REVIEWS Peroral endoscopic myotomy: an evolving treatment for achalasia Robert Bechara, Haruo Ikeda and Haruhiro Inoue Abstract | Peroral endoscopic myotomy (POEM) was first performed in Japan in 2008 for uncomplicated achalasia. With excellent results, it was adopted by highly skilled endoscopists around the world and the indications for POEM were expanded to include advanced sigmoid achalasia, failed surgical myotomy, patients with previous endoscopic treatments and even other spastic oesophageal motility disorders. With increased uptake and performance of POEM, variations in technique and improved management of adverse events have been developed. Now, 6 years since the first case and with >3,000 procedures performed worldwide, longterm data has shown the efficacy of POEM to be long-lasting. A growing body of literature also exists pertaining to the learning curve, application of novel technologies, extended indications and physiologic changes with POEM. Ultimately, this once experimental procedure is evolving towards becoming the preferred treatment for achalasia and other spastic oesophageal motility disorders. Bechara, R. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 2 June 2015; doi:10.1038/nrgastro.2015.87
Introduction
Digestive Diseases Centre, Showa University Koto-Toyosu Hospital, Toyosu 5‑1‑38, Koto-Ku, Tokyo 135‑8577, Japan (R.B., H. Ikeda, H. Inoue).
Achalasia is a rare spastic oesophageal motility disorder with an incidence of 5 per 1,000,000 persons per year and a prevalence of 8 per 100,000 persons.1 The condition is characterized by the loss of inhibitory motor neuron function, probably secondary to an autoimmune process, resulting in impaired lower oesophageal sphincter (LES) relaxation and loss of peristaltic contractions leading to impaired bolus propulsion and stasis. Patients typically experience dysphagia, regurgitation, chest pain, weight loss and heartburn.2–4 Treatment options have included pneumatic dilation, laparoscopic Heller myotomy (LHM), botulinum toxin injection and pharmacological therapy.2,5 Of the listed treatments, LHM has the most robust data with respect to clinical success rates and durability.6–9 The first account of an endoscopic myotomy for achalasia was in Venezuela in 1980 by Ortega et al.10 in which they described two 1 cm long myotomies performed through the mucosa to a depth of 3 mm at the LES. As the myotomy was performed through the mucosa without direct visualization of the muscle, in addition to the limitation of the myotomy length, the technique was not embraced and there were no further reports of an endoscopic myotomy procedure for the next 26 years. During this time, the field of minimally invasive surgery was evolving and the LHM was introduced in Scotland in 1991 by Shimi et al.11 and was soon followed by the description of a thoracoscopic approach in the USA in 1992 by Pellegrini et al.12 In 2007, Pasricha et al.13 in the USA described endoscopic myotomy in a porcine model, in which a mucosal incision was made 5 cm above the gastro-oesophageal junction (GEJ) and a biliary dilating
Correspondence to: R.B. bechara.robert@ gmail.com
Competing interests The authors declare no competing interests.
balloon was placed into the submucosal space to create a tunnel down to the GEJ where a selective circular muscle myotomy was performed using a needle knife. Finally, in Japan in 2008, our team performed the first human endoscopic myotomy through a submucosal tunnelling technique, coined POEM. In 2010, Inoue et al.14 published the first series of POEM in 17 patients showing promising clinical results for the treatment of oesophageal achalasia.
Indications and contraindications
Initially, POEM was performed only in nonsigmoid achalasia. However, the indications were expanded to include sigmoid-type achalasia after the success of the procedure in the first five patients reported by Inoue et al.14 With uptake of the procedure in countries around the world, indications for POEM were further expanded to include other spastic oesophageal motility disorders, previous failed surgical myotomy, those with multiple previous endoscopic treatments, elderly people and children.15–19 No consensus with regards to the formal indications for POEM exists, but with current safety and efficacy data and an experienced operator, it can be considered as a first-line treatment for all achalasia, reserving oesophagectomy for terminal disease. Spastic oesophageal motility disorders such as Jackhammer oesophagus, diffuse oesophageal spasm (DES), hypertensive lower oesophageal sphincter (HTLES) and Nutcracker oesophagus can also be treated with POEM;17,20–25 how ever, these motility disorders are less common than achalasia and so less evidence exists for the efficacy of POEM as a treatment. With respect to contraindications for POEM, no universally established criteria are available at this time. On the basis of the data collected from the iPOEMS survey, it is generally agreed that absolute
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REVIEWS Key points ■■ Peroral endoscopic myotomy (POEM) is a novel endoscopic procedure initially developed for achalasia, combining the performance of surgical myotomy with safety profile of an endoscopic procedure ■■ POEM offers advantages over the current treatment standards, namely pneumatic dilation and surgical myotomy, such as easy control over the length and position of the myotomy ■■ POEM can also be successfully applied to patients with advanced sigmoid achalasia, failed surgical myotomy, multiple previous treatments and even other spastic oesophageal motility disorders ■■ The most common adverse events are insufflation-related complications and mucosal injury, both of which are generally well managed and without clinical morbidity ■■ International collaboration is required to determine optimal position, length and selectivity (full thickness versus selective myotomy) of standard myotomy, standardize adverse event reporting and develop a formal training curriculum
to using the endoscopy suite.18 We believe POEM should be performed under general anaesthetic with endo tracheal intubation to achieve a positive intrathoracic pressure, preventing the occurrence of mediastinal emphysema. In addition, no unplanned patient movement occurs, which could result in serious complications. In a series of 46 patients, Wang et al.31 performed POEM in seven patients with intravenous sedation and without endotracheal intubation. The procedures performed with intravenous sedation had increased procedural time, increased bleeding rates, mucosal perforation, pneumothoracies, pneumoperitoneum and subcutaneous emphysema. These results reinforce the necessity for the compulsory use of general anaesthesia with endotracheal intubation for POEM.
The technique and its variations a
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Figure 1 | Important luminal landmarks in Reviews POEM. a| |Gastroenterology Spine, b | aortic arch, Nature & Hepatology c | trachea, d | left main bronchus, e | GEJ in retroflexion and f | GEJ in forward view. Abbreviations: GEJ, gastro-oesophageal junction; POEM, peroral endoscopic myotomy. Blue dots represent the extrinsic structure.
contraindications should include: prior oesophageal radiation treatment; prior extensive oesophageal mucosal resection or ablation in the POEM field (where the tunnel will be); severe pulmonary disease; severe coagulopathy; and cirrhosis with portal hypertension.26
Pre-procedure considerations
Between 1–5 days before POEM, patients are given a liquid diet to minimize residual food in the oesophagus.26 An increased incidence of oesophageal candidiasis is associated with POEM and so some centres administer an empiric antifungal agent for 3–5 days prior to the procedure.17,27,28 Other centres rinse the patients’ mouth and oesophagus with saline and chlorhexidine to minimize the risk of infection.29 All centres administer preprocedure prophylactic antibiotics (cephalosporin or quinolone, with or without ornidazole or metronidazole). In a small study comparing patients that received preprocedure antibiotics and those that did not, no difference in infectious complications or adverse events was found between groups.30 Most centres use the operating room to perform POEM, but with increasing experience and rare occurrence of complications, some centres have switched
Examination and identification of landmarks The oesophagus is first suctioned and cleared of any residual fluid and debris. After which, a detailed examin ation of the oesophagus and GEJ is performed. During this examination, the spine, trachea, left main bronchus, aortic arch and GEJ are identified and any abnormal spastic contractions noted (Figure 1; see also Figure 2 for a depiction of anatomy). Identification of landmarks ensures that the desired location of the submucosal tunnel and myotomy are achieved. The trachea is identified anteriorly (12 o’clock) and the spine posteriorly (6 o’clock), the aortic arch is usually visible at ~23 cm from the incisors. In patients with severe sigmoidization of the oesophagus, the location of these landmarks might be altered, which increases the difficulty in achieving the desired location of the submucosal tunnel and myotomy. Submucosal injection and mucosal incision The purpose of the initial submucosal injection is to expand the submucosa so the muscle–submucosal plane is safely and easily accessed for submucosal dissection and submucosal tunnel formation (see Supplementary Video 1 online). In the tunnel, the submucosal injections maintain a visual contrast of the tissue planes, enabling precise dissection and preventing mucosal injury. Various injection solutions (all equally effective; see Supplementary Table 1 online) are used by different centres and choice is made on the basis of local availability, cost and operator preference. Some centres report using dilute adrenaline (1:250,000) as an adjunct to decrease minor oozing and confirm passage into the gastric cardia (blanched mucosa seen on retroflexion in the stomach). During POEM, multiple injections are performed often to a total volume of 100–150 cc and therefore our practice is to not include adrenaline owing to its marginal benefit and risk for cardiopulmonary sequelae.32 The myotomy positions include anterior (11–1 o’clock), posterior (5–7 o’clock), lateral greater curve (8 o’clock), and lateral lesser curve (3 o’clock). At our centre, the posterior (5 o’clock) myotomy is the standard (Figure 2). After landmark identification, the site of mucosal incision is chosen, which for standard myotomy is 13–15 cm above the GEJ. Approximately 10 cc of solution with
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REVIEWS contrast agent (indigocarmine or methylene blue) is injected into the submucosa and a 1.5 cm mucosal incision is made with a needle knife. To avoid mucosal injury, the submucosal tunnel is dissected as close as possible to the circular muscle, as minor thermal damage to the muscle is of no clinical consequence, but thermal damage to the mucosa can result in perforation.
Creation of the submucosal tunnel After an adequate mucosal flap is created, submucosal entry is achieved and the submucosal tunnel is carefully extended 2–3 cm into the gastric cardia. During creation of the tunnel, the operator must be diligent in maintaining the perpendicular orientation of the circular muscle fibres to avoid spiralling of the tunnel, which can result in an unintended location of the GEJ myotomy. Generally, major bleeding on the oesophageal side of the tunnel is infrequent as large submucosal vessels in the oesophagus are uncommon. However, with chronic stasis or recurrent candida oesophagitis, neovascularization can occur, resulting in increased vessel density and frequency of bleeding. Haemostasis of minor bleeding or prophylactic coagulation of small vessels can be achieved with the needle knife. Coagulation forceps are required for more substantial bleeding with prophylactic coagulation of larger vessels or bleeding on the mucosal side. Bleeding on the mucosal side of the tunnel should be managed with the utmost of caution with sparing use of coagulation as aggressive coagulation can lead to mucosal perforation. During the formation of the submucosal tunnel, an injection catheter with a needle or spray tip (unless using a water-jet assisted knife) is used to perform repeated injections of solution with contrast agent. At our centre, the spray tip catheter is preferred as it avoids unintended puncture of hidden vessels without decreasing the efficacy of submucosal injection. As one advances through the submucosal tunnel reaching the gastric side, vessel density and diameter increases, necessitating particular care as prophylactic coagulation of large vessels with forceps might be required for adequate tunnel advancement. In addition, the mucosa at the gastric cardia is thinner and as such the risk of mucosal perforation is highest compared with other areas. Various signs that indicate location of the submucosal tunnel are shown in Figure 3. In 2014, a novel technique to confirm the location of the distal tunnel was described by Baldaque-Silva et al.33 After the operator completes the tunnel to the perceived 2–3 cm into the cardia, a second ultra-slim gastroscope is inserted transnasally, advanced into the stomach and retroflexed. With transillumination of the gastroscope in the tunnel, the precise location of the distal end is identified.33 This innovation led to the extension of the tunnel by 2 cm in the two patients described, indicating that perhaps the other signs are not as reliable as previously thought. Pending further studies it might prove to be an important modification of the POEM procedure. Endoscopic myotomy To perform a selective circular muscle myotomy (and avoid performing a full-thickness myotomy), it is essential
Anterior vagal trunk 12 o’clock
Left lung
9 o’clock
3 o’clock
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Right lung
Azygous vein 6 o’clock Posterior vagal trunk
Thoracic duct
Spine
Figure 2 | Anatomy surrounding the gastro-oesophageal Nature Reviews | Gastroenterology & Hepatology junction to consider during POEM. Abbreviation: POEM, peroral endoscopic myotomy.
that the initial incision is precise. Initial precision is not a concern if a full-thickness myotomy is intended (see section on full-thickness versus selective myotomy). A mechanical advantage is gained after full-thickness myotomy to progress splitting the thin longitudinal fibres. To prevent cutting the longitudinal fibres, the initial incision is performed stepwise until the inter-muscle space is reached and the circular fibres can be selectively cut whilst preserving the longitudinal fibres (Figure 4). The total length of a standard myotomy is 10–12 cm, including a 2–3 cm cardiomyotomy. At the GEJ and on the gastric side, the tissue planes are less distinct than in the oesophagus and particular care is required to ensure a safe and adequate selective myotomy. From experience with LHM, the efficacy of the myotomy hinges strongly on achieving an adequate 2–3 cm cardiomyotomy.34–36 Thus, if the operator is uncertain of the adequacy of the selective myotomy, then a cautious stepwise progression to a full thickness myotomy might be required, as an incomplete cardiomyotomy is the most common cause of a treatment failure and symptom recurrence.37–39
Closure of mucosal entry After the myotomy is completed and haemostasis is confirmed, a prophylactic antibiotic (gentamicin 60 mg in 20 cc normal saline) is instilled into the submucosal tunnel and the mucosal entry site is closed with 4–6 standard endoscopic clips. Positioning the initial clip just beyond the distal edge of the mucosal incision is a key step that often gets overlooked when closing the mucosal entry site. This clip positioning allows for improved oppos ition of the proximal edges, analogous to a surgical stay suture. Using this simple technique, all mucosal incisions at our centre have been successfully closed. Alternative closure methods include over the scope clips (OTSC®, Ovesco Endoscopy, Tübingen, Germany), fully covered self-expanding metal stents (FCSEMS), endoscopic
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REVIEWS a
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Figure 3 | Landmarks and signs indicative of location in the submucosal tunnel. Nature Reviews | Gastroenterology & Hepatology a | Spindle vein,* b | palisade vessels,‡ c | narrowing of tunnel with muscular bundles of LES,§ d | increased vascularity and capaciousness at the gastric side,§ e | bluish hue of contrast from distal tunnel viewed in retroflexion in the stomach § and f | transillumination method with clear identification of distal tunnel§. Insertion depth not shown. *Low usefulness as a landmark. ‡Moderate as a landmark. §High usefulness as a landmark. Abbreviations: LES, lower oesophageal sphincter.
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Figure 4 | POEM procedure. a | Mucosal submucosal injection, Natureincision Reviewsafter | Gastroenterology & Hepatology b | creation of submucosal tunnel via endoscopic submucosal dissection, c | completed submucosal tunnel d | selective circular muscle myotomy, e | completed myotomy and f | closure of mucosal entry with clips. Abbreviation: POEM, peroral endoscopic myotomy. See also Supplementary Video 1 online.
suturing devices and a combination of endoloops with clips. Currently, there is no evidence demonstrating superiority of any of the alternative techniques and standard endoscopic clips continue to be the mainstay for mucosal entry site closure. Two case reports with a total of three patients have reported that the mucosal entry site could not be successfully closed with standard endoscopic clips, but application of OTSC®led to successful closure without complication.40,41 In a patient with advanced achalasia with sigmoidization, the mucosal entry site was friable and the mucosal entry could not be closed with standard endoscopic clips.42 An OTSC®was placed, closing two-thirds of the defect and a FCSEMS was used to seal the remaining defect. After 6 weeks, the entry site was completely healed and the FCSEMS was removed
without complication. The OverStitch™ endoscopic suturing system (Apollo Endosurgery, Austin, USA) has also been used successfully as an alternative method of mucosal entry site closure.17,43 Entry site closure with a combination of clips and endoloops has been described as a salvage closure method. A patient developed a fever and an elevated white blood cell count 3 days after undergoing an uncomplicated POEM procedure with clips closure.44 Subsequent endoscopy revealed a rupture of the mucosal incision site due to oedema. Using clips to anchor the distal, mid and proximal mucosal margins and ensnaring each segment with an endoloop, the defect was effectively closed.
Post-procedure management Post-procedure investigations and advancement of diet vary between centres, as does the length of stay, which ranges from 1–5 days for patients without complications.26 All centres withhold oral food and fluid from the patient after the procedure, with the majority of centres initiating a liquid diet within 24 h. After mucosal integrity is confirmed with endoscopy and an oesophagram, the diet is subsequently advanced to a regular diet over 1–14 days. At our centre, after confirmation of mucosal integrity, the patient is started on clear fluids for 24 h, then a pureed or soft diet over 2 days and finally a regular diet by day 4 (discharge day). Of note, the average length of stay for LHM in Japan is 7–10 days compared with 2–3 days in Western hospitals and is a result of cultural differences, lower health-care cost in Japan than in the West and patient expectation. In Japan, patients are generally kept in hospital until they are at or near their functional baseline. This practice is reflected in length of stay for POEM, for which the average duration in Japan is 4 days compared with 1–2 days in the USA and Europe.45,46 Some centres have performed routine CT scans on all patients after POEM in search of prognostic radiological signs; however, no clinically relevant information was gained in these patients and so routine post-procedure CT is not recommended in asymptomatic patients.47 Prophylactic antibiotics are given 30 min before POEM and are continued for 2–7 days. At our centre, patients receive antibiotics for a total of 5 days. By contrast, 1–2 days of prophylactic antibiotics are generally administered to patients undergoing LHM. All patients undergoing POEM should receive prophylactic antibiotics due to the substantial mortality and morbidity of mediastinitis (with post-surgical reports of mortality of up to 47%48,49), but the optimal duration of therapy is unknown.
Management after discharge
Follow-up should be arranged within 3–6 months after discharge or sooner if issues arise. At follow-up, an Eckardt score, endoscopy, manometry and timed barium oesophagram should be arranged and, if available, oesophageal distensibility and 24 h oesophageal pH testing. These investigations document clinical, radiologic and manometric treatment success, functional changes to the GEJ and identify pathological gastro-oesophageal reflux. Our practice has been to conduct subsequent
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REVIEWS clinical follow-up at 1 year and annually thereafter. The annual follow-up is performed indefinitely. Surveillance endoscopy for squamous cancer in patients with achalasia is controversial. The American Society for Gastrointestinal Endoscopy guidelines, which have not been updated for almost 10 years, state that evidence to support a recommendation for routine screening for squamous cancer in patients with achalasia is insufficient. However, the initiation of screening for cancer 15 years after symptoms onset is suggested to be reasonable. A recommendation of screening intervals is not given owing to insufficient evidence.50 Patients who have had achalasia for >10 years and/or the presence of oesophageal dilation are thought to be at the highest risk of developing cancer.51,52 The incidence of cancer in patients with achalasia ranges from 0.04–0.58% per year with a prevalence ranging from 0.4–6.1%.51,53–61 An international survey of achalasia experts, did not reach a consensus regarding the perceived lifetime risk of oesophageal cancer, with screening performed by 53% of the experts.62 Of those that performed screening, the screening interval ranged from every 2–5 years and was initiated 1–10 years after diagnosis of achalasia.62 In the future, novel technologies such as the endocytoscope might aid in supplementing evidence to guide the optimal screening intervals by stratifying patients according to their risk of developing cancer. The endocytoscope GIF‑Y0001 (Olympus medical systems, Tokyo, Japan) is a prototype endoscope that has ×450 magnification allowing real-time detailed endoscopic examination of live tissue. With the use of the endocytoscope and immunohistochemistry Minami et al.63 examined the oesophageal epithelium before and after POEM. After POEM, there was normalization of the size and shape of epithelial cells. In addition, there was a decrease in the mean levels of Ki67 and p53 positive staining, which have been shown to correlate with malignant progression as well as dysplasia.64–66 One can speculate that pending further studies and maturation of this technology, it might hold value for risk stratification of oesophageal cancers in patients with achalasia and help determine optimal screening intervals. In our practice, the suggested post-POEM investigations for achalasia including oesophageal cancer screening on the basis of extrapolation, adaptation of previous achalasia guidelines and experience are summarized in Box 1.2,67,68
Safety and adverse events
There have been >3,000 POEM procedures performed worldwide with no reported mortalities or requirement for conversion to an open surgical procedure. Two reports of oesophageal perforations that required subsequent laparoscopic and thoracoscopic intervention have occurred.28,69 One patient did not adhere to the post-procedure diet, ate solid food, retched and developed a contained perforation that required laparoscopy and drain placement.28 The second patient had a perforation that required thoracoscopic drainage.69 Both patients recovered and were discharged home without sequelae. Other potential adverse events associated with POEM, include: bleeding (immediate and delayed); dehiscence of mucosal entry
Box 1 | Follow-up times and investigations after POEM Postprocedure (24–48 h) ■■ Oesophagram ■■ Upper endoscopy ■■ Haematology and biochemistry if clinically indicated ■■ Standard postprocedure clinical care Short-term (3–6 months) ■■ Oesophagram ■■ Upper endoscopy ■■ Manometry, pH monitor* and distensibility* ■■ Eckardt Score Long-term (>1 year) ■■ Oesophagram (only if symptomatic) ■■ Endoscopy every 1–3 years ■■ Manometry, pH monitor, distensibility (only if symptomatic) ■■ Eckardt score *If available.
site; peritonitis; mediastinitis; pneumonia; pneumoperitoneum; pneumomediastinum; pneumothorax; thoracic effusions; and atelectasis.70 Fortunately, severe adverse events are rare with an incidence of less than 0.1%,71 with the most commonly occurring adverse events (mucosal injury and pneumoperitoneum) managed easily and without consequence to the patients long-term health. Another outcome of concern associated with POEM is gastro-oesophageal reflux. To date, there have been no reports of severe oesophagitis resulting in peptic stricture or patients with PPI-refractory reflux. In the 2011 European achalasia trial, the reflux rates for LHM and pneumatic dilation based on 24 h oesophageal pH testing were 23% and 15%, respectively.72 In a systematic review and meta-analysis of LHM published in 2009, the incidence of reflux was 8.8%.9 Similar to LHM, the incidence of reflux in POEM was reported as 10.9% in a systematic review and meta-analysis published in 2014.70 However, the reported incidence of reflux among studies included in these systematic reviews and meta-analyses were made on the basis of a definition of reflux that was hetero geneous between studies and included; abnormal acid exposure on 24 h oesophageal pH testing (gold standard for diagnosing reflux), oesophagitis on endoscopy, positive score on self-assessment questionnaire or patient self‑reporting of reflux symptoms. The heterogeneity in defining reflux is commonly encountered in the literature. In a meta-analysis comparing LHM and pneumatic dilation for the treatment of achalasia, only two trials reported reflux incidence using 24 h oesophageal pH testing.72,73 A meta-analysis of these two studies showed the reflux incidence after LHM and pneumatic dilation was 17.4% (95% CI, 12.1– 24.3) and 19.7% (95% CI, 13.8–27.2), respectively.6 In the only comparative study of LHM versus POEM that used 24 h oesophageal pH testing (Table 1), there was no statistically significant difference in reflux incidence (LHM 32% and POEM 39%; P = 0.7).45 Thus, based on the current literature, there does not seem to be a statistically significant difference in post-procedure incidence of reflux. With the completion of a randomized trial comparing LHM
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REVIEWS Table 1 | Persistent postoperative symptoms Heller (%)
POEM (%)
P
Early symptoms* Heartburn Dysphagia to solid Dysphagia to liquid Reflux Chest pain
n = 63 3 10 3 6 5
n = 37 11 5 0 5 5
– 0.2 0.4 0.4 0.6 0.6
Long-term symptoms‡ Heartburn Dysphagia to solid Dysphagia to liquid Reflux Chest pain
n = 38 16 29 8 3 5
n = 27 7 0 0 4 0
– 0.3 0.001 0.2 0.7 0.3
*Symptom score ≥2, within 2 weeks of surgery. ‡Symptom score ≥2, more than 6 months after surgery. Reproduced with permission from Lippincott Williams & Wilkins © Bhayahni, N. H. et al. Ann. Surg. 259, 1098–1103 (2014).
to POEM in 2019, which will include pre-POEM and post‑POEM 24-hour oesophageal pH testing, high‑quality evidence will be available.74 The most comprehensive adverse event data comes from the iPOEMS survey, which reported major nonfatal adverse events occurring in 3.2% of 841 patients.26 In the large European achalasia trial, there was a 4% perforation rate for pneumatic dilation and a 12% rate of mucosal tear for LHM.72 With increased operator experience it has been shown that the adverse event rate of POEM generally decreases.75 However, without consistent adverse event reporting and classification, a precise adverse event incidence will be difficult to extract. Now with widespread experience, POEM has been performed safely and effectively in patients of increasing complexity and morbidity, such as those with previous bariatric surgery, situs inversus, complete heart block and nonagenarians.18,76–78
Insufflation-related adverse events The most commonly occurring adverse event associated with POEM are related to insufflation:70 pneumomedia stinum; capnomediastinum; pneumoperitoneum; capnoperitoneum; pneumothorax; and subcutaneous emphysema (hence forth the terms pneumomediastinum and pneumoperitoneum will be used to refer to both CO2 and air in the mediastinum and peritoneum, respectively). All of which can be treated conservatively as with subcutaneous emphysema and pneumomediastinum, or with needle decompression and chest tube placement as with tense pneumoperitoneum and pneumothorax, respectively. The insufflation method, tubing and technique used are essential to minimize insufflation related adverse events. From studies of oesophageal endoscopic submucosal dissection (ESD), it has been shown that CO2 insufflation substantially reduces the amount of pneumomediastinum compared with air insufflation.79,80 In POEM, the working field can be in direct continuity with the mediastinum and/or peritoneum. Thus, with air absorbed 150 times slower than CO2, it is essential that CO2 be used to decrease the volume of gas within the subperitoneal, peritoneal, mediastinal and luminal space to diminish the potential of insufflation-related complications.31,47,78,81–83 Another important factor is the total volume of gas
insufflated, which is dependent on the flow rate of the tubing used and the frequency and duration of insuf flation. The use of low-flow CO2 tubing has been shown to reduce insufflation-related adverse events as demonstrated by Familiari et al.84 in a series of 100 patients undergoing POEM. In the first 79 patients, medium-flow or high-flow CO2 tubing was used, which resulted in tense pneumoperitoneum in 36.7% of patients.84 For the remaining 21 patients, low-flow CO2 tubing was used and no events of tense pneumoperitoneum occurred.84 In addition, the frequency and duration the operator depresses the insufflation button directly influences the total volume of gas insufflated. Accordingly, the endoscopist needs to eliminate excessive and needless insufflation to further minimize the total volume of gas. Therefore, judicious and conscientious use of insufflation, with low-flow CO2 offers the greatest reduction in the risk of insufflation-related adverse events.
Radiological findings With regards to asymptomatic radiological findings, Tamiya et al.85 reported on a series of 58 patients who had undergone oesophageal ESD. Routine post-procedure CT revealed that 100% of patients had pleural or mediastinal effusions and 31% had mediastinal air, all of which were asymptomatic and without clinical sequelae. Similar findings have been shown in other series of oesophageal ESD with asymptomatic pneumomediastinum in up to 62% of patients.82,86 In a retrospective series by Cai et al.47 300 patients underwent a routine CT scan within 30 h of POEM, with air insufflation used in 157 (52.3%) patients. The majority of patients had radiological changes such as pneumonitis, pneumomediastinum, pneumoperitoneum, focal atelectasis and pleural effusions with most being asymptomatic. When comparing CO2 to air insufflation, a greater proportion of patients receiving air insufflation developed symptomatic insufflation-related adverse events. In their univariate analysis, full-thickness myotomy was associated with increased pneumomediastinum, pneumoperitoneum and thoracic effusions. However, this effect was lost in the multivariate analysis, which revealed only increasing age to be associated with an increased rate of pneumothorax and use of CO2 insufflation was associated with fewer insufflationrelated adverse events compared with air insufflation. Routine post-procedure CT in asymptomatic patients was concluded to be of no clinical benefit. Yang et al.87 also reported on a series of 108 POEM procedures with post-procedure CT that showed pneumoperitoneum and/ or pneumomediastinum in 53.7% of cases with no correlation of asymptomatic insufflation-related CT findings and clinical complication rate. Mucosal perforation Mucosal perforations are one of the more common adverse events encountered with the POEM procedure. As POEM involves submucosal dissection with subsequent myotomy, the mucosa is the only barrier maintaining luminal integrity. Therefore, preserving an intact mucosa is of critical importance. The incidence of mucosal perforation ranges from 0–25%, with an overall rate of
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REVIEWS 3) were within the first three procedures performed thus, limiting the generalizability of this finding. In the series reviewed in Supplementary Table 1, of those that reported mucosal perforation only one patient with perforation had an unsuccessful POEM (post-POEM Eckardt score >3).28 Thus, mucosal perforations in POEM are not uncommon occurrences, but can be managed safely, effectively and probably without compromised clinical efficacy when performed by experienced operators. However, with increased long-term follow-up, detailed analysis of treatment failures is required to help determine if a true correlation exists between intraprocedural perforation and treatment failure or symptom recurrence.
Bleeding Minor intraprocedural bleeding is commonly encountered and can be managed with the needle knife or haemostatic forceps. Severe intraprocedural bleeding that precludes completion of POEM has not been reported. In addition, minor intraprocedural bleeding is sparsely
reported in case series; however, anecdotally, it is commonly encountered. In a study by Cai et al.93 comparing a water-jet-assisted knife versus a triangle tip knife, the mean number of regular haemostatic and coagulation forceps events was 5.2 and 1.65, respectively (events included prophylactic haemostasis of vessels not actively bleeding) in 100 patients undergoing POEM. Thus, analogous to the ESD operator, the POEM operator should be familiar and proficient with haemostatic techniques as they are frequently performed. In 428 consecutive POEM procedures in 428 patients with achalasia, Li et al.91 reported a delayed bleeding rate of 0.7%. Three patients required urgent endoscopy for haematemesis. In one patient, the bleeding site could not be found and a Blakemore–Sengstaken tube was immediately placed, inflating the gastric and oesophageal balloons and achieving haemostasis. In the two other patients, the active bleeding sites were identified at the edges of cut muscle, treated with haemostatic forceps and placement of a Blakemore–Sengstaken tube. If a Blakemore– Sengstaken tube is used for haemostasis of uncontrolled bleeding after a completed myotomy and inflation of the oesophageal balloon cannot be avoided, it should be performed with extreme caution; after a completed myotomy, a barrier no longer exists between the submucosal tunnel and mediastinum and bleeding might continue into the mediastinum, which is potentially catastrophic. Minami et al.94 described two patients with post-procedure bleeding in a series of 28 patients. Both patients were managed conservatively without endoscopic treatment. With the rare occurrence of severe and delayed bleeding with POEM, there is no consensus as to optimal method to achieve haemostasis. In addition, although not reported in patients who have had POEM, arterial oesophageal bleeds of various aetiologies have been successfully treated by interventional radiology and can be considered a treatment option in patients who have undergone POEM and have refractory bleeding.95–99
Reporting of adverse events The heterogeneity in reporting and classifying adverse events associated with POEM partially accounts for the variability in adverse event rates described in the published literature. Specifically, some series do not classify mucosal perforations repaired intraprocedurally or successfully decompressed pneumoperitoneum as adverse events. In an attempt to account for this diversity in reporting, all pneumoperitoneum requiring decompression, subcutaneous emphysema, symptomatic pneumo thorax, or fever that required a change in antibiotic treatment and all mucosal perforations are included as adverse events in Supplementary Table 1. Asymptomatic radiological findings were not included as adverse events. To improve the quality and reliability of adverse event reporting, a standard classification system should be used, such as the Clavian–Dindo classification.100 POEMspecific classifications can also be developed as was done by Sharata et al.17 who proposed the Portland oesophagotomy classification. Eventually, with international collaboration and discourse through events such as the POEM
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25.0 25.7 25.0 23.3 18.8 11.3 6.4 4.9 5.4 6.7 11.1 16.4 21.4 23.8 24.5 23.8
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Figure 5 | Endoscopic, radiological, manometric and distensibility changes before and after POEM. Pre-POEM shown on Nature Reviews | Gastroenterology & Hepatology the left and post-POEM on the right. a | Endoscopic, b | radiological, c | high-resolution manometry and d | distensibility. Abbreviation: POEM, peroral endoscopic myotomy.
International Conference, a clear, concise adverse event classification and reporting method should be agreed upon and universally implemented.
Efficacy
Objective measures of effective treatment response in patients with achalasia include timed barium oesophagram, LES pressure, integrated relaxation pressure and GEJ distensibility as measured by the Endolumenal Functional Lumen Imaging Probe (EndoFLIP®, Crospon, Galway, Ireland). Clinical efficacy is defined by the Eckardt scoring system. A post-treatment Eckardt score of
Introduction
Digestive Diseases Centre, Showa University Koto-Toyosu Hospital, Toyosu 5‑1‑38, Koto-Ku, Tokyo 135‑8577, Japan (R.B., H. Ikeda, H. Inoue).
Achalasia is a rare spastic oesophageal motility disorder with an incidence of 5 per 1,000,000 persons per year and a prevalence of 8 per 100,000 persons.1 The condition is characterized by the loss of inhibitory motor neuron function, probably secondary to an autoimmune process, resulting in impaired lower oesophageal sphincter (LES) relaxation and loss of peristaltic contractions leading to impaired bolus propulsion and stasis. Patients typically experience dysphagia, regurgitation, chest pain, weight loss and heartburn.2–4 Treatment options have included pneumatic dilation, laparoscopic Heller myotomy (LHM), botulinum toxin injection and pharmacological therapy.2,5 Of the listed treatments, LHM has the most robust data with respect to clinical success rates and durability.6–9 The first account of an endoscopic myotomy for achalasia was in Venezuela in 1980 by Ortega et al.10 in which they described two 1 cm long myotomies performed through the mucosa to a depth of 3 mm at the LES. As the myotomy was performed through the mucosa without direct visualization of the muscle, in addition to the limitation of the myotomy length, the technique was not embraced and there were no further reports of an endoscopic myotomy procedure for the next 26 years. During this time, the field of minimally invasive surgery was evolving and the LHM was introduced in Scotland in 1991 by Shimi et al.11 and was soon followed by the description of a thoracoscopic approach in the USA in 1992 by Pellegrini et al.12 In 2007, Pasricha et al.13 in the USA described endoscopic myotomy in a porcine model, in which a mucosal incision was made 5 cm above the gastro-oesophageal junction (GEJ) and a biliary dilating
Correspondence to: R.B. bechara.robert@ gmail.com
Competing interests The authors declare no competing interests.
balloon was placed into the submucosal space to create a tunnel down to the GEJ where a selective circular muscle myotomy was performed using a needle knife. Finally, in Japan in 2008, our team performed the first human endoscopic myotomy through a submucosal tunnelling technique, coined POEM. In 2010, Inoue et al.14 published the first series of POEM in 17 patients showing promising clinical results for the treatment of oesophageal achalasia.
Indications and contraindications
Initially, POEM was performed only in nonsigmoid achalasia. However, the indications were expanded to include sigmoid-type achalasia after the success of the procedure in the first five patients reported by Inoue et al.14 With uptake of the procedure in countries around the world, indications for POEM were further expanded to include other spastic oesophageal motility disorders, previous failed surgical myotomy, those with multiple previous endoscopic treatments, elderly people and children.15–19 No consensus with regards to the formal indications for POEM exists, but with current safety and efficacy data and an experienced operator, it can be considered as a first-line treatment for all achalasia, reserving oesophagectomy for terminal disease. Spastic oesophageal motility disorders such as Jackhammer oesophagus, diffuse oesophageal spasm (DES), hypertensive lower oesophageal sphincter (HTLES) and Nutcracker oesophagus can also be treated with POEM;17,20–25 how ever, these motility disorders are less common than achalasia and so less evidence exists for the efficacy of POEM as a treatment. With respect to contraindications for POEM, no universally established criteria are available at this time. On the basis of the data collected from the iPOEMS survey, it is generally agreed that absolute
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REVIEWS Key points ■■ Peroral endoscopic myotomy (POEM) is a novel endoscopic procedure initially developed for achalasia, combining the performance of surgical myotomy with safety profile of an endoscopic procedure ■■ POEM offers advantages over the current treatment standards, namely pneumatic dilation and surgical myotomy, such as easy control over the length and position of the myotomy ■■ POEM can also be successfully applied to patients with advanced sigmoid achalasia, failed surgical myotomy, multiple previous treatments and even other spastic oesophageal motility disorders ■■ The most common adverse events are insufflation-related complications and mucosal injury, both of which are generally well managed and without clinical morbidity ■■ International collaboration is required to determine optimal position, length and selectivity (full thickness versus selective myotomy) of standard myotomy, standardize adverse event reporting and develop a formal training curriculum
to using the endoscopy suite.18 We believe POEM should be performed under general anaesthetic with endo tracheal intubation to achieve a positive intrathoracic pressure, preventing the occurrence of mediastinal emphysema. In addition, no unplanned patient movement occurs, which could result in serious complications. In a series of 46 patients, Wang et al.31 performed POEM in seven patients with intravenous sedation and without endotracheal intubation. The procedures performed with intravenous sedation had increased procedural time, increased bleeding rates, mucosal perforation, pneumothoracies, pneumoperitoneum and subcutaneous emphysema. These results reinforce the necessity for the compulsory use of general anaesthesia with endotracheal intubation for POEM.
The technique and its variations a
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Figure 1 | Important luminal landmarks in Reviews POEM. a| |Gastroenterology Spine, b | aortic arch, Nature & Hepatology c | trachea, d | left main bronchus, e | GEJ in retroflexion and f | GEJ in forward view. Abbreviations: GEJ, gastro-oesophageal junction; POEM, peroral endoscopic myotomy. Blue dots represent the extrinsic structure.
contraindications should include: prior oesophageal radiation treatment; prior extensive oesophageal mucosal resection or ablation in the POEM field (where the tunnel will be); severe pulmonary disease; severe coagulopathy; and cirrhosis with portal hypertension.26
Pre-procedure considerations
Between 1–5 days before POEM, patients are given a liquid diet to minimize residual food in the oesophagus.26 An increased incidence of oesophageal candidiasis is associated with POEM and so some centres administer an empiric antifungal agent for 3–5 days prior to the procedure.17,27,28 Other centres rinse the patients’ mouth and oesophagus with saline and chlorhexidine to minimize the risk of infection.29 All centres administer preprocedure prophylactic antibiotics (cephalosporin or quinolone, with or without ornidazole or metronidazole). In a small study comparing patients that received preprocedure antibiotics and those that did not, no difference in infectious complications or adverse events was found between groups.30 Most centres use the operating room to perform POEM, but with increasing experience and rare occurrence of complications, some centres have switched
Examination and identification of landmarks The oesophagus is first suctioned and cleared of any residual fluid and debris. After which, a detailed examin ation of the oesophagus and GEJ is performed. During this examination, the spine, trachea, left main bronchus, aortic arch and GEJ are identified and any abnormal spastic contractions noted (Figure 1; see also Figure 2 for a depiction of anatomy). Identification of landmarks ensures that the desired location of the submucosal tunnel and myotomy are achieved. The trachea is identified anteriorly (12 o’clock) and the spine posteriorly (6 o’clock), the aortic arch is usually visible at ~23 cm from the incisors. In patients with severe sigmoidization of the oesophagus, the location of these landmarks might be altered, which increases the difficulty in achieving the desired location of the submucosal tunnel and myotomy. Submucosal injection and mucosal incision The purpose of the initial submucosal injection is to expand the submucosa so the muscle–submucosal plane is safely and easily accessed for submucosal dissection and submucosal tunnel formation (see Supplementary Video 1 online). In the tunnel, the submucosal injections maintain a visual contrast of the tissue planes, enabling precise dissection and preventing mucosal injury. Various injection solutions (all equally effective; see Supplementary Table 1 online) are used by different centres and choice is made on the basis of local availability, cost and operator preference. Some centres report using dilute adrenaline (1:250,000) as an adjunct to decrease minor oozing and confirm passage into the gastric cardia (blanched mucosa seen on retroflexion in the stomach). During POEM, multiple injections are performed often to a total volume of 100–150 cc and therefore our practice is to not include adrenaline owing to its marginal benefit and risk for cardiopulmonary sequelae.32 The myotomy positions include anterior (11–1 o’clock), posterior (5–7 o’clock), lateral greater curve (8 o’clock), and lateral lesser curve (3 o’clock). At our centre, the posterior (5 o’clock) myotomy is the standard (Figure 2). After landmark identification, the site of mucosal incision is chosen, which for standard myotomy is 13–15 cm above the GEJ. Approximately 10 cc of solution with
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REVIEWS contrast agent (indigocarmine or methylene blue) is injected into the submucosa and a 1.5 cm mucosal incision is made with a needle knife. To avoid mucosal injury, the submucosal tunnel is dissected as close as possible to the circular muscle, as minor thermal damage to the muscle is of no clinical consequence, but thermal damage to the mucosa can result in perforation.
Creation of the submucosal tunnel After an adequate mucosal flap is created, submucosal entry is achieved and the submucosal tunnel is carefully extended 2–3 cm into the gastric cardia. During creation of the tunnel, the operator must be diligent in maintaining the perpendicular orientation of the circular muscle fibres to avoid spiralling of the tunnel, which can result in an unintended location of the GEJ myotomy. Generally, major bleeding on the oesophageal side of the tunnel is infrequent as large submucosal vessels in the oesophagus are uncommon. However, with chronic stasis or recurrent candida oesophagitis, neovascularization can occur, resulting in increased vessel density and frequency of bleeding. Haemostasis of minor bleeding or prophylactic coagulation of small vessels can be achieved with the needle knife. Coagulation forceps are required for more substantial bleeding with prophylactic coagulation of larger vessels or bleeding on the mucosal side. Bleeding on the mucosal side of the tunnel should be managed with the utmost of caution with sparing use of coagulation as aggressive coagulation can lead to mucosal perforation. During the formation of the submucosal tunnel, an injection catheter with a needle or spray tip (unless using a water-jet assisted knife) is used to perform repeated injections of solution with contrast agent. At our centre, the spray tip catheter is preferred as it avoids unintended puncture of hidden vessels without decreasing the efficacy of submucosal injection. As one advances through the submucosal tunnel reaching the gastric side, vessel density and diameter increases, necessitating particular care as prophylactic coagulation of large vessels with forceps might be required for adequate tunnel advancement. In addition, the mucosa at the gastric cardia is thinner and as such the risk of mucosal perforation is highest compared with other areas. Various signs that indicate location of the submucosal tunnel are shown in Figure 3. In 2014, a novel technique to confirm the location of the distal tunnel was described by Baldaque-Silva et al.33 After the operator completes the tunnel to the perceived 2–3 cm into the cardia, a second ultra-slim gastroscope is inserted transnasally, advanced into the stomach and retroflexed. With transillumination of the gastroscope in the tunnel, the precise location of the distal end is identified.33 This innovation led to the extension of the tunnel by 2 cm in the two patients described, indicating that perhaps the other signs are not as reliable as previously thought. Pending further studies it might prove to be an important modification of the POEM procedure. Endoscopic myotomy To perform a selective circular muscle myotomy (and avoid performing a full-thickness myotomy), it is essential
Anterior vagal trunk 12 o’clock
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Azygous vein 6 o’clock Posterior vagal trunk
Thoracic duct
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Figure 2 | Anatomy surrounding the gastro-oesophageal Nature Reviews | Gastroenterology & Hepatology junction to consider during POEM. Abbreviation: POEM, peroral endoscopic myotomy.
that the initial incision is precise. Initial precision is not a concern if a full-thickness myotomy is intended (see section on full-thickness versus selective myotomy). A mechanical advantage is gained after full-thickness myotomy to progress splitting the thin longitudinal fibres. To prevent cutting the longitudinal fibres, the initial incision is performed stepwise until the inter-muscle space is reached and the circular fibres can be selectively cut whilst preserving the longitudinal fibres (Figure 4). The total length of a standard myotomy is 10–12 cm, including a 2–3 cm cardiomyotomy. At the GEJ and on the gastric side, the tissue planes are less distinct than in the oesophagus and particular care is required to ensure a safe and adequate selective myotomy. From experience with LHM, the efficacy of the myotomy hinges strongly on achieving an adequate 2–3 cm cardiomyotomy.34–36 Thus, if the operator is uncertain of the adequacy of the selective myotomy, then a cautious stepwise progression to a full thickness myotomy might be required, as an incomplete cardiomyotomy is the most common cause of a treatment failure and symptom recurrence.37–39
Closure of mucosal entry After the myotomy is completed and haemostasis is confirmed, a prophylactic antibiotic (gentamicin 60 mg in 20 cc normal saline) is instilled into the submucosal tunnel and the mucosal entry site is closed with 4–6 standard endoscopic clips. Positioning the initial clip just beyond the distal edge of the mucosal incision is a key step that often gets overlooked when closing the mucosal entry site. This clip positioning allows for improved oppos ition of the proximal edges, analogous to a surgical stay suture. Using this simple technique, all mucosal incisions at our centre have been successfully closed. Alternative closure methods include over the scope clips (OTSC®, Ovesco Endoscopy, Tübingen, Germany), fully covered self-expanding metal stents (FCSEMS), endoscopic
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Figure 3 | Landmarks and signs indicative of location in the submucosal tunnel. Nature Reviews | Gastroenterology & Hepatology a | Spindle vein,* b | palisade vessels,‡ c | narrowing of tunnel with muscular bundles of LES,§ d | increased vascularity and capaciousness at the gastric side,§ e | bluish hue of contrast from distal tunnel viewed in retroflexion in the stomach § and f | transillumination method with clear identification of distal tunnel§. Insertion depth not shown. *Low usefulness as a landmark. ‡Moderate as a landmark. §High usefulness as a landmark. Abbreviations: LES, lower oesophageal sphincter.
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Figure 4 | POEM procedure. a | Mucosal submucosal injection, Natureincision Reviewsafter | Gastroenterology & Hepatology b | creation of submucosal tunnel via endoscopic submucosal dissection, c | completed submucosal tunnel d | selective circular muscle myotomy, e | completed myotomy and f | closure of mucosal entry with clips. Abbreviation: POEM, peroral endoscopic myotomy. See also Supplementary Video 1 online.
suturing devices and a combination of endoloops with clips. Currently, there is no evidence demonstrating superiority of any of the alternative techniques and standard endoscopic clips continue to be the mainstay for mucosal entry site closure. Two case reports with a total of three patients have reported that the mucosal entry site could not be successfully closed with standard endoscopic clips, but application of OTSC®led to successful closure without complication.40,41 In a patient with advanced achalasia with sigmoidization, the mucosal entry site was friable and the mucosal entry could not be closed with standard endoscopic clips.42 An OTSC®was placed, closing two-thirds of the defect and a FCSEMS was used to seal the remaining defect. After 6 weeks, the entry site was completely healed and the FCSEMS was removed
without complication. The OverStitch™ endoscopic suturing system (Apollo Endosurgery, Austin, USA) has also been used successfully as an alternative method of mucosal entry site closure.17,43 Entry site closure with a combination of clips and endoloops has been described as a salvage closure method. A patient developed a fever and an elevated white blood cell count 3 days after undergoing an uncomplicated POEM procedure with clips closure.44 Subsequent endoscopy revealed a rupture of the mucosal incision site due to oedema. Using clips to anchor the distal, mid and proximal mucosal margins and ensnaring each segment with an endoloop, the defect was effectively closed.
Post-procedure management Post-procedure investigations and advancement of diet vary between centres, as does the length of stay, which ranges from 1–5 days for patients without complications.26 All centres withhold oral food and fluid from the patient after the procedure, with the majority of centres initiating a liquid diet within 24 h. After mucosal integrity is confirmed with endoscopy and an oesophagram, the diet is subsequently advanced to a regular diet over 1–14 days. At our centre, after confirmation of mucosal integrity, the patient is started on clear fluids for 24 h, then a pureed or soft diet over 2 days and finally a regular diet by day 4 (discharge day). Of note, the average length of stay for LHM in Japan is 7–10 days compared with 2–3 days in Western hospitals and is a result of cultural differences, lower health-care cost in Japan than in the West and patient expectation. In Japan, patients are generally kept in hospital until they are at or near their functional baseline. This practice is reflected in length of stay for POEM, for which the average duration in Japan is 4 days compared with 1–2 days in the USA and Europe.45,46 Some centres have performed routine CT scans on all patients after POEM in search of prognostic radiological signs; however, no clinically relevant information was gained in these patients and so routine post-procedure CT is not recommended in asymptomatic patients.47 Prophylactic antibiotics are given 30 min before POEM and are continued for 2–7 days. At our centre, patients receive antibiotics for a total of 5 days. By contrast, 1–2 days of prophylactic antibiotics are generally administered to patients undergoing LHM. All patients undergoing POEM should receive prophylactic antibiotics due to the substantial mortality and morbidity of mediastinitis (with post-surgical reports of mortality of up to 47%48,49), but the optimal duration of therapy is unknown.
Management after discharge
Follow-up should be arranged within 3–6 months after discharge or sooner if issues arise. At follow-up, an Eckardt score, endoscopy, manometry and timed barium oesophagram should be arranged and, if available, oesophageal distensibility and 24 h oesophageal pH testing. These investigations document clinical, radiologic and manometric treatment success, functional changes to the GEJ and identify pathological gastro-oesophageal reflux. Our practice has been to conduct subsequent
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REVIEWS clinical follow-up at 1 year and annually thereafter. The annual follow-up is performed indefinitely. Surveillance endoscopy for squamous cancer in patients with achalasia is controversial. The American Society for Gastrointestinal Endoscopy guidelines, which have not been updated for almost 10 years, state that evidence to support a recommendation for routine screening for squamous cancer in patients with achalasia is insufficient. However, the initiation of screening for cancer 15 years after symptoms onset is suggested to be reasonable. A recommendation of screening intervals is not given owing to insufficient evidence.50 Patients who have had achalasia for >10 years and/or the presence of oesophageal dilation are thought to be at the highest risk of developing cancer.51,52 The incidence of cancer in patients with achalasia ranges from 0.04–0.58% per year with a prevalence ranging from 0.4–6.1%.51,53–61 An international survey of achalasia experts, did not reach a consensus regarding the perceived lifetime risk of oesophageal cancer, with screening performed by 53% of the experts.62 Of those that performed screening, the screening interval ranged from every 2–5 years and was initiated 1–10 years after diagnosis of achalasia.62 In the future, novel technologies such as the endocytoscope might aid in supplementing evidence to guide the optimal screening intervals by stratifying patients according to their risk of developing cancer. The endocytoscope GIF‑Y0001 (Olympus medical systems, Tokyo, Japan) is a prototype endoscope that has ×450 magnification allowing real-time detailed endoscopic examination of live tissue. With the use of the endocytoscope and immunohistochemistry Minami et al.63 examined the oesophageal epithelium before and after POEM. After POEM, there was normalization of the size and shape of epithelial cells. In addition, there was a decrease in the mean levels of Ki67 and p53 positive staining, which have been shown to correlate with malignant progression as well as dysplasia.64–66 One can speculate that pending further studies and maturation of this technology, it might hold value for risk stratification of oesophageal cancers in patients with achalasia and help determine optimal screening intervals. In our practice, the suggested post-POEM investigations for achalasia including oesophageal cancer screening on the basis of extrapolation, adaptation of previous achalasia guidelines and experience are summarized in Box 1.2,67,68
Safety and adverse events
There have been >3,000 POEM procedures performed worldwide with no reported mortalities or requirement for conversion to an open surgical procedure. Two reports of oesophageal perforations that required subsequent laparoscopic and thoracoscopic intervention have occurred.28,69 One patient did not adhere to the post-procedure diet, ate solid food, retched and developed a contained perforation that required laparoscopy and drain placement.28 The second patient had a perforation that required thoracoscopic drainage.69 Both patients recovered and were discharged home without sequelae. Other potential adverse events associated with POEM, include: bleeding (immediate and delayed); dehiscence of mucosal entry
Box 1 | Follow-up times and investigations after POEM Postprocedure (24–48 h) ■■ Oesophagram ■■ Upper endoscopy ■■ Haematology and biochemistry if clinically indicated ■■ Standard postprocedure clinical care Short-term (3–6 months) ■■ Oesophagram ■■ Upper endoscopy ■■ Manometry, pH monitor* and distensibility* ■■ Eckardt Score Long-term (>1 year) ■■ Oesophagram (only if symptomatic) ■■ Endoscopy every 1–3 years ■■ Manometry, pH monitor, distensibility (only if symptomatic) ■■ Eckardt score *If available.
site; peritonitis; mediastinitis; pneumonia; pneumoperitoneum; pneumomediastinum; pneumothorax; thoracic effusions; and atelectasis.70 Fortunately, severe adverse events are rare with an incidence of less than 0.1%,71 with the most commonly occurring adverse events (mucosal injury and pneumoperitoneum) managed easily and without consequence to the patients long-term health. Another outcome of concern associated with POEM is gastro-oesophageal reflux. To date, there have been no reports of severe oesophagitis resulting in peptic stricture or patients with PPI-refractory reflux. In the 2011 European achalasia trial, the reflux rates for LHM and pneumatic dilation based on 24 h oesophageal pH testing were 23% and 15%, respectively.72 In a systematic review and meta-analysis of LHM published in 2009, the incidence of reflux was 8.8%.9 Similar to LHM, the incidence of reflux in POEM was reported as 10.9% in a systematic review and meta-analysis published in 2014.70 However, the reported incidence of reflux among studies included in these systematic reviews and meta-analyses were made on the basis of a definition of reflux that was hetero geneous between studies and included; abnormal acid exposure on 24 h oesophageal pH testing (gold standard for diagnosing reflux), oesophagitis on endoscopy, positive score on self-assessment questionnaire or patient self‑reporting of reflux symptoms. The heterogeneity in defining reflux is commonly encountered in the literature. In a meta-analysis comparing LHM and pneumatic dilation for the treatment of achalasia, only two trials reported reflux incidence using 24 h oesophageal pH testing.72,73 A meta-analysis of these two studies showed the reflux incidence after LHM and pneumatic dilation was 17.4% (95% CI, 12.1– 24.3) and 19.7% (95% CI, 13.8–27.2), respectively.6 In the only comparative study of LHM versus POEM that used 24 h oesophageal pH testing (Table 1), there was no statistically significant difference in reflux incidence (LHM 32% and POEM 39%; P = 0.7).45 Thus, based on the current literature, there does not seem to be a statistically significant difference in post-procedure incidence of reflux. With the completion of a randomized trial comparing LHM
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REVIEWS Table 1 | Persistent postoperative symptoms Heller (%)
POEM (%)
P
Early symptoms* Heartburn Dysphagia to solid Dysphagia to liquid Reflux Chest pain
n = 63 3 10 3 6 5
n = 37 11 5 0 5 5
– 0.2 0.4 0.4 0.6 0.6
Long-term symptoms‡ Heartburn Dysphagia to solid Dysphagia to liquid Reflux Chest pain
n = 38 16 29 8 3 5
n = 27 7 0 0 4 0
– 0.3 0.001 0.2 0.7 0.3
*Symptom score ≥2, within 2 weeks of surgery. ‡Symptom score ≥2, more than 6 months after surgery. Reproduced with permission from Lippincott Williams & Wilkins © Bhayahni, N. H. et al. Ann. Surg. 259, 1098–1103 (2014).
to POEM in 2019, which will include pre-POEM and post‑POEM 24-hour oesophageal pH testing, high‑quality evidence will be available.74 The most comprehensive adverse event data comes from the iPOEMS survey, which reported major nonfatal adverse events occurring in 3.2% of 841 patients.26 In the large European achalasia trial, there was a 4% perforation rate for pneumatic dilation and a 12% rate of mucosal tear for LHM.72 With increased operator experience it has been shown that the adverse event rate of POEM generally decreases.75 However, without consistent adverse event reporting and classification, a precise adverse event incidence will be difficult to extract. Now with widespread experience, POEM has been performed safely and effectively in patients of increasing complexity and morbidity, such as those with previous bariatric surgery, situs inversus, complete heart block and nonagenarians.18,76–78
Insufflation-related adverse events The most commonly occurring adverse event associated with POEM are related to insufflation:70 pneumomedia stinum; capnomediastinum; pneumoperitoneum; capnoperitoneum; pneumothorax; and subcutaneous emphysema (hence forth the terms pneumomediastinum and pneumoperitoneum will be used to refer to both CO2 and air in the mediastinum and peritoneum, respectively). All of which can be treated conservatively as with subcutaneous emphysema and pneumomediastinum, or with needle decompression and chest tube placement as with tense pneumoperitoneum and pneumothorax, respectively. The insufflation method, tubing and technique used are essential to minimize insufflation related adverse events. From studies of oesophageal endoscopic submucosal dissection (ESD), it has been shown that CO2 insufflation substantially reduces the amount of pneumomediastinum compared with air insufflation.79,80 In POEM, the working field can be in direct continuity with the mediastinum and/or peritoneum. Thus, with air absorbed 150 times slower than CO2, it is essential that CO2 be used to decrease the volume of gas within the subperitoneal, peritoneal, mediastinal and luminal space to diminish the potential of insufflation-related complications.31,47,78,81–83 Another important factor is the total volume of gas
insufflated, which is dependent on the flow rate of the tubing used and the frequency and duration of insuf flation. The use of low-flow CO2 tubing has been shown to reduce insufflation-related adverse events as demonstrated by Familiari et al.84 in a series of 100 patients undergoing POEM. In the first 79 patients, medium-flow or high-flow CO2 tubing was used, which resulted in tense pneumoperitoneum in 36.7% of patients.84 For the remaining 21 patients, low-flow CO2 tubing was used and no events of tense pneumoperitoneum occurred.84 In addition, the frequency and duration the operator depresses the insufflation button directly influences the total volume of gas insufflated. Accordingly, the endoscopist needs to eliminate excessive and needless insufflation to further minimize the total volume of gas. Therefore, judicious and conscientious use of insufflation, with low-flow CO2 offers the greatest reduction in the risk of insufflation-related adverse events.
Radiological findings With regards to asymptomatic radiological findings, Tamiya et al.85 reported on a series of 58 patients who had undergone oesophageal ESD. Routine post-procedure CT revealed that 100% of patients had pleural or mediastinal effusions and 31% had mediastinal air, all of which were asymptomatic and without clinical sequelae. Similar findings have been shown in other series of oesophageal ESD with asymptomatic pneumomediastinum in up to 62% of patients.82,86 In a retrospective series by Cai et al.47 300 patients underwent a routine CT scan within 30 h of POEM, with air insufflation used in 157 (52.3%) patients. The majority of patients had radiological changes such as pneumonitis, pneumomediastinum, pneumoperitoneum, focal atelectasis and pleural effusions with most being asymptomatic. When comparing CO2 to air insufflation, a greater proportion of patients receiving air insufflation developed symptomatic insufflation-related adverse events. In their univariate analysis, full-thickness myotomy was associated with increased pneumomediastinum, pneumoperitoneum and thoracic effusions. However, this effect was lost in the multivariate analysis, which revealed only increasing age to be associated with an increased rate of pneumothorax and use of CO2 insufflation was associated with fewer insufflationrelated adverse events compared with air insufflation. Routine post-procedure CT in asymptomatic patients was concluded to be of no clinical benefit. Yang et al.87 also reported on a series of 108 POEM procedures with post-procedure CT that showed pneumoperitoneum and/ or pneumomediastinum in 53.7% of cases with no correlation of asymptomatic insufflation-related CT findings and clinical complication rate. Mucosal perforation Mucosal perforations are one of the more common adverse events encountered with the POEM procedure. As POEM involves submucosal dissection with subsequent myotomy, the mucosa is the only barrier maintaining luminal integrity. Therefore, preserving an intact mucosa is of critical importance. The incidence of mucosal perforation ranges from 0–25%, with an overall rate of
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REVIEWS 3) were within the first three procedures performed thus, limiting the generalizability of this finding. In the series reviewed in Supplementary Table 1, of those that reported mucosal perforation only one patient with perforation had an unsuccessful POEM (post-POEM Eckardt score >3).28 Thus, mucosal perforations in POEM are not uncommon occurrences, but can be managed safely, effectively and probably without compromised clinical efficacy when performed by experienced operators. However, with increased long-term follow-up, detailed analysis of treatment failures is required to help determine if a true correlation exists between intraprocedural perforation and treatment failure or symptom recurrence.
Bleeding Minor intraprocedural bleeding is commonly encountered and can be managed with the needle knife or haemostatic forceps. Severe intraprocedural bleeding that precludes completion of POEM has not been reported. In addition, minor intraprocedural bleeding is sparsely
reported in case series; however, anecdotally, it is commonly encountered. In a study by Cai et al.93 comparing a water-jet-assisted knife versus a triangle tip knife, the mean number of regular haemostatic and coagulation forceps events was 5.2 and 1.65, respectively (events included prophylactic haemostasis of vessels not actively bleeding) in 100 patients undergoing POEM. Thus, analogous to the ESD operator, the POEM operator should be familiar and proficient with haemostatic techniques as they are frequently performed. In 428 consecutive POEM procedures in 428 patients with achalasia, Li et al.91 reported a delayed bleeding rate of 0.7%. Three patients required urgent endoscopy for haematemesis. In one patient, the bleeding site could not be found and a Blakemore–Sengstaken tube was immediately placed, inflating the gastric and oesophageal balloons and achieving haemostasis. In the two other patients, the active bleeding sites were identified at the edges of cut muscle, treated with haemostatic forceps and placement of a Blakemore–Sengstaken tube. If a Blakemore– Sengstaken tube is used for haemostasis of uncontrolled bleeding after a completed myotomy and inflation of the oesophageal balloon cannot be avoided, it should be performed with extreme caution; after a completed myotomy, a barrier no longer exists between the submucosal tunnel and mediastinum and bleeding might continue into the mediastinum, which is potentially catastrophic. Minami et al.94 described two patients with post-procedure bleeding in a series of 28 patients. Both patients were managed conservatively without endoscopic treatment. With the rare occurrence of severe and delayed bleeding with POEM, there is no consensus as to optimal method to achieve haemostasis. In addition, although not reported in patients who have had POEM, arterial oesophageal bleeds of various aetiologies have been successfully treated by interventional radiology and can be considered a treatment option in patients who have undergone POEM and have refractory bleeding.95–99
Reporting of adverse events The heterogeneity in reporting and classifying adverse events associated with POEM partially accounts for the variability in adverse event rates described in the published literature. Specifically, some series do not classify mucosal perforations repaired intraprocedurally or successfully decompressed pneumoperitoneum as adverse events. In an attempt to account for this diversity in reporting, all pneumoperitoneum requiring decompression, subcutaneous emphysema, symptomatic pneumo thorax, or fever that required a change in antibiotic treatment and all mucosal perforations are included as adverse events in Supplementary Table 1. Asymptomatic radiological findings were not included as adverse events. To improve the quality and reliability of adverse event reporting, a standard classification system should be used, such as the Clavian–Dindo classification.100 POEMspecific classifications can also be developed as was done by Sharata et al.17 who proposed the Portland oesophagotomy classification. Eventually, with international collaboration and discourse through events such as the POEM
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b
c
d
25.0 25.7 25.0 23.3 18.8 11.3 6.4 4.9 5.4 6.7 11.1 16.4 21.4 23.8 24.5 23.8
18.9 18.8 18.4 18.1 16.7 14.9 13.9 13.8 13.4 12.3 12.8 14.6 18.6 22.5 23.7 23.5
Figure 5 | Endoscopic, radiological, manometric and distensibility changes before and after POEM. Pre-POEM shown on Nature Reviews | Gastroenterology & Hepatology the left and post-POEM on the right. a | Endoscopic, b | radiological, c | high-resolution manometry and d | distensibility. Abbreviation: POEM, peroral endoscopic myotomy.
International Conference, a clear, concise adverse event classification and reporting method should be agreed upon and universally implemented.
Efficacy
Objective measures of effective treatment response in patients with achalasia include timed barium oesophagram, LES pressure, integrated relaxation pressure and GEJ distensibility as measured by the Endolumenal Functional Lumen Imaging Probe (EndoFLIP®, Crospon, Galway, Ireland). Clinical efficacy is defined by the Eckardt scoring system. A post-treatment Eckardt score of
