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1 Digestive Endoscopy 2016; 28: doi: /den Original Article Peroral endoscopic myotomy for achalasia cardia: Treatment analysis and follow up of over 200 consecutive patients at a single center Mohan Ramchandani, 1 D. Nageshwar Reddy, 1 Santosh Darisetty, 2 Rama Kotla, 2 Radhika Chavan, 1 Rakesh Kalpala, 1 Domenico Galasso, 4 Sundeep Lakhtakia 1 and G. V. Rao 3 Departments of 1 Gastroenterology, 2 Anesthesiology, 3 Surgical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India, and 4 Digestive Endoscopy Unit, A. Gemelli Hospital, Università Cattolica del Sacro Cuore, Rome, Italy Background and Aim: Peroral endoscopic myotomy (POEM) is a recently introduced technique for the treatment of achalasia cardia (AC). Data regarding safety and efficacy are still emerging. We report our experience of POEM emphasizing its safety, efficacy and follow-up data. Methods: Patients with AC (220; mean age 39 years, range 9 74 years) underwent POEM from January 2013 to August 2014 for AC. Retrospective analysis of prospectively collected data was done. POEM was carried out by the standard technique of mucosal incision, submucosal tunneling, and myotomy of the esophageal and gastric muscle bundles followed by closure of the mucosal incision by hemoclips. Eckardt score, high-resolution manometry (HRM) and timed barium esophagogram (TBE) were used to evaluate the results. Post-procedure patients were followed up. Results: Technical success rate of POEM was 96%. At 1 year, clinical success rate was 92%. Mean Eckardt score was 7.2 ± 1.55 prior to POEM and 1.18 ± 0.74 after POEM (P = 0.001). There was significant improvement of esophageal emptying on TBE (38.4 ± 14.0 % vs 71.5 ± 16.1 % (P = 0.001). Pre-procedure and post-procedure mean lower esophageal sphincter pressure was 37.5 ± 14.5 mmhg and 15.2 ± 6.3 mmhg, respectively. (P = 0.001) Erosive esophagitis was seen in 16% of patients who underwent POEM. There were no major adverse events. Conclusions: Study demonstrates excellent safety profile of POEM with significant relief of symptoms, reduced pressure at HRM and improved emptying at TBE. Further prospective studies are required to compare with other treatment modalities. Key words: Achalasia cardia, Minimally invasive surgery, natural orifice transluminal endoscopic surgery, POEM, Per oral endoscopic myotomy INTRODUCTION ACHALASIA CARDIA (AC) is an idiopathic disorder of esophageal motility characterized by failure of lower esophageal sphincter (LES) relaxation and aperistalsis of the esophageal body. 1 3 Pathophysiologically, AC is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus and results in dysphagia, regurgitation, and esophageal dilation. Choices of treatment vary from medication to surgery. Medical and endoscopic treatment classically includes the use of various drugs, endoscopic pneumatic dilatation and botulinum toxin injection. Surgically, AC can be treated by carrying out myotomy by laparoscopic or open access. 1 4 Corresponding: D. Nageshwar Reddy, Department of Gastroenterology, Asian Institute of Gastroenterology, , Somajiguda, Hyderabad , India. aigindia@yahoo.co.in Received 15 January 2015; accepted 22 May After the introduction of scarless natural orifice transluminal endoscopic surgery (NOTES) 5 8 in the last decade, many developments have occurred, especially in the technique of transluminal access through the submucosal tunnel approach. This technique was first introduced by Sumiyama et al. 9 in 2007 using submucosal endoscopy which offsets the mucostomy and myotomy sites. By means of the mucosal flap safety-valve technique, rapid secure closure of mucosal incision by clips can be achieved. Pasricha et al. 10 further studied this technique in animal models and successfully carried out endoscopic LES myotomy. In 2010, this novel per oral endoscopic myotomy (POEM) method was initially carried out in humans by Inoue et al. 11 and, since then, many large case series have been reported on POEM worldwide. Continued accumulation of safety and efficacy data of this relatively new procedure is warranted. We report our single-center experience carrying out POEM in 220 symptomatic patients (103 women, 117 men) presenting with AC. bs_bs_banner 19

2 20 M. Ramchandani et al. Digestive Endoscopy 2016; 28: METHODS Patients THIS STUDY IS a retrospective analysis of prospectively collected data. POEM was approved by our institutional review board and it was proposed to all patients presenting with AC from January 2013 to August Patients with primary AC diagnosed by established methods (barium swallow study, high-resolution manometry [HRM], upper gastrointestinal [GI] endoscopy) were included in this study. Early exclusion criteria (for the first 25 patients) included age <18 years, inability to tolerate general anesthesia, sigmoid esophagus and patient refusal. Once the learning curve was completed, the only contraindications that remained were inability to undergo general anesthesia and patient refusal. Previous endoscopic treatment (including repeated balloon dilatation and botulinum toxin injection) and previous surgical treatment (open or laparoscopic Heller s myotomy [LHM]), sigmoid esophagus or situs inversus totalis 12 were not considered exclusion criteria. All patients underwent preoperative physical examination, symptom evaluation, esophagogastroduodenoscopy (EGD), HRM and timed barium esophagogram 13 (TBE). Manometry was carried out with a 16-channel water perfused catheter that had eight channels 1 cm apart at the lower end and the remaining eight channels 3 cm apart (Dentsleeve International Pty Ltd; Mui Scientific, Ontario, Canada). Data were analyzed using Trace 1.2 V software (Geoff Hebbard, Royal Melbourne Hospital, Victoria, Australia). Symptoms were evaluated according to the Eckardt score 14 in patients presenting with AC. Standardized, validated symptom assessment form with scores for dysphagia, regurgitation, chest pain, and weight loss were recorded. Based on HRM, the Chicago classification 15 was used to identify the subtypes of AC. Operative data were collected prospectively. Morbidity was defined as any complication requiring additional procedures or prolonging hospital stay >3days. All patients were scheduled for follow-up visits at 3 months, 6 months and 1 year after the procedure to evaluate the outcome and adverse events. At the 3- and 6-month follow-up visits, physical examination and symptom evaluation were done. At the 1-year visit, patients underwent additional investigations including timed barium swallow, esophageal manometry and EGD. A postoperative Eckardt score 3 for patients affected by AC was considered a successful outcome. In cases of persistent symptoms, patients were offered additional treatment including pneumatic balloon dilatation (PBD) or botulinum toxin injection. Technique Patients were kept on a liquid diet for 1 2 days prior to the procedure. Prophylactic antibiotics were given on the day of procedure and continued during the entire period of hospitalization. Patients were later switched to oral antibiotics after discharge for up to 7 days. Patients with esophageal candidiasis were initially treated with clotrimazole lozenges and oral antifungal for 1 week before the procedure. Patients were placed supine and general anesthesia was given. EGD was done with routine upper gastrointestinal endoscope (Olympus GIF HQ 190; Olympus Corp., Tokyo, Japan) with tapered tip transparent cap (DH-28GR; Fujifilm, Tokyo, Japan) fitted onto the distal end of the scope to facilitate submucosal dissection. Choice of the site of myotomy (anterior at 2 o clock position vs posterior at 5o clock position) 16 was left to endoscopist (DNR and MR) preference. However, posterior myotomy was preferred in patients who underwent LHM previously. A 2-cm mucosal entry was made after making a submucosal wheal by injecting normal saline with indigocarmine submucosally at least 3 4 cm proximal to the high-pressure zone identified at preoperative HRM. 17 A submucosal tunnel was then created using a combination of blunt dissection, carbon dioxide (CO 2 ) insufflation, hydro-dissection, and careful electrocautery. The tunnel was extended past the gastroesophageal junction (GEJ) and at least 2 cm onto the gastric cardia. Gastric extent of submucosal tunnel was confirmed by visualizing blanched gastric mucosa. A proximal-to-distal circular muscle myotomy was next carried out, taking care to preserve the longitudinal muscle layers of the upper esophagus. Full-thickness myotomy was done at the lower end of esophagus and cardia. Smooth passage of the endoscope through the GEJ and a retroflexed evaluation of the LES confirmed adequate myotomy. The mucosal incision was then closed using standard endoscopic clips. All patients were evaluated with a water-soluble contrast esophagogram on the second postoperative day. If normal, they were then started on a pureed diet and subsequently discharged. They maintained this diet for 1 week and then were allowed regular food. Statistics Data were prospectively collected, and comparison of pre- and post-procedure parameters was done. Data are presented as mean ± standard deviation. Student s paired t-test was used for continuous variables and proportion test for categorical variables. P-value <0.05 was considered statistically significant.

3 Digestive Endoscopy 2016; 28: POEM for achalasia cardia 21 RESULTS ATOTAL OF 225 patients with esophageal motility disorders underwent POEM in our department during the study period (Table 1). Of these, 220 patients (mean age 39 years, range 9 74 years, 117 men) had AC including type I(n =67),typeII(n = 145) and type III (n = 8). Three patients had diffuse esophageal spasm and two had jackhammer esophagus; thus, these five patients were excluded from the analysis. Seventy-seven patients were previously treated by pneumatic balloon dilatation, 10 by LHM, whereas three underwent both LHM and PBD and one patient was treated with botulinum toxin injection. Forty-five patients had sigmoid achalasia (type S1: 38 patients; and type S2: seven patients). 11 Mean pre-procedure Eckardt score was 7.1 (range 3 11) and LES pressure was 36.7 mmhg (range ). POEM was successfully completed in 212/220 (96%) patients with AC (Table 2). Anterior myotomy (2 o clock) was done in 190 (86%) patients whereas 30 patients underwent posterior myotomy (5 o clock position). All patients who had previously undergone LHM were treated with posterior myotomy. In eight patients, POEM could not be completed because of submucosal fibrosis in six patients (three patients with multiple PBD, two patients with prior LHM and one idiopathic) and inadvertent mucosal incision enlargement in two patients. In two patients in whom the initial procedure was aborted as a result of mucosal tear, POEM was later successfully carried out by posterior approach. The remaining six Table 1 Demographics of study patients No. patients 225 Indication for POEM Achalasia cardia 220 Type 1 67 Type II 145 Type III 8 Diffuse esophageal spasm 2 Jackhammer esophagus 3 Mean age, years (± SD, range) (n = 220) 39.3 (9 74) Male : Female 117:103 Disease duration (months) 19.9 (3 98) Previous therapy Botulinum toxin injection 1 Pneumatic balloon dilatation 77 (35%) Heller s myotomy 10 (4.5%) PBD and LHM 3 Sigmoid achalasia 45 S1 38 S2 7 LHM, laparoscopic Heller s myotomy; PBD, pneumatic balloon dilatation; POEM, peroral endoscopic myotomy. Table 2 Operative finding, adverse events and post operative follow up Site of myotomy Anterior 190 Posterior 30 Operating time (min) 88.0 ± 27.3 (38 180) Length of myotomy (cm) 12.0 (6 19) Esophageal (cm) 8.6 (3 16) Gastric (cm) 3.4 (1 5) Technical success 212/220 (96%) Reason for technical failure Submucosal fibrosis 6 (3%) Mucosal incision enlargement 2 (0.9%) Adverse events Clinically significant bleeding 0 Mucosal injury 14 (6.4%) Self-limiting subcutaneous emphysema 32 (14.5%) Capnoperitoneum requiring drainage 40 (18.2%) Capnothorax 3 (1.4%) Retroperitoneal air requiring temporary 28 (12.7%) stopping of procedure Feeding, days, median (range) 2 (1 4) Hospital stay, days, mean (range) 2.7 (2 5) 30-day readmission rate 0 No. clips, median (range) 6 (3 18) Perioperative complications 0 30 days 0 patients were treated by balloon dilatation (n = 3), botulinum toxin injection (n = 2), and esophagectomy (n = 1). In 24 patients, guidewire and fluoroscopic assistance was taken for reorienting submucosal dissection in a vertical downward direction in cases of sigmoid achalasia (Fig. 1). In eight patients with achalasia, the GEJ was spastic, thus making the submucosal tunnel technically difficult. In these cases, myotomy was carried out at the GEJ without submucosal tunneling (Fig. 2). Small myotomy was initially carried out followed by injection of saline in the submucosal space to delineate the submucosal plane. After defining the submucosal plane, myotomy was carefully carried out further without injuring the mucosa. Mean operating time was 88 min ranging from 38 min to 180 min. Mean length of 12.0 cm of myotomy was carried out including mean length of 8.6 cm on the esophageal side and mean length of 3.4 cm on the gastric side. Mild subcutaneous emphysema was seen in 32 patients. Intraoperative clinically significant abdominal distention (as assessed by anesthesiologist) was observed in 60 cases (27%) during the procedure as a result of capnoperitoneum and or retroperitoneal CO 2 (identified with fluoroscopy). Peritoneal CO 2 was drained using conventional i.v. cannula. In patients with significant abdominal distention and retroperitoneal CO 2, the POEM procedure was briefly stopped until

4 22 M. Ramchandani et al. Digestive Endoscopy 2016; 28: Figure 1 (Panel 1) (A) Endoscopic picture showing submucosal tunneling in a patient with sigmoid esophagus. (B) Fluoroscopic picture showing the wrong direction of tunneling. (C) Arrow showing the tunnel going in the lateral direction. (Panel 2) (A) Guidewire passed in the gastric lumen. (B) Correction of scope direction in the submucosal tunnel according to the guidewire. (C) Endoscopic view of correct direction of tunneling. (Panel 3) (A) Saline with indigocarmine injected with spray catheter in corrected scope position. (B) Separation of mucosa and submucosa is seen. (C) Submucosal tunnel extending into the gastric side. Figure 2 (A) Spastic circular muscle at gastroesophageal junction, myotomy carried out before submucosal dissection. (B) Delineation of submucosal space (arrow) after initial myotomy.

5 Digestive Endoscopy 2016; 28: POEM for achalasia cardia 23 the CO 2 was absorbed. Initial 100 cases were done using low-flow gas tube (MAJ-1742) attached to CO 2 insufflator (UCR; Olympus Corp.) and later cases were done using extra-low-flow gas tube (MAJ-1816; Olympus Corp.). The incidence of clinically significant capnoperitoneum was less commonly seen in the later 120 cases when extra-low-flow CO 2 was used (Table 3). Inadvertent mucosal injuries were seen in 14 (6.4%) patients which were successfully closed using hemoclips at the end of the procedure. Three patients developed intraprocedural capnothorax which was managed by intercostal drainage. Follow-up data were available in 149 patients including 102 patients at 1 year (mean 13.4 months; range months) and an additional 47 patients at 6 months (mean 7.21 months, range 6 9 months). At 6 months follow up, 140 patients out of 149 patients had Eckardt score 3 with clinical success of 94%, whereas on intention-to-treat (ITT) analysis, clinical success was 87.5% (140/160, including eight patients with initial technical failure and three patients who were lost to follow up). No adverse events were recorded during follow up. Mean Eckardt score significantly decreased from 7.12 ± 1.16 at baseline to 1.25 ±1.08(P = 0.001) at the date of interview. One-year follow up One-year follow-up data are shown in Table 4. Patients were instructed for follow-up visit at 1 year for symptomatic and objective assessment. At 1 year, clinical success was 92% (94/102) on per-protocol analysis and 83% (94/113, including eight patients with technical failure and three patients who were lost to follow up) on ITT analysis. Mean Eckardt score was 7.20 ± 1.55 prior to POEM and 1.18 ± 0.74 after POEM (P = 0.001). TBE was compared in 82 patients. Mean pre-procedure emptying at 5 min was 38.4 ± 14.0 and mean post-procedure emptying at 5 min was 71.5 ± 16.1% (P = 0.001). High-resolution manometry was done in 86 patients. Pre-procedure mean LES pressure was 37.5 ± 14.5 mmhg and post-procedure mean LES pressure was 15.2 ± 6.3 mmhg (P = 0.001). At 1 year follow up, 22 patients (21.6%) had gastroesophageal reflux as assessed by clinical history and symptom analysis. EGD revealed erosive esophagitis in 14/84 (16.6% of patients [Los Angeles grade A in 10 and grade B in four patients]). None of the patients had grade C or D esophagitis. Eight patients failed to have symptomatic improvement at 1 year and four of these were successfully treated by PBD. Of these eight patients, six had sigmoid esophagus and two had type III AC. DISCUSSION THERE ARE VARIOUS treatment modalities available for the treatment of AC including various drugs (calcium channel blockers, nitrates, 5-phosphodiesterase inhibitors, anticholinergics, beta adrenergic agonists and theophylline), botulinum toxin (Botox, Allergan pharmaceuticals Ireland, Westport Co. Mayo, Ireland) injection, PBD and surgical open or laparoscopic myotomy. 18 Of these available treatment modalities, the Table 3 Insufflation related adverse events: Comparison between Low flow and extra low flow gas tubes Low-flow gas tube (MAJ-1742) (n = 100) Extra-low-flow gas tube (MAJ-1816) (n = 120) P-value Self-limiting subcutaneous emphysema Capnoperitoneum requiring drainage Capnothorax Retroperitoneal air requiring temporary stopping of procedure MAJ-1742, Olympus Corp., Tokyo, Japan; MAJ-1816, Olympus Corp. Table 4 Follow up data at 12 months Pre-procedure Post-procedure P-value Eckardt score (N = 102) 7.20 ± ± 0.74 P = Percentage emptying at 5 min on timed barium swallow (n = 82) 38.4 ± ± 16.1 P =0.001 Erosive esophagitis on EGD (n = 84) 0 14 (16.6%) P =0.001 LES pressure on high-resolution manometry (mmhg) (n = 86) 37.5 ± ± 6.3 P = Total no. patients: 113; technical failure: 8; lost to follow up: 3; total no. patients analyzed: 102. EGD, esophagogastroduodenoscopy; LES, lower esophageal sphincter.

6 24 M. Ramchandani et al. Digestive Endoscopy 2016; 28: most commonly used are PBD and LHM, which have been proven to have similar therapeutic results at 2-year follow up. 19 POEM has emerged as the competitive modality of treatment in recent years for AC. The practical advantage of POEM is that, by avoiding body wall trauma and extensive dissection of the esophageal hiatus, 20 the procedure is mostly pain-free and allows patients to resume normal activities a couple of days after the procedure. The present series is the largest single-center series of POEM reported from the Indian subcontinent. The results show that this modality of treatment for patients with AC is highly effective, resulting in a >90% success rate at the end of 1-year follow up. The present study represents a large group of patients that are usually difficult to treat, including patients with sigmoid esophagus and patients that underwent previous endoscopic treatment such as balloon dilatation or botulinum toxin injection or surgical treatment. Studies have already demonstrated the efficacy of POEM not only in terms of dysphagia relief but also in improvement of esophageal manometry. 21,22 In the present series, we confirmed the excellent outcome of POEM with 1-year follow up of >100 patients. More than 90% of patients maintained an Eckardt score of 3 at 1-year follow up. Symptoms recurred in eight patients, of which half were treated successfully by PBD. The present study demonstrates the excellent safety profile of POEM with significant relief of symptoms, reduction of LES pressure and improvement of esophageal emptying. Capnoperitoneum and submucosal emphysema are an inevitable part of the procedure 23 which can be recognized during the procedure and be easily managed if clinically significant. We have shown that insufflation-related adverse events were less common when we used extra-low-flow CO 2. Other factors such as operator experience, route of myotomy etc. can be additional factors responsible for the lower rate of these adverse events in the later part of the study. In the absence of multivariate analysis, the benefit of extra-low-flow CO 2 cannot be confirmed in this study; however, further innovative techniques and devices to manage the optimum flow of CO 2 in the submucosal tunnel are warranted. Figure 3 Timed barium esophagogram (TBE) in a case of type III achalasia cardia. (A,C) Pre-peroral endoscopic myotomy (POEM) TBE at 1 and 5 min, respectively. (B,D) Post-POEM TBE at 1 and 5 min, respectively.

7 Digestive Endoscopy 2016; 28: POEM for achalasia cardia 25 POEM provides a distinct advantage over LHM in managing type III AC. 24 These patients require longer esophageal myotomy which can be easily accomplished during POEM. In our series, eight patients underwent POEM for type III AC with good symptomatic and objective responses (Fig. 3) and the longest myotomy done was 19 cm. Another advantage of POEM is that it can be done with a reasonable success rate in patients who have undergone previous endoscopic or surgical procedures. 25,26 POEM should be a preferred approach over repeat LHM in managing patients with recurrent or persistent symptoms after LHM. POEM provides an opportunity to go in opposite planes to avoid scars and tissue adhesions in the region of the previous operation. This series demonstrated the efficacy of POEM in sigmoid achalasia, 45 (20%) patients had sigmoid achalasia and the technical success POEM in this group was 88%. The technical difficulty observed during POEM of tortuous and dilated esophagus is maintaining the downward vertical direction. We report the innovative technique of passing the guidewire in the stomach through the esophagus. Taking a guide from this wire under fluoroscopy, the scope in the submucosal tunnel can be realigned in the correct direction. Carrying out difficult cases such as sigmoid achalasia under fluoroscopic guidance may be of help. Limitation of the present study is, of course, its retrospective evaluation. We did not carry out ph studies for the assessment of gastroesophageal reflux disease (GERD); however, symptom evaluation and EGD were done for evaluation of post-procedure GERD. The true incidence of GERD cannot be assessed in this study because of the retrospective design and the significant rate of patients with no follow up. In conclusion, our experience of 220 POEM patients with AC with 1 year follow up of more than 100 patients demonstrates excellent relief of symptoms, reduced pressure at HRM and improved emptying at TBE. We still require longterm objective follow up to better understand the long-term success rate of the procedure as well as any long-term effects of POEM. To date, no randomized controlled trial has compared POEM to endoscopic dilatation or surgical myotomy. Further prospective randomized trials are required to compare POEM with current standard treatment modalities. CONFLICT OF INTEREST AUTHORS DECLARE NO conflict of interests for this article. REFERENCES 1 Vaezi MF, Richter JE. Diagnosis and management of achalasia. American College of Gastroenterology Practice Parameter Committee. Am. J. Gastroenterol. 1999; 94: Francis DL, Katzka DA. Achalasia: Update on the disease and its treatment. Gastroenterology 2010; 139: Reynolds JC, Parkman HP. Achalasia. Gastroenterol. Clin. 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8 26 M. Ramchandani et al. Digestive Endoscopy 2016; 28: Simić AP, Radovanović NS, Skrobić OM, Raznatović ZJ, Pesko PM. Significance of limited hiatal dissection in surgery for achalasia. J. Gastrointest. Surg. 2010; 14: Familiari P, Gigante G, Marchese M et al. Peroral Endoscopic Myotomy for Esophageal Achalasia: Outcomes of the First 100 Patients with Short-term Follow-up. Ann. Surg Oct 30. [Epub ahead of print] 22 Talukdar R, Inoue H, Reddy DN. Efficacy of peroral endoscopic myotomy (POEM) in the treatment of achalasia: A systematic review and meta-analysis. Surg. Endosc Dec 25. [Epub ahead of print] 23 Yang S, Zeng MS, Zhang ZY, Zhang HL, Liang L, Zhang XW. Pneumomediastinum and pneumoperitoneum on computed tomography after peroral endoscopic myotomy (POEM): Postoperative changes or complications? Acta Radiol Oct 2. [Epub ahead of print] 24 Sharata AM, Dunst CM, Pescarus R et al. Peroral Endoscopic Myotomy (POEM) for Esophageal Primary Motility Disorders: Analysis of 100 Consecutive Patients. J. Gastrointest. Surg. 2015; 19(1): Orenstein SB, Raigani S, Wu YV et al. Peroral endoscopic myotomy (POEM) leads to similar results in patients with and without prior endoscopic or surgical therapy. Surg. Endosc. 2015; 29(5): Onimaru M, Inoue H, Ikeda H et al. Peroral endoscopic myotomy is a viable option for failed surgical esophagocardiomyotomy instead of redo surgical Heller myotomy: a single center prospective study. J. Am. Coll. Surg. 2013; 217: