Third space endoscopy (TSE) has emerged as a natural orifice transluminal endoscopic surgery (NOTES) procedure for the treatment of a variety of GI disorders. In addition to the “classic” per-oral endoscopic myotomy (POEM) for achalasia, TSE encompasses a breadth of procedures such as submucosal tunnelling endoscopic resection (STER) for subepithelial tumours, peroral endoscopic pyloromyotomy (POP)/or gastric POEM (G-POEM) for gastroparesis, POEM for Zenker's diverticulum (Z-POEM) or any diverticulum (D-POEM), per-rectal endoscopic myotomy (PREM) for Hirschsprung's disease and peroral endoscopic tunnelling for restoration of oesophagus (POETRE) for oesophageal strictures.

POEM, the prototypical procedure, and the precursor of all other per-oral endoscopic myotomies, evolved from the experience of endoscopic submucosal dissection (ESD) and submucosal tunnelling with a mucosal flap. Since first described [1,2], POEM has thrived and risen to the forefront vying with laparoscopic Heller myotomy (LHM) as a safe and effective treatment option for achalasia [3]. Concurrently, the widespread use of POEM and its diversification to include extended indications (spastic oesophageal disorders, oesophageal diverticula …) and at locations other than the oesophagus has provided an insight into the potential complications encountered. This has prompted several societies to publish practice guidelines regarding some of these TSE procedures [[4], [5], [6], [7], [8], [9], [10]].

POEM is a standardized procedure that follows four sequential steps: 1- mucosal incision, 2- submucosal tunnelling, 3- selective or complete myotomy and 4- closure of access mucosotomy. Thereupon, the mucosal layer, post-myotomy, becomes the sole barrier separating the mediastinum/peritoneum from the gut lumen. As such, each of the 4 steps should be carried meticulously as failure to do so may create complications that, if left unrecognized, engender serious adversity. Furthermore, the uniqueness, complexity, and invasiveness of TSE fosters distinct challenges not typically encountered during lumenal endoscopy.

The purpose of this review is to highlight pitfalls and complications related to TSE, to help recognize the risk factors that may lead to adverse events (AEs) and to recommend appropriate salvage interventions in the scope of the current evidence. Given that the realm of TSE is substantial, and the pertinent topics are expansive, the review will particularly focus on POEM-the epitome of TSE. Comments will be made regarding certain TSE procedures when specific attention is thought to be necessary, or interventions to be particular to that specific procedure.