Third Space Endoscopy

Abstract

Third space endoscopy has evolved significantly over the last one decade. It refers to the endoscopic procedures performed in the space between muscularis mucosae and muscularis propria of the gastrointestinal tract. Presently it has a wide range of potential applications ranging from motility disorders treatment, submucosal tumors resection and diverticulae management. The main technique while performing third space endoscopic procedure is creating a submucosal tunnel, performing the desired procedure and closing the mucosal defects. Per oral endoscopic myotomy (POEM) is the most commonly performed third space endoscopy procedure. It has now become the procedure of choice for type 3 Achalasia Cardia and has shown comparable efficacy to laparoscopic Heller’s myotomy. This review comprehensively covers the various aspect of third space endoscopy procedure including their indication, contraindications, methods with their outcomes.

Introduction

Scar less surgery has always fascinated the surgeons and patients alike. As the technology has improved in vision and optics, laparoscopic surgery has become the mainstream. Still the incision less surgery eludes the medical field.

As the surgical field was developing, parallel development in the flexible endoscopes was going on during the period. Flexible endoscopes allowed us to go deep into the stomach and intestine to visualize the lumen. Intraluminal procedures like polypectomies and stricture dilatation are performed relatively with ease now a days with these endoscopes.

In between, there were thoughts of moving into the peritoneum from the lumen, through its wall and performing few surgical procedures [1], which was known as Natural orifice transluminal endoscopic surgery (NOTES). “NOTES” was universally handicapped by the poor closing techniques of the lumen after the procedure.

Much new advancements were practised to perfect the lumen closure technique. A mucosal flap technique was discovered where a potential space was created between muscularis mucosae and muscularis propria by injecting a fluid and expanding the space, thus allowing dissection within the space. This technique allowed the closure of the mucosal side relatively well. Soon other applications of this technique were discovered and the era of third space endoscopy started.

What Is Actually the Third Space Endoscopy?

First space refers to the lumen; Second space is outside lumen, usually peritoneal cavity. Third space refers to the potential space between muscularis mucosa and muscularis propria. Initially multiple experiments were done on animal models and the accessories and instruments were invented to perfect this technique. First POEM (Per oral endoscopic myotomy) in a human subject was first performed in 2008 [2]. Since then, POEM has become the most commonly performed third space surgery worldwide.

Many other new applications of the third space have been invented since then. These are enumerated as below:

• 1. POEM (Per Oral Endoscopic Myotomy)

• 2. Z-POEM (Zenker’s Per Oral Endoscopic Myotomy)

• 3. D-POEM (Diverticulum Per Oral Endoscopic Myotomy)

• 4. G-POEM (Gastric Per Oral Endoscopic Myotomy)

• 5. STER ( Submucosal Tunnelling and Endoscopic Resection)

Per Oral Endoscopic Myotomy (POEM)

POEM is usually done for the treatment of achalasia cardia. It can be performed as the initial procedure and also for the recurrent cases, both post endoscopic as well as post surgical achalasia management.

The indications to do POEM are [3]:

1. Achalasia (Types 1, 2 and 3)

2. Previous failed Heller’s myotomy

3. Previous failed pneumatic dilatation

4. Previous failed botulism toxin injection

5. Diffuse esophageal spasm

6. Jackhammer esophagus

The contraindications to do POEMS are [3]:

1. History of radiation therapy to esophagus

2. Previous ablation/resection of esophageal mucosa

3. Cirrhosis with portal hypertension

4. Any other comorbid condition of a patient making him/her unfit for surgery.

Preoperative evaluation: Preoperative upper gastrointestinal (UGI) endoscopy, manometry and anaesthesia work up should be done before starting the procedure.

UGI endoscopy is mainstay of diagnosis and also rules out any proximal mass lesion or stricture for which treatment might be different and YGIE also eliminates any evidence of gastroesophageal (GE) junction growth which can mimick as achalasia (secondary achalasia). Manometry is a useful tool for diagnosis as well as prognosis and can serve as an effective talisman for recovery and failure if any. In era of high definition UGI endoscopy and manometry, barium UGI series are left redundant except in very few rare situations.

Patient has to be nil per mouth for 12 h before the procedure and it is not a bad idea to place a nasoesophageal tube for lavage and suction of the residual food in the dilated oesophagus just before the procedure. Preoperative antibiotics should be started 12 h before the procedure.

Using room air for doing POEM procedures may lead to more incidences of pneumomediastinum, gas embolism and cardiac arrest. Thus POEM is typically performed using the carbon dioxide gas. General anaesthesia and endotracheal intubation is advocated to minimize any risk of aspiration.

Instruments Required:

• 1. Flexible UGI endoscope preferably with HD vision.

• 2. Electrosurgical unit

• 3. Water Jet

• 4. CO2 insufflator

• 5. Transparent distal cap attachment

• 6. Saline mixed with methylene blue or indigo carmine

• 7. J knife (Fig. 1)

• 8. Soft Coagulation grasper forceps

• 9. Hemoclips

Fig. 1

J knife (Inset showing tip of J Knife used for dissection)

Steps of Poem

Mucosal Incision: A high definition scope with an attached distal cap is inserted into the esophagus. The first step is to identify the site of mucosal incision.

Two types of approaches are described (Anterior & Posterior). Posterior approach is usually done at a 5 o’clock position just adjacent to the spine impression around 8–10 cm proximal to GEJ junction. In the anterior approach, mucosal incision is made at 2 o’ clock position approximately 8–10 cm proximal to GEJ junction. Both the approaches are similar in most aspects and considered equally effective for the treatment of achalasia [4]. However in a patient of previously failed surgical Heller’s myotomy, a posterior approach is favoured. In spasmodic disorders of oesophagus a more proximal site is chosen as the myotomy in these cases can be quite long.

At the pre-decided site of mucosal incision, mucosal injection of saline mixed with methylene blue or indigo carmine is done to create a submucosal bleb (Fig. 2). This step raises the mucosa over the muscularis propria. It thus provides a space to make an incision limited to mucosa and submucosa but not reaching up to the muscularis propria as it provides a cushion effect. After raising this submucosal bleb a linear incision is made using the knife and electrosurgical cautery (Fig. 3). Careful dissection of the surrounding submucosal tissue is done to facilitate the entry of scope into the submucosal area. The edges of the mucosal incision site may be trimmed with electrosurgical cautery to prevent bleeding and later facilitating easy mucosal closure.

Fig. 2

Submucosal bleb after methylene blue or indigo carmine

Fig. 3

Linear mucosal incision

Creation of submucosal tunnel: A submucosal tunnel is then created with the dissection of submucosal tissue (Fig. 4). The submucosal tissue is also injected with saline mixed with methylene blue to facilitate dissection. Dissection is done with a knife using an electrosurgical unit. Maintaining orientation is of utmost importance during this step. Utmost care should be taken to preserve the mucosal integrity. Any large vessel seen is coagulated by soft coagulation grasper. The submucosal tunnel is extended till 3–5 cm from the gastroesophageal junction (GEJ). The GEJ is identified by appearance of small blood vessels, longitudinal muscle fibres and narrowing of the submucosal space. This can be confirmed during endoscopy by the blanching of mucosa just below cardia. If the endoscopist doesn't want to remove his scope from the tunnel then another ultrathin scope can be passed by the side and blanching below cardia can be noted to see the adequacy of submucosal tunnel length.

Fig. 4

Creation of sub mucosal tunnel (Image Courtesy: Dr Pravin Suryavanshi)

Myotomy: After creating this submucosal tunnel, Myotomy is performed (Fig. 5). The circular muscle fibres are cut starting 3–4 cm above GEJ and till 2 cm below GEJ. Ideally selective circular fibre myotomy is performed but it becomes really difficult to distinguish between circular and longitudinal fibres. Endoscopist many times perform a full thickness myotomy as no difference is seen between partial thickness and full thickness myotomy [5]. It is more important to maintain mucosal integrity rather than worrying about the myotomy thickness. Adequate myotomy can be assessed by the ease of passing scope across the GE junction.

Fig. 5

Creation of myotomy (Image Courtesy: Dr Pravin Suryavanshi)

Closure: After doing the myotomy, a careful examination of the submucosal tunnel is done to rule out any bleeding sources or any site of mucosal injury. The scope is taken out from the submucosal tunnel and the mucosal incision site is closed using clips (Fig. 6). Adequate closure is essential to prevent contamination of the submucosal tunnel or mediastinum.

Fig. 6

Closure of mucosal incision

Methods used to close the mucosal incision are

• Clips

• Endoscopic suturing

• OTSC (Over the scope clip)

Usually, hemoclips are most commonly used given that they are cheaper, easily applicable and removable. Endoscopic suturing is relatively new technique, yet to be easily available commercially. Over the scope clip is a recent addition in clips which has to be loaded on scope, their cost and difficulty in removing if misfired has limited their use.

The patient can be kept nil by mouth for next 12 h. A gastrografin swallow is done to rule out any leak. Patients can be started orally on a soft diet after 48 h. Oral antibiotics should be prescribed for the next 7 days and Proton Pump inhibitors should be advised for the next 2 weeks. Figure 7 is a schematic diagram of the space of dissection in POEM (Fig. 7).

Fig. 7

Schematic diagram showing space of dissection in PEOM

Outcomes of Poem

POEM has now established itself as a safe and reliable surgery for achalasia cardia. Multiple meta-analyses of various studies have been done now. Clinical success reported is around 98% in one year follow up [6]. In the long-term results have shown a sustained clinical efficacy of 83–95% [7, 8].

Adverse Effects of POEM

POEM is very safe procedures as the incidence of serious adverse effects are very low [6]. The adverse effects may be due to:-

• a. Insufflations related adverse effects: Use of carbon dioxide decreases the events related to insufflation. Still complications commonly associated with POEM procedures are subcutaneous emphysema (7.5%), pneumothorax (1.2%), pneumomediastinum (1.1%), and pneumoperitoneum (6.8%) [8]. Usually these adverse effects have no clinical significance and rarely require any intervention or change in management. If there is a clinically significant pneumo-peritoneum or pneumo-mediastinum it may require decompression by needle insertion.

• b. Mucosal injuries (Figs. 8 and 9 ): During POEM, mucosa is the only barrier left between the lumen and mediastinum/ peritoneum. Any potential breach in this barrier may lead to infection of these spaces. So it is of utmost importance to maintain the integrity of these spaces. But even after taking outmost care, mucosal injuries do occur during POEM procedure. The incidence of mucosal injuries is 4.8% during a POEM procedure [8]. These occur most commonly during the learning curve of the endoscopist with the most common site being near the gastroesophageal junction as there is very less space between muscle layer and mucosal layer. Mucosal injuries range from just discoloration of the mucosal surface to complete damage to the mucosa. Every effort should be taken to carefully inspect the mucosal surface after completion of the procedure. If mucosal breach is detected then the closure should be done using the hemoclips. Larger defects can be closed using the “Over The Scope Clips” (OTSC) or by using endosutures. Rarely surgery may be required to manage much larger defects.

• c. Bleeding: POEM involves a lot of cutting and dissection. Bleeding can occur at any step of mucosal incision, dissection of submucosal tissue or during myotomy. Most of the bleeding is minor and can be controlled with the electro cautery knife itself. If any large calibre vessels, especially near gastroesophageal junction is encountered they can be handled using a coagulation forceps. Bleeding requiring any further intervention or blood transfusion is extremely rare and occurs in only 0.2% of cases [8].

• d. Pain: Pain after POEM procedure is described in up to 79% of the patients in the postoperative period [8]. It is usually mild and can be easily managed by using Non-Steroidal Anti Inflammatory Drug (NSAID)or by Paracetamol.

• e. Aspiration Pneumonia: The incidence of aspiration is usually low but can occur in 0.1% of the patients [8]. These can be prevented by keeping the patient on a liquid diet for two days prior to the procedure. Any residual liquid should also be sucked out prior to the mucosal incision.

• f. Infections: Loss of mucosal barrier can lead to introduction of bacteria into the third space and cause infection. It may lead to dangerous complications like mediastinitis, empyema, pleural effusion requiring drainage or pneumonia.

• g. Gastro Esophageal Reflux Disease (GERD): All treatment options of achalasia management have GERD as a potential adverse effect. Various studies have shown that GERD is an adverse effect in the range of 13–88% [9,10,11], but clinically significant GERD is less common. Erosive esophagitis occurs in 7 - 50% of the patients [9]. Most of these patients can be managed with long term Proton Pump Inhibitors (PPI).

Fig. 8

Mucosal rent at EG junction (Image Courtesy: Dr Pravin Suryavanshi)

Fig. 9

Mucosal rent from submucosal site (Image Courtesy: Dr Pravin Suryavanshi)

Comparison of POEM vs Laparoscopic Heller’s Myotomy

Traditionally in recent decades Laparoscopic Heller’s Myotomy (LHM) is regarded as the gold standard for treatment of achalasia. Pneumatic balloon dilatation was the only endoscopic method available but wasn’t very effective.

There are several meta-analysis now comparing the efficacy of POEM procedure with other methods [10, 11] where it has been shown that postoperative dysphagia resolution is better with POEM than LHM [12]. POEM is found to be superiorto LHM in management of type 3 achalasia and other esophageal spasmodic disorders as the length of myotomy in POEM can be increased in these cases. Therefore it is now the management of choice in type 3 achalasia and esophageal spasmodic disorders. It is equal to LHM in management of Type 1 and Type 2 achalasia.

There is no difference in GERD symptoms between POEM & LHM, but erosive esophagitis secondary to reflux tends to be more common after POEM [12].

Z-POEM (Zenker’s Per Oral Endoscopic Myotomy)

Z-POEM is used for the treatment of Zenker’s diverticulum [13]. Zenker’s diverticulum is a pulsion diverticulum at the upper end of the esophagus. It can lead to dysphagia and can also lead to aspiration. The usual treatment of Zenker’s diverticulum has been by open surgery and septostomy using either endoscopy or flexible endoscopy. Third space endoscopy technique is now being also used in management of Zenker’s diverticulum. In this technique, a submucosal tunnel is created on the septum and the muscular septum is cut beneath the mucosa. The advantage of Z-POEM over the endoscopic septostomy is that the muscular septum can be cut for a longer length and thus chances of recurrence are lesser as compared to the septostomy (Fig. 10). However, the success rate of endoscopic septostomy is 91% which is similar to that of Z-POEM which is around 92% [13]. Recurrences can be successfully managed by a repeat septostomy.

Fig. 10

Schematic diagram showing site of myotomy in Zenker’s Diverticulum

D-POEM (Diverticulum Per Oral Endoscopic Myotomy)

D-POEM is used for management of esophageal diverticula other than the Zenker’s diverticulum. It is simple, safe and effective to relieve symptoms such as dysphagia, reflux and chest pain caused by esophageal diverticulum, while avoiding invasive surgery. The technique is similar to Z-POEM. Here after creating the submucosal tunnel, the muscular septum is divided and then the mucosal incision site is closed.

G-POEM (Gastric Per Oral Endoscopic Myotomy)

After the success of POEM in achalasia, a similar procedure was developed for the management of gastroparesis in the stomach, where a submucosal tunnel is created from 7 to 8 cm proximal to pylorus and pyloromyotomy is done (Fig. 11) [14]. The results are so far good in gastroparesis but not for diabetic patients. So a careful evaluation and selection of patients is mandatory before doing this procedure. As in POEM where GERD is a major symptom post procedure, bile reflux is a common sequel after G-POEM.

Fig. 11

Schematic diagram showing G-POEM being done

STER (Sub Mucosal Tunnelling and Endoscopic Resection)

Subepithelial tumours in GI tract are traditionally removed when the size is more than 3 cm. With the advent of third space endoscopy technique a submucosal tunnel is created 4–5 cm proximal to the lesion and the lesion is dissected from the surrounding tissue using electrosurgical knives. The tumour is then removed through the mucosal opening site. This technique can be challenging if the tumour is located in fundus or lesser curvature of the stomach, tumour is larger >4.5 cm in size, tumour is multilobulated or adherent to the deep structures.

Conclusion

Third space endoscopy has evolved over the last decade after the introduction of the first case of POEM in 2008. It is now the method of choice for the type 3 achalasia and other esophageal spasmodic disorders. For the management of type 1 and type 2 achalasia also it compares equally with LHM. Third space endoscopy is evolving in the management of oesophageal diverticula and gastroparesis. STER is now being routinely performed for excision of subepithelial tumours.

Key Clinical Points

• 1. First space refers to the lumen; second space is outside lumen, usually peritoneal cavity third space refers to the potential space between muscularis mucosa and muscularis propria. POEM is the most commonly performed third space procedure.

• 2. POEM can be performed as the initial procedure and also for the recurrence post endoscopic as well as post-surgical achalasia management. It is particularly useful in type 3 achalasia.

• 3. UGI endoscopy is mainstay of diagnosis and also rules out any proximal mass lesion, stricture for which treatment might be different) and also eliminates any evidence of GE junction growth which an mimick as achalasia (Secondary achalasia).

• 4. Anterior and Posterior approaches are similar in most aspects and considered equally effective for the treatment of achalasia. However in a previously surgical failed Heller’s myotomy a posterior approach is favoured

• 5. After myotomy is performed, circular muscle fibres are cut starting 3–4 cm above GEJ and till 2 cm below GEJ. Ideally selective circular fibre myotomy is performed but it becomes really difficult to distinguish between circular and longitudinal fibres. No difference is seen between partial thickness and full thickness myotomy.

• 6. Mucosal closure is very important. Usually hemoclips are most commonly used given that they are cheaper, easily applicable and removable.

• 7. POEM is very safe procedures as the incidence of serious adverse effects are very low.

Editor’s Note

References: Main chapter references are included after the “References Editor’s Note” section.

Third space endoscopy has emerged as an attractive option in upper gastrointestinal motility disorders like achalasia, esophageal diverticular disease, esophageal strictures and gastroparesis. Recently its use has been expanded to encompass resection of submucosal tumors like GIST (gastrointestinal stromal tumors) and leiomyomas.

Newer Evolving Application of Third Space Endoscopic Techniques

Authors are investigating the translation of the concept to treat

• lower gastrointestinal motility disorders as well like Hirschsprung disease denoted as PREM (per rectal endoscopic myotomy), analogous to POEM (per oral endoscopic myotomy) [1].

• POETRE (per oral endoscopic tunnelling for restoration of the esophagus) is another emerging technique described in complete esophageal occlusion seen after chemoradiation [2].

• The other potential arenas of its application being investigated are in mediastinoscopy, thoracoscopy and peritoneoscopy [3].

• Implantation of gastrointestinal pacemakers to treat motility disorders (investigational)

Results of POEM Versus Laparoscopic Hellers Myotomy

The prominent application currently has been in the treatment of achalasia cardia. Table EN1 enlists various published meta-analyses comparing outcome of laparoscopic Hellers myotomy (LHM) and Peroral endoscopic myotomy [4–13]. Most studies report better dysphagia control with POEM than LHM [4–7, 9, 11, 12].

The quoted advantages of POEM are that it is a scarless surgery and has a relatively shorter operative time and hospital stay [6–8]. Complications and serious adverse events have been comparable between POEM and LHM across studies [6–13]. One of the noted disadvantages of POEM in treatment of achalasia is the higher incidence of GERD (gastroesophageal reflux disease) as compared to Laparoscopic Hellers myotomy in both subjective and objective assessments as evidenced by higher GERD symptoms, abnormal pH studies and erosive esophagitis [4, 8, 9, 14].

POEM has been observed to have better dysphagia relief than PD (pneumatic dilatation) with comparable adverse events [9–11]. As most Hellers myotomy is coupled with a fundoplication, addition of an trans oral endoscopic treatment of GERD to POEM viz: transoral incisionless fundoplication or electrical stimulators might be able to decrease the incidence of GERD and thus emerge as a potential topic of research in the near future. POEM can also be considered as a safe alternative in failed Hellers myotomy [15].

Techniques to Improve Visualization and Dissection in POEM

Third space endoscopy essentially uses the SEMF (submucosal endoscopy with mucosal flap technique) [16]. Technical issues like ensuring a good vision and haemostasis in POEM are paramount. Use of a lighted LED probe to help improve visibility in submucosal tunnel creation as also for assessing completeness of myotomy has been proposed to be beneficial in this regard [17]. Use of saline jet or water pump assisted dissection, balloon dilators and various knives are being evaluated.

References for Editor’s notes

• 1. Bapaye A, Wagholikar G, Jog S, Kothurkar A, Purandare S, Dubale N, Pujari R, Mahadik M, Vyas V, Bapaye J. Per rectal endoscopic myotomy for the treatment of adult Hirschsprung's disease: First human case (with video). Dig Endosc. 2016 Sep;28(6):680–4. https://doi.org/10.1111/den.12689. Epub 2016 Jul 29. PMID: 27307403.

• 2. Wagh MS, Draganov PV. Per-oral endoscopic tunneling for restoration of the esophagus: a novel endoscopic submucosal dissection technique for therapy of complete esophageal obstruction. GastrointestEndosc. 2017 Apr;85(4):722–27. https://doi.org/10.1016/j.gie.2016.08.035. Epub 2016 Sep 7. PMID: 27612924.

• 3. Manolakis AC, Inoue H, Ueno A, Shimamura Y. 2007-2019: a “Third”-Space Odyssey in the Endoscopic Management of Gastrointestinal Tract Diseases. Curr Treat Options Gastroenterol. 2019 Jun;17(2):202–20. https://doi.org/10.1007/s11938-019-00233-6. PMID: 31037613.

• 4. Schlottmann F, Luckett DJ, Fine J, Shaheen NJ, Patti MG. Laparoscopic Heller Myotomy Versus Peroral Endoscopic Myotomy (POEM) for Achalasia: A Systematic Review and Meta-analysis. Ann Surg. 2018 Mar;267(3):451–60. https://doi.org/10.1097/SLA.0000000000002311. PMID: 28549006.

• 5. Andolfi C, Fisichella PM. Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes. Br J Surg. 2019 Mar;106(4):332–41. https://doi.org/10.1002/bjs.11049. Epub 2019 Jan 28. PMID: 30690706.

• 6. Martins RK, Ribeiro IB, DE Moura DTH, Hathorn KE, Bernardo WM, DE Moura EGH. Peroral (POEM) or surgical myotomy for the treatment of achalasia: a systematic review and meta-analysis. Arq Gastroenterol. 2020 Jan-Mar;57(1):79–86. https://doi.org/10.1590/S0004-2803.202000000-14. PMID: 32294740.

• 7. Awaiz A, Yunus RM, Khan S, Memon B, Memon MA. Systematic review and meta-analysis of perioperative outcomes of peroral endoscopic myotomy (POEM) and laparoscopic heller myotomy (LHM) for Achalasia. SurgLaparoscEndoscPercutan Tech. 2017 Jun;27(3):123–31. https://doi.org/10.1097/SLE.0000000000000402. PMID: 28472017.

• 8. Marano L, Pallabazzer G, Solito B, Santi S, Pigazzi A, De Luca R, Biondo FG, Spaziani A, Longaroni M, Di Martino N, Boccardi V, Patriti A. Surgery or peroral esophageal myotomy for achalasia: a systematic review and meta-analysis. medicine (Baltimore). 2016 Mar;95(10):e3001. https://doi.org/10.1097/MD.0000000000003001. PMID: 26962813; PMCID: PMC4998894.

• 9. Aiolfi A, Bona D, Riva CG, Micheletto G, Rausa E, Campanelli G, Olmo G, Bonitta G, Bonavina L. Systematic review and Bayesian network meta-analysis comparing laparoscopic heller myotomy, pneumatic dilatation, and peroral endoscopic myotomy for Esophageal Achalasia. J Laparoendosc Adv Surg Tech A. 2020 Feb;30(2):147–155. https://doi.org/10.1089/lap.2019.0432. Epub 2019 Jul 31. PMID: 31364910.

• 10. Facciorusso A, Singh S, Abbas Fehmi SM,Annese V, Lipham J, Yadlapati R. Comparative efficacy of first-line therapeutic interventions for achalasia: a systematic review and network meta-analysis. SurgEndosc. 2020 Aug 27:https://doi.org/10.1007/s00464-020-07920-x. Epub ahead of print. PMID: 32856150; PMCID: PMC8011535.

• 11. Mundre P, Black CJ, Mohammed N, Ford AC. Efficacy of surgical or endoscopic treatment of idiopathic achalasia: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2021 Jan;6(1):30–38. https://doi.org/10.1016/S2468-1253(20)30296-X. Epub 2020 Oct 6. PMID: 33035470.

• 12. Zhang Y, Wang H, Chen X, Liu L, Wang H, Liu B, Guo J, Jia H. Per-oral endoscopic myotomy versus laparoscopic heller myotomy for Achalasia: a meta-analysis of nonrandomized comparative studies. Medicine (Baltimore). 2016 Feb;95(6):e2736. https://doi.org/10.1097/MD.0000000000002736. PMID: 26871816; PMCID: PMC4753912.

• 13. Wei M, Yang T, Yang X, Wang Z, Zhou Z. Peroral esophageal myotomy versus laparoscopic Heller's myotomy for achalasia: a meta-analysis. J Laparoendosc Adv Surg Tech A. 2015 Feb;25(2):123–29. https://doi.org/10.1089/lap.2014.0454. PMID: 25683071.

• 14. Repici A, Fuccio L, Maselli R, Mazza F, Correale L, Mandolesi D, Bellisario C, Sethi A, Khashab MA, Rösch T, Hassan C. GERD after per-oral endoscopic myotomy as compared with Heller’s myotomy with fundoplication: a systematic review with meta-analysis. Gastrointest Endosc. 2018 Apr;87(4):934–943.e18. https://doi.org/10.1016/j.gie.2017.10.022. Epub 2017 Nov 2. PMID: 29102729.

• 15. Fernandez-Ananin S, Fernández AF, Balagué C, Sacoto D, Targarona EM. What to do when Heller’s myotomy fails? Pneumatic dilatation, laparoscopic remyotomy or peroral endoscopic myotomy: A systematic review. J Minim Access Surg. 2018 Jul-Sep;14(3):177–84. https://doi.org/10.4103/jmas.JMAS_94_17. PMID: 29319024; PMCID: PMC6001296.

• 16. Nabi Z, Nageshwar Reddy D, Ramchandani M. Recent advances in third-space endoscopy. Gastroenterol Hepatol (N Y). 2018 Apr;14(4):224–32. PMID: 29942220; PMCID: PMC6009186.

• 17. Hernández Mondragón OV, ZamarripaMottú R, Solórzano Pineda O, Gutierrez Aguilar RA, García Contreras LF. Feasibility of using an led-probe in third-space endoscopy: a clinical study. BMC Gastroenterol. 2020 May 5;20(1):132. https://doi.org/10.1186/s12876-020-01260-9. PMID: 32370759; PMCID: PMC7201688.

Table EN1 Meta-analyses comparing POEM (Per oral endoscopic myotomy) with LHM (Laparoscopic Hellers myotomy)