Gastroparesis is a syndrome characterized by delayed gastric emptying with associated symptoms. Gastric emptying is a complex process and pyloric dysfunction may play a key role in select subsets of patients with gastroparesis. Diagnostic tests to measure pyloric physiology are now available and have the potential to be more widely used in clinical practice. Targeted therapies including botulinum toxin, transpyloric stent placement, surgical pyloroplasty and endoscopic pyloromyotomy have been developed. Data are emerging regarding efficacy and durability, but these therapies may play a prominent role in select patients with gastroparesis and pyloric dysfunction.
Key points
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A subset of patients with gastroparesis may have pyloric dysfunction.
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Pyloric dysfunction has traditionally been assessed via manometry; however, several promising new technologies, especially wireless capsule motility and impedance planimetry, may make assessment of pyloric function more practical and help better define patients who may respond to targeted intervention.
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Botulinum toxin for gastroparesis has been controversial, and 2 randomized controlled trials do not show benefit; however, both trials were small and the patients studied were not stratified based on pyloric physiology.
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Transpyloric stent placement, endoscopic pyloromyotomy, and surgical pyloroplasty are promising treatment options for select patients; however, more data are needed regarding safety, long-term durability, and applicability.
Introduction
Gastroparesis is a syndrome characterized by delayed gastric emptying with associated symptoms, including nausea, vomiting, early satiety, bloating, and abdominal pain. Although the diagnosis is established by objective measurement of gastric emptying, symptoms can vary significantly among affected individuals and the syndrome itself is heterogeneous. Normal gastric emptying is a complex series of events that requires appropriate function and coordination of multiple interrelated processes, including the smooth muscle of the gut, interstitial cells of Cajal, afferent and efferent neurons, and the sympathetic and parasympathetic nervous systems. Problems with any of these components can lead to impaired emptying and associated symptoms. Gastroparesis is a functional disorder with a common set of symptoms but likely multiple different pathways by which those symptoms can be achieved.
Multiple mechanisms are thought to be responsible for gastroparesis symptoms in affected individuals. The proposed causes include problems with fundic accommodation, gastric arrhythmia, impaired contractile ability, abnormalities of the small bowel with resultant aberrant gastric feedback, vagal injury/neuropathy, and pyloric dysfunction, with many affected patients potentially having multiple causes. Pyloric dysfunction in particular has received significant attention and may be a significant contributor to symptom pathogenesis in a portion of affected patients with gastroparesis. This dysfunction can consist of pyloric restriction or pylorospasm and may offer the potential for localized therapy for a select subset of patients with gastroparesis.
Diagnostic evaluation
There are multiple modalities by which pyloric function can be assessed but no true gold standard, as the pylorus has multiple properties that can be assessed independently and may be associated with symptom pathogenesis. In routine clinical practice, barium fluoroscopy and endoscopy are the two methods of evaluation most commonly performed. Fluoroscopy can suggest a functional obstruction at the pylorus, but interpretation is often subjective and varies across institutions. Likewise, endoscopy may suggest restriction or spasm at the pylorus, but interpretation is subjective and depends on multiple factors, such as the degree of insufflation, that are impossible to standardize in clinical practice. Scintigraphy is currently viewed as the gold standard with regard to gastric emptying but offers scant data with regard to pyloric function.
When objective data are desired to further evaluate pyloric function, the traditional method of evaluation has been antroduodenal or pyloric manometry (ADM). This evaluation involves placement of a manometry catheter, via either endoscopy or fluoroscopy, which traverses the pylorus and enters the proximal small bowel. This study allows measurement of pyloric pressure and coordination. Dooley and colleagues initially evaluated the pyloric pressure in 1985 with a seminal paper, following the next year by Mearin, Camilleri, and Malagelada. Mearin and colleague evaluated 24 patients with diabetes with nausea/vomiting versus 12 healthy controls and found that patients with symptoms were significantly more likely to have prolonged pyloric pressurization and more intense contraction, which they termed pylorospasm . Since that publication, manometry has been viewed as the most reliable way to measure pyloric pressures. However, it is not widely available, is limited to tertiary medical centers, is invasive and time consuming, and is associated with frequent catheter migration. The pylorus in particular is challenging to visualize because the length of the sphincter is relatively short (2 cm), migration of the catheter is common, and the sensors are widely spaced apart. Desipio and colleagues from Temple University attempted to eliminate this issue by using a high-resolution ADM catheter. They recruited 12 subjects and were able to place the catheter successfully in 10. Normative data were obtained for pyloric width, basal pressure, and contractile pressure. An abstract published described the squeeze pressure in symptomatic patients, but data with regard to high-resolution ADM data in symptomatic patients are limited. Also, the cost of high-resolution manometry catheters and the high likelihood that sensors could be damaged in the course of endoscopic placement discourage routine clinical usage at this point in time.
Recently, there have been several new developments that have suggested novel methods by which pyloric function could be assessed. The wireless motility capsule (SmartPill, Given Imaging, Israel) is a wireless, ingestible medical device that measures pH, pressure, and temperature throughout the gastrointestinal tract and was approved by the Food and Drug Administration for evaluation of gastric emptying in 2006. As opposed to manometry, this device is mobile and not fixed in space. Most data to date evaluating the wireless motility capsule have used gastric transit time for evaluation of gastric function, although limited data also exist with regard to gastric pressure amplitude and contractile frequency. In one intriguing abstract that has not yet been published in manuscript form, Roland and colleagues attempted to measure intrapyloric pressures via the wireless motility capsule and suggested that this measurement seemed to predict scintigraphic meal emptying. At present, the jury is still out as to whether the wireless motility capsule can reliably isolate and measure pyloric pressure; however, if the technique of measuring intrapyloric pressure can be standardized and normative data can be obtained, then it is possible that this device may make measurement of pyloric pressure more practical in clinical practice.
Recently, the Endolumenal Functional Lumen Imaging Probe (EndoFLIP; EndoFlip, Crospon, Ireland) was developed and presents a novel method to assess pyloric function. This device uses impedance planimetry to record cross-sectional area and minimum diameter of any hollow structure. By combining that information with intraballoon pressure and volume measurements, it is possible to measure distensibility and compliance of any sphincter. This device was approved by the Food and Drug Administration in 2010 but has only recently entered routine clinical practice. Most of the data to date using this technology from the gastrointestinal standpoint involve measurement of the esophagogastric junction for patients with achalasia or measurement of esophageal distensibility in affected patients with eosinophilic esophagitis. However, recently, this technology has also been applied to measurement of pyloric sphincter distensibility. Two abstracts were published on this topic at Digestive Disease Week 2014 and another at the Federation of Neurogastroenterology and Motility, which suggests that this information may be of clinical utility. Research is rapidly emerging regarding impedance planimetry and gastric distention, and it is hoped that peer-reviewed published information will be available soon to guide decision making.
In summary, although several techniques exist by which pyloric function can be assessed, there are little validated data to reliably guide pyloric evaluation. Endoscopy and barium are usually the first steps in clinical practice but are plagued by subjectivity and lack of clear objective criteria to distinguish abnormality. Antroduodenal/pyloric manometry is considered the reference standard but is limited by invasiveness, space between sensors, catheter migration, and lack of clear normative data. Wireless motility capsule and impedance planimetry are both emerging technologies that seem quite promising; however, most of these data with regard to pyloric function specifically are only available in abstract form, and normative data to guide clinical management have not yet been established.
Therapy
Despite the difficulty in assessing pyloric function, there has been great interest in therapy aimed at decreasing pylorospasm or disrupting the integrity of the pyloric sphincter. This interest has been largely driven by the limited options available to treat gastroparesis and the significant impairment in quality of life that these patients experience. To date, there has been no evidence that medical or dietary therapy alone makes a difference in pyloric function; therapeutic attempts have been entirely endoscopic or surgical. Currently, there are 4 main approaches that have been explored: endoscopic botulinum toxin injection, transpyloric channel stent placement, surgical pyloromyotomy, and most recently endoscopic pyloromyotomy.
Botulinum Toxin
Botulinum toxin is a neurotoxic protein that binds to presynaptic cholinergic receptors and inhibits acetylcholine release, leading to muscle relaxation. This neurotoxic protein was initially used in the gastrointestinal tract for treatment of achalasia by Pasricha and colleagues approximately 20 years ago. Since that point, it has been used in numerous other gastrointestinal conditions, including esophageal spasm, anal fissures, and constipation. Given the observation that pyloric pressures were sometimes elevated on antroduodenal manometry, a supposition of pyloric spasm, and the relatively safety of botulinum toxin injection in the gastrointestinal system, it was hypothesized that botulinum toxin injection to the pyloric sphincter may potentially relieve pylorospasm, decrease outflow obstruction, and improve gastric emptying in patients with gastroparesis.
Sharma and colleagues presented the first report of intrapyloric botulinum toxin injection for a patient with gastroparesis in 1998 in abstract form at the annual meeting of the American College of Gastroenterology. This initial report was followed in 2002 by 3 manuscripts by other investigators evaluating intrapyloric botulinum toxin injection for patients with delayed gastric emptying. Ezzeddine and colleagues reported on injection of botulinum toxin in 6 patients with refractory symptoms in the context of diabetic gastroparesis. They reported a 55% improvement in symptoms and 52% improvement in gastric emptying after injection and these patients were followed for a total of 6 weeks. Lacy and colleagues reported on injection of botulinum toxin to 3 patients with refractory symptoms in the context of diabetic gastroparesis and objective abnormalities on antroduodenal manometry and scintigraphy. All 3 patients reported clinical improvement, although radiographic improvement was not universal. Finally, Miller and colleagues from Temple University reported on the use of intrapyloric botulinum toxin injection for patients with idiopathic gastroparesis with refractory symptoms and reported improvement in their pilot study in both symptoms and gastric emptying.
Subsequent open-label and retrospective studies followed over the next few years, all of which showed improvement in symptoms and improvement in gastric emptying when measured. These data led to 2 randomized, double-blind, placebo-controlled trials. The first was performed by Arts and colleagues from Leuven University in Belgium. They evaluated 23 patients with gastroparesis (19 idiopathic) in crossover fashion. The patients received either 100 units of botulinum toxin or saline on the first endoscopy and then received the second option on a subsequent endoscopy 4 weeks later. Symptom scores and gastric emptying were evaluated at the beginning of the protocol and then 4 weeks after each injection. The patients reported improvement in symptoms and had objective improvement in gastric emptying after receiving both saline injection and botulinum toxin; however, there was no statistically significant difference between saline and botulinum toxin. The second study was performed by Friedenberg and colleagues at Temple University. In their study, 32 patients with gastroparesis were randomized to receive either placebo (saline injection) or botulinum toxin (200 units). At a 1-month follow-up, 37.5% randomized to botulinum toxin achieved improvement as defined by the study, as compared with 56.3% of those patients randomized to placebo. Both groups were also noted to have improvement in objective gastric emptying, without significant difference between the two. These studies did not take into account the possible normal pyloric pressure in approximately 50% of the patients with gastroparesis.
Although the publication of 2 randomized trials showing no benefit for botulinum toxin injection as compared with placebo would seem to be a death blow to the use of botulinum toxin for gastroparesis in clinical practice, other data have been published since that point that suggest that botulinum toxin may improve symptoms in a defined clinical subset. In the largest series published to date and the most intriguing, investigators in Michigan evaluated a retrospective series of 179 patients with gastroparesis who received botulinum toxin injection between 2001 and 2007, with 87 patients of the group receiving 307 follow-up injections. There was a decrease in symptoms 1 to 4 months after injection in 51.4% of patients. When higher doses of botulinum toxin were used, then that percentage increased, with 76.7% of patients reporting improvement after a dose of 200 units. Of those patients who responded to an initial injection and underwent further therapy, 73.4% also responded to a second injection. Other factors that predicted response included female gender, age less than 50 years, and a nondiabetic, nonsurgical cause.
A systematic review published in 2010 evaluated this issue and concluded after review of 15 reports that “there is no evidence to recommend botulinum toxin injection for the treatment of gastroparesis.” This finding was highlighted in the recent American College of Gastroenterology’s clinical guideline on the management of gastroparesis where they gave a strong recommendation with a high level of evidence that “intrapyloric injection of botulinum toxin is not recommended for patients with gastroparesis based on randomized controlled trials,” with the caveat that “there is a need for further study in patients with documented ‘pylorospasm’.” In practice, however, botulinum toxin injection is still performed at many centers (including the authors’ center) for refractory patients with gastroparesis who have not responded to conventional therapy and in whom pyloric dysfunction is suspected; although it is not routine and the data from randomized trials are discouraging, there may be subgroups that benefit, and it is important to recognize that both the published randomized trials had small sample sizes. The authors echo the recommendation of the American College of Gastroenterology’s clinical guideline that there is a need for a further study in carefully identified patients with suspected pylorospasm.
Transpyloric Stent Placement
Given the limited data to suggest that distention or disruption of the pylorus can result in symptomatic improvement in patients with refractory symptoms related to gastroparesis, investigators at Johns Hopkins recently hypothesized that transpyloric endoscopic stent placement may improve symptoms in refractory patients with suspected pyloric dysfunction. Three cases were presented wherein a double-layered, full-covered, self-expandable metallic stent was placed through the endoscope and positioned across the pylorus, with improvement in gastric emptying and symptoms in all 3 patients. This presentation was followed by a brief report presented in abstract form only of open-label stent placement in 17 patients with refractory symptoms, with symptom improvement in 14 patients (82%) and radiographic improvement in all patients who underwent follow-up imaging. However, stent migration was a concern and long-term durability was not assessed. The investigators hypothesized that transpyloric stent placement may play a potential role as salvage therapy in patients suspected to have pyloric dysfunction with documented gastroparesis and refractory symptoms; however, further data are required to evaluate efficacy, durability, and safety. A prospective pilot study is planned; but at present, the role of this technique remains unclear until more data are available. Moreover, if benefit is proven in prospective studies, the role of the transpyloric stent will need to be defined as it could potentially serve as both therapy and as a diagnostic test/bridge before pyloromyotomy.
Surgical Pyloroplasty
Surgical pyloroplasty has been used as a gastric drainage procedure after elective vagotomy and in response to mechanical obstruction for the past 4 decades. However, reports of surgical pyloroplasty for gastroparesis are limited. Recently, Hibbard and investigators from the Oregon Clinic presented their retrospective review of 28 patients (21 idiopathic, 7 diabetic) who underwent minimally invasive pyloroplasty alone as the treatment of gastroparesis between 2007 and 2010. The operation was performed entirely laparoscopically (Heineke-Mikulicz pyloroplasty) in 26 patients. In 2 patients, a transoral endoscopic circular stapled pyloroplasty with laparoscopic assistance was used. The investigators reported a significant reduction in prokinetic use, from 89% to 14%. Gastric emptying was assessed via scintigraphy and measured via half-time. This time decreased from 320 minutes to 112 minutes and normalized in 71% of patients. Finally, symptoms improved significantly at 1-month and 3-month intervals. Overall, 83% of patients reported improvement at the 1-month follow-up.
This study was followed by several additional reports suggesting a benefit with surgical intervention directed toward pyloric disruption. Sarosiek and colleagues from Texas Tech University evaluated the addition of surgical pyloroplasty to gastric electrical stimulation for patients with symptomatic gastroparesis undergoing surgical intervention. In their study, 49 patients underwent placement of a gastric electrical stimulator and 26 of those patients also received a surgical pyloroplasty. When the patients who received both a gastric electrical stimulator and pyloroplasty were compared with the control group that received only the gastric electrical stimulator, the gastric emptying time was substantially accelerated (64% improvement vs 7% improvement). Symptoms improved in both groups. Toro and colleagues from Emory University presented their data on laparoscopic surgical pyloroplasty (hand-sewn Heineke-Mikulicz configuration) from 2006 through 2013. Of the 50 patients who underwent surgical intervention, 34 (68%) had prior foregut surgery and 32 (64%) underwent concomitant procedures along with pyloroplasty. Postoperative symptom improvement was reported in 82%. The gastric emptying time was measured by scintigraphy and recorded via half-time. This time decreased from 180 minutes to 60 minutes postoperatively. The readmission rate was 14%, but no patients required conversion to an open procedure or had reported intraoperative complications. Finally, Datta and investigators from the University of Pennsylvania recently reported on their experience with rescue pyloroplasty for the treatment of delayed gastric emptying after esophagectomy. They also performed a Heineke-Mikulicz pyloroplasty and reported on 13 patients who had refractory symptoms despite medical therapy. In addition, before surgery, these patients had undergone 3.4 ± 1.0 endoscopic balloon dilatations and 7 patients (54%) received intrapyloric botulinum toxin injection. After pyloroplasty, nausea, vomiting, bloating, prokinetic use, and parenteral/enteral nutrition dependence decreased. Nine of the 13 patients were identified as pyloroplasty treatment successes.
Putting this information together, there does seem to be decent data to suggest that surgical pyloroplasty can accelerate gastric emptying and improve symptoms in select patients with a suspicion for pyloric dysfunction and refractory symptoms, with the 2 largest studies to date reporting clinical improvement in 82% and 83% of patients, respectively. However, to date, there are no randomized trials evaluating surgical pyloroplasty for delayed gastric emptying; most of the published literature seems to focus on gastroparesis related to an underlying postsurgical cause. Although promising, more data are needed.
Endoscopic Pyloromyotomy
Given recent advancements in submucosal endoscopic dissection techniques, endoscopic myotomy has now become possible. Kawai and colleagues evaluated the feasibility and reported the first animal experiments evaluating endoscopic pyloromyotomy in 8 pigs in 2012. The first human report was from Khashab and colleagues at Johns Hopkins in late 2013. They reported on a single patient with diabetic gastroparesis with multiple hospitalizations related to refractory nausea and vomiting. She underwent placement of a transpyloric stent with resolution of symptoms, but her symptoms recurred several weeks afterward in the context of stent migration. She refused surgical intervention, and after much discussion the decision was made to proceed with endoscopic pyloromyotomy. There were no procedural complications, and the patient was discharged home after 48 hours. At the 12-week follow-up, her symptoms were markedly improved. Postprocedure imaging showed delayed gastric emptying; however, a preprocedure comparison was not available, as she had been vomiting too profusely to tolerate gastric scintigraphy. This initial report was followed by a second report evaluating endoscopic pyloromyotomy in a 38-year-old woman with postsurgical gastroparesis from Chaves and colleagues from Brazil in early 2014 and by a third report in a 54-year-old woman with postesophagectomy gastroparesis from Chung and colleagues in France.
Most recently, Shlomovitz and colleagues from Oregon reported on their experience with 7 patients (4 idiopathic, 2 postsurgical, 1 normal gastric emptying). Technical success was reported in all 7 with no immediate procedural complications, although one patient had a gastrointestinal bleed 2 weeks after the procedure and required endoscopic clipping of a pyloric channel ulcer and one patient developed a hospital-acquired pneumonia. All of the patients also underwent concomitant procedures and, because of this, 6 procedures were performed under laparoscopic guidance (with the seventh procedure being purely endoscopic). Three-month follow-up gastric emptying studies were available for 5 of 7 patients at the time of publication and showed normalization of gastric emptying in 4 of 5 patients (80%) at 4 hours. Six of 7 patients reported significant improvement in symptoms. The lone nonresponder underwent laparoscopic pyloroplasty, which also failed to significantly improve her symptoms.
At present, endoscopic pyloromyotomy seems to be in its infancy; however, given the rapid expansion of per-oral endoscopic myotomy for achalasia and the similar technical skills required, one can assume that this will become more feasible and more widely available in upcoming years. Further data, preferably prospective and controlled, are needed to show efficacy, safety, and durability.
Summary
Gastroparesis is defined by the presence of symptoms in the context of delayed gastric emptying; however, it is clear that multiple mechanisms are likely involved and that there are likely distinct clinical subgroups that may respond more optimally to tailored therapy. Scintigraphy is an imperfect test with loose correlation between gastric emptying, symptoms, and therapeutic response. Pyloric dysfunction may play a role in a subset of patients with gastroparesis. In the past, the diagnosis of pyloric dysfunction was limited because of the technical limitations of pyloric manometry and lack of widespread availability of this technology. However, with the increasing use of high-resolution manometry, the wireless motility capsule, and impedance planimetry, the armamentarium of pyloric evaluation has significantly changed; there may now be the potential to evaluate the pylorus in a manner not previously possible. On the other side of the equation, treatment of pyloric dysfunction has become more robust. Although the use of botulinum toxin is controversial and has not shown a benefit in randomized trials, transpyloric stent placement and pyloroplasty (laparoscopic and endoscopic) are emerging options with good preliminary data.
It is an exciting time for investigators of gastroparesis, and the next steps from the angle of pyloric dysfunction seem clear. Prospective studies need to be done evaluating the diagnostic technologies detailed earlier in well-defined clinical cohorts who are followed prospectively long-term. Therapeutic trials need to be done evaluating the new treatment options for pyloric dysfunction in a prospective randomized controlled fashion. Ideally, the patients entering these trials should also have a thorough pyloric diagnostic evaluation to determine whether any distinct clinical subgroups can be identified who preferentially derive treatment from these modalities. The developments that we have seen in the last few years are very exciting, but they are just a harbinger of what is to come.
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