Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle

OBJECTIVES: We aimed to determine if botulinum toxin injection into the pyloric sphincter improves gastric emptying and reduces symptoms in patients with idiopathic gastroparesis. METHODS: Patients with idiopathic gastroparesis not responding to prokinetic therapy underwent botulinum toxin (80-100 U, 20 U/ml) injection into the pyloric sphincter. Gastric emptying scintigraphy was performed before and 4 wk after treatment. Total symptom scores were obtained from the sum of eight upper GI symptoms graded on a scale from 0 (none) to 4 (extreme). RESULTS: Ten patients were entered into the study. The mean percentage of solid gastric retention at 4 h improved from 27+/-6% (normal < 10%) before botulinum toxin injection into the pylorus to 14+/-4% (p = 0.038) 4 wk after treatment. The symptom score decreased from 15.3+/-1.7 at baseline to 9.0+/-1.9 (p = 0.006) at 4 wk, a 38+/-9% decrease. Improvement in symptoms tended to correlate with improved gastric emptying of solids (r = 0.565, p 0.086). CONCLUSIONS: This initial pilot study suggests that botulinum toxin injection into the pylorus in patients with idiopathic gastroparesis improves both gastric emptying and symptoms.     

Pyloric injection of botulinum toxin for treatment of diabetic gastroparesis

BACKGROUND: Diabetic gastroparesis is a common clinical problem. The pathophysiology includes prolonged pyloric contractions that may cause functional resistance to gastric outflow. Botulinum toxin was injected into the pyloric sphincter in an attempt to decrease pyloric resistance and improve gastric emptying. METHODS: Six patients with diabetic gastroparesis and an abnormal solid phase gastric emptying study underwent upper endoscopy during which 100 units of botulinum toxin were injected into the pyloric sphincter. Gastric emptying studies were obtained at 48 hours and 6 weeks after injection. Patients were questioned about symptoms of gastroparesis, and a symptom score was obtained at baseline and at 2 weeks and 6 weeks after injection. OBSERVATIONS: There was a mean improvement in the subjective symptom score at 2 weeks of 55% (range 14% to 80%). This improvement was maintained at 6 weeks. There was a 52% improvement in gastric emptying at 2 and 6 weeks. CONCLUSION: Pyloric injection of botulinum toxin can improve symptoms and gastric emptying in patients with diabetic gastroparesis. Further evaluation of pyloric injection of botulinum toxin as a treatment for diabetic gastroparesis is warranted.     

Beyond gastric emptying: a "toxic" lesson about gastroparesis

The first published controlled trial of intrapyloric botulinum toxin for gastroparesis failed to demonstrate a significant effect of treatment on symptoms, despite an improvement in gastric emptying. In this editorial, I discuss the limitations and implications of this study, with particular emphasis on what the use of botulinum toxin can teach us about the pathophysiology of gastroparesis and other gastrointestinal smooth muscle disorders.     

Diagnostic and therapeutic approach to patients with gastroparesis

Gastroparesis is a chronic alteration of gastric motility characterized by symptoms suggestive of mechanical obstruction and delayed gastric emptying in the absence of obstruction. Gastroparesis can be idiopathic or attributable to neuropathy or myopathy as in diabetes mellitus and scleroderma or can occur after vagotomy. Diagnosis is based on symptoms (nausea, vomiting, abdominal distension and early satiety), physical examination (capotement) and on complementary investigations, the procedure of choice being isotope gastric emptying tests. Treatment depends on the clinical repercussions. In most patients, gastroparesis can be controlled by prokinetic drugs, dietary measures, exclusion of drugs that alter gastric emptying, and exhaustive control of blood glucose levels. In patients with severe gastroparesis, hospital nutritional measures (intravenous and/or enteral), gastric decompression and intravenous antiemetic and prokinetic agents are required. Aggressive nutritional therapies (parenteral or enteral nasojejunal nutrition), intrapyloric injection of botulinum toxin, implantation of a gastric stimulation device, or gastrectomy should only be used in patients unresponsive to conservative treatment or if there is selective alteration of gastric motility.     

Endoscopic treatment of gastroparesis

Gastroparesis has traditionally been a largely medically managed disease with refractory symptoms typically falling under the umbrella of the surgical domain.Surgical options include, but are not limited to, gastrostomy,jejunostomy, pyloromyotomy, or pyloroplasty,and the Food and Drug Administration approvedgastric electrical stimulation implantation. Endoscopic management of gastroparesis most commonly involves intrapyloric botulinum toxin injection; however, there exists a variety of endoscopic approaches on the horizon that have the potential to radically shift standard of care.Endoscopic management of gastroparesis seeks to treat delayed gastric emptying with a less invasive approach compared to the surgical approach. This review will serve to highlight such innovative and potentially transformative, endoscopic interventions available to gastroenterologists in the management of gastroparesis.     

Endoscopic Pyloric Injection of Botulinum Toxin-A for the Treatment of Postvagotomy Gastroparesis

ObjectivesTo evaluate the efficacy of botulinum toxin-A in the treatment of postvagotomy gastroparesis.MethodsThis open-labeled trial identified and recruited 11 subjects who developed symptomatic gastroparesis after a vagotomy (9 fundoplication, 1 trauma, and 1 exploratory laparotomy). Gastroparesis was defined as an abnormal solid-phase gastric emptying test using the standardized 4-hour radionuclide eggbeater meal method and vagotomy was confirmed with a sham meal challenge test. To complete the study, subjects should have completed the 6-month follow-up visit after their pylorus was injected with botulinum toxin-A injection in a 4-quadrant manner. Patients either received 100 (n = 2) or 200 (n = 9) units of botulinum toxin. Questionnaires recorded symptom severity of gastroparesis at baseline and at monthly intervals for 6 months after the therapy was completed by the patients.ResultsOf the 11 subjects initially recruited, 10 finished the 6-month follow-up visit (7 women). Mean age was 51 years (range, 31–84 years). Mean symptom score at baseline was 16 (95% CI 13–19) and showed a numerical decline to 9 (P > 0.05) over the 6-month period after the procedure (95% CI 5–13). Seven (70%) patients observed >30% improvement in the total symptom score. No complications were recorded.ConclusionsIn conclusion, this open-label study in patients with postvagotomy gastroparesis patients reveals a reduction of gastroparetic symptoms at 1 and 3 months after treatment with pyloric injection of botulinum toxin-A, with return of symptoms by 6 months. Thus, botulinum toxin treatment does not produce a sustained reduction in gastroparetic symptoms in this clinical setting.     

Factors Associated with Symptom Response to Pyloric Injection of Botulinum Toxin in a Large Series of Gastroparesis Patients

Case series report symptom reductions after pyloric botulinum toxin injection in gastroparesis, but small controlled trials show no benefit. Factors that enhance response to therapy are undefined. A retrospective analysis of 179 gastroparetics undergoing pyloric botulinum toxin injection from 2001 to 2007 assessed responses relating to drug dosing, demographic factors, comorbidities, and gastric function. Overall, there was a decrease in gastroparetic symptoms 1–4 months after pyloric botulinum toxin injection in 92 patients (51.4%). Increasing the botulinum toxin dose significantly improved clinical responses of patients who provided information on symptoms after therapy (100 units: 54.2%; 200 units: 76.7%; P = 0.02). Other factors that improved response to botulinum toxin included female gender, age <50 years, and nondiabetic nonpostsurgical etiology (all P < 0.05). Eighty-seven patients received 307 follow-up injections. A clinical response to a second injection was observed in 73.4% of evaluable patients. In conclusion, responses to pyloric botulinum toxin depended on dose and were maintained on repeat injection. Subgroup analyses defined subgroups likely to benefit. These findings provide the foundation for large, controlled trials of high-dose botulinum toxin in selected gastroparesis subsets.     

Botulinum toxin for the treatment of gastroparesis: a preliminary report

Gastroparesis is a disorder of gastric motility that results in delayed gastric emptying. Common symptoms include early satiety, postprandial fullness, epigastric pain, nausea, vomiting, and weight loss. The underlying etiologies of gastroparesis are many and include diabetes, prior gastric surgery, collagen vascular disorders, and a previous viral illness. Up to one third of cases are classified as idiopathic. Treatment typically consists of a change in diet to small volume, frequent meals and the use of the prokinetic agents metoclopramide, cisapride, erythromycin, or domperidone. Botulinum toxin has recently been shown to be effective in treating disorders of smooth muscle hypertonicity in the GI tract. This case report describes three patients with severe gastroparesis whose symptoms persisted despite dietary changes and the use of high dose prokinetic agents. All three were treated with intrasphincteric injection of the pylorus with botulinum toxin and all had significant symptomatic improvement afterwards. Possible mechanisms of action of botulinum toxin on the pylorus and its effects in patients with gastroparesis are discussed.     

Pyloric Injection of Botulinum Toxin for the Treatment of Refractory GERD Accompanied with Gastroparesis: A Preliminary Report

Gastroesophageal reflux disease (GERD) refractory to conventional medical treatment is frequently associated with gastroparesis, a complex condition with no definitive treatment to date. We first developed a scoring system to assess the severity and frequency of both reflux- and gastroparesis-related symptoms. We then tested, for the first time, the hypothesis that endoscopic pyloric botulinum toxin injection alleviates both of these symptom types. Eleven patients (four males) with GERD (confirmed by esophageal pH monitoring) plus gastroparesis (confirmed by gastric emptying study) underwent toxin injection. Patients had no concomitant disease and were not allowed to use prokinetics before or after treatment. Injection significantly improved both gastroparesis- and reflux-related symptoms in the majority of patients but the duration of symptom relief was relatively short. Responders to treatment had significantly higher total reflux symptom scores (before injection) than nonresponders. All but one of the patients in whom gastroparesis symptoms improved also showed response in reflux symptoms, which supports our hypothesis. We believe that response to toxin injection is a reliable predictor of response to subsequent surgery following the recurrence of symptoms.     

不同阶段糖尿病胃运动障碍诊治对策

糖尿病患者常见胃运动障碍,表现为上腹胀、早饱、上腹不适、恶心、呕吐等症状以及胃排空延迟,胃排空延迟影响降血糖药的药代动力学,造成餐后血糖升高与降血糖药或胰岛素的血浓度高峰不匹配,进而影响血糖的控制与稳定。糖尿病不同阶段胃运动障碍表现形式不同。核素法是最常用的胃排空诊断方法。糖尿病胃运动障碍的处理包括饮食调节、促动力药以减轻症状、控制血糖,针对胃轻瘫的治疗包括胃电刺激、内镜下幽门注射肉毒杆菌毒素A、内镜下放置鼻胃空肠营养管或经皮内镜下胃（空肠）造瘘、外科手术等。     

Gastroparesis: clinical update

Gastroparesis refers to chronically abnormal gastric motility characterized by symptoms suggestive of mechanical obstruction and delayed gastric emptying in the absence of mechanical obstruction. It may be idiopathic or attributable to neuropathic or myopathic abnormalities, such as diabetes mellitus, postvagotomy, postviral infection, and scleroderma. Dietary and behavioral modification, prokinetic drugs, and surgical interventions have been used in managing patients with gastroparesis. Although mild gastroparesis is usually well managed with these treatment options, severe gastroparesis may be very difficult to control and may require referral to a specialist center if symptoms are intractable despite pharmacological therapy and dietetic support. New advances in drug therapy, botulinum toxin injection, and gastric electrical stimulation techniques have been introduced and might provide new hope to patients with refractory gastroparesis. This article critically reviews the advances in the field from the perspective of the clinician.     

The difficult patient with gastroparesis

Gastroparesis is often difficult to manage. First of all, exact criteria for making a diagnosis of gastroparesis have not been established, and merely finding delayed gastric emptying does not justify the label. Furthermore, the relationship between symptoms and gastric emptying rate is poor, and the number of therapies with proven efficacy is extremely limited. A number of technical investigations are helpful to establish the anatomy and motor function of the upper gastrointestinal tract. In most cases where gastroparesis can be presumed or established, prokinetic therapy will be tried. A number of agents are available, with variable efficacy and tolerance. Rarely, in case of debilitating refractory symptoms, experimental or invasive therapies can be tried such as injection of botulinum toxin, enteral feeding tube insertion, gastric electrical stimulation or surgery.     

Objective and subjective results of a randomized,double-blind,placebo-controlled trial using cisapride to treat gastroparesis

Cisapride, a relatively new gastrointestinal prokinetic agent, has been reported to increase gastric emptying and improve symptoms of gastroparesis. We investigated these effects of cisapride in patients with severe idiopathic and diabetic gastroparesis during an eight-week trial. The study design was a two-week single-blind placebo run in period to exclude placebo responders, followed by a six-week randomized, double-blind, placebo-controlled treatment phase. Delayed gastric emptying of solids on radionuclide scan and a minimum symptom intensity score were inclusion criteria. Forty-three patients were entered: four placebo responders and one other patient were excluded, leaving 19 patients randomized to cisapride (20 mg per os three times a day before meals), and 19 patients to placebo. Seven individual symptoms of gastroparesis were scored in a daily diary and reviewed at two-week visits. Sixteen patients in the cisapride group were able to complete the trial compared to 12 on placebo. The gastric emptying study was repeated at the end of treatment or at the time of withdrawal for those who dropped out. Cisapride significantly increased solid gastric emptying relative to baseline (P=0.005) whereas placebo did not (P>0.10). Cisapride did not significantly improve any symptom of gastroparesis relative to baseline or to placebo. We conclude that in a population of severe, refractory gastroparetic patients cisapride significantly accelerates gastric emptying of a solid meal without significantly reducing symptoms during a short-term treatment trial compared to placebo. Further trials of cisapride in less advanced and end-stage gastroparetics than studied here or combining cisapride with other prokinetic agents or antiemetics, are warranted.Financial support was provided by Janssen Pharmaceutica. This study took place in the General Clinical Research Center of the University of Virginia Medical Center and was supported by NIH grant M01-RR 00847.     

Treatment of symptomatic nonachalasia esophageal motor disorders with botulinum toxin injection at the lower esophageal sphincter

The purpose of this study was to determine if botulinum toxin injection at the lower esophageal sphincter improves symptoms in patients with nonachalasia spastic esophageal motility disorders. Fifteen patients with nonachalasia spastic esophageal motility disorders (diffuse esophageal spasm, nonspecific esophageal motility disorders, and lower esophageal sphincter dysfunction) unresponsive to medical therapy underwent endoscopic injection of botulinum toxin at the level of the gastroesophageal junction. Symptoms were scored (0=no symptoms, 1=mild, 2=moderate, 3=severe and 4=very severe) before treatment, at seven days and every 30 days after treatment. There was significant improvement in chest pain, dysphagia, and regurgitation at 7, 30, 60 and 90 days after treatment. At one month after treatment, 11 of 15 (73%) patients had a good or excellent response to treatment. At the last patient interview (mean follow-up of 10.6 months), five (33%) patients continued to have a good to excellent response, whereas 10 (67%) underwent subsequent treatment with repeat botulinum toxin, pneumatic dilation, or bougienage. We conclude that botulinum toxin injection at the gastroesophageal junction leads to significant symptom improvement in patients with nonachalasia esophageal motility disorders. These results suggest that botulinum toxin may be an effective treatment option in some of these patients not responsive to conventional medical therapy.     

Severe idiopathic gastroparesis due to neuronal and interstitial cells of Cajal degeneration: pathological findings and management

Delayed gastric emptying can be due to muscular, neural, or humoral abnormalities. In the absence of an identified cause, gastroparesis is labelled as idiopathic. We present the case of a patient with severe idiopathic gastroparesis. Pharmacological approaches failed, as well as reduction in gastric emptying resistance with pyloric injection of botulinum toxin and pyloroplasty. Therefore, subtotal gastrectomy was performed. Histological and immunohistochemical study of the resected specimen showed hypoganglionosis, neuronal dysplasia, and a marked reduction in both myenteric and intramuscular interstitial cells of Cajal. To our knowledge, this is the first time these rare histological findings have been described in a patient with idiopathic gastroparesis.     

Long-term efficacy of oral cisapride in symptomatic upper gut dysmotility

We conducted a 12-month trial of cisapride (10 mg three times a day) in 21 patients with gastric stasis due to clinically and manometrically diagnosed gastroparesis (N=9; seven due to diabetes) or chronic intestinal pseudo-obstruction (N=12). Radionuclide solid-liquid gastric emptying tests were performed at baseline and at the end of the 12-month period. Symptoms were assessed monthly by diary and every three months by the investigators; frequency and severity of symptoms were scored in a standardized manner. For the whole group of 21 patients, gastric emptying of both solids and liquids improved significantly after one year of cisapride (P<0.05). Among chronic intestinal pseudoobstruction patients, there was predominantly an improvement in gastric emptying of solids; in contrast, patients with gastroparesis had a greater improvement in liquid emptying. Total symptom score improved significantly in the gastroparesis group (median score: 8 at baseline vs 6 at one year,P<0.05) but not in the chronic intestinal pseudoobstruction patients (median score at baseline 10 vs 9 at one year). Similarly, body weight showed a trend towards improvement in the gastroparesis group. No significant side effects were noted. We conclude that during a 12-month open trial, cisapride was effective in improving gastric emptying in patients with gastric stasis and consistently improved symptoms in those with gastroparesis.     

Effect of metoclopramide in diabetic gastroparesis

The aims of our study were to: determine the effect of metoclopramide parenterally and orally on delayed gastric emptying of a radionuclide test meal in symptomatic patients with diabetic gastroparesis not explained by ulceration or other mechanical problems; and evaluate in a double-blind crossover fashion the efficacy of metoclopramide in relieving the symptoms of diabetic gastroparesis. Thirteen patients with subjective evidence of gastric stasis had delayed gastric emptying of an isotope-labeled semisolid meal which was significantly accelerated (p less than 0.05) after 10 mg of metoclopramide parenterally. Patients then received metoclopramide 10 mg and placebo before meals and prior to retiring for 3 weeks in a randomized double-blind crossover design. During metoclopramide therapy nausea, vomiting, anorexia, fullness, and bloating were significantly (p less than 0.05) ameliorated compared to placebo with an overall mean symptom reduction of 52.6%. Gastric emptying studies after completion of the trial is seven patients, subjectively improved and receiving open-labeled metoclopramide, showed significantly less gastric retention. Individual improvements in gastric emptying after parenteral or oral metoclopramide, however, could not be correlated with symptom change during the treatment trial. We conclude that metoclopramide is an important therapeutic adjunct in the management of diabetic gastroparesis and its therapeutic effects are mediated through its prokinetic properties as well as centrally mediated antiemetic actions.     

Severe gastroparesis: new treatment alternatives

Dopamine antagonists, such as metoclopramide and domperidone, and the motilin receptor agonist erythromycin have been the cornerstones in drug treatment of severe gastroparesis for more than a decade. No new drugs have been approved for treatment of this disorder in this period. Instead, the 5-HT4 agonist cisapride has been withdrawn due to side-effects. The effectiveness of intrapyloric botulinum toxin for gastroparesis remains to be shown. In the last decade, gastric electrical stimulation (GES) with a fully implantable device has evolved as a promising treatment, with significant effects on nausea and vomiting in most patients with severe, drug-refractory diabetic gastroparesis and postsurgical gastroparesis. A proportion of patients with severe idiopathic gastroparesis and patients with idiopathic nausea and vomiting also respond. More research is needed to achieve precise selection of responders/non-responders to GES, and to study the potential benefit of GES in other patient groups suffering from severe nausea or vomiting.     

Controlled trial of botulinum toxin injection versus placebo and pneumatic dilation in achalasia

BACKGROUND & AIMS: Intrasphincteric injection of botulinum toxin has been suggested as an alternative treatment modality in esophageal achalasia. A controlled trial comparing botulinum toxin, placebo, and pneumatic dilation is reported. METHODS: Sixteen patients received random intrasphincteric injections of either botulinum toxin or saline. The efficacy of treatment was assessed by symptom score, esophageal manometry, and scintigraphy. In case of failure, pneumatic dilation was performed. RESULTS: One month after injection, symptoms had improved in all patients treated with botulinum toxin (symptom score, 0.9 +/- 0.6 vs. 5.5 +/- 1.4; P < 0.02). In the placebo group, symptoms were unchanged in all patients, who were all dilated. Lower esophageal sphincter pressure decreased by 49% after treatment with botulinum toxin (P < 0.03) and by 72% after dilation (P < 0.01). Similarly, esophageal retention decreased by 47% after treatment with botulinum toxin (P < 0.02) and by 59% after dilation (P < 0.02). No significant difference in symptom score and esophageal function test results was found between patients treated with botulinum toxin injections and those undergoing dilation. However, 7 of the 8 patients in the botulinum toxin group required a second injection because of recurrent dysphagia. CONCLUSIONS: Treatment of achalasia with botulinum toxin was as effective as pneumatic dilation in relieving symptoms and improving esophageal function. The effect of the first injection was temporary, but the effect of the second injection lasted longer. (Gastroenterology 1996 Dec;111(6):1418-24)     

Delayed gastric emptying: Whom to test, how to test, and what to do

Opinion statement Gastroparesis, or delayed gastric emptying, is a common cause of chronic nausea and vomiting as seen in a gastroenterology practice. Diabetic, postsurgical, and idiopathic causes remain the three most common forms of gastroparesis. In addition to nausea and vomiting, symptoms of gastroparesis may include early satiety, postprandial fullness, and abdominal pain. Physiologic changes that may explain symptoms in patients with gastroparesis, in addition to delayed gastric emptying, include impaired fundic accommodation, antral hypomotility, gastric dysrhythmias, pylorospasm, and perhaps visceral hypersensitivity. Diagnosis of gastroparesis is best determined using a radioisotope-labeled solid meal with scintigraphic imaging for at least 2 hours, and preferably 4 hours, postprandially. Most commonly, a 99mTc sulfur colloid-labeled egg sandwich with imaging at 0, 1, 2, and 4 hours is used. Extension of the gastric emptying test to 4 hours improves the accuracy of the test, but unfortunately, this is not commonly performed at many centers. Emptying of liquids remains normal until the late stages of gastroparesis and is less useful. The aims of treatment should be to control symptoms and maintain adequate nutrition and hydration. Patients should be advised to eat small meals and to limit their intake of fat and fiber. Additional dietary recommendations may include increasing caloric intake in the form of liquids. For diabetic patients, control of blood glucose levels is important, as symptom exacerbation is frequently associated with poor glycemic control. Specific treatment often begins with metoclopramide, 10 mg, up to four times daily, after a discussion of possible side effects with the patient. An antiemetic agent, such as prochlorperazine, 5 to 10 mg orally or 25 mg by suppository, can be added on an as-needed basis every 4 to 6 hours to control nausea. If these antiemetic medications are not effective, or if side effects develop, orally dissolving ondansetron, 8 mg every 8 to 12 hours, can be tried on an as-needed basis. If this regimen is unsuccessful, then alternative prokinetic agents—erythromycin, 125 mg, or tegaserod, 6 mg, prior to meals—can be tried. For cases refractory to these treatments, referral to a center with US Food and Drug Administration permission to use domperidone should be considered. Alternatively, symptom modulators such as low-dose tricyclic antidepressants can be tried to reduce symptoms, but these do not improve gastric emptying. In patients for whom all medical therapy fails, other options that are tried at experienced centers include the injection of botulinum toxin into the pylorus, placement of a feeding jejunostomy, and/or placement of a gastric electrical stimulator.