The 2018 ISDE achalasia guidelines

Summary

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Summary Table of statements and recommendations

Topic and number	Statement	Consensus agreement score	Recommendation
Diagnosis of achalasia
	1 High-resolution manometry is the test of choice for the diagnosis of achalasia (compared to conventional manometry)	94.2%	We recommend the use of HRM for the diagnosis of esophageal achalasia. Conditional recommendation; GRADE low.
	2 The Chicago Classification is a useful tool to define the clinically relevant phenotypes of achalasia.	90.4%	We recommend classification of achalasia according to the Chicago Classification. Good practice recommendation
	3 The timed barium esophagram offers an objective evaluation of the diseases and of the outcome after treatment (compared to traditional barium esophagram).	90%.	We recommend the adoption of TBS in the diagnostic pathway of achalasia and to evaluate the outcome of treatment. Conditional recommendation; GRADE low.
	4 Endoscopy should be performed in patients with suspected achalasia to exclude malignancy of the esophagogastric junction.	98.1%	We recommend performing UGI endoscopy in adult with the suspected diagnosis of achalasia to exclude neoplastic pseudoachalasia. Good practice recommendation.
	5 The Eckardt score is a simple tool to measure symptom severity in achalasia patients, but it should be integrated with objective measures such esophagogram and manometry.	86.5%	We recommend the use of the Eckardt score as part of the initial and follow-up assessment in patients with achalasia. Good practice recommendation.
Treatment of achalasia
Medical treatment with nitrates, calcium blockers, or phosphodiesterase
	6 There is no convincing evidence that medical treatment with nitrates is effective for symptomatic relief in adults with achalasia.	86.5%	We recommend against the use of nitrates, calcium blockers, or phosphodiesterase treatment for achalasia. GRADE: low.
	7 There is no convincing evidence that medical treatment with calcium blockers is effective for (short term) symptomatic relief in adults with achalasia.	88.2%
	8 In adults with achalasia, there is no evidence that medical treatment with phospho-diesterase inhibitors is effective for symptomatic relief.	84.3%
Botulinum toxin injection (BTI)
	9 BTI has limited application in young patients (aged less than 50 years).	92.3%	We recommend against the use of BTI in patients under 50 years of age, for control of symptoms. GRADE: very low: We recommend against BTI as an effective therapy (control of symptoms) for achalasia in patients fit for surgery (LHM) or pneumatic dilatation GRADE: moderate.
	10 BTI should be reserved for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation	94.3%
	11 Repeat treatments with Botox are safe, but less effective than initial treatment	82.4%	Recommendation: Botox injection can be safely repeated, but the clinician and the patients should be aware that their efficacy is lower than in initial treatment. Conditional recommendation. GRADE: low.
	12 There is no evidence for supporting the injection of Botox in the lower esophageal body (in addition to injection in the LES) in type III achalasia patients.	92.1%	We recommend against BTI in the esophageal body, even in the presence of type III achalasia. GRADE: very low.
	13 There is no evidence that patients undergoing repeat BTI of the LES should be treated with increasing dosage of BT.	96.1%	We recommend against the use of increasing BT dosage at retreatment. GRADE: very low.
Pneumatic dilatation
	14 In patients with achalasia, graded PD is an effective treatment in terms of improvement of symptoms and swallowing function.	90.4%	We recommend graded pneumatic dilatations as an effective treatment (control of symptoms including dysphagia) for esophageal achalasia. Strong recommendation GRADE: moderate. Patients wishing longer term remission may opt for surgical treatment.
	15 In patients with achalasia who have received PD, the best post procedural test to assess if a perforation occurred is a Gastrografin (iodine contrast) swallow.	80.8%	We recommend that after PD patients are observed for 4 hours. Water-soluble iodine contrast (Gastrografin) esophagogram (or CT scan with oral contrast) should be performed if any symptoms, even if moderate, suggest that perforation is present after dilatation. We recommend against the routine use of contrast esophagram or computed tomography shortly after PD. Conditional recommendation. GRADE: low.
	16 There is only limited evidence that pneumatic dilatation may be used as first-line therapy in megaesophagus (diameter >6 cm & sigmoid shaped).	82.4%	We make no recommendation about pneumatic dilatation as first-line therapy in megaesophagus GRADE: very low.
	17 There is no evidence that patients undergoing graded dilation should be treated with proton pump inhibitors as maintenance therapy after the procedure, unless symptomatic or positive at 24-hour pH-monitoring.	94.3%	We recommend against the prophylactic use of PPI after PD, unless GERD symptoms are present or objective evidence of reflux is demonstrated. Conditional recommendation GRADE: very low.
Peroral endoscopic myotomy (POEM)
	18 Treatment of achalasia patients with POEM, results in similar outcomes on swallowing functions compared with alternative treatment (Heller myotomy or PD), at least at medium term follow-up (2–4 years).	88.4%	We recommend POEM as an effective therapy (control of symptoms) for achalasia both in short- and medium-term follow-up with results comparable to Heller myotomy for symptom improvement. Conditional recommendation. GRADE: very low. We recommend POEM as an effective therapy (control of symptoms) for achalasia both in short- and medium-term follow-up with results comparable to pneumatic dilations for control of symptoms. Conditional recommendation. GRADE: low.
	19 Treatment of achalasia with POEM is associated with a higher incidence of GERD compared to alternative therapies (Heller myotomy with fundoplication or PD).	96.2%	We recommend that pretreatment information on the risk of GERD should be provided to the patient and follow-up acid suppression therapy considered after POEM. Good practice recommendation. Patients who seek a nonsurgical treatment (PD) or surgical treatment with a lower incidence of postprocedure GERD (Heller myotomy) should be counseled that these options exist.
	20 There is no evidence that previous treatment of patients with achalasia with PD or Botox reduces the technical feasibility of POEM and results in poorer outcomes.	86.6%	We recommend POEM as feasible and effective for symptom relief in patients previously treated with previous endoscopic therapies. Conditional recommendation; GRADE: very low.
	21 POEM is an appropriate treatment for symptom persistence/recurrence after laparoscopic myotomy.	88.2%	We recommend the use of POEM for symptom relief, as an option for treating recurrences after LHM. Conditional recommendation. GRADE: low.
	22 Attaining proficiency with the POEM procedure involves a stepwise approach to education and a defined learning curve for both medical and surgical endoscopists.	90.2%	We recommend that appropriate training with in vivo/in vitro animal model and adequate proctorship should be considered before starting a clinical program of POEM. Good practice recommendation.
Alternative treatments: retrievable stents and intrasphincteric injection with ethanolamine oleate or polidocanol
	23 There is little evidence to support that modified retrievable stent placement at the LES is an effective treatment for patients with achalasia.	98%	We recommend against temporary (retrievable or absorbable) stents and intrasphincteric injection with ethanolamine oleate for achalasia. Conditional recommendation. GRADE: low.
	24 There is no or little evidence to support the use of endoscopic sclerotherapy with ethanolamine oleate or polidocanol as an effective first treatment for patients with achalasia.	96%	We recommend against temporary (retrievable or absorbable) stents and intrasphincteric injection with ethanolamine oleate or polidocanol for achalasia. Conditional recommendation. GRADE: low.
Laparoscopic Heller myotomy
	25 The best outcomes for LHM are achieved in (Chicago) type I & type II achalasia patients.	90.4%	We recommend laparoscopic Heller myotomy for control of symptoms in Chicago type I and type II achalasia. Strong recommendation. GRADE: moderate.
	26 Laparoscopic Heller myotomy should include a myotomy 6 cm into the esophagus and 2 to 3 cm into the stomach as measured from the GEJ, for effective symptom control in achalasia patients.	94.2%	We recommend that Laparoscopic Heller cardiomyotomy should be extended at least (6 cm proximal to the GEJ and at least 2 cm distal to the GEJ. Conditional recommendation. GRADE: low.
	27 Partial fundoplication should be added to laparoscopic myotomy in patients with achalasia to reduce the risk of subsequent gastroesophageal reflux.	94.2%	We recommend that a partial (posterior or anterior fundoplication) but not a complete 360° wrap should be added to reduce the long-term risk (5 years) of developing gastroesophageal reflux and dysphagia after myotomy. Strong recommendation. GRADE: moderate.
	28 Laparoscopic Heller myotomy with a partial fundoplication is as effective at improving swallowing function as laparoscopic Heller myotomy alone.	82.7%	We recommend a partial fundoplication should be used when performing Heller myotomy to prevent subsequent development of gastro-esophageal reflux without compromising the adequate control of dysphagia. We recommend against LHM alone due to the risk development of gastro-esophageal reflux. Strong recommendation. GRADE: High.
	29 LHM (or other therapies as POEM or PD) should be considered as the first-line treatment option in achalasia patients with sigmoid esophagus (compared to esophagectomy).	86.5%	We recommend standard endoscopic or surgical therapies in surgically naïve achalasia patients with sigmoid-shaped esophagus, leaving esophagectomy as secondary option in case of failure of first line therapy. Conditional recommendation. GRADE: very low.
Recurrence of achalasia after treatment
	30 Symptom improvement is the most relevant clinical parameter for defining the success of surgical or endoscopic treatment for achalasia.	90.4%	We recommend assessment of symptomatic improvement as the best measure of success after treatment of achalasia. Good practice recommendation.
	31 In adults with achalasia, there is no universal definition of failure after any treatment.	88.4%	Recommendation: see next statement.
	32 Recurrent symptoms after achalasia treatment should routinely undergo repeat objective testing.	100%	We recommend objective testing in patients who suffer recurrent symptoms after treatment of achalasia including UGI endoscopy, barium swallow, manometry, and 24-hour pH monitoring. Good practice recommendation.
	33 The timed barium swallow objectively demonstrates the failure of achalasia treatment in patients with persistent/recurrent symptoms.	82.7%	We recommend TBS as a reliable method to assess recurrence of achalasia. Conditional recommendation. GRADE: Low.
Risk of cancer
	34 Achalasia patients carry a moderately increased risk of development of squamous esophageal cancer 10 years or more from the primary treatment of achalasia.	86.5%	We recommend that achalasia patients should be informed that a moderately increased risk of esophageal cancer is present in male after at least 10 years from the initial treatment of the disease. Good practice recommendation. We make no recommendation about routine endoscopy or endoscopy intervals after any treatment.
Management of treatment failures
	35 Patients with achalasia who do not respond to initial treatment with graded PD, should be referred for Heller myotomy or POEM.	94.2%	We recommend that in patients who are fit for surgery and have symptomatic recurrences after several pneumatic dilations, Heller myotomy, or POEM should be considered. Conditional recommendation. GRADE: of evidence low.
	36 Laparoscopic esophageal myotomy is a safe, feasible and effective treatment after failed Botox injection for achalasia.	96.2%	We recommend LHM as an effective therapy for symptom recurrence after primary treatment with BTI. Conditional recommendation. GRADE: very low.
	37 PD, compared with repeat myotomy or POEM, is the first option for treatment after failed Heller myotomy for achalasia.	80.8%	We recommend pneumatic dilation as a safe and effective treatment of symptom recurrences after LHM. Conditional recommendation. GRADE: Low.
	38 There is insufficient evidence that laparoscopic myotomy or redo POEM offer better results than PDs after failed POEM.	82.4%	We make no recommendation about laparoscopic myotomy or redo POEM offering better symptomatic relief than pneumatic dilations after failed POEM. Further research is recommended to provide high-quality data and guide clinical decisions.
Diagnosis and treatment of end stage achalasia
	39 Barium swallow esophagram, compared with manometry, is the best diagnostic method for defining end stage achalasia (i.e. that which requires esophagectomy).	94.1%	We recommend the use of barium swallow as the most accurate investigation to properly define end-stage achalasia. Good practice recommendation.
	40 Esophagectomy is indicated in patients with persistent or recurrent achalasia after failure of previous less invasive treatments (PD, POEM, LHM) and radiologic progression of the disease.	80.8%	We recommend esophagectomy in patients with end-stage achalasia who have failed other less invasive interventions. Conditional recommendation. GRADE: Low.
Achalasia in children
	41 Children with suspected achalasia should follow the same diagnostic pathway as that of adult patients.	96%	We recommend that children with a provisional diagnosis of achalasia should undergo the same work-up as in the adult population. Good practice recommendation.
	42 Surgical or endoscopic myotomy (compared to dilation) is the preferred treatment for pediatric patients with idiopathic achalasia (IA), especially for those aged 5 years or more.	80%	We recommend myotomy (either through a laparoscopic or flexible endoscopy approach as the preferred treatment in children). Conditional recommendation. Grade: very low.
	43 BTI is not an appropriate first-line therapy in very young children with achalasia.	81.6%	We recommend against BTI as a first-line therapy in very young children with achalasia (with exceptions for those children who are medically frail and at high-risk for surgical intervention). Conditional recommendation. Grade: very low.
	44 The long-term outcome of achalasia treatment in children should be assessed by symptoms, function, physical growth, and general development.	94.4%	We recommend that the long-term outcome of achalasia treatment in children should be closely monitored by symptoms, swallowing function, physical growth, and general development. Good practice recommendation.
Diagnosis and management of achalasia secondary to Chagas disease
	45 There are minor differences between the clinical presentation of IA and achalasia secondary to Chagas disease.	86.2%	We recommend that diagnostic techniques used for IA should also be used for CDE, due to the similarities in manometric and clinical features. Conditional recommendation. GRADE: low.
	46 There are no differences in the treatment of idiopathic achalasia and achalasia specific to Chagas disease.	90%	We recommend that all treatments for IA may be used for CDE for symptom relief. Conditional recommendation. GRADE: low.

INTRODUCTION

Achalasia is a relatively rare esophageal motor disorder characterized by the absence of swallow-induced relaxation of the lower esophageal sphincter (LES) and by absence of peristalsis along the esophageal body. Consequently, the transit of the food into the stomach is impaired and the patient typically experiences dysphagia. Other symptoms reported are regurgitation of saliva or undigested food, respiratory symptoms (nocturnal cough, recurrent aspiration, and pneumonia), heartburn, and chest pain.¹ The most common form of achalasia is idiopathic and is mostly observed sporadically. In idiopathic achalasia (IA), the disease occurs secondary to the destruction of the myenteric plexus that coordinates both peristaltic contraction and LES relaxations.^2-4 A similar clinical picture can be present in patients with local or distant cancer (pseudoachalasia)^5,6 or in patients with Chagas’ disease,⁷ both characterized by the destruction of the myenteric plexus either by infiltrating tumors or by circulating autoantibodies or by Trypanosoma cruzi infection.

The incidence of achalasia is similar in most countries, with no differences in gender and race, although its incidence increases with age. It has been consistently estimated that the incidence varies between 0.7 to 1.6 per 100,000 inhabitants/year.^8-11 The prevalence of achalasia was currently estimated to be 10 per 100,000 inhabitants. Newer studies in the era of high-resolution esophageal manometry (HRM) suggest that these numbers are low, and that the actual incidence is 2 to 3/100,000 with a much higher prevalence.^12-14

Achalasia is a chronic disease and all the current treatment options can only palliate symptoms, but not cure the disease. As a result, many achalasia patients undergo multiple treatments throughout their lifetime.¹

The diagnosis of achalasia is based on tests which include: esophageal manometry that measures the pressure generated in the LES and in the esophageal body; barium esophagram and upper gastrointestinal endoscopy, mainly to rule out the presence of cancer (pseudoachalasia) and possible complications of the disease (candidiasis).

Achalasia treatments are aimed at reducing the pressure of the LES either using medication like botulinum toxin injection (BTI) into the LES or disrupting the LES muscle by stretching its fibers with dilators or by dividing it surgically or endoscopically (myotomy).¹⁵

However, over the last 10 years, there has been significant evolution of the management of achalasia with the introduction of new diagnostic tools as high-resolution manometry (HRM)^16,17 and treatment options as peroral endoscopic myotomy (POEM)¹⁸, temporary stent insertion and injection of chemical substances in the LES.

Achalasia is a disease treated by both gastroenterologists and surgeons and two American scientific societies of gastroenterologists and surgeons (ACG & SAGES) have produced guidelines for achalasia.^19,20 This new ISDE Clinical Guideline for Achalasia (I-GOAL), however, is distinctive in that it is interdisciplinary and international. Our guideline aims to offer all stakeholders (physicians and surgeons, patients, and health policy managers) a useful and up-to-date resource for applying the best evidence-based principles to the diagnosis and management of achalasia, and achalasia of Chagas’ disease. The guideline is also based on a unique interactive methodology that allows the development of statements on diseases where there are few high-quality studies and scant evidence to support strong recommendations.²¹

METHODS

All forms of achalasia (adult, pediatric, achalasia related to Chagas disease and achalasia related to triple A, Down syndrome, or other genetic diseases) were considered.

The ‘Working Group’ comprised 51 members from medical and surgical specialties and included three patient representatives and two conveners (GZ and DL). Participants were selected among ISDE members with a specific interest in managing achalasia by the two conveners. Other members of the team included a scientific consultant who coordinated the process and edited submitted statements (CB), and a web developer (SG). CB and SG (non-voting group members) initially developed the process to be applied during the development of the guidelines. The group was geographically diverse with members from the USA (19), Italy (8), UK (3), Belgium (4), Australia (2), Brazil (7), Germany (2), France (2), Netherlands (1), Japan (1), China (1), Argentina (1). Panels were created by inviting participants from both gastroenterology and surgery to work in study groups led by a Chairperson.

We systematically searched for evidence, selected evidence, and integrated this with three rounds of an eDelphi process to obtain consensus on key areas:

• Diagnostic workup,

• Definition of the disease,

• Severity of presentation,

• Medical treatment,

• BTI,

• Pneumatic dilatation (PD),

• POEM,

• Other endoscopic treatments,

• Laparoscopic myotomy,

• Definition of recurrence,

• Follow up and risk of cancer,

• Management of end stage achalasia,

• Treatment options for failure,

• Achalasia in children,

• Achalasia secondary to Chagas’ disease

• Achalasia secondary to genetic diseases.

We excluded ‘secondary achalasia’ as this is not a well-defined condition.

Our approach combined the principles of evidence-based medicine supported by systematic literature reviews with the use of an iterative anonymous voting process^22-24 and the method used is accredited for guideline production by NICE UK.²⁵ The online platform permitted anonymous individual feedback and changes of views during the process, together with controlled feedback of evidence regulated by the coordinator (CB) and the consensus chair (GZ). The group was initially asked to identify areas where there is uncertainty in management and to provide clinical questions, structured by population, intervention, comparator, and outcome (PICO).

Keywords identified from the clinical questions were used to construct literature searches in electronic databases (Appendix of search strategies),

The principal steps in the process were: (1) selection of the consensus group and identification of clinical questions; (2) development of draft statements by the panels; (3) systematic literature reviews to identify evidence to support each statement; (4) production of evidence-based discussions using the selected evidence; (5) 3 rounds of iterative voting and commenting. The initial stage was the development of statements followed by a comprehensive literature review. Statements were prepared that described the population, the intervention or management strategy, whether a comparison strategy was applicable, and the outcomes being assessed. Participants were assigned to panels corresponding to statements and developed pertinent summaries for each statement using the available literature. These summaries were written by the panel members and included all the relevant evidence identified for each statement, making specific reference to any studies that were assessed but which did not contribute additional evidence. The Summary Statements were then posted online for voting and feedback to guide refinement.

The respondents were asked to choose one of the following for each statement; agree strongly (A+), agree with reservation (A), undecided (U), disagree (D) or disagree strongly (D+). Participants voted on statements, assessments were made on the basis of the participants’ comments and judgments were informed of the supporting evidence. We defined consensus as 80% of respondents strongly agree or agree with reservation. When agreement was not reached, we rephrased the statement to see if this would provoke stronger agreement. If no strong agreement was reached after at least two rounds of voting, it was eliminated.

We electronically collected conflict of interest declarations at each stage of the voting process, electronically, at voting. The study is a secondary analysis of published work and did not involve human subjects or interventions therefore it did not require ethics committee review. However, the study was overseen by the ISDE and was subject to the review of ISDE’s ethics committee.

GRADE

We used the GRADE system^26,27 to describe the quality of the evidence and the strength of recommendation. We used GRADE terminology for statements and recommendations.²⁸ The lack of effect estimates and potential selection bias inherent in the included observational studies meant that much of the evidence was very low or low-quality evidence.

Evidence from randomized controlled trial (RCT) data is initially given a high-quality rating but is downgraded if the study methodology has a risk of bias i.e. there is unexplained clinically relevant heterogeneity, evidence is indirect, there is important uncertainty around the estimate of effect or there is evidence for publication bias. As a result, it is possible for RCT data to have a very low quality of evidence if several of these concerns are present. Evidence from observational studies starts at low quality but can be upgraded if the effect size is large, there is a dose response and all plausible confounding would act in the opposite direction to the effect noted. After completion of the consensus process, we used the GRADE approach to make recommendations, producing grade profiles²⁹ and we quantified the strength of recommendations.^30,31 A strong recommendation suggests that the intervention should be offered to most patients most of the time whereas a conditional recommendation suggests that there is either lower quality evidence, the balance between benefits and downsides is closely balanced and/or important uncertainty about patients’ values and preferences exists. GRADE ratings were not applied when recommendations were considered to refer to universally accepted good practice³² rather than evidence-based decisions on two or more competing management strategies.

Systematic literature search

Three authors (MS, RS, and LF) independently searched electronic databases MEDLINE (via Pubmed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from 2000 to December 2016 for English-language articles. Exclusion criteria included studies on esophageal spastic motor disorders other than achalasia, case series reporting outcomes with less than ten patients and case reports. We used the PICO scheme to build our search strategy using search terms describing the patient and intervention. An updated search using the MeSH term ‘[esophageal achalasia]’ was repeated in December 2017 and newly published articles or requested by participants were added to the main database up to January 2018 which coincided with our third and final round of voting. The references of the included articles were hand-searched to identify additional relevant studies. Participants were allowed to suggest more references (also outside the original time frame period) if they deemed them appropriate for the study.

Prior to the first voting round, users were able to select from this database and the convener (GZ) and a research assistant (SM) used these bibliographies to provide evidence-based discussions to associate with each statement available for review by the panel. Participants were also invited to add new literature at each round of the process. In this way, the group identified a list of primary references specific to each statement and these were used to develop the statement discussion. Panel chairs were responsible for the final selection of evidence and editing statement discussions, with moderation by CB and GZ. The literature search technique permitted inclusion of additional articles during the consensus process that might have been missed during initial searches (including newly published articles added at updates). Before including articles for citation, the articles were reviewed by panel members and the convener (GZ). GZ reviewed the studies obtained at the updated search in December 2017 and add relevant studies to the online database; these were then included in the evidence-based discussions. Appendix 1 describes the precise search terms used for each PICO statement and the PRISMA search strategy and flowchart generated.

RESULTS

Literature search

Out of 3183 articles were initially retrieved (including 61 articles added with the updated 2017 search) and 128 were added by the panelists; 22 articles were added after the updated literature search in January 2018. In total, 466 articles were considered for the preparation of the Guidelines. A detailed PRISMA figure for each of the key areas is provided in the online supplement (Figs. S1–15)

We found that the overall GRADE quality of evidence related to all the statements was low, or at best moderate although the consensus process resulted in a high level of consensus for many statements. At the final round of consensus, we achieved consensus (≥80% agreement) on 47/57 statements, 10 statements were not accepted. Of these 10, at least 50% of the participants who voted agreed with the statement, but they failed to reach consensus according to our criteria. Two statements (on PD for treatment of recurrence after surgery) were similar in content and were combined for the purposes of this guideline manuscript.

We selected, on the basis of the agreement level and clinical relevance, 46 statements that represent the following key clinically relevant areas: 1. Diagnosis of achalasia, 2. Management of primary disease; 3. Definition of failures; 4. Risk of cancer and follow-up of achalasia patients; 5 Management of failures; 6. Definition diagnosis and treatment of ‘end stage achalasia’; 7. Management of achalasia in children; 8. Diagnosis and management of achalasia in Chagas disease. These 46 statements form the basis of this guideline. All the statements were archived: (http://www.mdpub.org/igoal).

Diagnosis of achalasia

1. HRM is the test of choice for the diagnosis of achalasia (compared to conventional manometry).

Agree: 94.2% [D + (2%); D (0); U (3.8%); A (26.9%); A + (67.3%)]

HRM records intraluminal pressures circumferentially at 1 cm intervals over a 36 cm segment along the length of the esophagus. These pressure data are transformed into a topographic color contour plot. HRM is easier to perform than conventional manometry, the learning curve for recognizing the color contour patterns is shorter, and inter-rater and intra-rater agreement for the Chicago classification of achalasia subtypes is very good to excellent.^33,34 HRM has generated a new metric for esophagogastric junction (EGJ) relaxation known as the "integrated relaxation pressure" (IRP) measured within the swallowing window from the initiation of a swallow and Upper Esophageal Sphincter (UES) relaxation until the arrival of the peristaltic contraction at the LES or after 10 seconds in absence of peristalsis. Relaxation pressure is reported as the lowest value persisting for 4 seconds after the swallow and can distinguish between the LES and crural diaphragm components.³⁵ One study found a two-fold increase in the diagnosis of achalasia compared to conventional manometry from 12% to 26%.³⁶ Based on a series of 62 patients with well-defined achalasia 4-second IRP >15 mmHg as had a sensitivity of 97% and only 3% false negative rate. This was a considerable diagnostic improvement over the single sensor nadir >7 mmHg, which only had a sensitivity of 52% with a striking 48% false negative rate.³⁷ Despite evidence supporting the use of HRM, this test has not yet been widely adopted, especially in nonacademic hospitals.³⁸

Recommendation: we conditionally recommend the use of HRM for the diagnosis of esophageal achalasia (compared to conventional manometry). GRADE: low.

2. The Chicago Classification is a useful tool to define the clinically relevant phenotypes of achalasia.

Agree: 90.4% [D + (1.9%); D (1.9%); 3 (5.8%); A (44.2%); A + (46.2%)]

The Chicago Classification 3.0 was created to define clinically relevant phenotypes for esophageal motor patterns that are associated with the chief complaint of dysphagia using 10 5 mL water swallows. By utilizing the integrated relaxation pressure, specific metrics of propagation and pressurization patterns, the Chicago Classification 3.0 provides a systematic classification scheme that can define achalasia into distinct subtypes (I, II, III) and variants that may indicate evolving/early achalasia (EGJ outflow obstruction) or achalasia in the context of a low LES pressure (absent contractility).^16,39 The subtypes of achalasia are defined on the basis of the patterns of esophageal body contractility and pressurization once an elevated integrated relaxation pressure establishes that there is resistance to bolus transit at the esophagogastric junction. This approach provides a more systematic mechanism for classifying achalasia based on an algorithm with specific criteria and a high level of agreement between interpreters. Thus, the Chicago Classification 3.0 is a more robust and standardized method to classify achalasia compared to conventional manometry and barium esophagraphy, which fail to distinguish patterns beyond vigorous achalasia. This classification scheme does not capture all achalasia patients as early achalasia can be seen with propagating contractions and an elevated IRP (EGJ outflow obstruction)³⁹ and in the late stages where esophageal dilatation occurs and intraesophageal pressures are too low to generate an elevated IRP in the context of absent contractility.

Type II achalasia has the best prognosis and while type III tends to have the worst prognosis.^16,40-44 Type I may represent a more advanced stage of achalasia and its prognosis is variable, but in general is worse than Type II.

Recommendation: we recommend classification of achalasia according to the Chicago Classification. Good practice recommendation.

3. The timed barium esophagram offers an objective evaluation of the diseases and of the outcome after treatment (compared to traditional barium esophagram).

Agree: 90%. [D + (2%); D (4%); U (4%); A (50%); A + (40%)

In the timed barium esophagram (also known as the timed barium swallow (TBS)),⁴⁵ the patient drinks 100–200 mL of low density (45% weight by volume) barium sulfate over one minute in the upright position. Frontal spot films of the esophagus are obtained at 0, 1, 2, and 5 minutes. The height of the barium column is measured from the distal esophagus, identified by the ‘bird-beak’ appearances of barium, to the top of the distinct barium column. Width (diameter) of the esophagus can be measured at the widest part of the barium column perpendicular to the long axis of the esophagus. The degree of esophageal emptying is estimated either qualitatively by comparing the barium height on images taken at 1 and 5 min or by measuring the height and width of each image, calculating a rough area for both and determining the percent change in area.⁴⁶ The TBS is a reproducible technique for estimating esophageal emptying with almost perfect interobserver agreement.⁴⁵ TBS predicts the likelihood of symptom recurrence after pneumatic dilation or surgical myotomy.⁴⁷ Rohof et al. observed that the esophageal retention was a good predictor of treatment failure in long-standing achalasia and proposed using the TBS rather than manometry to decide on retreatment.⁴⁸ TBS is not yet widely adopted, however, and many centers still use barium swallow esophagogram.

TBS studies provide data for diagnosis and to predict improvement after treatment. A 50% improvement in emptying and >5 cm of stasis at 5 minutes⁴⁸ were good predictors of treatment failure and recurrence. A recent study on 188 achalasia patients, 46 EGJ outlet obstruction, and 146 patients with dysphagia from other causes, based on ROC analysis, barium column height of 5 cm at 1 minute showed the highest sensitivity of 86% and specificity of 71%, while the barium column height of 2 cm at 5 minutes had the highest sensitivity of 80% and specificity of 86% in differentiating achalasia for the other two groups.⁴⁹ Two studies, however, do not support the positive prognostic ability of TBS.^50,51

Recommendation: we conditionally recommend the use of TBS in the diagnostic pathway of achalasia and to evaluate the outcome of treatment. GRADE: low.

4. Endoscopy should be performed in patients with suspected achalasia to exclude malignancy of the esophagogastric junction.

Agree: 98.1% [D + (0%); D (0%); U (1.9%); A (9.6%); A + (88.5%)]

Endoscopy has a low diagnostic yield⁵² in the diagnostic workup of achalasia and its primary role is in ruling out a pseudoachalasia (secondary achalasia) or mechanical obstruction.^53-58 Three clinical features are thought to be suggestive of cancer as a cause of pseudoachalasia: short duration of dysphagia (<1 year), serious weight loss (>6.8 kg), and age over 55 years. The presence of any of these features should raise a suspicion of cancer, even though they have a low predictive accuracy.^19,59 Mucosal ulceration or nodularity, reduced compliance of the gastroesophageal junction, or an inability to pass the endoscope into the stomach are the most common EGD findings of pseudoachalasia. Endoscopic biopsy is used for the diagnosis of secondary pseudoachalasia.^60-64

Recommendation: We recommend performing UGI endoscopy in adult with the suspected diagnosis of achalasia to exclude neoplastic pseudoachalasia. Good practice recommendation.

5. The Eckardt score is a simple tool to measure symptom severity in achalasia patients, but it should be integrated with objective measures such esophagogram and manometry.

Agree: 86.5% [D + (0%); D (2%); U (11.5%); A (42.3%) A + (44.2%)]

The Eckardt score (ES) is a simple measure to assess achalasia outcome and focuses on 4 symptom components: dysphagia, regurgitation, retrosternal pain, and weight loss. The 4 components are graded from 0 to 3, and patients are classified as having a good outcome if ES is <3 or a poor outcome if ES ≥3.⁶⁵ Although this measure is the most widely used and accepted questionnaire for achalasia disease severity, it has not been validated outside of comparisons with physiologic measures and has not been vetted as a patient reported outcome measure.^66,67 In a paper published after the consensus process ended, it was reported that the Eckardt score did not fulfill criteria for a validated symptom score, and the chest pain and weight loss components may decrease the reliability and validity of this score.⁶⁸

Recommendation: we recommend the use of the Eckardt score as part of the initial and follow-up assessment in patients with achalasia. Good practice recommendation.

Treatment of achalasia

Medical treatment

6. There is no convincing evidence that medical treatment with nitrates is effective for symptomatic relief in adults with achalasia. Agree: 86.5%

[D + (3.8%); D (5.5%); U (6.9%); A (56.9%); A + (26.9%)]

7. There is no convincing evidence that medical treatment with calcium blockers is effective for (short term) symptomatic relief in adults with achalasia.

Agree: 88.2% [D + (0%); D (2%); U (9.8%); A (54.9%); A + (33.3%)]

8. In adults with achalasia, there is no evidence that medical treatment with phosphodiesterase inhibitors is effective for symptomatic relief.

Agree: 84.3% [D + (0%); D (2%); U (13.7%); A (54.9%); A + (29.4%)]

There is no convincing evidence for using any of these medications for short term relief of achalasia symptoms.^69-83

Recommendations: we recommend against the use of nitrates, calcium blockers or phosphodiesterase inhibitors treatment for symptomatic relief of achalasia. GRADE: low.

Botulinum toxin injection ‘Botox’ (BTI)

9. BTI has limited application in young patients (aged less than 50 years).

Agree: 92.3% [D + (0%); D (5.8%); U (1.9%); A (42.3%); A + (50%)]

We found no evidence to support the use of BTI in patients <50 years.^84-90 We did not specifically address its utility in patients under 50 years of age who are at high-risk for surgical or other procedures.

10. BTI should be reserved for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation.

Agree: 94.3% [D + (0%); D (3.8%); U (1.9%); A (46.2%); A + (48.1%)]

BTI in the LES in achalasia has a very high safety profile and even mild adverse event with heartburn or chest pain are observed in less than 10% of patients treated.⁹¹ In a RCT comparing Heller myotomy with BTI, the results in the 2 groups were comparable at 6 months, although symptom scores improved more in surgical patients (82% vs. 66%). At 2-year follow-up, only 34% of BTI patients versus 87.5% of the Heller patients were asymptomatic.⁹² Similarly, four randomized trials and a Cochrane meta-analysis comparing BTI with pneumatic dilations (PD) consistently reported a higher cumulative rate of remission rate at 1 year after treatment.^85,86,93-96

Recommendations: we recommend against the use of BTI in patients under 50 years of age, for control of symptoms. GRADE: very low:

We recommend against BTI as an effective therapy (control of symptoms) for achalasia in patients fit for surgery (LHM) GRADE: moderate.

We recommend against BTI as an effective therapy (control of symptoms) for achalasia in patients fit for pneumatic dilatation GRADE: moderate.

11. Repeat treatments with BTI are safe, but less effective than initial treatment.

We found that repeated treatments may be successful, if there are contraindications to invasive, but more durable treatments. BTI efficacy, however, may decrease over time. In an open study⁹⁷ followed up 35 patients treated with BTI, 12 (34.3%) relapsed and were retreated, 4 out of 12 did not respond after re-treatment. In a controlled trial,⁸⁵ 7 of the 8 patients in the botulinum toxin group required a second injection because of recurrent dysphagia, the effect of the second injection lasted for at least 6 months in all treated patients, compared with only two thirds in the trials by Pasricha in 1994⁹⁸ and was still evident in 80% of this series at 1 year of follow-up. In this study, symptoms recurred in the long-term responders about 1 year after the initial injection. However, in such patients, further injections at this stage retained their efficacy. In a retrospective⁸⁹ study of 25 patients with achalasia of the 16 patients who responded to the initial injection, two were lost to follow-up and in the remaining 14 patients, the outcome was still satisfactory in nine patients after a mean of 2.5 years. The five patients who experienced only a short-term clinical success received a second or third injection of botulinum toxin, but their symptoms never improved substantially for more than 6 months. In a pilot, open trial by Martinek in 2003,⁹⁹ anterograde and retrograde BTIs were given. After a single BTI, 11 responders reported a relapse and 2 patients remained asymptomatic. The median symptom-free interval was 17 months (range: 8–28). Five patients with a relapse underwent BT reinjection. Three of them remained asymptomatic and two experienced the second relapse. After BT reinjection, the median symptom-free interval was 16 months (range: 10–19). All other patients with a relapse and without BT reinjection were treated with either balloon dilation or surgery and remained asymptomatic.^{84,85,89,98,99}

Agree: 82.4%, [D + (2%); D (2%); U (13.6%); A (60.8%); A + (21.6%)]

Recommendation: we conditionally recommend that for symptom relief, BTI injection can be safely repeated, but clinicians and patients should be aware that their efficacy is lower than in initial treatment. GRADE: low.

12. There is no evidence that patients with 3 type III achalasia should receive additional Botox injections in the lower esophagus in addition to injections in the LES to improve function and symptoms.

Agree: 92.1% [D + (0%); D (2%); U (5.9%); A (68.6%); A + (23.5%)]

We found no direct evidence to support the use of BTI in the lower esophagus in patients with type III achalasia).^17,91-93,100

Recommendation: we recommend against BTI in the esophageal body, even in the presence of type III achalasia. GRADE: very low.

13. There is no evidence that patients undergoing repeat BTI of the LES should be treated with increasing dosage of Botulinum toxin.

Agree: 96.1% [D + (0%); D (0%); U (3.9%); A (56.9%); A + (39.2%)]

We found no evidence to support an increasing dosage of (BT) when patients need retreatment.

Recommendation: we recommend against the use of increasing (BT) dosage at retreatment. GRADE: very low.

Pneumatic dilatation

14. In patients with achalasia, graded PD is an effective treatment in terms of improvement of symptoms and swallowing function.

Agree: 90.4% [D + (0%); D (3.8%); U (5.8%); A (32.7%); A + (57.7%)]

Graded PD consists of a series of dilations starting with a 30 mm balloon, and depending on the response, followed by dilations using 35 mm and in some cases, a 40-mm balloon. Dilation is aimed at reducing the LES pressure in achalasia and reducing the resistance to bolus flow with consequent improvement in symptoms. There is no evidence about optimum duration of inflation, the balloon pressure to be applied or the interval between the successive dilations.

Graded PD is effective as an initial treatment in terms of symptoms including dysphagia, but success rates decline over time and retreatment may be required. Success rates largely vary depending on the criteria used to define success and the duration of follow-up and they are significantly increased by allowing redilation in case of recurrent symptoms.^101-104 In the European RCT comparing PD versus laparoscopic Heller's myotomy for idiopathic achalasia, 96% of patients responded successfully to the initial series of pneumatic dilation.¹⁰⁵ Success rates (intention-to-treat) dropped from 90% at 1 year to 86% at 2 years and 82% at 5 years.¹⁰⁵ West et al. in 2002 showed a further reduction with even longer follow-up, with success rates dropping to 60%, 50%, and 40% in patients with a follow-up between 5 and 9 years, 10 and 14 years and >15 years.¹⁰⁶

One quarter to one third of dilated patients will require redilation during the following 4–5 years.^101,105 An Australian study reported that 18% will relapse by 2 years, 41% by 5 years, and 60% by 10 years.¹⁰⁷ Furthermore, a review summarizing four studies of patients who had two or more dilations showed that 92%, 84%, 78%, and 64% patients were in remission at 1, 2, 3, and 5 years.¹⁰⁸

In comparison with surgical therapy (LHM) in a RCT,¹⁰⁹ the clinical response and the variables related to good results in 92 patients with achalasia who were randomized to receive either PD or laparoscopic Heller myotomy (LHM) with partial fundoplication were evaluated. Three months after treatment, 73% of the patients from PD group and 84% of the surgery group had good results (P = 0.19). After 2 years of follow-up, 54% of the PD group and 60% of the surgery group (P = not significant) were symptom free. They concluded that surgical treatment and PD for achalasia are equally effective after 2 years of follow-up. However, some randomized trials comparing PD and LHM^110-112 showed better control of the outcomes of symptom control, GERD, and dysphagia respectively, after LHM. For symptom remission, LHM was not superior to PD in one meta-analysis,¹¹³ however, other meta-analyses^114,115 have shown better treatment success,¹¹⁴ and response rate (control of symptoms)¹¹⁵ for LHM.

Recommendation: we recommend graded pneumatic dilatations as an effective treatment (control of symptoms including dysphagia) for esophageal achalasia. GRADE: moderate. Patients wishing longer term remission (without further dilatation) may opt for surgical treatment.

15. In patients with achalasia who have received pneumatic dilation, the best postprocedural test to assess if a perforation occurred is a Gastrografin (iodine contrast) swallow.

Agree: 80.8% [D + (1.9%); D (5.8%); U (11.5%); A (48.1%); A + (32.7%)]

Perforation is a serious complication of PD and should be diagnosed immediately to prevent soiling of the mediastinum or thoracic cavity with luminal contents. The rate of perforation after PD varies from 2% to 5.4% and is associated with patients who are older than 65 years, high amplitude of contraction in the distal esophagus and the use of Witzel dilators.¹¹⁶ Perforation symptoms include epigastric pain, chest pain, left shoulder pain, dyspnea, fever, and moderate amount of hematemesis.¹¹⁷ Intake of water will typically elicit epigastric or chest pain. Whether all patients should undergo postprocedure X-ray of the esophagus is unclear: one study by Zori 2016 compared elective radiological evaluation based on clinical suspicion versus routine esophagograms in all patients in a total population of 119 patients.¹¹⁸ Although only three perforations occurred, no perforations were missed in the group where an esophagogram was taken if there was clinical suspicion of perforation, suggesting that the radiological evaluation could be performed only in case of clinical suspicion.

Recommendation: we recommend that after PD patients are observed for 4 hours, water-soluble iodine contrast (Gastrografin) esophagogram (or CT scan with oral contrast) should be performed if any symptoms, even if moderate, suggest that perforation is present after dilatation. We recommend against the routine use of contrast esophagram or computed tomography shortly after PD. GRADE: low.

16. There is only limited evidence that pneumatic dilatation may be used as first-line therapy in megaesophagus (diameter >6 cm & sigmoid shaped).

Khan et al. reported their experience in 9 patients with megaesophagus (>7 cm diameter) out of 110 who underwent pneumatic dilation. In this cohort, it was possible to dilate adequately, in all nine cases without complications, with good symptomatic improvement at 12-month follow-up.¹¹⁹ Although there are no studies that definitively show that esophageal diameter determines outcome, pneumatic dilation is considered difficult in patients with sigmoid esophagus and associated with a higher rate of complications.

Agree: 82.4% [D + (2%); D (2%); 7 (13.6%); A (66.7%); A + (15.7%)]

Recommendation: we make no recommendation about pneumatic dilatation as first line therapy in megaesophagus. GRADE: very low.

17. There is no evidence that patients undergoing graded dilation should be treated with proton pump inhibitors as maintenance therapy after the procedure, unless symptomatic or positive at 24-hour pH-monitoring.

There are several studies which report on the development of GERD-related disease following pneumatic dilation and other treatments.^{105,112,120-123} However, none of these studies provided information, which would result in all patients being treated prophylactically with acid suppressive therapy after such interventions. The utility of wireless pH monitoring to detect GERD was confirmed in a case series, (not included in our initial assessment of the literature).¹²⁴ In such cases, or when symptoms are present, PPI therapy should be offered. In conclusion, none of the examined studies reported the necessity on using PPI after PD as prophylaxis but given the high risk of GERD in such patients, the threshold for suspecting it should be low and PPI should be prescribed whenever symptoms occur, or GERD is confirmed by pH monitoring.

Agree: 94.3 [D + (0%); D (1.9%); U (3.8%); A (63.5%); A + (30.8%)]

Recommendation: we recommend against the prophylactic use of PPI after PD, unless GERD symptoms are present or objective evidence of reflux is demonstrated¹²⁴ GRADE: very low.

Peroral endoscopic myotomy

18. Treatment of achalasia patients with POEM, results in similar outcomes on swallowing functions compared with alternative treatment (Heller myotomy or pneumatic dilation), at least at medium-term follow-up (2–4 years).

Agree: 88.4 % [D + (0%); D (5.8%); U (5.8%); A (55.8%); A + (32.6%)]

The efficacy of POEM procedure has been mainly evaluated with changes in the Eckardt score to assess symptom improvement and timed barium esophagogram and manometry to assess the functional outcomes. Published studies report therapeutic success in 82–100% of patients, with dramatic reductions in the Eckardt score as well as the LES pressure.^37,125,126 Medium-term outcomes for POEM are now available in the literature with the longest follow-up now at 5 years.¹²⁷ The NOSCAR white paper¹²⁸ reports an >82% clinical success rate among 16 expert centers (841 patients) and a meta-analysis of 1122 patients shows a pooled overall failure rate (Eckardt >3) between 3.2% and 8%.^128–130 While there are multiple institutional and pooled retrospective comparisons between LHM and POEM,^130-136 there have been no comparable comparisons between POEM outcomes and achalasia balloon dilation other than an abstract of a RCT, (which was not included in our initial literature review as it was an abstract), with 133 patients who were therapy-naïve randomly assigned to POEM or PD, and which showed higher 1 year therapeutic success in the POEM group.¹³⁷ Most authors make an indirect inference to the relative equivalence of PD and LHM.

Comparative studies between POEM and LHM have uniformly shown equivalence or slight superiority to POEM in most intraoperative or postoperative domains.^131,133,135 Zhang et al. recently reported the outcome of POEM in a cohort of 33 patients with type III achalasia: at a median follow-up of 27 months 29 patients (87.8%) were asymptomatic with an Eckardt score >3.¹³² Guo et al. analyzed the long-term outcome of POEM in 67 patients (mean follow-up: 40.1 ± 2.8 months) and reported a good symptomatic result (Eckardt score <3) in 59 patients (88%).¹³⁸ However, patients with type III achalasia were more likely to experience treatment failure. To date there is still insufficient evidence that POEM results in similar improvement in function and symptoms in all achalasia subtypes due to the paucity of data, short follow-up period, and lack of objective postoperative esophageal testing.¹³⁹

Recommendations: we conditionally recommend POEM as an effective therapy (control of symptoms) for achalasia both in short- and medium-term follow-up with results comparable to Heller myotomy for symptom improvement. GRADE: very low.

We conditionally recommend POEM as an effective therapy (control of symptoms) for achalasia both in short- and medium-term follow-up with results comparable to pneumatic dilations for control of symptoms. GRADE: low

19. Treatment of achalasia with POEM is associated with a higher incidence of GERD compared to alternative therapies (Heller myotomy with fundoplication or pneumatic dilation).

Agree: 96.2% [D + (0%); D (1.9%); U (1.9%); A (46.2%); A + (50%)]

When performing surgical myotomy of the LES both the longitudinal and the circular fibers are divided, and a partial fundoplication is typically added to prevent gastroesophageal reflux (Dor or Toupet procedure). This raises the question if POEM is associated with high incidence of postoperative GERD. Outcome data regarding the incidence of GERD after POEM are currently limited. The NOSCAR 2015 white paper on POEM cites 12 studies with only 3 reporting pH monitoring data, on objective testing, the rate of GERD after POEM was 20% to 46%.¹⁴⁰ Patel in 2016 reviewed 22 studies (19 case series and 3 comparative studies) and reported only two additional studies that employed esophageal ambulatory pH monitoring in POEM. One study on 41 patients demonstrated GERD in 4/13 (30.7%) and another study on 100 patients documented GERD in 39/73 (53.4%).¹³⁰ Bhayani in 2014, however, reported on 101 patients who underwent postoperative 24-hour pH testing following Heller (48%) and POEM (76%).¹³¹ Postoperatively, 39% of POEM and 32% of HM had abnormal acid exposure (P = 0.7). Inoue reported on their series of 500 patients (no pH monitoring) and demonstrated that 268 of 414 patients (64.7%) had endoscopic findings of reflux esophagitis and (16.8%) complained of GERD symptoms such as heartburn or regurgitation.¹²⁷ In a multicenter trial of 205 patients in total,³⁷ of 197 patients with available clinical data, 18%% had reflux esophagitis after POEM and 37.5% had abnormal esophageal acid exposure.¹⁴¹ A systematic review by Schlottmann¹⁴² compared data between LHM and POEM and showed that while POEM was more effective in relieving dysphagia, the patients were more likely to develop GERD symptoms (OR 1.69, 95% CI 1.33–2.14, P < 0.0001), GERD related erosive esophagitis (OR 9.31, 95% CI 4.71–18.85 P < 0.0001, and abnormal pH monitoring (OR 4.30, 95% CI 2.96–6.27, P < 0.0001).^141,143,144

Recommendation: Pretreatment information on the risk of GERD should be provided to the patient and follow-up acid suppression therapy) considered after POEM. Good practice recommendation.

Patients who seek a nonsurgical treatment (PD) or surgical treatment with a lower incidence of postprocedure GERD (Heller myotomy) should be counseled that these options exist.

20. There is no evidence that previous treatment of patients with achalasia with pneumatic dilation or BTI reduces the technical feasibility of POEM and results in poorer outcomes.

Agree: 86.6% [D + (0%); D (1.9%); U (11.5%); A (71.2%); A + (15.4%)]

Technical feasibility of POEM and outcome after dilatation or BTI treatment have never been specifically addressed by a prospective study. There are case series^145-150 reporting on patients with prior PD or BTI. These studied the outcomes and/or technical difficulty of POEM in those cases to achalasia patients without prior treatment. All of them reported that previous treatment did not affect the performance or early outcome of POEM.

Recommendation: we recommend POEM as feasible and effective for symptom relief in patients previously treated with previous endoscopic therapies. Conditional recommendation; GRADE: very low.

21. POEM is an appropriate treatment for symptom persistence/recurrence after laparoscopic myotomy.

Agree: 88.2% [D + (0%); D (7.8%); U (4%); A (64.7%); A + (23.5%)]

There are several studies that have examined the use of POEM in the treatment of recurrent achalasia after the failure of an initial intervention: these studies demonstrate that POEM is effective after initial failed intervention with minimal complications; the sample size in each individual study has been typically small (typically 2 to 3 patients).^140,148,151 In studies specifically identifying patients with failed LHM, positive outcomes and minimal complications with POEM as second-line intervention were observed.

In a case study of 12 patients with failed LHM undergoing POEM as second-line treatment, 91.7% had improvement of dysphagia based on the Eckardt score.¹⁵² In a recent retrospective multicenter cohort study of 180 achalasia,³⁷ a significantly lower proportion of patients in the HM group had a clinical response to POEM (81%) than in the non-HM group (94% P = 0.01). POEM may be less effective as a second-line treatment after LHM than in naïve patients but remains a viable option after failed LHM.^153,154

Recommendation: we conditionally recommend the use of POEM for symptom relief, as an option for treating recurrences after LHM. GRADE: low.

22. Attaining proficiency with the POEM procedure involves a stepwise approach to education and a defined learning curve for both medical and surgical endoscopists.

Agree: 90.2% [D + (0%); D (0%); U (9.8%); A (25.5%); A + (64.7%)]

POEM is a complex procedure that requires mastering specific endoscopic skills and understanding certain visual cues to completely and safely achieve an appropriate myotomy. The current literature is limited and definition of a minimal learning curve with current recommendations ranging between 7 and 40 procedures is needed to achieve proficiency.^155-158 Preclinical training using videos, experience using cadaver or animal models, observations of human cases and mentoring by experts have all been recommended when introducing POEM in clinical practice (NOSCAR 2014).¹²⁹

Recommendation: appropriate training with in vivo / in vitro animal model and adequate proctorship is recommended before starting a clinical program of POEM. Good clinical practice.

Alternative treatments: retrievable stents and intrasphincteric injection with ethanolamine oleate or polidocanol

23. There is little evidence to support that modified retrievable stent placement at the LES is an effective treatment for patients with achalasia.

Agree: 98% [D + (0%); D (0%); U (2%); A (52.9%); A + (45.1%)]

24. There is no or little evidence to support the use of endoscopic sclerotherapy with ethanolamine oleate or polidocanol as an effective first treatment for patients with achalasia.

Agree: 96% [D + (0); D (0); U (5.8%); A (29.4%); A + (66.6%)].

Despite the number of studies retrieved in our searches, there is no convincing evidence for using any of these treatments for relief of achalasia symptoms.^159-171

Recommendation: We recommend against temporary (retrievable or absorbable) stents and intrasphincteric injection with ethanolamine oleate or polidocanol for achalasia. GRADE: low.

Laparoscopic Heller myotomy

25. The best outcomes for LHM are achieved in (Chicago) type I & type II achalasia patients.

Agree: 90.4% [D + (0%); D (3.8%); U (5.8%); A (46.2%); A + (44.2%)]

A meta-analysis of three randomized controlled trials^105,110,112 found that LHM was significantly more effective than PBD after 12-month follow-up.¹¹⁵

Type II achalasia patients were significantly more likely to respond to pneumatic dilatation and LHM (100%), as compared to type I (56%) and type III (29%).¹⁷ In 246 consecutive patients who underwent LHM and found that treatment failure rates were significantly different among the subtypes of achalasia: type I 14.6%, type II 4.7%, and type III 30.4% (P = 0.0007).⁴¹ In a post-hoc analysis of the European RCT, a higher percentage of patients with type II achalasia were treated successfully with PD or LHM than patients with type I or III achalasia.⁴⁰ Both LHM and PD have a lower effectiveness in type III, but LHM has a better outcome of PD in type III. This was confirmed by a meta-analysis encompassing nine observational studies, and 727 patients which showed that type II achalasia was associated with the best prognosis after LHM, while type III achalasia had the worst prognosis: ‘The pooled OR between the subtypes of achalasia after PBD or LHM showed that the best and worse treatment outcomes were found in patients with type II and III achalasia, respectively (type I vs. type II after PBD: OR 0.16, 95% CI 0.08–0.36, P = 0.000; type I vs. type III after PBD: OR 3.64, 95% CI 1.55–8.53, P = 0.003; type II vs. type III after PBD: OR 27.18, 95% CI 9.08–81.35, P = 0.000; type I vs. type II after LHM: OR 0.26, 95% CI 0.12–0.56, P = 0.001; type I vs. type III after LHM: OR 1.89, 95% CI 0.80–4.50, P = 0.148; type II vs. type III after LHM: OR 6.86, 95% CI 2.72–17.28, P = 0.000).’¹⁷²

‘Spastic’ forms of achalasia (Type III according to the Chicago classification) are rare and they represent approximately 10 to 15% of all patients with achalasia; there are no specific trials comparing other treatments to LHM in type III. All the trials comparing PD to LHM consistently show that LHM is at least as effective as PD, and that this effect is durable (5-year follow-up)¹¹¹ and three meta-analyses ^114,115,172 suggest that LHM is even more effective than PD, meaning that in 90% of achalasia patients LHM is very effective.

Recommendation: we recommend laparoscopic Heller myotomy for control of symptoms in Chicago type I and type II achalasia. Strong recommendation. GRADE: moderate.

26. Laparoscopic Heller myotomy should include a myotomy 6 cm into the esophagus and 2 to 3 cm into the stomach as measured from the GEJ, for effective symptom control in achalasia patients.

Agree: 94.2% [D + (2%); D (0%); U (3.8%); A (40.4%); A + (53.8%)]

The primary aim of surgical myotomy is to divide the muscle bundles of the LES complex, to reduce the esophageal outflow obstruction.^16,173,174 Anatomical, and physiological studies using manometry and endoscopic ultrasonography or in combination showed that the EGJ muscle complex and the sling fibers contribute substantially to the high-pressure zone and should therefore be included in the myotomy.^174,175 The need to perform an adequate myotomy distally onto the stomach should be emphasized.^176,177 (The most appropriate length of the myotomy may depend on the direction in which it is performed: the sling fibers have a different width on the left and right gastric sides of the cardia, and slightly diverting the myotomy leftward (as is normally done), in the narrower portion, ensures that most of the bundles constituting the sling fibers are divided with a myotomy 2 cm long.^173-178 Two studies supported extending the myotomy up to 3 cm in the stomach and claimed a reduction of dysphagia recurrence in patients.^179,180 The proximal extent of the myotomy during LHM is typically 6 to 8 cm cephalad to the EGJ, but no study has compared outcomes between differential proximal myotomy lengths.¹⁷⁴ This proximal extent is typically the maximum length that can be safely achieved via a laparoscopic, transhiatal approach, but has little physiologic basis, as the high-pressure zone of the EGJ complex is on average less than 4 cm in total length, with less than 2 cm lying cephalad to the squamocolumnar junction.

Recommendation: we conditionally recommend that Laparoscopic Heller cardiomyotomy should be extended at least (6 cm proximal to the GEJ and at least 2 cm distal to the GEJ. GRADE: low.

27. Partial fundoplication should be added to laparoscopic myotomy in patients with achalasia to reduce the risk of subsequent gastro-esophageal reflux.

Agree: 94.2% [D + (0%); D (2%); U (3.8%); A (21.2%); A + (73.1%)]

Symptomatic gastroesophageal reflux has been reported to occur in up to 48% of patients after myotomy for achalasia.^143,180-187 While some studies advocated a Nissen (360°) fundoplication after myotomy,^184,185 there is a general consensus that a complete 360° wrap can lead to an increased rate of postoperative dysphagia.^186-189 A RCT comparing anterior partial fundoplication (Dor) versus 360° fundoplication (Nissen) confirmed that the recurrence rate of dysphagia was significantly higher among patients who received a 360° fundoplication without a significant difference in reflux control.¹⁹⁰ There is no consensus regarding the choice between anterior Dor (180°) and posterior Toupet (270°) (partial) fundoplications.^191-193

Recommendation: we recommend that a partial (posterior or anterior fundoplication) but not a complete 360° wrap should be added to reduce the long-term risk (5years) of developing gastroesophageal reflux and dysphagia after myotomy. GRADE: moderate.

28. Laparoscopic Heller myotomy with a partial fundoplication is as effective at improving swallowing function as laparoscopic Heller myotomy alone.

Agree: 82.7% [D + (7.7%); D (3.8%); U (5.8%); A (36.5%); A + (46.2%)]

Laparoscopic cardiomyotomy (Heller's procedure) with antireflux fundoplication has been shown to result in effective relief of dysphagia symptoms with a low incidence of postoperative GERD resulting in an improved quality of life and the relief of dysphagia is not hampered by the addition of a partial fundoplication.^192,194,195 LHM was compared with LHM and Dor anterior partial 180° fundoplication in a RCT; there were no differences in the baseline characteristics between study groups. Pathologic gastroesophageal reflux occurred in 10 of 21 patients (47.6%) after LHM and in 2 of 22 patients (9.1%) after LHM plus Dor fundoplication (P = 0.005).¹⁴³ The Eckardt postoperative dysphagia score and the postoperative resting and nadir pressure of the LES were similar in the two groups. A systematic review¹⁹⁵ compared the safety and efficacy of endoscopic and surgical treatments for esophageal achalasia. Other studies assessing the same issue have shown that the incidence of postoperative GER was lower when a fundoplication was added to a laparoscopic myotomy (31.5% without a fundoplication versus 8.8% with; OR 6.3; 95% CI, 2.0 to19.4; P = 0.003) and the control of dysphagia was similar.^{177,191,195-198,193,199}

Recommendation: we recommend a partial fundoplication should be used when performing Heller myotomy to prevent subsequent development of gastro-esophageal reflux without compromising the adequate control of dysphagia.

We recommend against LHM alone due to the risk development of gastro-esophageal reflux. GRADE: High.

29. LHM (or other therapies such as POEM or PD) should be considered as the first-line treatment option in achalasia patients with sigmoid esophagus (compared to esophagectomy).

Agree: 86.5% [D + (0%); D (0%); U (13.5%); A (42.3%); A + (44.2%)]

A severely dilated and sigmoid-shaped esophagus is considered the final endpoint associated with long-standing untreated esophageal achalasia or the result of recurrences after failure of previous treatments. In these patients, esophagectomy is considered a definitive treatment, but this option carries a high morbidity and an increased risk of mortality. Some studies have shown good results of LHM even in advanced phase of the disease suggesting that esophagectomy should be reserved for patients who have failed cardiomyotomy and other interventions.^144,200-203 Mineo et al. reported their experience in six patients and LHM proved to be effective in improving subjective, objective, and quality of life outcome measures in patients with sigmoid esophagus.²⁰⁰ In a larger series of 33 patients with sigmoid achalasia, Faccani et al reported that LHM was effective in relieving dysphagia in these patients.²⁰² Sweet and colleagues showed that the outcome of LHM was not influenced by the degree of esophageal dilation.²⁰³ Excellent or good results were obtained in 91% of patients, and none required esophagectomy. More recently, Panchanatheeswaran et al. showed that LHM provided significant improvement of dysphagia, regurgitation, and quality of life in a small study of eight patients with sigmoid esophagus.²⁰¹ The results of LHM in such patients are not as good as in less advanced disease.¹⁷⁷ Occasionally, a good outcome of POEM in sigmoid esophagus has been reported, but the experience level with this approach is low since the procedure in this setting is technically difficult.²⁰⁴

Recommendation: we conditionally recommend standard endoscopic or surgical therapies in surgically naïve achalasia patients with sigmoid-shaped esophagus, leaving esophagectomy as secondary option in case of failure of first line therapy. GRADE: very low.

Recurrence of achalasia after treatment

30. Symptom improvement is the most relevant clinical parameter for defining the success of surgical or endoscopic treatment for achalasia.

Agree: 90.4% [D + (0%); D (3.8%); U (5.8%); A (57.7%); A + (32.7%)]

The aim of therapy in achalasia is to palliate the symptoms of dysphagia and regurgitation. Therefore, symptom scores have been introduced to assess outcomes of such treatments, including BTI, PD (PD), surgical (LHM) or endoscopic myotomy (POEM). The most widely used is the Eckardt score.²⁰⁵ Adequate relief of patients’ symptoms (i.e., a good treatment outcome) is usually defined by a decrease in the Eckardt score to 3 or less, whereas a score higher than 3 is usually associated with treatment failure.^{105,141,206,207} Some authors have also used a less strict definition for failure by setting the threshold level for failure to 4,²⁰⁷ or have used different symptom scores,^{111,177,208-211} none of which have been widely accepted.

Recommendation: we recommend assessment of symptomatic improvement as the best measure of success after treatment of achalasia. Good practice recommendation

31. In adults with achalasia, there is no universal definition of failure after any treatment.

Agree: 88.4% [D + (0%); D (5.8%); U (5.8%); A (59.6%); A + (28.8%)]

Achalasia recurrence may occur after any treatment although with variable rates.^{42,65,99,101,102,104,212-226} Achalasia recurrence is defined as the development of symptoms compatible with achalasia after initial improvement resulting from an endoscopic (BTI, PD, peroral esophageal myotomy (POEM)) or surgical intervention (laparoscopic or open myotomy).^42,214,227 Possible etiologies of recurrent symptoms include scarring across the myotomy, an incorrect or too tight fundoplication, GERD, peptic stricture, end-stage achalasia, and malignancy.²²⁸ Many reports do not differentiate between persistence and recurrence of symptoms by separating patients who have experienced initial improvement from those whose symptoms never sufficiently improved.^227,229,230 Moreover persistence or recurrence of symptoms is differently defined in some cases as an Eckardt score that fails to fall to 3 or less with treatment or increases to >3 following initial successful therapy.^42,231 Others have used failure to reduce a symptom score by at least 50%.²³² A thorough evaluation of such patients is performed with esophageal manometry, upper endoscopy, contrast esophagraphy,^{153,229,233-235} and sometimes computed tomography and/or esophageal pH testing.^154,228 These are important to document and quantify symptoms of recurrence, although there is no universal definition of failure of treatment.

Recommendation: see next statement.

32. Recurrent symptoms after achalasia treatment should routinely undergo repeat objective testing.

Agree: 100% [D + (0%); D (0%); U (0%); A (34.6%); A + (56.4%)].

Symptoms are typically interpreted in the framework of a standard scoring system originally designed for assessment of untreated achalasia.⁶⁵ However, recurrent symptoms may be more etiologically complex and difficult to interpret, and a standard scoring system may fail to adequately account for other components such as acid reflux^{101,104,212,213,215-219} or differentiate recurrent achalasia from a peptic stricture. A careful evaluation of the nature of the recurrent symptoms, aimed at understanding the physiology and anatomy, by means of upper endoscopy, manometry, and a contrast esophagraphy is required before the diagnosis of recurrent achalasia is made.^104,153,228 A correct diagnosis of recurrent achalasia provides the foundation for the decision as to whether the reintervention is indicated, and the type of intervention in order to accomplish a high success rate. The decision to investigate further should be balanced carefully with potential risks and costs of further investigations. For example, patients undergoing first PD after confident diagnosis of achalasia may need a second dilatation (35 mm) and it may be logical to proceed with that, before undertaking further investigation.^{104,153,227,228,233,236,42,65,99,101,102,212-226}

Symptom recurrence is not necessarily related to failure of achalasia therapy, and evaluation is required to determine the etiology of such symptoms. Recurrent symptoms may indicate recurrence of achalasia, but since no universal definition of recurrent achalasia exists and given the complexity of the disease, objective tests are warranted. Note: persistent symptoms such as those which persist after initial PD may be viewed differently and patients could proceed to the second dilatation before investigations.

Recommendation: we recommend objective testing in patients who suffer recurrent symptoms after treatment of achalasia including UGI endoscopy, barium swallow, manometry, and 24-H pH monitoring. Good practice recommendation

33. The timed barium swallow objectively demonstrates the failure of achalasia treatment in patients with persistent/recurrent symptoms.

Agree: 82.7% [D + (1.9%); D (5.8%); U (9.6%); A (55.8%); A + (26.9%)]

Several reports have confirmed the usefulness of the TBS as the best assessment of failure after treatment of achalasia with botulinum toxin,²³⁷ PD,^{154,229,230,235,238} Heller myotomy,²³⁵ or POEM.^154,230 Vaezi et al.²³² showed that TBS was a better predictor of long-term success after PD than symptom assessment, but recent study by van Hoeij did not support this finding.²³⁹ Other studies have also questioned the value of TBS for predicting recurrence.¹²³

Recommendation: we conditionally recommend TBS as a reliable method to assess recurrence of achalasia. GRADE: Low

Risk of cancer

34. Achalasia patients carry a moderately increased risk of development of squamous esophageal cancer 10 years or more from the primary treatment of achalasia.

Agree: 86.5% [D + (1.9%); D (5.8%); U (7.7%); A (61.5%); A + (25%)]

There has been an historic association between esophageal achalasia and cancer. Two early studies reported a high percentage of patients with achalasia dying of esophageal cancer (6 out of 125, 5%) or developing cancer during a 5-year follow-up (4 out of 124, 2%), with a 140-fold increased risk of developing cancer.^106,240 In more recent and better designed studies, the risk of cancer appears to be only 10 to 50 times higher compared than seen in the general population.^177,241,242

Esophageal cancer may arise from the chronic inflammation of the esophageal mucosa due to food debris and saliva stasis, especially in presence of suboptimal treatment. Hypothetically, this inflammation will lead to epithelial hyperplasia, dysplasia, and eventually to squamous cancer. An alternative etiology is that the posttreatment gastroesophageal reflux causes the development of Barrett's esophagus and adenocarcinoma.^121,243,244 One large Dutch study on 448 patients (who underwent primary treatment pneumatic dilatation) with a follow-up of 15 years, showed an increased risk for esophageal cancer of 28 (CI 17–46). The majority of these cancers (12) were squamous, except three adenocarcinomas.²⁴⁵ Two studies examined the mortality for esophageal cancer in achalasia patients: the first study was conducted in Italy and involved the follow-up of a single-center cohort of 229 patients treated with Heller myotomy (follow-up 12 years). The second study was conducted in Sweden on a national cohort of 2897 achalasia patients with a mean follow-up of 9.9 years.^242,246 Despite their relatively short follow-up, both studies reported a similar increase in the standardized incidence ratio of death for esophageal squamous cancer only in males of 11 (95% CI 1.33–39.7) and 13.8 (95% CI 8.1–20.4), respectively. The incidence of cancer in the Swedish study did not vary with different treatments approaches; and the excess risk was limited to squamous cancer. Pertinently, there was a long interval reported in all these studies between the diagnosis/mortality for esophageal cancer and the initial treatment of achalasia. Although we found no evidence about routine endoscopy in this group of patients, endoscopy may be used on a single patient basis and/or in case of suboptimal control of symptoms.

Recommendation: we recommend that achalasia patients should be informed that a moderately increased risk of esophageal cancer is present in male after at least 10 years from the initial treatment of the disease. Good practice recommendation.

We make no recommendation about routine endoscopy surveillance or endoscopy intervals after any treatment.

Management of treatment failures

35. Patients with achalasia who do not respond to initial treatment with graded pneumatic dilation, should be referred for Heller myotomy or POEM.

Agree: 94.2% [D + (0%); D (0%); U (5.8%); A (32.7%); A + (61.5%)]

In general, patients with achalasia have an excellent response to graded PDs;^1,101 when symptomatic recurrence after graded PD occurs, and if patients are fit for surgery, Heller myotomy is effective.^{15,19,104,247} However, Snyder et al. compared the failure rates of laparoscopic Heller myotomy in patients who underwent no or only one preoperative endoscopic intervention compared to multiple interventions.^247,248 The incidence of surgical failure was 7% in the first group compared to 28% in the latter. Finley et al. performed a multivariate regression controlling for age and sex and showed that the preoperative dilation and injection of botulinum toxin were associated with significantly worse late postoperative dysphagia.²⁴⁹ In a large series of 400 patients treated with laparoscopic Heller myotomy, success rates were lower if patients had prior endoscopic treatment of either both BTI or PD albeit not statistically significant.¹⁷⁷ Finally, in a series of 200 LHM patients,²⁵⁰ multivariate analysis identified an increased failure in patients with prior endoscopic treatments (17% vs. 4%). It is however unclear from these studies to what extent previous botulinum toxin or PD is responsible for this reduction in the success rate.

Recommendation: we conditionally recommend that in patients who are fit for surgery and have symptomatic recurrences after several pneumatic dilations, Heller myotomy, or POEM should be considered. GRADE: of evidence low.

36. Laparoscopic esophageal myotomy is a safe, feasible, and effective treatment after failed BTI for achalasia.

Agree: 96.2% [D + (0%); D (0%); U (3.8%); A (38.5%); A + (57.7%)]

BTI in the LES is a safe and effective treatment for esophageal achalasia, but its effect is not durable. PDs,²⁵¹ LHM, and POEM may be used in patients with recurrences after BTI. In a study comparing BTI and LHM,⁹² 10 out of 25 patients with recurrent symptoms after BTI were treated with LHM, with good results in 9. It must be emphasized that some reports have shown that LHM after BTI is more difficult,^252,253 leading to higher incidence of intraoperative complications including mucosal injury although these findings were not confirmed by others.^254,255 Less satisfactory outcomes were reported in patients undergoing LHM after BTI,^253,256 as compared to patients undergoing surgery as primary treatment. In another study,²⁵⁵ the logistic regression analysis showed that prior treatment with two BTI sessions, or the combination of BTI with PD, were significantly associated with unsatisfactory outcomes after subsequent surgery. In conclusion, LHM is effective treatment after failed BTI but prior BTI may affect outcomes and the incidences of perioperative complications.

Recommendation: we conditionally recommend LHM as an effective therapy for symptom recurrence after primary treatment with BTI. GRADE: very low.

37. PD, compared with repeat myotomy or POEM, is the first option for treatment after failed Heller myotomy for achalasia.

Agree: 80.8% [D + (0%); D (5.7%), U (13.5%); A (59.1%); A + (21.7%)]

Following LHM, 10–20% of patients with achalasia will relapse in the mid- to long-term and need further treatment. There is no consensus in the literature on the best way to approach these patients: PD, BTI, POEM, redo-myotomy, or even esophagectomy have all been reported.

PD is safe and effective in relieving achalasia symptoms after failed myotomy in 50% to 95% of patients.^{223,236,257-261} All these reports were retrospective and were limited in the number of treated patients (12 to 30 cases). In a large series of 400 patients, there were 39 failures of LHM treated with PD. Patients received 2 or more PDs. The success rate was 75%.¹⁷⁷

This success rate is still lower than rates reported in patients treated with PD as primary treatment (50% to 67% vs. 74% to 86%),^90,104,259 in spite of the more frequent use of the 4.0 cm dilator. The best success rate (78% to 95%) was reported by adopting an ‘on demand’ dilation protocol, by offering further PD on relapse.^223,236,257 In all reported series, the procedure was very safe with no perforations. In 2017 Schlottmann et al. reported their experience treating patients after failure of LHM: of the 19 patients with LHM failure 12 responded to PDs (63%) and 4 to PD and BTIs (20%); overall, 84% of the patients were successfully managed by endoscopic treatments.²⁶² Comparing patients treated with PD after failed myotomy to patients directly undergoing additional surgery showed that the efficacy of PD and redo-surgery in treating symptoms and improving esophageal emptying (as evaluated by timed barium swallow) were similar.⁹⁰ In comparison, Ngamruengphong et al. reported on 90 patients with failed LHM treated by POEM and demonstrated clinical success rate in 81% of patients.³⁷ Therefore, PD is a safe and effective treatment of recurrence after LHM (although to a lesser degree than in patients undergoing primary dilation treatment), therefore it is reasonable to offer the patient this possibility before planning more invasive therapies as LHM or POEM.

Recommendation: we conditionally recommend pneumatic dilation as a safe and effective treatment of symptom recurrences after LHM. GRADE: Low

38. There is insufficient evidence that the laparoscopic myotomy or re-do POEM offer better results than pneumatic dilations after failed POEM.

Agree: 82.4% [D + (0%); D (5.8%); U (11.8%); A (66.7%); A + (15.7%)]

Recurrent or persistent symptoms following POEM do occur and there is no general agreement as to how these relapsing patients should be managed. One recent paper from Shanghai²³⁴ reported on 15 patients with recurrent symptoms after POEM (Eckardt score >3), (1% of 1454 patients in whom POEM was performed). All 15 were treated with repeat POEM as salvage therapy. Relief of symptoms at 11 ± 6 months was reported in all the patients expressed as mean Eckardt score decreasing from 5.6 ± 1.1 to 1.2 ± 1.1. In two European and 1 North-American tertiary-care hospitals, evaluating patients enrolled in ongoing trials,^227,263 43 patients with recurrent symptoms after POEM were identified, representing 9.8% of 441 treated patients. PDs up to 35 mm were performed in 15 of these patients with effective outcomes seen in only 3. Further dilations with a 40-mm balloon were not effective. Eight patients underwent a repeat POEM, which was effective in 5, and 11 underwent rescue LHM, that was effective in 5. Although these numbers failed to reach statistical significance for the small sample size, PD showed poor efficacy in treating patients with a failed POEM, as compared to LHM or redo POEM. After a failed POEM, repeated treatment with a new POEM or LHM appears to be better options than PD. It should be noted, however, that most studies highlighted that repeated POEM may be technically demanding, due to fibrosis from the initial treatment.^227,263

Recommendation: we make no recommendation about laparoscopic myotomy or redo POEM offering better symptomatic relief than pneumatic dilations after failed POEM. Further research is recommended to provide high quality data and guide clinical decisions.

Diagnosis and treatment of end stage achalasia

39. Barium swallow esophagram, compared with manometry, is the best diagnostic method for defining end stage achalasia (i.e. that which requires esophagectomy).

Agree: 94.1% [D + (2%); D (2%); U (2%); A (59.5%); A + (34.6%)]

Barium esophography provides the best information regarding esophageal anatomy associated with end-stage achalasia. Anatomic features are better appreciated on esophagogram as compared to endoscopy and include assessment of esophageal diameter, retention of food and saliva, a sigmoid appearance of the esophageal body and a sump-shaped portion of the distal esophagus and of the gastroesophageal junction.²⁶⁴ The presence of extensive esophageal debris may also signal the need for drainage and anesthesia assistance prior to endoscopic evaluation. Several reports have utilized barium studies to assess end-stage achalasia and indicate the need for esophagectomy.^265-267 Other tests had only a secondary role in defining end-stage achalasia, for example, endoscopy to assess for stasis esophagitis, reflux stricture, or cancer.^264-266 Manometry may prove difficult because of the technical challenges with insertion in a dilated, tortuous, fluid, and food filled esophagus.²⁶⁸

Recommendation: we recommend the use of barium swallow as the most accurate investigation to properly define end-stage achalasia. Good practice recommendation.

40. Esophagectomy is indicated in patients with persistent or recurrent achalasia after failure of previous less invasive treatments (PD, POEM, LHM) and radiologic progression of the disease.

Agree: 80.8% [D + (0%); D (3.8%); U (15.4%); A (40.4%); A + (40.4%)]

When all conservative strategies failed, esophagectomy is the last resort to manage achalasia. Esophagectomy is associated with a high rate of complications and surgical mortality rate. All effort must therefore be focused on managing patients with recurrent symptoms after surgery with less invasive treatments, such as POEM or repeated myotomy or ‘on demand’ PD. However, patients should be carefully followed up to promptly identify when esophagectomy is necessary, before a patient's condition and nutritional status deteriorates and increases the risk and complexity of esophageal resection. Good or excellent results of esophagectomy in 37 achalasia patients were reported by Miller²⁶⁹ in the ‘open’ surgical era, but the complication rate associated with esophagectomy was high (32.4%) and the perioperative mortality was 5.4%. A predictive factor for the need of esophagectomy is the presence of a massively dilated esophagus (>6 cm).^235,270 Loviscek subdivided his patients with esophagus >6 cm into those with a tortuous megaesophagus and all the patients who underwent an esophagectomy (4/504) were in this last group. Overall, esophagectomy was required in less than 1% of their entire population of 504 patients, but it was ultimately required in 17% of those who relapsed after previous surgical treatment.²³⁵

Recommendation: we conditionally recommend esophagectomy in patients with end-stage achalasia who have failed other interventions. GRADE Low

Achalasia in children

41. Children with suspected achalasia should follow the same diagnostic pathway as that of adult patients.

Agree: 96% [D + (0%); D (2%); U (2%); A (66%); A + (30%)]

There are no systematic studies defining the optimal diagnostic regime in children. Older children (aged 10 to 17) can and should undergo a work-up similar to adults; with endoscopy, high-resolution manometry and a standard or timed barium swallow study.

Obtaining some of these studies in infants and small children may be difficult due to size mismatch and compliance. In a cohort of 42 pediatric patients,²⁷¹ all had a barium study and endoscopy. 38 patients had manometry with 4 being too young to tolerate the test. Unlike adults, biopsies of the GEJ are not mandatory for the pediatric population due to low risk of cancer in this population.

Recommendation: we recommend that children with a provisional diagnosis of achalasia should undergo the same work-up as in the adult population. Good practice recommendation.

42. Surgical or endoscopic myotomy (compared to dilation) is the preferred treatment for pediatric patients with idiopathic achalasia, especially for those aged 5 years or more.

Agree: 80% [D + (0%); D (6%); U (14%); A (56%); A + (24%)]

All treatments for achalasia have been shown to be safe and effective in the pediatric population.^272-276 Transthoracic open or thoracoscopic approaches²⁷⁵ have been mostly abandoned due to access trauma, poor outcomes in the adult experience and inability to add a partial fundoplication. Instead, an open abdominal or laparoscopic approach is now the only accepted method accepted in pediatric patients.

While open Heller myotomy is long established and safe, most centers have converted to less invasive laparoscopic access. Pastor et al., in a large single center retrospective study documents this institutional conversion from open to laparoscopic Heller and confirms its equal effectiveness and patient benefit.²⁷⁷ Pneumatic balloon dilation remains a popular option for the pediatric population, though less so than for adults due, once again, to concerns over the potential need of multiple reinterventions over the patient's lifespan. Another concern is the issue of balloon size mismatch for the younger children, which limits application of balloon dilation to children over the age of 5 years. DiNardo et al. reported an 87% success rate of PD in pediatric patients >5 years with 6 years follow-up although patients required an average of three treatments.²⁷⁴ LHM is often considered the first-line treatment for pediatric achalasia. Numerous papers have shown it to be a safe and effective therapy. Similar to laparoscopic adult surgery, it is usually accompanied by a partial fundoplication, with no conclusion regarding the superiority of a Dor or Toupet fundoplication. Lee et al. presented a retrospective comparison between surgery or PD.²⁷⁸ They concluded that, in the pediatric population, laparoscopic Heller with partial fundoplication was the best treatment for achalasia.

Today, there are several case series describing POEM in the pediatric population and showing it is both feasible and safe^273,279,280 but there are only a few series from pediatric hospitals introducing the new approach into their treatment algorithm.²⁷⁹ Outcomes were the same regardless of who performed the procedure. As with PD, there were concerns that the size of therapeutic endoscopic instrumentation might be too large for small infants although the youngest patients in case series are 5 years old and in anecdotal patients as young as 2 years have been done. Data to date has shown POEM to be equivalent if not better than PD or LHM in relief of dysphagia.^273,281 While some investigators have suggested that the reflux prevention may be less essential in the pediatric population,^282,283 it may be that POEM is the ultimate preferred initial strategy in the pediatric population, but it should be borne in mind that abnormal reflux after POEM has the potential to lead to dysplasia or adenocarcinoma in the esophagus in later life.

Recommendation: we conditionally recommend myotomy (either through a laparoscopic or flexible endoscopy approach) as the preferred treatment in children. GRADE: very low.

43. BTI is not an appropriate first-line therapy in very young children with achalasia.

Agree: 81.6% [D + (0%); D (6.2%); U (12.2%); A (36.7%); A + (44.9%)]

BTI likewise has good short-term effect (Ip 2000) but the short duration of its efficacy (Ip 2000), makes it unappealing in pediatric patients.^{271,273,281,283,284}

Recommendation: we recommend against BTI as a first-line therapy in very young children with achalasia, with exceptions for those children who are medically frail and at high-risk for surgical intervention. Conditional recommendation. GRADE: very low.

44. The long-term outcome of achalasia treatment in children should be assessed by symptoms, function, physical growth, and general development.

Agree: 94% [D + (0%); D (0%); U (6%); A (46%); A + (48%)]

All series of pediatric achalasia treatments have in common that the treatment immediately improves the patients' QOL and reverses weight loss and failure to thrive.^285-287 Most patients will need repeat treatments over time, particularly patients having BTI or PD as an initial treatment. Smits et al., described the longitudinal experience in the Netherlands where 88% of PD treated patients had repeat treatment therapy required in 22% of patients after Heller myotomy.²⁸⁷ A further 26-year single institution series showed that 83% of PD treated patients had repeated interventions versus 30% of the myotomy patients.²⁷⁷ In this series, of the 83% who had repeated interventions, 53% of the initial PD patients had repeated PD and 30% went on eventually to myotomy. The initial myotomy patients who required repeated interventions had either redo myotomy or in one case, an esophagectomy. Long term follow-up demonstrates a recurrent need for interventions and a relatively high incidence of residual or recurrent symptoms. In the Dutch longitudinal study, with 10-year follow-up, Eckardt scores >3 was seen in 45% of patients (equal between PD and HM). GERD symptoms were also common at long-term follow-up with 76% of initial Heller patients reporting GERD symptoms and 33% of post PD patients. These symptoms impact QOL with scores for general and achalasia specific QOL being lower in almost all domains compared to age matched population norms.²⁸⁷

Recommendation: we recommend that the long-term outcome of achalasia treatment in children should be closely monitored by symptoms, swallowing function, physical growth, and general development. Good practice recommendation.

Diagnosis and management of achalasia secondary to Chagas disease

45. There are minor differences between the clinical presentation of idiopathic achalasia and achalasia secondary to Chagas disease.

Agree: 86.2% [D + (0%); D (2%); U (11.8%); A (64.7%); A + (21.5%)]

Chagas disease esophagopathy (CDE) is caused by the infection of the flagellated protozoan Trypanosoma cruzi, which causes the destruction of the esophageal autonomic nervous system leading to a clinical presentation similar to IA.^288-291 Although IA and CDE are very similar, some differences have been observed between them. The common pathological pathways in IA and CDE are the loss of neurons of the myenteric plexus of the esophagus.^291,292 However, in IA there is a selective loss of inhibitory neurons, whereas in CDE both excitatory and inhibitory neurons are compromised. Several studies have shown that LES pressure in IA is increased,^{289,291,293,294} conversely, in CDE, LES pressure may be decreased, normal or increased.^{288,293,295-298} The two diseases present a hypersensitivity of the LES to gastrin, and a predominance of alfa-adrenergic innervation,^289,293 but a different response to botulinum toxin injection that causes the pressure to decrease in IA but only a partial response in CDE. From a manometric point of view, most patients with CDE have low amplitude contractions.

These differences in the two diseases do not significantly influence the clinical presentation: solid food dysphagia is the most prevalent symptom (98.8% of cases); regurgitation, halitosis, pyrosis, and chest pain were present in more than 60% of CDE patients.²⁹⁹ In patients with IA, the age of presentation is similar between both nonadvanced and advanced achalasia, although symptom duration is significantly longer in the latter. Given that the two diseases have similar motor abnormalities of the LES and esophageal body, the possibilities of treatment are much the same and the choice of the best option for each patient depends on the clinical and radiological presentation and on the experience of the medical service that will perform the therapy.^{288,290,292,293} In conclusion, IA and CDE present some minor differences in esophageal motility, but manometric and clinical findings are similar.

Recommendation: we conditionally recommend that diagnostic techniques used for IA should also be used for CDE, due to the similarities in manometric and clinical features. GRADE: low.

46. There are no differences in the treatment of idiopathic achalasia and achalasia specific to Chagas disease.

Agree: 90% [D + (0%); D (2%); U (8%); A (62%); A + (28%)]

All treatments for IA may be used in patients with CDE. In these patients, however, a careful preoperative evaluation is mandatory for the associated involvement of heart, colon, and gallbladder.^7,300 While the progression of CDE is slow, late presentation is common and most of these patients present with esophageal dilation in which can be massive in 10 to 40% of them. In one study⁸⁷ BTI was effective in 58% of patients at 6 month follow-up. Good and/or excellent results have been obtained by PD, though a recurrence rate up to 30% was reported.^7,300-302 Heller myotomy (or some modification of it) with anterior or posterior partial fundoplication has been adopted.^300,303-305 A significant number of patients with CDE present for the first time to treatment with end-stage disease, with atonic and dilated esophagus, and esophagectomy is required as primary therapy,^306-309 although several groups opted for a first less invasive approach.³¹⁰ Given the high number of patients with a massively dilated esophagus and the risk of esophagectomy, alternative procedures have been suggested including: cardioplasty plus truncal vagotomy and Roux-en-Y partial gastrectomy, Thal-Hatafuku operation, or Merendino operation.^{7,307,311-313} Currently, the indications for esophageal resection are: end-stage disease, both as the initial treatment or after failure of conservative operations; concomitant premalignant or malignant lesions of the esophagus; and esophageal perforation unsuitable for repair during diagnostic tests, therapeutic endoscopy or intraoperatively.^{7,300,306,308,309}

Recommendation: we conditionally recommend that all treatments for IA may be used for CDE for symptom relief. GRADE: low.

Appendix 1: search strategies

The search strategy for Medline included the following key-words: ‘Esophageal achalasia’ ‘AND/OR’ ‘Esophageal Manometry’ ‘High Resolution Esophageal manometry’; ‘Chicago classification’; ‘Barium Swallow’; ‘Timed barium swallow’; ‘Endoscopy’; ‘Pseudoachalasia’; ‘Symptom’ ‘Score Symptom’ ‘Medical treatment’; ‘Nitrates’; ‘Calcium blockers’; ‘Sildenafil’; ‘Botulinum Toxin’; ‘Pneumatic Dilatation’; Graded Pneumatic Dilatation’; ‘Esophageal Perforation’; ‘Complication’; ‘Per-oral endoscopic myotomy (POEM)’; ‘Heller Myotomy’; ‘Laparoscopic Heller Myotomy’; ‘Fundoplication’; ‘Recurrence’; ‘Failure’; Megaesophagus’ ‘End-stage Achalasia’; ‘Esophagectomy’; ‘Esophageal Resection’; ‘Re-intervention’; ‘Chagas Disease’; ‘Children’; Genetic Disease.

The search strategies for the other databases were adapted to the specific vocabulary of each database. In December 2017, we conducted a further search limited to the year 2017 (up to December 2017) to update the references (using the MeSH term: esophageal achalasia).

Acknowledgments

These Guidelines were funded by:

ISDE International Society for Esophageal Diseases

Morgagni Foundation –ESO- ONLUS

Department of Surgical, Oncological and Gastroenterologica Sciences, University of Padua, Padua, Italy.

ALMA –ONLUS (Association of Patients with Achalasia)

(in order of contribution)

The Guidelines were endorsed by:

ISDE International society for Esophageal Diseases

Coordinamento Malattie Rare Regione Veneto