule (WMC) compared to gastric transit measured by GES. Identification of abnormalities beyond gastric transit delay in gastroparesis may yield novel targets for pharmacological therapies. Methods Forty‐three subjects with symptoms of gastroparesis and previous abnormal GES within 2 years were enrolled in the study. Subjects underwent simultaneous GES and WMC to assess gastric transit. Gastric and small bowel pressure profiles were measured by WMC to determine the contribution of pressure to diagnostic gain realized with WMC. Key Results Fifty‐one percent of subjects had abnormal GES while 70% of subjects had either abnormal gastric emptying time (GET) or antroduodenal pressure. Gastric emptying time was abnormal in 60% of subjects while gastric or small bowel pressure was abnormal in 47% of subjects. The overall diagnostic gain of WMC compared to GES was 19% (P = 0.04). Seven percent of subjects had abnormal small bowel pressure profiles when both GES and GET were normal. Conclusions & Inferences (i) Gastroparesis is a heterogeneous disorder and testing only solid food emptying by scintigraphy may miss a significant amount of pathology. (ii) Measuring complementary aspects of gastric and small bowel function simultaneously results in greater detection of physiologic abnormalities that may underlie patient symptoms.     

Two‐channel gastric pacing in patients with diabetic gastroparesis

Background Our primary goals were to investigate the effects of two‐channel gastric pacing on gastric myoelectrical activity, and energy consumption with the secondary intent to monitor gastric emptying and symptoms in patients with severe diabetic gastroparesis. Methods Four pairs of temporary pacing wires were inserted on the serosa of the stomach at the time of laparotomy to place the Enterra? System in 19 patients with severe gastroparesis not responding to standard medical therapies. Two of the pairs were for electrical stimulation and the other two for recording. Five days after surgery the optimal pacing parameters for the entrainment of gastric slow waves in each patient were identified by serosal recordings. Two‐channel gastric pacing was then initiated for 6 weeks using a newly developed external multi‐channel pulse generator. Electrogastrogram (EGG), Total Symptom Score (TSS), and a 4‐h gastric emptying test were assessed at baseline and after 6 weeks of active gastric pacing. Enterra? device was turned OFF during the duration of this study. Key Results Two‐channel gastric pacing at 1.1 times the intrinsic frequency entrained gastric slow waves and normalized gastric dysrhythmia. After 6 weeks of gastric pacing, tachygastria was decreased from 15 ± 3 to 5 ± 1% in the fasting state and from 10 ± 2 to 5 ± 1% postprandially (P < 0.05), mean TSS was reduced from 21.3 ± 1.1 to 7.0 ± 1.5 (P < 0.05) and mean 4‐h gastric retention improved from 42 to 28% (P = 0.05). Conclusions & Inferences Two‐channel gastric pacing is a novel treatment approach which is able to normalize and enhance gastric slow wave activity as well as accelerate gastric emptying in patients with diabetic gastroparesis with a goal safety profile.     

Measurement of gastric emptying of a high‐nutrient liquid by 3D ultrasonography in diabetic gastroparesis

Background Gastric emptying (GE) is delayed in 30–50% of patients with longstanding diabetes. Scintigraphy represents the ‘gold standard’ for measurement of GE, but is associated with a radiation burden. Three‐dimensional (3D) ultrasonography has recently been demonstrated to provide a valid measure of liquid GE in healthy subjects; however, the technique has not been validated in patients with gastroparesis. The primary aim of this study was to compare measurements of GE of a high‐nutrient glucose drink by 3D ultrasonography and scintigraphy in diabetic gastroparesis. Methods Ten patients (eight type 1, two type 2, 6M, 4F, aged 46.1 ± 4.5 years, BMI 29.1 ± 1.6 kg m^?2, duration 19.6 ± 3.3 years) with diabetic gastroparesis [defined as retention at 100 min of solid (100 g minced beef) ≥61% and/or 50% emptying time (T50) of liquid (150 mL 10% dextrose) ≥31 min], were studied. Concurrent measurements of GE by scintigraphy and 3D ultrasonography were performed following ingestion of 75 g glucose in 300 mL water labeled with 20 MBq ^99mTc‐sulfur colloid. Key Results There was no significant difference in GE between the two techniques (T50s: scintigraphy – 103.3 ± 10.0 min VS 3D ultrasonography – 98.8 ± 10.4 min; P = 0.60). There was a significant correlation between scintigraphic and ultrasonographic T50s (r = 0.67, P = 0.03). The limits of agreement for the T50s were ?57.22 min and +48.22 min (mean difference ?4.5 min). Blood glucose after the drink was greater when GE was relatively more rapid (e.g. at t = 60 min; scintigraphy: r = ?0.65, P = 0.04; 3D ultrasonography: r = ?0.78, P = 0.008). Conclusions & Inferences Three‐dimensional ultrasonography appears to provide a valid, and non‐invasive, measure of GE of high‐nutrient liquids in diabetic gastroparesis.     

Symptom responses, long-term outcomes and adverse events beyond 3 years of high-frequency gastric electrical stimulation for gastroparesis

The aims were to determine symptom responses and long-term outcomes in gastroparetic patients receiving gastric electrical stimulation (GES) therapy beyond 3 years by presenting per protocol analysis and intention-to-treat (ITT) analysis. Data collected at baseline, 1 year and beyond 3 years in 55 patients included total symptom scores (TSS), nutritional status, weight, hospitalizations, the use of prokinetic and/or antiemetic medications, HbA1c in diabetics and adverse events. Of the 55 patients, 10 died of non-pacemaker-related complications, six had the devices removed and two could not be reached. The remaining 37 patients had the device activated for a mean of 45 months. Both per protocol and ITT analysis demonstrated that TSS, hospitalization days and the use of medications were all significantly reduced at 1 year and were sustained beyond 3 years. Average TSS decreased by 62.5% for the 37 patients completing 3 years of GES. At implantation, 15/37 patients required nutritional support and only five continued beyond 3 years. Mean HbA1c level in diabetics was significantly reduced from 9.5 to 7.9% at 3 years. We conclude that a significant improvement in symptoms and all measures of clinical outcome can be maintained for greater than 3 years with GES in patients with refractory gastroparesis.     

Assessment of symptoms during gastric emptying scintigraphy to correlate symptoms to delayed gastric emptying

Background Symptoms of gastroparesis based on patient recall correlate poorly with gastric emptying. The aim of this study is to determine if symptoms recorded during gastric emptying scintigraphy (GES) correlate with gastric emptying and with symptoms based on patient recall. Methods Patients undergoing GES completed the Patient Assessment of GI Symptoms (PAGI‐SYM) assessing symptoms over the prior 2 weeks and a questionnaire for which patients graded six symptoms during GES. A Symptom Severity Index (SSI) represented the mean of six symptoms at each time point. Key Results A total of 560 patients underwent GES for clinical evaluation of symptoms. Of 388 patients included in the study: 232 patients had normal GES (NGES), 156 delayed GES (DGES), and 11 rapid GES (RGES). Symptom severity index increased pre to postprandial for each group: NGES: 0.51 ± 0.07 to 0.92 ± 0.03, DGES: 0.60 ± 0.09 to 1.13 ± 0.05, and RGES: 0.56 ± 0.12 to 0.79 ± 0.13. Delayed gastric emptying scintigraphy patients had a higher postprandial SSI than NGES patients (1.13 ± 0.05 vs 0.92 ± 0.03, P < 0.05). Postprandial symptoms of stomach fullness (1.9 ± 0.12 vs 1.5 ± 0.09; P = 0.011), bloating (1.4 ± 0.11 vs 1.1 ± 0.09; P = 0.033), and abdominal pain (1.1 ± 0.08 vs 0.7 ± 0.12; P = 0.012) were higher in DGES than NGES. Symptom severity based on PAGI‐SYM for 2 weeks prior to GES correlated with symptoms during the test for nausea (NGES, r = 0.61; DGES, r = 0.70), stomach fullness (NGES, r = 0.47; DGES, r = 0.60), and bloating (NGES, r = 0.62, DGES, r = 0.66). Conclusions & Inferences Stomach fullness, bloating, and abdominal pain recorded during GES were higher in patients with delayed gastric emptying than in patients with normal gastric emptying. Symptoms recorded during GES correlated with those during daily life by patient recall.     

Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium

Background Cellular changes associated with diabetic (DG) and idiopathic gastroparesis (IG) have recently been described from patients enrolled in the Gastroparesis Clinical Research Consortium. The association of these cellular changes with gastroparesis symptoms and gastric emptying is unknown. The aim of this study was to relate cellular changes to symptoms and gastric emptying in patients with gastroparesis. Methods Earlier, using full thickness gastric body biopsies from 20 DG, 20 IG, and 20 matched controls, we found decreased interstitial cells of Cajal (ICC) and enteric nerves and an increase in immune cells in both DG and IG. Here, demographic, symptoms [gastroparesis cardinal symptom index score (GCSI)], and gastric emptying were related to cellular alterations using Pearson’s correlation coefficients. Key Results Interstitial cells of Cajal counts inversely correlated with 4 h gastric retention in DG but not in IG (r = ?0.6, P = 0.008, DG, r = 0.2, P = 0.4, IG). There was also a significant correlation between loss of ICC and enteric nerves in DG but not in IG (r = 0.5, P = 0.03 for DG, r = 0.3, P = 0.16, IG). Idiopathic gastroparesis with a myenteric immune infiltrate scored higher on the average GCSI (3.6 ± 0.7 vs 2.7 ± 0.9, P = 0.05) and nausea score (3.8 ± 0.9 vs 2.6 ± 1.0, P = 0.02) as compared to those without an infiltrate. Conclusions & Inferences In DG, loss of ICC is associated with delayed gastric emptying. Interstitial cells of Cajal or enteric nerve loss did not correlate with symptom severity. Overall clinical severity and nausea in IG is associated with a myenteric immune infiltrate. Thus, full thickness gastric biopsies can help define specific cellular abnormalities in gastroparesis, some of which are associated with physiological and clinical characteristics of gastroparesis.     

Gastric electrical stimulation versus per-oral pyloromyotomy for the treatment of nausea and vomiting associated with gastroparesis: An observational study of two cohorts

Background

Both gastric electrical stimulation (GES) and gastric-peroral endoscopic myotomy (G-POEM) can be offered to patients with gastroparesis and predominant nausea and vomiting. The study's aim was to compare GES and G-POEM efficacy on nausea and vomiting scores in patients with gastroparesis.

Methods

Two multicenter cohorts of patients with medically refractory gastroparesis with predominant nausea and vomiting (defined as a score >2 on nausea and vomiting subscale that varied from 0 to 4) were treated either with GES (n = 34) or G-POEM (n = 30) and were followed for 24 months (M). Clinical response was defined as a decrease of ≥1 point in nausea and vomiting subscale without premature exclusion due to switch from one to the other technique before M24. Changes in symptomatic scales and quality of life were also monitored.

Key Results

Patients from both groups were comparable although the mean score of nausea and vomiting subscale was higher in GES (3.0) compared to G-POEM group (2.6; p = 0.01). At M24, clinical response was achieved in 21/34 (61.7%) patients with GES and in 21/30 (70.0%; p = 0.60) patients with G-POEM. Mean scores of nausea and vomiting subscale decreased at M24 in both GES (from 3.0 to 1.6; p < 0.001) and G-POEM (from 2.6 to 1.2; p < 0.001) groups, although there was no difference between groups (difference adjusted from baseline: −0.28 [−0.77; 0.19]; p = 0.24). Likewise, symptomatic and quality of life scores improved at M24 in both groups, without difference according to treatment group.

Conclusions and Inferences

At M24, we did not observe significant difference in efficacy of GES and G-POEM in medically refractory gastroparesis with predominant nausea and vomiting.