Clinical Case

Nitin K. Ahuja, MD, MS

50-year-old woman was referred to the neurogastroenterology and motility clinic with a chief complaint of nausea and vomiting, present and progressive for the past year. She had a history of well-controlled diabetes and multiple myeloma status post stem cell transplant. From a baseline weight of 300 pounds, she had lost 150 pounds over the prior year. A gastric emptying test performed a few months prior revealed approximately 80% meal retention at 4 hours. A @nitinkahuja

She had tried multiple medications without symptomatic benefit, including prokinetics (metoclopramide, prucalopride), antinauseants (ondansetron, promethazine, lorazepam, scopolamine, dronabinol), and neuromodulators (olanzapine, buspirone). Additionally, a history of QTc prolongation (550 msec) had made her provider team reluctant to consider other agents. At the end of our visit, a decision was made to pursue an EGD with pyloric botulinum toxin injection and, if unhelpful, consideration of an enteral feeding tube. She was admitted to the hospital shortly thereafter for symptom exacerbation, and an EGD with botulinum toxin injection (200 units in a four-quadrant distribution) was performed on an inpatient basis (Figure 1).

Figure 1. Pre-pyloric stomach above); pylorus s/p 200 unit botulinum toxin injection (below)

She was discharged tolerating an oral diet without difficulty. In clinic followup one month later, she reported significant and persistent symptom improvement and had gained back close to 20 pounds. In light of slowly recurrent symptoms, a repeat pyloric Botox injection was performed six months later, again with marked benefit.

The therapeutic use of botulinum toxin in gastroparesis remains controversial. Its first published use at the pylorus was in 1998 (three years after the first report of botulinum toxin being successfully used at the lower esophageal sphincter in achalasia). Open-label case series of pyloric botulinum toxin injection have shown a substantial rates of symptom benefit, often just shy of 50%, though the effects are reliably temporary (usually on the order of months). Two small randomized controlled trials, however, showed no significant benefit of pyloric botulinum toxin injection for either gastroparesis symptoms or gastric emptying when compared to a saline placebo.

On the basis of the RCT data, current society guidelines recommend against offering botulinum toxin as conventional gastroparesis therapy. The skeptic’s reading of these data, however, is that they may have been underpowered (n=32 in the larger of the two RCTs) to detect significant differences between study arms, particularly given that pyloric dysfunction likely affects only a minority of the gastroparesis population at large. Recognizing that gastric emptying delay elides a wide range of organ-specific pathology, including gastric dysrhythmia, impaired fundic accommodation, and sensory neuropathy, many gastroparesis patients are simply not predisposed to respond to botulinum toxin injection at a mechanistic level (Figure 2).

not predisposed to respond to botulinum toxin injection at a mechanistic level (Figure 2).

Motility Program at the University of Pennsylvania, we utilize a range of techniques in both clinical and research contexts – including FLIP, botulinum toxin, G-POEM, electrical stimulation, and various approved and investigational medications – in order to better understand and manage this complex cohort of patients.

Figure 2. Pyloric dysfunction is one of several potential mechanisms for the clinical manifestations of gastroparesis.

Additional technologies directed toward pyloric dysfunction in gastroparesis have been developed with variable success. Published case series of pyloric stents demonstrated reasonable rates of clinical response but were associated with significant practical challenges related to stent migration. More recently, exciting results have emerged from the paradigm of gastric per-oral endoscopic myotomy (G-POEM), though data thus far remain limited to aggregated case series. Diagnostically, novel tools like the functional lumen imaging probe (FLIP) have been studied as a means of identifying pyloric dysfunction in gastroparesis, thus enriching the population poised to benefit from pyloric therapy. Anecdotally, symptomatic response to botulinum toxin is often used as a retrospective marker of pyloric dysfunction, though the ability of such responses to predict benefit from more definitive procedures like G-POEM remains unproven.

Particularly in the context of a diagnosis like gastroparesis, providers are reasonably inclined to maintain a grasp on any therapeutic option that may offer potential benefit, including those undermined by ostensibly rigorous trials. Research is active and ongoing at our institution and elsewhere into the optimal approach to recognizing and treating pyloric dysfunction in gastroparesis. Within the Neurogastroenterology and

References 1. Bromer MQ, Friedenberg F, Miller LS, et al. Endoscopic pyloric injection of botulinum toxin A for the treatment of refractory gastroparesis. Gastrointest Endosc 2005;61:833-9. 2. Arts J, Holvoet L, Caenepeel P, et al. Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis. Aliment Pharmacol Ther. 2007;26(9):1251-8. 3. Friedenberg FK, Palit A, Parkman HP, et al. Botulinum toxin A for the treatment of delayed gastric emptying. Am J Gastroenterol 2008;103:416-23. 4. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108(1):18-37. 5. Khashab MA, Besharati S, Ngamruengphong S, et al. Refractory gastroparesis can be successfully managed with endoscopic transpyloric stent placement and fixation (with video). Gastrointest Endosc 2015;82:1106-9. 6. Dacha S, Mekaroonkamol P, Li L, et al. Outcomes and quality-of-life assessment after gastric per-oral endoscopic pyloromyotomy (with video). Gastrointestinal Endoscopy 2017; 86(2): 282-89. 7. Gourcerol G, Tissier F, Melchior C, et al. Impaired fasting pyloric compliance in gastroparesis and the therapeutic response to pyloric dilatation. Aliment Pharmacol Ther 2015;41:360-7.