Third-space endoscopy – can we see light at the end of the tunnel?Referring to Kahaleh M et al. p. 1053–1058
06 November 2018 (online)
“Third-space endoscopy” as a term was coined by Khashab and Pasricha in 2013 . Also called “submucosal endoscopy,” this endoscopic procedure is unique in that it utilizes the principle of a mucosal-flap valve to create a tunnel in the potential submucosal layer via a proximally placed mucosal incision. This access route is then used to operate in the deeper layers of the gastrointestinal (GI) tract; following which the incision is closed using endoscopic clips.
“The true challenge however is to identify the optimum patient likely to benefit from G-POEM. To date, no study has addressed this issue effectively.”
When Sumiyama et al.  reported the first submucosal tunneling for access to the peritoneal cavity and Pasricha et al.  took the idea forward by performing endoscopic submucosal tunneling and myotomy in porcine models, little did one realize the stage that had been set for the forthcoming decade of interventional endoscopy. Inoue et al.  reported the first human peroral endoscopic myotomy (POEM) for achalasia cardia in 2010. Endoscopists worldwide responded with both awe and skepticism. A decade has elapsed since then. In these 10 years, POEM has been criticized, embraced, loved, and finally accepted as a valid treatment modality for achalasia, albeit with some concerns about post-POEM gastroesophageal reflux disease (GERD) .
The unprecedented success of POEM led to the advent of a variety of third-space endoscopic procedures. Endoscopic submucosal pyloromyotomy was conceptualized in porcine models by Kawai et al. in 2012 , and this was followed by the first human pyloromyotomy (G-POEM) for refractory gastroparesis, which was reported by Khashab et al. in 2013 . The same principle has also been reported for endoscopic submucosal septotomy for Zenker’s diverticulum (STESD)  and for endoscopic myotomy of the spastic rectosigmoid aganglionic segment in Hirschsprung’s disease (per-rectal endoscopic myotomy [PREM]) . In addition, subepithelial lesions are being resected by submucosal tunnelling endoscopic resection (STER) .
In this current issue of Endoscopy, Kahaleh et al. report the results of G-POEM for refractory gastroparesis in a single-arm retrospective multicenter cohort of 33 patients . Short- and medium-term results demonstrate an impressive 85 % symptom relief at a median of 11.5 months post-procedure with few mild adverse events (2/33; 6 %). These results concur with the results of our earlier similar multicenter study of 30 patients, which reported 86 % clinical success and a 7 % rate of mild adverse events at a median of 5.5 months . An additional significant outcome of the current study is the sustained response at long-term follow-up of nearly 1 year. However, is it all that simple?
Gastroparesis is a complex disorder wherein impaired gastric dysmotility and pylorospasm both play a variable role in its pathophysiology. Impaired gastric body motility is likely the primary cause for diabetic gastroparesis (autonomic neuropathy), whereas pylorospasm may be an important factor in post-operative gastroparesis (after vagal injury or vagotomy). Notably, Gonzalez et al.  have reported inferior results of G-POEM for diabetic gastroparesis as compared with either post-surgical or idiopathic gastroparesis (57 % vs. 80 % and 93 % at 3 months; 43 % vs. 50 % and 92 % at 6 months). Diabetes and female sex were found to be predictors of failure in univariate analysis. Although this was not confirmed in multivariate analysis (owing to small sample size), the study raised concerns about the efficacy of G-POEM in patients with diabetes. Another study by Dacha et al.  reported that all three of their failures occurred in patients with diabetic gastroparesis. Unfortunately, the current study does not present subgroup analysis of the outcomes.
The diagnosis and evaluation of gastroparesis are predominantly based on symptoms (gastroparesis cardinal symptoms index [GCSI]); objective testing is limited to gastric emptying scintigraphy (GES). Patient symptom and satisfaction scores are often subjective and have an inherent bias because patients often modify their diet according to their symptoms. The authors report significant mean improvement in the GCSI, GES, and a reduction in the gastric retention volume as metrics of successful response. How GES improvement correlates with symptom response could be the objective of another future study.
Given these current data and that from earlier studies, G-POEM is feasible, safe, and demonstrates excellent efficacy for a certain group of patients with refractory gastroparesis. The procedure shows sustained efficacy at 1 year of follow-up. The true challenge however is to identify the optimum patient likely to benefit from this procedure. To date, no study has addressed this issue effectively. Hopefully, future research can better guide us in this regard.
Another issue requiring consideration is the incidence of duodenogastric biliary reflux that can occur after G-POEM. Based on the POEM experience, where reflux was initially under-reported but has later emerged as a significant post-POEM concern , reflux after G-POEM is likely to face a similar fate. The long-term consequences of this reflux are currently unknown. One must remember that reflux after POEM is treatable, whereas reflux after G-POEM is currently impossible to treat. However, the symptom benefit provided by G-POEM may outweigh the negative consequences of reflux in these difficult-to-treat patients.
The study by Kahaleh et al.  is important in the context that it adds significantly to the global experience of G-POEM and third-space endoscopy. However, it falls short in addressing some important issues. Several publications over the last decade have amply proven the efficacy and safety of third-space endoscopy procedures. What is necessary is for future research to be directed towards obtaining objective comparative data that enable clinicians to make decisions. High quality prospective randomized studies comparing third-space endoscopy to the standard-of-care laparoscopic techniques need to be designed. Studies must also be designed to identify the potential challenges and address any limitations of this novel specialty.
The advent of third-space endoscopy has given rise to several “unimaginable” endoscopic surgical procedures that are based on surgical principles but are being performed by surgeons and gastroenterologists alike. Optimum training and credentialing for third-space endoscopy is therefore required, especially with its increasing popularity and widespread use. Physicians need to imbibe surgical principles, hand – eye coordination skills, and must develop the vision to identify tissue planes, whereas surgeons must learn advanced flexible endoscopy skills.
In conclusion, to quote the Hollywood icon Spiderman: “With great power comes great responsibility!” Third-space endoscopy has empowered the endoscopist to operate in the third space beyond the confines of his conventional intraluminal domain. The optimum and judicious wielding of this power in the patients’ best interest remains however the sole responsibility of the endoscopist.
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