Advertisement
Original article Clinical endoscopy: Editorial| Volume 90, ISSUE 5, P761-762, November 2019

Download started.

Ok

Pyloric interventions for gastroparesis: Does a “flippant” approach help us select the right patients?

      Abbreviations:

      BoNT (botulinum toxin), FLI (functional luminal imaging), G-POEM (gastric peroral endoscopic myotomy)
      Gastroparesis is a chronic and generally unrelenting disorder that wreaks havoc with the lives of patients, many of whom are young women in their prime. Pharmacologic approaches offer partial symptomatic relief, but patients often continue to suffer. This has understandably led to a variety of alternative approaches, including surgical or minimally invasive interventions, none of which have really been shown to be effective. In recent years, such approaches have targeted the pylorus, based on an appealing, but yet to be truly validated, hypothesis that pyloric dysfunction impedes gastric emptying, largely based on the seminal findings by Mearin and colleagues
      • Mearin F.
      • Camilleri M.
      • Malagelada J.R.
      Pyloric dysfunction in diabetics with recurrent nausea and vomiting.
      from the Mayo Clinic, who first identified “pylorospasms” in patients with gastroparesis. This has led many to the analogy that if achalasia can be treated successfully by ablating the distal (lower) sphincter in the esophagus, then gastroparesis should also respond to a reduction in pyloric sphincter pressure.
      Borrowing from the achalasia tool kit, investigators have therefore tried dilation, botulinum toxin (BoNT), and, more recently, gastric peroral endoscopic myotomy (G-POEM). Of these, BoNT injections into the pylorus have been the most well studied. Two randomized controlled trials (albeit small) showed no difference in the clinical outcome after BoNT and saline solution injections.
      • Arts J.
      • Holvoet L.
      • Caenepeel P.
      • et al.
      Clinical trial: a randomized-controlled crossover study of intrapyloric injection of botulinum toxin in gastroparesis.
      • Friedenberg F.K.
      • Palit A.
      • Parkman H.P.
      • et al.
      Botulinum toxin A for the treatment of delayed gastric emptying.
      The most simple explanation, of course, is that the “pyloric hypothesis” is wrong and that the pathophysiologic basis of symptoms in gastroparesis is far more complex, comprising loss of proximal accommodation, contractile defects in the body and antrum, and sensory (vagal and spinal) neuropathy. Therefore, it is not surprising that unlike the dysphagia experienced by patients with achalasia, gastroparesis symptoms (nausea, vomiting, fullness, early satiety, pain) may not respond to a simple reduction in outflow resistance, regardless of how robust the intervention is.
      Nevertheless, interest in targeting the pylorus has not flagged, perhaps because of a mixture of therapeutic zeal and patient desperation. Advocates of this approach have argued that the failure of pyloric injections of BoNT may be due to many other factors, chief among which is the inability to identify patients in whom pyloric dysfunction is the dominant pathophysiologic feature.
      • Pasricha T.S.
      • Pasricha P.J.
      Botulinum toxin injection for treatment of gastroparesis.
      In this regard, the limiting factor has been the lack of a convenient and reliable tool to measure pyloric function. The use of antroduodenal manometry, which was how “pylorospasms” were first identified in gastroparesis, is unfamiliar to most endoscopists and is limited to a few medical centers. More recently, attention has turned to functional luminal imaging (FLI), which uses balloon-based impedance planimetry, another technology first developed for the esophagus and embodied in the commercially available probe called endoFLIP. FLI can measure the cross-sectional area and pressure of any segment of the gut, allowing for the calculation of “distensibility,” which arguably is a more relevant metric than simple static pressures. It has shown promise for both expanding our understanding of the causes of dysphagia and predicting responses to lower esophageal sphincter targeting.
      • Hirano I.
      • Pandolfino J.E.
      • Boeckxstaens G.E.
      Functional lumen imaging probe for the management of esophageal disorders: expert review from the Clinical Practice Updates Committee of the AGA Institute.
      Although its use in gastroparesis is in its infancy, FLI has revealed decreased pyloric distensibility in these patients and may correlate with multiple gastroparetic symptoms, quality of life, and, to some extent, delays in gastric emptying.
      • Gourcerol G.
      • Tissier F.
      • Melchior C.
      • et al.
      Impaired fasting pyloric compliance in gastroparesis and the therapeutic response to pyloric dilatation.
      • Malik Z.
      • Sankineni A.
      • Parkman H.P.
      Assessing pyloric sphincter pathophysiology using EndoFLIP in patients with gastroparesis.
      • Snape W.J.
      • Lin M.S.
      • Agarwal N.
      • et al.
      Evaluation of the pylorus with concurrent intraluminal pressure and EndoFLIP in patients with nausea and vomiting.
      With this as background, Desprez et al,
      • Desprez C.
      • Melchior C.
      • Wuestenberghs F.
      • et al.
      Pyloric distensibility measurement predicts symptomatic response to intrapyloric botulinum toxin injection.
      reporting in the current issue of this journal, studied the effects of intrapyloric BoNT in 35 patients with gastroparesis, all of whom had FLI measurements before the injection. Using their previous “cutoff” of a distensibility index of 10 mm2/mm Hg,
      • Gourcerol G.
      • Tissier F.
      • Melchior C.
      • et al.
      Impaired fasting pyloric compliance in gastroparesis and the therapeutic response to pyloric dilatation.
      they found that 19 patients (a little over half) had impaired pyloric compliance. In this subset of patients, total symptom score decreased significantly at 3 months, but no improvement was seen in patients with normal pyloric distensibility. Of note, nausea did not improve in the former group, although fullness and bloating did, along with an improvement in quality-of-life scores. A modest improvement in gastric emptying (<20%) was also seen in the low-distensibility group, although average values in the former group still remained far above normal.
      The authors are to be congratulated for continuing to pursue a rational pathophysiologic approach to the treatment of gastroparesis, and their study provides valuable additional information on the putative role of pyloric dysfunction as a cause of symptoms. But, as they suggest, did pyloric distensibility really predict symptomatic and quality-of-life responses after BoNT injection? To agree with this, we would need to see a responder analysis by subgroups (ie, how many patients in each group would be considered to have experienced meaningful improvement), which the authors did not provide, probably because the symptom score they used is not validated so a minimally important clinically important difference is not known. However, from Figure 2 in the article it is clear that some patients in the low-distensibility group did not show any change in their scores, whereas a few in the normal-distensibility group showed lower scores (and in at least 1 case, dramatically). An alternative approach would have been to provide some kind of sensitivity analysis by varying the distensibility cutoff: the authors report no difference when they lowered it to 8 or 9 mm2/mm Hg, but it would have been important to study the outcome after it was raised to 11 or 12 or higher, to inspire confidence that the value of 10 is truly discriminatory.
      Perhaps most importantly, we do not know what the posttreatment sphincter distensibility was in these patients. As with the lower esophageal sphincter in achalasia, posttreatment sphincter measurements may correlate best with long-term outcome.
      • Khashab M.A.
      • Besharati S.
      • Ngamruengphong S.
      • et al.
      Refractory gastroparesis can be successfully managed with endoscopic transpyloric stent placement and fixation (with video).
      This is particularly true for a treatment such as BoNT, which may or may not always lower the sphincter tone. Thus, it can be argued that patients with “normal” distensibility may have not shown the expected pharmacologic response to BoNT, for technical or physiologic reasons, which is why their emptying also did not improve.
      Therefore, we can conclude from this study that as a group, patients with lower distensibility have a better outcome on the average. This could be a simple chance association or a true causal relationship; at this point; we just do not know. Further, these results do not allow us to use pretreatment pyloric distensibility in an individual patient to calculate the odds of improvement. Nevertheless, this study is an important step forward to sustain the “pyloric hypothesis,” and the results should inspire investigators to come up with even more informative study designs on targeted interventions, including BoNT, and the even more investigative procedure of G-POEM. These studies should include larger numbers, the ability to define a true responder, the establishment of clinically relevant normative values for FLI (including pre- and posttreatment) gastric metrics, and, most importantly, sham control individuals. These are difficult and expensive studies to perform, but they are sorely needed if we are to make meaningful advances in this area. In the absence of such evidence, we cannot and should not promote pyloric interventions for our patients outside of research protocols.

      Disclosure

      The author disclosed no financial relationships relevant to this publication.

      References

        • Mearin F.
        • Camilleri M.
        • Malagelada J.R.
        Pyloric dysfunction in diabetics with recurrent nausea and vomiting.
        Gastroenterology. 1986; 90: 1919-1925
        • 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: 1251-1258
        • Friedenberg F.K.
        • Palit A.
        • Parkman H.P.
        • et al.
        Botulinum toxin A for the treatment of delayed gastric emptying.
        Am J Gastroenterol. 2008; 103: 416-423
        • Pasricha T.S.
        • Pasricha P.J.
        Botulinum toxin injection for treatment of gastroparesis.
        Gastrointest Endosc Clin N Am. 2019; 29: 97-106
        • Hirano I.
        • Pandolfino J.E.
        • Boeckxstaens G.E.
        Functional lumen imaging probe for the management of esophageal disorders: expert review from the Clinical Practice Updates Committee of the AGA Institute.
        Clin Gastroenterol Hepatol. 2017; 15: 325-334
        • 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: 360-367
        • Malik Z.
        • Sankineni A.
        • Parkman H.P.
        Assessing pyloric sphincter pathophysiology using EndoFLIP in patients with gastroparesis.
        Neurogastroenterol Motil. 2015; 27: 524-531
        • Snape W.J.
        • Lin M.S.
        • Agarwal N.
        • et al.
        Evaluation of the pylorus with concurrent intraluminal pressure and EndoFLIP in patients with nausea and vomiting.
        Neurogastroenterol Motil. 2016; 28: 758-764
        • Desprez C.
        • Melchior C.
        • Wuestenberghs F.
        • et al.
        Pyloric distensibility measurement predicts symptomatic response to intrapyloric botulinum toxin injection.
        Gastrointest Endosc. 2019; 90: 754-760
        • Khashab M.A.
        • 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: 1106-1109

      Linked Article