Cajal Cell Counts are Important Predictors of Outcomes in Drug Refractory Gastroparesis Patients With Neurostimulation.

BACKGROUND AND AIMS: Cajal cells serve as the pacemaker cells of the gastrointestinal tract and regulates peristalsis. On the baisis of that fact, it has been hypothesized that a decrease in Cajal cells can lead to gastroparesis and other motility issues. Treatment with medications has a limited efficacy and most resort to gastric electrical stimulation (GES) devices for symptomatic relief. We believe that the number of Cajal cells present is directly proportional to symptomatic relief with GES. MATERIALS AND METHODS: Twenty-three (white female) subjects were recruited from the gastric motility clinic University of Mississipi for this study with the criteria of drug refractory gastropersis. Symptoms were measured using Likert scale and gastric emptying times were measured pre-GES and post-GES. Serosal electrogram measurements were recorded during surgical placement of permanent electrical stimulator under various modes. Cajal cell count scoring via immunohistochemistry were performed during the implantaion of the GES. RESULTS: The data were grouped in 2 categories based on the Cajal cells that is ≥2.00 and <2.00. Subjects with higher Cajal cells reported a statiscially improvement in gastroperesis symptoms. Significant differences were also noted in the first hour gastric emptying study. The mean group difference is 17.5 (95% confidence interval, 1.41-33.58; P=0.035). Serosal amplitude differences were noted being significantly higher in the group with ≥2 cajal cells. CONCLUSIONS: Electrograms obtained after GES demonstrates immediate improvement in gastric electrical activity and gastroparesis symptoms in patients with relatively higher Cajal cell counts when compared with patients with extensive loss of Cajal cells.

Gastric neuromuscular histology in patients with refractory gastroparesis: Relationships to etiology, gastric emptying, and response to gastric electric stimulation.

BACKGROUND: The aims of this study were to describe the histology in gastroparesis, specifically to relate histopathology to etiology of gastroparesis (idiopathic and diabetic gastroparesis), gastric emptying, and clinical response to gastric electric stimulation. METHODS: Full thickness gastric body sections obtained during insertion of gastric stimulator in gastroparetics were stained with Hematoxylin & Eosin, Masson Trichrome and immunohistochemical stains for Neuron-Specific Enolase and c-Kit. KEY RESULTS: In all, 145 gastroparetics (71 diabetics, 71 idiopathic, 2 post-surgical, and 1 chronic intestinal pseudo-obstruction) had full thickness gastric body biopsies. A lymphocytic infiltrate was seen in the intermyenteric plexus in 22 diabetic and 23 idiopathic gastroparesis patients. Fibrosis was present in the inner circular layer in 13 diabetic and 15 idiopathics and in the outer longitudinal layer in 46 diabetic and 51 idiopathics. Diabetic gastroparesis had less ganglion cells (3.27±1.82 vs 4.81±2.81/hpf; P<.01) and less ganglia (0.90±0.44 vs 1.10±0.50/hpf; P=.01) than idiopathic gastroparesis. Interstitial cells of Cajal (ICC) count was slightly lower in the inner circular layer in diabetic than idiopathics (2.77±1.47 vs 3.18±1.34/hpf; P=.08). Delayed gastric emptying was associated with reduced ICCs in the myenteric plexus. Global therapeutic response to gastric electric stimulation was inversely related to ganglia/hpf (R=-.22; P=.008). In diabetics, improvements in nausea, vomiting, and abdominal pain were inversely related to fibrosis. CONCLUSION AND INFERENCES: Histologic assessment of full thickness gastric biopsy specimens allows correlation of histopathology to the gastroparesis disease process, its etiology, gastric emptying, and response to gastric electric stimulation treatment.

[Functional and motor gastrointestinal disorders]. / Trastornos funcionales y motores digestivos.

This article discusses the most interesting studies on functional and motor gastrointestinal disorders presented at Digestive Diseases Week (DDW), 2015. Researchers are still seeking biomarkers for irritable bowel syndrome and have presented new data. One study confirmed that the use of low-dose antidepressants has an antinociceptive effect without altering the psychological features of patients with functional dyspepsia. A contribution that could have immediate application is the use of transcutaneous electroacupuncture, which has demonstrated effectiveness in controlling nausea in patients with gastroparesis. New data have come to light on the importance of diet in irritable bowel syndrome, although the effectiveness of a low-FODMAP diet seems to be losing momentum with time. Multiple data were presented on the long-term efficacy of rifaximin therapy in patients with irritable bowel syndrome and diarrhoea. In addition, among other contributions, and more as a curiosity, a study evaluated the effect of histamine in the diet of patients with irritable bowel syndrome.

Gastric electrical stimulation for abdominal pain in patients with symptoms of gastroparesis.

Abdominal pain physiology may be better understood studying electrophysiology, histology, and symptom scores in patients with the symptoms of gastroparesis (Gp) treated with gastric electrical stimulation (GES). Ninety-five Gp patients' symptoms were recorded at baseline and during temporary and permanent GES. Gastric-emptying times and cutaneous, mucosal, and serosal electrogastrograms were obtained. S100-stained, full-thickness gastric biopsies were compared with autopsy controls. Sixty-eight patients reported severe pain at baseline. Severe pain patients' mean pain scores decreased with temporary GES from 3.62 to 1.29 (P < 0.001) and nonsevere pain from 1.26 to 0.67 (P = 0.01). With permanent GES, severe mean pain scores fell to 2.30 (P < 0.001); nonsevere pain changed to 1.60 (P = 0.221). Mean follow-up was 275 days. Mean cutaneous, mucosal, and serosal frequencies and frequency-to-amplitude ratios were markedly higher than literature controls. For patients with Gp overall and subdivided by etiology and severity of pain, S-100 neuronal fibers were significantly reduced in both muscularis propria layers. GES improved severe pain associated with symptoms of Gp. This severe pain is associated with abnormal electrogastrographic activity and loss of S100 neuronal fibers in the stomach's inner and outer muscularis propria and, therefore, could be the result of gastric neuropathy.

Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping.

BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) generate slow waves. Disrupted ICC networks and gastric dysrhythmias are each associated with gastroparesis. However, there are no data on the initiation and propagation of slow waves in gastroparesis because research tools have lacked spatial resolution. We applied high-resolution electrical mapping to quantify and classify gastroparesis slow-wave abnormalities in spatiotemporal detail. METHODS: Serosal high-resolution mapping was performed using flexible arrays (256 electrodes; 36 cm(2)) at stimulator implantation in 12 patients with diabetic or idiopathic gastroparesis. Data were analyzed by isochronal mapping, velocity and amplitude field mapping, and propagation animation. ICC numbers were determined from gastric biopsy specimens. RESULTS: Mean ICC counts were reduced in patients with gastroparesis (2.3 vs 5.4 bodies/field; P < .001). Slow-wave abnormalities were detected by high-resolution mapping in 11 of 12 patients. Several new patterns were observed and classified as abnormal initiation (10/12; stable ectopic pacemakers or diffuse focal events; median, 3.3 cycles/min; range, 2.1-5.7 cycles/min) or abnormal conduction (7/10; reduced velocities or conduction blocks; median, 2.9 cycles/min; range, 2.1-3.6 cycles/min). Circumferential conduction emerged during aberrant initiation or incomplete block and was associated with velocity elevation (7.3 vs 2.9 mm s(-1); P = .002) and increased amplitudes beyond a low base value (415 vs 170 µV; P = .002). CONCLUSIONS: High-resolution mapping revealed new categories of abnormal human slow-wave activity. Abnormalities of slow-wave initiation and conduction occur in gastroparesis, often at normal frequency, which could be missed by tests that lack spatial resolution. Irregular initiation, aberrant conduction, and low amplitude activity could contribute to the pathogenesis of gastroparesis.

Ameliorating effects and mechanisms of electroacupuncture on gastric dysrhythmia, delayed emptying, and impaired accommodation in diabetic rats.

The aim of this study was to investigate the effects and mechanisms of electroacupuncture (EA) on gastric accommodation, gastric dysrhythmia, and gastric emptying (GE) in streptozotocin (STZ)-induced diabetic rats. Five experiments were performed in five groups of STZ-induced diabetic rats to study the effects of EA at ST-36 (Zusanli) on gastric slow-wave dysrhythmia, delayed GE and intestinal transit, impaired gastric accommodation, and the mechanisms of EA involving the autonomic and opioidergic pathways. We found the following: 1) EA improved gastric dysrhythmia in the diabetic rats. The normal percentage of slow waves was 55.4 +/- 2.9% at baseline and significantly increased to 69.2 +/- 2.2% with EA (P = 0.01); this effect was blocked by naloxone. 2) EA resulted in a 21.4% increase in GE and 18.2% increase in small intestinal transit in the diabetic rats. 3) EA restored diabetes-induced impairment in gastric accommodation. Gastric accommodation was 0.98 +/- 0.13 ml with sham EA and significantly increased to 1.21 +/- 0.15 ml with EA (P = 0.01), and this effect was blocked by naloxone. 4) EA increased vagal activity assessed by the spectral analysis of the heart rate variability. We concluded that EA at ST-36 improves gastric dysrhythmia, delayed GE and intestinal transit, and impaired accommodation in STZ-induced diabetic rats, and the improvement seems to be mainly mediated via the vagal pathway. EA may have a promising therapeutic potential for diabetic gastroparesis.

Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis.

Our goal was to investigate associations between the status of interstitial cells of Cajal (ICC) and electrogastrogram (EGG) parameters, gastric emptying and symptoms in a large cohort of patients with gastroparesis. Forty-one patients with refractory gastroparesis who were referred for gastric electrical stimulation (GES) underwent full thickness gastric (antrum) biopsy during the surgery to place the GES device. The biopsy samples were stained with c-kit and scored for the presence of ICC based on criteria obtained from 10 controls. All patients underwent EGG recordings, a 4-h standardized scintigraphic gastric emptying study and symptom assessment prior to the surgery. Based on antral biopsy, 15 patients (36%) had almost no ICC (ICC- group) and 26 patients had adequate cell numbers (ICC+ group). EGG recordings in the ICC- group displayed significantly less normal slow waves than in the ICC+ group both in the fasting and fed states. Tachygastria in the ICC- group was significantly more than in the ICC+ group both in the fasting (32 +/- 8%vs 11 +/- 2%) and fed states (27 +/- 9%vs 12 +/- 2%). There was no statistical difference in gastric emptying, symptom severity of gastroparesis, aetiology, age and gender between the two groups. Severely depleted ICC occurs in up to 36% of gastroparetic patients and significantly correlates with an abnormal EGG. Severely depleted ICC does not correlate with the severity of gastroparesis as assessed by gastric emptying or symptom status but did result in a poorer symptomatic response to GES. These data suggest that the EGG may have a role for predicting ICC status during clinical evaluation of gastroparetic patients.

Absence of the interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings.

The interstitial cells of Cajal (ICCs) are fundamental in the generation of gastric slow waves. The role of these cells in gastroparesis has not been established. We studied 14 gastroparetic patients (9 diabetic, 4 idiopathic, and 1 postsurgical) for whom standard medical therapy had failed and who had been treated with a gastric electrical stimulator for at least 3 months. All patients had a full-thickness antral gastric wall biopsy at the time of surgery. The biopsy samples were stained with c-kit and scored for the presence of ICCs. Baseline electrogastrogram recordings were obtained for 30 minutes in the fasting state and for 2 hours after a test meal. The patients assessed their total symptom score at baseline and at 3 months. Five patients had almost no ICCs and were compared with nine patients with 20% to normal cell numbers. Both groups did respond symptomatically to gastric electrical stimulation. However, patients with depleted ICCs had significantly more tachygastria and had significantly greater total symptom scores at baseline and after 3 months of gastric electrical stimulation. ICCs are absent in some patients (up to a third) with diabetic or idiopathic gastroparesis, and the absence of these cells is associated with abnormalities of gastric slow waves, worse symptoms, and less improvement with gastric electrical stimulation.