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Factors underlying gastroparesis are not well defined. We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .

INTRODUCTION Gastric electrical stimulation (GES) has been recommended for drug refractory patients with gastroparesis, but no clear baseline predictors of symptom response exist. We hypothesized that long-term predictors to GES for foregut and hindgut symptoms exist, particularly when using augmented energies. PATIENTS We evaluated 307 patients at baseline, 1 week post temporary GES, and one year after permanent GES. Baseline measures included upper and lower symptoms by patient-reported outcomes (PRO), solid and liquid gastric emptying (GET), cutaneous, mucosal, and serosal electrophysiology (EGG, m/s EG), BMI, and response to temporary stimulation. METHODS Foregut and hindgut PRO symptoms were analyzed for 12-month patient outcomes. All patients utilized a standardized energy algorithm with the majority of patients receiving medium energy at 12 months. Patients were categorized based on change in average GI symptom scores at the time of permanent GES compared to baseline using a 10% decrease over time as the cutoff between improvers versus non-improvers. RESULTS By permanent GES implant, average foregut and hindgut GI symptom scores reduced 42% in improved patients (n = 199) and increased 27% in non-improved patients (n = 108). Low BMI, baseline infrequent urination score, mucosal EG ratio, and proximal mucosal EG low-resolution amplitude remained significant factors for improvement status. CONCLUSIONS GES, for patients responding positively, improved both upper/foregut and lower/hindgut symptoms with most patients utilizing higher than nominal energies. Low baseline BMI and the presence of infrequent urination along with baseline gastric electrophysiology may help identify those patients with the best response to GES/bio-electric neuromodulation.

Background Inflammatory bowel disease (IBD) can have autoimmunity and/or intestinal barrier dysfunction as part of pathophysiology and may be refractory to all available treatment options. Serum-derived bovine immunoglobulin (SBI) binds microbial components with postulated downstream effects of normalized gut immune and barrier function, which may be useful for managing IBD. The purpose of our study was to evaluate the effectiveness of SBI in the management of refractory IBD, particularly symptoms of chronic diarrhea and loose stools. Methods We retrospectively analyzed charts for patients diagnosed with IBD (n = 40) who were refractory to standard treatment. Patients received oral SBI 5 g daily for a period of at least 6 weeks. Twelve patients with IBD fulfilled study inclusion criteria. Each patient graded the severity and frequency of gastrointestinal symptoms before starting SBI and at 6 weeks of treatment using a standardized patient assessment form. Means and standard deviations for all symptom scores at baseline and week 6 of treatment were analyzed. Results Mean symptom scores decreased significantly for nausea (P = 0.02 for severity and P = 0.03 for mean symptom score) and diarrhea (P = 0.0006, P = 0.0001 and P = 0.0001 for severity, frequency and mean symptom score, respectively). Conclusions Therapy with SBI alleviated some refractory gastrointestinal symptoms in patients with IBD, including nausea and diarrhea. Increased duration, dosage and/or frequency of SBI might provide additional symptom improvement and could be tested through controlled clinical trials with larger sample sizes and longer follow-up.

Introduction Gastric electrical stimulation (GES) is an emerging therapy for gastric motility disorders, showing improvement of gastroparesis related symptoms in previous studies. Interstitial cells of Cajal (ICC) and mast cells have been shown to have a relevant role in gastroparesis pathogenesis. However, the exact effects of GES in those cells is relatively unknown. Methods Full thickness biopsies (FTBx) of 20 patients with refractory gastroparesis were obtained at the time of GES placement and repeated when the device was exchanged (mean of 22.5 months between biopsies). A patient-reported outcomes survey was obtained during each office visit during this period. All biopsies were stained with cluster of differentiation 117 (CD117), S100, and mast cell tryptase antibodies and were analyzed. Results Half of the patients had a significant increase of ICC during the repeated biopsy compared with baseline (p=0.01) and the other half had significant decrease in ICC levels (p=0.006) but there was no noticeable difference in mast cells counts at baseline between groups. Mast cells analysis was performed in two different groups depending on ICC change from the baseline biopsy (CD117 increase vs CD117 decrease). There was only a significant increase of mast cells count within the CD117 worsened ICC group (p=0.007). Conclusion No significant increase in the number of mast cells count seen in patients who received a GES may indicate an improvement in overall inflammation in patients with refractory gastroparesis after GES placement.

Background The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis. Methods Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models. Results Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls. Conclusions A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. ClinicalTrials.gov Identifier NCT00398801, NCT01696747

Objective Bioelectrial signals known as slow waves play a key role in coordinating gastric motility. Slow wave dysrhythmias have been associated with a number of functional motility disorders. However, there have been limited human recordings obtained in the consious state or over an extended period of time. This study aimed to evaluate a robust ambulatory recording platform. Approach A commercially available multi-sensor recording system (Shimmer3, ShimmerSensing) was applied to acquire slow wave information from the stomach of six humans and four pigs. First, acute experiments were conducted in pigs to verify the accuracy of the recording module by comparing to a standard widely employed electrophysiological mapping system (ActiveTwo, BioSemi). Then, patients with medically refractory gastroparesis undergoing temporary gastric stimulator implantation were enrolled and gastric slow waves were recorded from mucosally-implanted electrodes for 5 d continuously. Accelerometer data was also collected to exclude data segments containing excessive patient motion artefact. Main results Slow wave signals and activation times from the Shimmer3 module were closely comparable to a standard electrophysiological mapping system. Slow waves were able to be recorded continuously for 5 d in human subjects. Over the 5 d, slow wave frequency was 2.8 ± 0.6 cpm and amplitude was 0.2 ± 0.3 mV. Significance A commercial multi-sensor recording module was validated for recording electrophysiological slow waves for 5 d, including in ambulatory patients. Multiple modules could be used simultaneously in the future to track the spatio-temporal propagation of slow waves. This framework can now allow for patho-electrophysiological studies to be undertaken to allow symptom correlation with dysrhythmic slow wave events.

Malignancy-associated gastroparesis (MAG) is a cause of morbidity in cancer patients but therapies are lacking. Gastric electrical stimulation (GES) is a novel treatment for MAG. Here, we describe 19 patients with MAG who underwent temporary GES placement. Nineteen patients (6 males, 13 females) with various malignancies were reviewed for symptom scores and physiologic measures at baseline and after temporary GES placement. Symptoms were scored by three variables: nausea (N), vomiting (V), and GI total symptom score (TSS). Physiologic profiles were measured by solid and liquid phase gastric emptying scans (GET) at 1, 2, and 4 h and cutaneous electrogastrogram (EGG) and mucosal electrogram (EG) frequencies. Symptoms were measured for 5 days after temporary endoscopic GES placement, and measures were repeated post GES placement. Baseline GET results displayed delayed gastric emptying in 16 of 19 patients (mean solid retention 21.7 % at 4 h, normal

We compared outcomes for two gastric electrical stimulation placement strategies, mini-laparotomy with adjunctive care (MLAC) versus laparoscopy without adjunctive care (LAPA). For electrode placement, the peritoneal cavity was accessed with either a single 2.5 to 3.0 cm midline incision (MLAC) or three trocar incisions (LAPA). For both groups, generator was placed subcutaneously over the anterior rectus sheath. For MLAC, adjunctive pain control measures were used for placement of both electrode and generator (transversus abdominus plane block). For LAPA, those that could not be completed by laparoscopy were converted to traditional open approach and kept in the analysis. MLAC (n = 128) resulted in shorter operative times than LAPA (n = 37) (median operative time: 87.5 vs 137.0 minutes, P ≤ 0.01). Hospital length of stay was also shorter for MLAC than for LAPA (median: 2.0 vs 3.0 days, P ≤ 0.01) without any increase in readmission rates to the hospital within 30 days of discharge (11.0 vs 16.2%, P = 0.39). After equalizing learning curves, these differences were even greater (median operative time: 84.5 vs 137.0 minutes, P < 0.01; median length of stay: 1.0 vs 3.0 days; P < 0.01) without increasing 30-day read-mission rates (9.1 vs 16.2%, P = 0.25). For implantation of gastric electrical stimulators, mini-laparotomy can result in improved outcomes when coupled with adjunctive pain control measures.

Affiliation of authors Lindsay McElmurray, Dr. Michael Hughes, Dr. Hani Rashed, Dr. William Kennedy, Dr. Gwen Wendelschafer-Crabb, Dr. Xiu Yang, Dr. Mostafa Fraig and Christina Pinkston are updated through this erratum.

Background/aims Patients with gastroparesis often have biliary/pancreatic and small bowel symptoms but the effects of gastric electrical stimulation on small bowel electrical activity of the mid-gut have not been studied. Animal model aim: Establish gastric and upper small bowel/biliary slow wave activity relationships with electrical stimulation. Human study aim: Demonstrate improvement in symptoms associated with proximal small bowel dysmotility in gastric stimulated patients. Materials and methods Animal model: In vivo evoked responses of duodenal and Sphincter of Oddi measures recorded during gastric electrical stimulation in a nonsurvival swine model (N = 3). High-resolution electrical slow wave mapping of frequency, amplitude, and their ratio, for duodenal and Sphincter of Oddi electrical activity were recorded. Human study: Patients (N = 8) underwent temporary gastric stimulation with small bowel electrodes. Subjective and objective data was collected before and after temporary gastric stimulation. Symptom scores, gastric emptying times, and mucosal electrograms via low-resolution mapping were recorded. Results Animal gastric stimulation resulted in some changes in electrical activity parameters, especially with the highest energies delivered but the changes were not statistically significant. Human study revealed improvement in symptom and illness severity scores, and changes in small bowel mucosal slow wave activity. Conclusions Gastric electrical stimulation in an animal model seems to show nonsignificant effects small bowel slow wave activity and myoelectric signaling, suggesting the existence of intrinsic neural connections. Human data shows more significance, with possible potential for therapeutic use of electrical stimulation in patients with gastroparesis and pancreato-biliary and small bowel symptoms of the mid-gut. This study was limited by the nonsurvival pig model, small sample size, and open label human study.

Dysrhythmic bioelectric slow wave activity have been implicated in major functional motility disorders such as gastroparesis and chronic unexplained nausea and vomiting, but its correlation to symptoms is still unclear. For patients with severe gastroparesis, high-frequency gastric stimulation is offered as a therapy in some centers. Temporary gastric electrical stimulation has also been proposed an approach to screen patients who would benefit from the implantation of a permanent stimulator. In this study we introduced novel methods for recording slow wave activity from the gastric mucosa during the entire temporary stimulation phase of 5 days, in 3 patients. An ambulatory recording system was applied to record 3 channels of mucosal slow wave activity, as well as three axis accelerometer data to monitor when the patient was mobile. Techniques were developed to detect large movements and these time periods were excluded from analyses of mucosal slow waves. The frequency and amplitude of the slow waves was calculated in a 5 min segment, with 75% overlap, for the entire duration. In feasibility studies, the slow wave frequency and amplitude for the patients were 3.0±0.96 cpm and 1.43±1.75 mV. Large variations in slow wave amplitude were seen in comparsion to slow wave frequency, which were concordant with previous studies. The use of the ambulatory system will allow for investigation of pathophysiology, correlation of electrophysiology data to patient symptoms and to determine the effects of post-prandial and noctural slow wave patterns. We anticipate that future use of slow wave information alongside patient symptoms may allow improved selection of patients for stimulaton techniques.

Background Gastroparesis is a complex clinical entity; many aspects of which remain unknown. Although most patients have idiopathic, diabetic, or postsurgical gastroparesis, many are thought to have measurable neuromuscular abnormalities. Immunotherapy has recently been utilized to treat suspected autoimmune gastrointestinal dysmotility. Methods Fourteen patients with symptoms of gastroparesis (Gp) who were refractory to drug/device were selected from 443 Gp patients from 2013 to 2015 who were treated at the University of Louisville motility center. All patients underwent a structural and psychiatric evaluation along with detailed psychological and behavioral examination to rule out eating disorders. We performed detailed neuromuscular evaluation and all 14 patients received at least 12 weeks of intravenous immunoglobulin (400 mg/kg infusion weekly). Response was defined subjectively (symptomatic improvement) using standardized IDIOM score system. Key Results All 14 patients had serological evidence and/or tissue evidence of immunological abnormality. Post-IVIG therapy, there was a significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain. Conclusions and Inferences Although limited by the absence of placebo group, the data illustrate the role of autoimmunity and neuromuscular evaluation in patients with gastroparesis and support the utility of a diagnostic trial of immunotherapy in an effort to improve therapeutic outcomes for such patients.