Esophageal achalasia is a primary motility disorder characterized by incomplete lower esophageal sphincter (LES) relaxation and loss of esophageal peristalsis. ¹ Consequently, the transit of swallowed food boluses through the esophagus is impaired and the patient typically experiences dysphagia. Backflow of saliva or undigested food can cause heartburn, regurgitation or vomiting, chest pain, and respiratory symptoms such as nocturnal cough, recurrent breathing difficulty, and pneumonia. Achalasia is a chronic disease that causes progressive irreversible loss of esophageal motor function. Achalasia is difficult to diagnose early, but it is important to identify and treat the condition before irreversible changes occur.

Over the last decade, novel diagnostic modalities, such as high-resolution manometry (HRM), as well as treatment advances such as peroral endoscopic myotomy (POEM), have greatly improved the success rate of achalasia treatment. However, these developments remain unknown to most but few gastrointestinal (GI) motility experts. We need clinical guidelines for the diagnosis and management of achalasia based on evidence-based medicine that will help to inform healthcare providers and patients.

The guidelines describe approaches to the practical management of adult patients with achalasia based on scientific evidence and expert consensus. The guidelines cover several options for the treatment of achalasia, summarize the benefits and harms of each, and provide information on the probable outcomes.

The present guidelines provide a practical, evidence-based guide for clinicians (gastroenterologists, upper GI tract surgeons, and general physicians), nurses, and paramedical teams. The guidelines are intended to help primary physicians and general health professionals to make achalasia management decisions; the guidelines are also designed to provide educational resource for medical students and healthcare providers, and to provide patients with the most up-to-date information on their conditions.

The guideline steering committee consisted of the Presidents and key members of the Korean Society of Neurogastroenterology and Motility (KSNM) and Asian Neurogastroenterology and Motility Association (ANMA). This committee established the guideline development strategy and approved the project budget. Development of the guidelines began in June 2018. The working group comprises 38 expert gastroenterologists, surgeons and methodologists, selected from among KSNM and ANMA members and other experts. Three workshops were conducted while developing the revised guidelines and the working group held 8 meetings.

The working group identified the most clinically significant questions using the nominal group technique. ² The guidelines were developed using both adaptation and de novo methods. The literature was searched for existing guidelines on achalasia. The search terms used were achalasia-related index words (“achalasia”) and guideline-related index words (“clinical protocols” OR “indication” OR “therapeutics” OR “therapy” OR “therapeutic use” OR “therapy*” OR “diagnosis” OR “guideline” OR “guidelines as topic” OR “guideline adherence” OR “practice guideline” OR “practice guideline as topic” OR “clinical guideline” OR “clinical practice guideline” OR “consensus” OR “recommendation” OR “workshop”). The inclusion criteria for the existing guidelines were as follows: (1) achalasia guidelines pertaining to adults, (2) written in English, and (3) published between January 2005 and July 2018. The exclusion criteria were as follows: (1) already developed via the adaptation process and (2) not supported by evidence-based medicine. Eight guidelines were identified. A systematic review was also conducted, to identify clinical recommendations requiring an update due to new evidence, particularly pertaining to POEM and laparoscopic Heller myotomy (LHM). The Medline, EMBASE, and Cochrane Library databases were searched for all relevant studies published during the period 2000-2018. The following index terms were used as search queries: ([POEM] OR [endoscopic myotomy]) AND ([laparoscopic myotomy] OR [surgical myotomy] OR [Heller myotomy] or [Heller’s myotomy]). The inclusion criteria were as follows: (1) published in English, (2) published between 2000 and 2018, and (3) pertaining to adult patients with achalasia. The exclusion criteria were as follows: (1) published in languages other than English, (2) animal studies, and (3) studies of adolescents or children (under the age of 19 years) (Supplementary Figure). We critically appraised the quality of the selected studies using the risk of bias tools described in the endoscopic treatment section developed by a de novo method and the Cochrane Risk of Bias Tool. ³ The level of evidence for achalasia treatment recommendation was assessed based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system (Table 1). ⁴ The treatment recommendations for primary esophageal achalasia were classified as “strong for” “weak for” “weak against” “strong against” or “no recommendation”. The evidence level, clinical applicability, and benefits and harms were the evaluation criteria.

Consensus was sought for the draft recommendations developed herein using the modified Delphi method. ⁵ An expert panel comprising members of the KSNM and ANMA, and other experts, reviewed the draft. The first draft consisted of 18 recommendations with one open question: 2 pertaining to the definition and epidemiology of achalasia, 6 pertaining to diagnoses, and 10 pertaining to treatments. The first draft was sent via e-mail to the experts and their responses were anonymized. A score of more than 4 on a 5-point Likert scale was considered to correspond to “agree” (with the recommendation in question); if more than two-thirds of all 47 respondents agreed with a recommendation, consensus was considered to have been reached thereon. Consensus was not reached on only 1 of the 18 recommendations on LHM. After the first round of appraisals, the working group presented the draft recommendations at an ANMA consensus meeting held on April 6, 2019. A second round of appraisals, of the modified recommendation for LHM, achieved a 93.9% consensus (31/33 experts). Two external experts (Y.T.B. [South Korea] and S.G [Thailand] reviewed the recommendations in terms of necessity, appropriateness, health care setting, level of care, and balance between benefits and harms. The final 18 recommendations/guidelines, and a flowchart for the diagnosis and treatment of esophageal achalasia, are presented in Table 2 and Figure 1, respectively.

This project was funded by the KSNM; there was no external source of support. All members of the working team confirmed via e-mail that they had no conflicts of interest related to the development of the guidelines, which will be updated every 3 to 5 years to take account of new evidences accumulated.

Definition

Statement 1: Achalasia is a primary motor disorder of the esophagus characterized by insufficient lower esophageal sphincter relaxation and loss of esophageal peristalsis.

• (Level of evidence, not applicable; strength of recommendation, not applicable)

• Experts' opinions: agree strongly (78.2%), agree with some reservations (19.6%), undecided (0.0%), disagree (2.2%), and disagree strongly (0.0%)

Achalasia is a primary esophageal motor disorder characterized by incomplete LES relaxation and an absence of esophageal peristalsis. ¹ The cause of achalasia is not clear yet. Idiopathic achalasia occurs secondary to destruction of the myenteric plexus, which involves both peristaltic contraction and LES relaxation. ⁶ The clinical presentation includes dysphagia to solids and liquids, regurgitation of bland undigested food or saliva, chest pain during eating, and weight loss. Objective symptom scoring systems, such as the Eckardt score, are important for determining the treatment response (Table 3). ¹ A subset of patients with achalasia experience heartburn, which often leads to misdiagnosis of achalasia as gastroesophageal reflux disease (GERD). ⁷ Achalasia can be diagnosed based on manometry, esophagography, or endoscopy findings. ¹ Pseudoachalasia, which shows similar clinical features but is caused by cancer or Trypanosoma cruzi infection, should be excluded. ⁸

Epidemiology of Achalasia

Statement 2: Achalasia is a very rare disorder of the esophagus that affects both sexes equally and is frequently diagnosed in patients aged 40 to 60 years.

• (Level of evidence, not applicable; strength of recommendation, not applicable)

• Experts’ opinions: agree strongly (34.8%), agree with some reservations (54.4%), undecided (6.5%), disagree (4.3%), and disagree strongly (0.0%)

Achalasia is a rare esophageal motility disorder. Population-based epidemiological data on achalasia are sparse and most existing studies used a retrospective design. ⁹ According to studies conducted in the 2000s, the incidence of achalasia is increasing and does not differ according to ethnicity. The incidence of achalasia is 0.03-0.27 per 100 000 persons per year in developing countries (Fig. 2). ^10,11 A recent large cohort study based on Dutch healthcare insurance data revealed an incidence of achalasia of 2.2 per 100 000 persons per year, ⁹ compared to 2.9 per 100 000 persons in a study using tertiary hospital data. ¹² The prevalence of achalasia also appears to be increasing slightly. A Dutch study reported a prevalence rate of 15.3 per 100 000 persons, ⁹ and other studies have reported prevalence rates of 2.5-32.6 per 100 000 persons. ^12,13 However, Kim et al ¹⁴ reported that the incidence and prevalence of achalasia were 0.4 and 6.3 per 100 000 persons, respectively, in population-based studies based on a Korean national healthcare database.

The numbers of male and female patients with achalasia were similar in several large-scale epidemiological studies. ^9,11,14,15 Although achalasia can occur at any age, it is most prevalent in patients aged 40 to 60 years. ^9,11,16 Asian epidemiological studies have reported similar data to Western studies.

Esophageal Manometry

Esophageal manometry is essential for assessing esophageal motor function in patients with achalasia. ¹ Barium esophagography and esophagogastroduodenoscopy (EGD) are used as complementary tests to manometry in the diagnosis and management of achalasia. ^17,18 However, neither EGD nor barium esophagography alone is sensitive enough to achieve a definitive diagnosis. EGD can be used as a supportive tool for diagnosis of achalasia in only one-third of patients, and esophagography in up to two-thirds of patients. Thus, patients suspected to have achalasia but who have shown normal results in EGD or esophagography studies must undergo esophageal motility tests. However, in patients with EGD or esophagography findings typical of achalasia, esophageal motility tests should be performed to confirm the diagnosis.

Statement 3: Esophageal manometry is a gold standard test for the diagnosis of achalasia.

• (Level of evidence, low; strength of recommendation, strong)

• Experts' opinions: agree strongly (76.1%), agree with some reservations (23.9%), undecided (0.0%), disagree (0.0%), and disagree strongly (0.0%)

Manometric findings of aperistalsis and incomplete LES relaxation without evidence of mechanical obstruction supports the diagnosis of achalasia (Fig. 3A). Other findings, such as increased basal LES and baseline esophageal body pressure with simultaneous non-propagating contractions, are also suggestive of achalasia, but are not required for its diagnosis. Though rare, variants of achalasia differing in the degree of incomplete LES relaxation and aperistalsis, as well as some characterized by complete LES relaxation, have been described. ¹⁹ Aperistalsis has been defined as a lack of esophageal body peristalsis and can present with different pressure patterns, such as a "quiescent" esophageal body, isobaric panesophageal pressurization, and simultaneous contractions. Achalasia variants presenting with propagating contractions, which could represent either early achalasia or, most commonly, a subclinical mechanical obstruction at the esophago-gastric junction, have also been described. This heterogeneity demonstrates the need for motility studies, where motor patterns can affect diagnosis and management.

Statement 4: High-resolution manometry is superior to conventional manometry for the diagnosis of achalasia.

• (Level of evidence, low; strength of recommendation, strong)

• Experts' opinions: agree strongly (71.8%), agree with some reservations (23.9%), undecided (4.3%), disagree (0.0%), and disagree strongly (0.0%)

Data are emerging suggesting that HRM may have greater sensitivity for diagnosing achalasia than conventional manometry. ²⁰ Conventional manometric techniques and tracing analysis (interval of 3-5 cm) can be utilized to depict the pressure profile of the smooth muscle esophagus; however, with HRM, the whole esophagus can be analyzed, which is useful for predicting not only the presence of achalasia, but also the treatment response. Esophageal pressure topography enables the differentiation of achalasia into 3 subtypes, which has implications for treatment outcomes. ²⁰ Although these achalasia subtypes can be defined by careful analysis of conventional tracings, they can be distinguished more easily and reproducibly by HRM. ²¹

Statement 5: The Chicago classification is useful for defining the clinically relevant phenotypes of achalasia.

• (Level of evidence, moderate; strength of recommendation, strong)

• Experts' opinions: agree strongly (50.0%), agree with some reservations (45.7%), undecided (4.3%), disagree (0.0%), and disagree strongly (0.0%)

Based on the relaxation pressure and propagation and pressurization parameters, the Chicago classification 3.0 is a system for classifying achalasia into distinct subtypes (I-III) and variants, ie, early achalasia with esophagogastric junction (EGJ) outflow obstruction (EGJOO) and achalasia associated with hypotonic LES (absence of contractility) (Fig. 3B). ^19-21 Type I achalasia, called classic achalasia, is characterized by an absence of esophageal body smooth muscle contractility and no esophageal pressurization. These findings are more typical of late-stage achalasia, in which there is loss of muscle tone and subsequent dilation of the esophageal body. Type II achalasia, which is the most common type, is characterized by periods of esophageal pressure and compression; the smooth muscle of the esophagus retains its tone and there is absent peristalsis with abnormal pan-esophageal high-pressure patterns. If 20.0% or more of the patient's swallows are characterized by this panesophageal pressurization, the achalasia is classified as type II. Type III achalasia, which is the least common type, is characterized by spastic contraction of the distal esophagus in at least 20.0% of swallows.

The achalasia subtypes have been linked to the treatment response in multiple studies, including a recent systematic review and meta-analysis of manometric findings. ²² These findings should be used to guide treatment decisions. Multiple studies have reported different treatment success rates among the 3 achalasia subtypes, particularly, type III showing a higher likelihood of treatment failure compared to type II achalasia. ^22,23 The inferior response of type III patients is often attributed to spastic contractions in the esophageal body. Pratap and colleagues found that type II predicted a good response to pneumatic dilatation. ²⁴ The European Achalasia Trial showed that treatment success rates for type II achalasia were high for both LHM (93.0%) and pneumatic balloon dilation (PBD; 100.0%). ²⁵ The follow-up data of the same trial confirmed that type III achalasia is indeed an important predictor of treatment failure, at least for PBD. Studies of LHM also found type III achalasia to be predictive of a poor treatment outcome. Patients with type III achalasia had the highest incidence of failure (22.2% vs 3.0% and 3.4% for types I and type II, respectively; P = 0.01). ^26-28 Finally, four studies reported that type III achalasia was associated with failure of POEM treatment. ^23,29-31

Barium Esophagography

Statement 6: Barium esophagography is recommended to diagnose achalasia in patients with esophageal dysphagia.

• (Level of evidence, low; strength of recommendation, strong)

• Experts' opinions: agree strongly (39.1%), agree with some reservations (54.4%), undecided (6.5%), disagree (0.0%), and disagree strongly (0.0%)

Barium esophagography is recommended to assess esophageal emptying and EGJ morphology in those with equivocal motility test results. ³² The diagnosis of achalasia can be supported by esophagographic findings, including dilation of the esophagus, a narrow EGJ with a “bird-beak” appearance, aperistalsis, and poor emptying of the barium (Fig. 4A). ³³ In advanced cases, a dilated esophageal body and high air-fluid level, in the absence of an intragastric air bubble or even a sigmoid-like appearance of the esophagus, may be present.

Statement 7: Timed barium esophagography enables assessment of the severity of achalasia and evaluation of the treatment outcome.

• (Level of evidence, moderate; strength of recommendation, strong)

• Experts' opinions: agree strongly (34.8%), agree with some reservations (58.7%), undecided (6.5%), disagree (0.0%), and disagree strongly (0.0%)

Timed barium esophagography (TBE) is a reproducible technique for estimating esophageal emptying with very high inter-observer agreement (Fig. 4B). Esophageal emptying is assessed with the patient in the upright position. The patient is instructed to drink 100-250 mL of low-density barium and the barium column height is measured from the end of the esophagus; the height at 5 minutes is used to determine the completeness of emptying. ³⁴ TBE predicts the likelihood of symptom recurrence after PD or surgical myotomy. ³⁵ Rohof et al ³⁴ found that esophageal retention was a good predictor of treatment failure in cases of long-standing achalasia and proposed basing the decision for retreatment on the TBE rather than manometry. Moreover, studies using TBE showed that it improved diagnosis and prediction of treatment outcome. In a recent study including achalasia patients, and those with EGJOO or dysphagia of other origin, a barium column height of 5 cm after 1 minute showed the highest sensitivity and specificity (of 94.0% and 71.0%, respectively) for differentiating untreated achalasia from EGJOO and non-achalasia based on receiver operating characteristic analysis. ³⁶

Endoscopy

Statement 8: Endoscopic assessment is recommended for achalasia patients to rule out pseudoachalasia caused by cancer and other esophageal diseases (eg, peptic stricture with acid reflux, structural disorders such as esophageal webs and rings, or esophageal inflammation).

• (Level of evidence, low; strength of recommendation, strong)

• Experts' opinions: agree strongly (78.2%), agree with some reservations (19.6%), undecided (2.2%), disagree (0.0%), and disagree strongly (0.0%)

EGD has a low diagnostic yield for achalasia; its primary role is exclusion of mechanical obstruction secondary to a peptic stricture or cancer in patients with dysphagia. ¹⁶ EGD can also rule out reflux esophagitis, structural lesions (strictures, webs, or rings), and eosinophilic esophagitis. A tumor infiltrating the gastroesophageal junction and cardia can mimic the clinical, radiological, and manometric findings of achalasia, resulting in impaired LES relaxation, esophageal dilatation, and absence of peristalsis. This condition is defined as "secondary achalasia" or "pseudoachalasia." Similar to the manometric features of achalasia, mechanical obstruction can result in both impaired EGJ relaxation and abnormal esophageal body function (aperistalsis or spastic contractions).

Dysphagia to solids and liquids, short-duration dysphagia (< 1 year), serious weight loss (> 6.8 kg), and age over 55 years should lead to suspicion of secondary achalasia; however, these signs are neither sensitive nor specific. ³⁷ Thus, in patients with HRM or esophagography findings of achalasia, endoscopic evaluation of the EGJ and cardia is needed to ensure that there is no infiltration of cancer. Mucosal ulceration or nodularity, reduced compliance of the EGJ, or an inability to pass the endoscope into the stomach are the most common endoscopic findings of pseudoachalasia. Endoscopic mucosal biopsy is used to diagnose secondary pseudoachalasia. When biopsy is negative but secondary achalasia is suspected, computed tomography or endoscopic ultrasonography can help to rule out pseudoachalasia. ^38,39

In idiopathic achalasia, the endoscopic findings at the EGJ range from normal-appearing (in about 40% of patients) to a thickened muscular ring that may have a rosette configuration on retroflexion, accompanied by signs of esophagitis such as friability, thickening, and even erosion secondary to food stasis (Fig. 5), as well as mild-to-moderate resistance to intubation of the EGJ. ⁴⁰ Saliva, liquid, and undigested food material may be seen in the esophagus in the absence of mucosal abnormality or tumor. ¹ As the disease progresses, luminal dilation and tortuosity make the diagnosis more obvious. ^41,42 Although endoscopy may suggest achalasia, other tests must be performed to confirm the diagnosis.

The goal of achalasia treatment is to promote relief of dysphagia and related complications. Several treatments can be tailored according to the patient’s overall health status. However, there is no specific therapy targeting the underlying disease process, because the pathogenesis of the impaired esophageal peristalsis and poor esophageal sphincter relaxation are unclear.

PBD, POEM, and LHM provide similarly effective long-term results for esophageal achalasia. In patients whose condition is too poor for endoscopic treatment or surgery, botulinum injection or oral medication might be helpful.

Oral Pharmacologic Treatment

Statement 9: Oral pharmacologic therapy can be considered for achalasia patients whose medical condition is unsuitable for endoscopic treatment or surgery.

• (Level of evidence, low; strength of recommendation, weak)

• Experts' opinions: agree strongly (21.8%), agree with some reservations (50%), undecided (21.8%), disagree (6.5%), and disagree strongly (0.0%)

Uncontrolled and small studies reported that a number of pharmacological agents, including calcium channel blockers, nitrates, anticholinergics, phosphodiesterase inhibitors, and β-adrenergic agonists, have been used for treating achalasia. These agents are effective in reducing LES pressure and temporarily relieving dysphagia, but do not improve LES relaxation or peristalsis. ⁴³ Calcium channel blockers transiently decrease LES pressure by 13.0-49.0%, facilitate esophageal emptying and improve symptom severity by 0.0-77.0%. ^44-47 Calcium channel blockers are associated with side effects, such as headache, hypotension, and peripheral edema. ⁴⁸ Anticholinergics (eg, cimetropium bromide) decrease LES pressure and accelerate esophageal transit. A double-blind, placebo-controlled trial showed that cimetropium bromide reduced LES pressure by 70.0% for about 45 minutes, and improved esophageal transit. ⁴⁹ The clinical response to pharmacologic agents is short-lived; they do not provide complete relief of symptoms and efficacy decreases substantially over time. ⁴⁵ Thus, these agents are commonly reserved for patients who cannot, or refuse to, undergo endoscopic or surgical therapy, and for those who have failed endoscopic or surgical therapy.

Botulinum Toxin Injection

Statement 10: Botulinum toxin injection is recommended for achalasia patients whose medical condition is unsuitable for endoscopic treatment or surgery.

• (Level of evidence, moderate; strength of recommendation, strong)

• Experts' opinions: agree strongly (42.5%), agree with some reservations (42.5%), undecided (10.7%), disagree (4.3%), and disagree strongly (0.0%)

Injection of botulinum toxin into the LES has been shown to improve the symptoms of achalasia (dysphasia, regurgitation, and chest pain), decrease the LES pressure, improve esophageal emptying, and increase the size of the LES aperture compared to injection of placebo (Table 4). ^50,51 However, although multiple trials have demonstrated short-term benefits of botulinum toxin injection, a single injection of botulinum toxin has only short-duration clinical effects with relapses within several months occurring frequently. ^51-59

Typically, 100 U of botulinum toxin is injected into 4 quadrant of LES each as 4 divided doses. There is wide variability in the timing of the botulinum toxin injections. A multicenter randomized study found no clear dose-response effect (doses of 50, 100, or 200 U) after 1 month, but 2 injections of 100 U botulinum toxin, 30 days apart, was the most effective therapeutic schedule. ⁶⁰ According to a 9-year retrospective chart review, botulinum toxin was used in 21.0% of achalasia patients. Symptom improvement persisted for a mean of 6.2 months, with a need for repeated injections (mean, 1.7; range: 1-7), and about 43.0% of patients required different, additional treatments. ⁶¹

Botulinum toxin injection can induce esophageal perforation or, inflammatory mediastinitis ⁶² and chest pain (4.3%) or heartburn (0.7%), ⁵⁸ but it is a relatively safe treatment because of the low probability of complications. Botulinum toxin injection is less efficacious than PBD and myotomy in inducing long-term remission of achalasia. ^51,63 However, if myotomy or PBD cannot be performed because the patient is in poor general condition, repeated botulinum toxin injection should be considered. Following repeated botulinum toxin injection, 50.0% of patients were asymptomatic. The median duration of the symptom-free period was 11.5 months after the first botulinum injection, and 10.5 months after the second. ⁶³

Pneumatic balloon dilatation

Statement 11: Pneumatic balloon dilatation is recommended as an initial treatment for patients with achalasia.

• (Level of evidence, moderate; strength of recommendation, strong)

• Experts' opinions: agree strongly (26.1%), agree with some reservations (54.4%), undecided (13.0%), disagree (6.5%), and disagree strongly (0.0%)

One of the most frequently used treatments for achalasia is PBD of the LES. ^59,64-72 Treatment parameters such as balloon size, number of dilations, inflation pressure, and duration vary according to the specialists or institutions. Depending on the general condition of the patient, graded PBD (with 30-mm, 35-mm, or 40-mm balloons) is considered one of the primary options for achalasia. ⁷³ According to a retrospective analysis of 209 patients, management of achalasia with initial dilation can provide good or excellent long-term results and high patient satisfaction rates. ⁷⁴ A prospective randomized European study of PBD and LHM reported that the therapeutic success rate was not significantly different between the 1- and 2-year follow-ups (P = 0.46). Also, there was no significant difference in the pressure at the LES (P = 0.27) or esophageal emptying, as assessed by the height of the barium column (P = 0.21) (Table 5). ^59,64-72

Peroral endoscopic myotomy

Statement 12: The outcomes of peroral endoscopic myotomy are comparable to those of laparoscopic Heller myotomy for treatment-naïve patients with achalasia.

• (Level of evidence, moderate; strength of recommendation, strong)

• Experts' opinions: agree strongly (63.0%), agree with some reservations (37.0%), undecided (0.0%), disagree (0.0%), and disagree strongly (0.0%)

LHM is a first-line treatment for achalasia that achieved excellent outcomes in 91.8% of patients after a follow-up of 83.2 months. ^75,76 However, LHM is an invasive and expensive procedure that requires general anesthesia. ^77,78 Previous meta-analyses of POEM showed a clinical success rate of 98.0%. ^79,80 In meta-analysis of the present guidelines, the clinical efficacy rate of POEM was 92.8% (95% confidence interval [CI], 91.1-94.1%) for the naïve and prior treatment-failed patients combined, and 93.7% (95% CI, 86.7-97.1%) for naïve patients. Additionally, in another meta-analysis, the postoperative Eckardt score was better for patients who underwent POEM versus those who underwent LHM (Fig. 6). ^81-86 Recent guidelines for achalasia stated that POEM has an efficacy similar to that of LHM. ⁸⁷ A study with a 3-year follow-up showed that POEM was comparable to LHM in terms of the postoperative Eckardt score and quality of life. ⁸⁸ A large, recently published large cohort study, with long-term follow-up, showed that the clinical success rate of POEM was 87.0% after a median follow-up of 49 months. ⁸⁹ Reflux-related adverse events can occur with both POEM and LHM. However, in contrast to LHM, which requires partial fundoplication to reduce pathologic acid reflux, POEM is typically performed without any anti-reflux procedure. ⁹⁰ Previous meta-analyses reported that acid reflux occurs more frequently after POEM than after LHM. ^91,92 However, there was no difference in the rate of reflux symptoms, pathologic acid reflux, or the requirement for proton pump inhibitors (PPIs) between the POEM and LHM groups. ⁸⁴

In summary, the high clinical efficacy of POEM, and the acceptable adverse event rate, are similar to those of LHM for treatment-naïve patients with achalasia. Nevertheless, long-term follow-up studies are required to define the role of POEM in the initial endoscopic treatment of achalasia.

Statement 13: Peroral endoscopic myotomy, rather than laparoscopic Heller myotomy, can be considered for the treatment of type III achalasia because it can offer extended myotomy.

• (Level of evidence, low; strength of recommendation, weak)

• Experts' opinions: agree strongly (43.4%), agree with some reservations (37.0%), undecided (17.4%), disagree (2.2%), and disagree strongly (0.0%)

Previous studies reported different success rates among the 3 achalasia subtypes; in particular, type III achalasia was associated with an increased risk of treatment failure compared to type II achalasia. ^22,23 Type III achalasia is characterized by pathological mechanisms involving the esophageal body and the LES. ⁹³ Therefore, the response rate to PBD or botulinum toxin injection is relatively low in patients with type III achalasia. In a study that reported treatment response according to achalasia subtype, the clinical success rate of the first session of PBD was 38.0% (3/8) for type I achalasia, 73.0% (19/26) for type II achalasia, and 0.0% (0/11) for type III achalasia. ³⁴ Botulinum toxin injection also showed low efficacy in patients with type III achalasia (type I, 0.0% [0/2]; type II, 86.0% [6/7]; type III, 22.0% [2/9]). In another study, the treatment response of PBD was 63.0% in type I achalasia, 90.0% in type II achalasia, and 33.0% in type III achalasia. ²⁴ Myotomy may have greater efficacy for the treatment of type III achalasia compared to PBD. A study involving 18 patients with type III achalasia demonstrated that LHM tended to have a clinical success rate superior to that of PBD, although the difference was not significant (86.0% vs 40.0%, P = 0.12). ⁹⁴

Although the treatment response rate of type III achalasia patients undergoing LHM is higher than that of those undergoing PBD, the efficacy of LHM for type III achalasia is inferior to that for other types of achalasia. In a previous study on LHM in patients with achalasia, the clinical success rate was 85.0%, 95.0%, and 70.0% for type I, type II, and type III achalasia, respectively (P < 0.001). ³¹

Unlike conventional treatments, such as PBD and LHM, POEM enables extended myotomy in patients with type III achalasia. Meta-analysis of studies comparing POEM and LHM showed that the length of myotomy was significantly greater for POEM than LHM. Also, operation time and length of hospital stay tended to be shorter for POEM than LHM. Another meta-analysis, of 8 studies on POEM for type III achalasia, demonstrated an overall clinical success rate of 91.6% (Table 6). ^92,95 Moreover, a multi-center retrospective cohort study including 75 patients with type III achalasia showed that the clinical response rate was higher in patients who underwent POEM than in those who underwent LHM (98.0% vs 81.0%, P = 0.01). ⁹²

The overall rate of adverse events in type III achalasia patients who underwent POEM was 11.2% in the meta-analysis discussed above. ⁹⁶ More than 70.0% of adverse events could be managed conservatively without further intervention. In some patients, the length of hospital stay was prolonged due to adverse events including pulmonary embolism, pneumothorax, capnoperitoneum, and bleeding. Inadvertent mucosotomies occurred in 3.0% of patients, who were managed by clipping. ⁹⁶ The rate of adverse events in patients with type III achalasia undergoing POEM seems to be acceptable.

Although large-scale randomized controlled trials (RCTs) are lacking, current evidence supports superior clinical efficacy of POEM over LHM in patients with type III achalasia, where the length of myotomy is greater for the former treatment modality. Given that, for patients with type III achalasia, the clinical success rate of POEM is good and the adverse event rate is acceptable, we recommend POEM over LHM for the treatment of type III achalasia.

Statement 14: Acid suppressive therapy is recommended for patients with reflux symptoms or esophageal erosion after peroral endoscopic myotomy, to prevent esophageal stricture.

• (Level of evidence, low; strength of recommendation, strong)

• Experts' opinions: agree strongly (47.8%), agree with some reservations (50.0%), undecided (2.2%), disagree (0.0%), and disagree strongly (0.0%)

One of the main adverse events associated with POEM is gastroesophageal reflux. Unlike LHM, in POEM no anti-reflux procedure is performed; however, no alteration of the diaphragmatic and gastroesophageal anatomy occurs in POEM, which potentially reduces the risk of reflux. Gastroesophageal reflux is evaluated after POEM according to symptoms, pH, and endoscopic findings. In meta-analysis of the present guidelines, the overall rates of reflux symptoms, abnormal pH, and reflux esophagitis, according to endoscopic examinations, were 20.3% (95% CI, 16.9-24.3%), 24.7% (95% CI, 20.0-30.0%), and 42.6% (95% CI, 34.1-51.5%), respectively. However, there is no significant difference of development of GERD between POEM and LHM (Fig. 7).

Although the definitions of symptoms, abnormal pH, and abnormal endoscopic findings were not standardized across the studies, POEM is clearly associated with an increased risk of post-procedural reflux. Therefore, acid suppressive therapy is recommended after POEM for patients with reflux symptom or esophagitis. Also, there is a dissociation among the rate of abnormal acid exposure and the rates of reflux symptoms and reflux esophagitis based on endoscopic examinations. Therefore, clinicians should evaluate asymptomatic patients via regular endoscopy examinations or pH monitoring.

In a previous meta-analysis, the rate of PPI use after POEM ranged from 2.6% to 27.8% (pooled estimate, 10.6%; 95% CI, 6.5-17.3%). ⁹⁰ However, the optimal duration and dose of PPI use are controversial. Most patients with post-procedural gastroesophageal reflux can be treated using a standard PPI dose. Also, the long-term effects of an abnormal pH in asymptomatic participants are unclear. Therefore, a short course of PPIs is recommended after POEM, although a more tailored approach based on symptoms, pH and endoscopy findings appears to be more appropriate.

Surgical Treatment

Statement 15: Laparoscopic Heller myotomy can be considered a first-line therapy for achalasia patients, and has similar expected clinical outcomes to pneumatic balloon dilation.

• (Level of evidence, moderate; strength of recommendation, weak)

• Experts' opinions: agree strongly (18.2%), agree with some reservations (75.8%), undecided (3.0%), disagree (3.0%), and disagree strongly (0.0%)

Surgical myotomy, also known as Heller myotomy, disrupts the muscle fibers of the LES. LHM is the preferred surgical technique because of its low morbidity rate and the rapid rate of recovery. ^97,98 In a systematic review involving 3086 patients, symptom improvement after LHM was achieved in 89.3% after a mean of 35.4 months (range: 8-83 months). ⁹⁷ Two prospective, randomized trials have compared PBD and LHM. ^99,100 Although LHM was more effective for symptom relief, these were small, low-quality trials and one failed to meet its recruitment target. Borges et al ¹⁰¹ reported that LHM and PBD for achalasia were equally effective, even at the 2-year follow-up. In a large, high-quality, multicenter randomized trial involving 201 patients, there was no significant difference in treatment success rate after 1, 2, and 5 years of follow-up. ^25,72 Rohof et al ⁹⁴ reported differences in outcomes according to the achalasia subtype. The success rate of PBD was significantly higher than that of LHM for type II achalasia (100.0% vs 93.0%, P < 0.05). ⁹⁴ However, the largest difference in symptom remission rates between PBD and LHM was observed in type III achalasia, although the difference was not statistically significant due to the small number of patients in this subgroup. In addition, type III achalasia patients treated by PBD had significantly greater esophageal stasis compared to type III patients treated by LHM. Therefore, patients with type III seem to respond better to LHM than to PBD. However, RCTs comparing the outcomes of LHM and PBD in the various achalasia subtypes are needed to draw definitive conclusions. It should also be noted that PBD is a more cost effective treatment option than LHM for achalasia. ^102,103

Statement 16: Partial fundoplication in addition to LHM is recommended to reduce the risk of subsequent GERD.

• (Level of evidence, low; strength of recommendation, strong)

• Experts' opinions: agree strongly (23.9%), agree with some reservations (56.5%), undecided (17.4%), disagree (2.2%), and disagree strongly (0.0%)

The antireflux barrier function of the LES is lost after myotomy, and the need to add an antireflux procedure to LHM has long been debated. In a meta-analysis, the rate of gastroesophageal reflux symptoms was reduced when fundoplication was added to myotomy (8.8% vs 31.5%, P = 0.001). ⁹⁷ However, the rate of postoperative dysphagia was higher after LHM plus Nissen fundoplication than after LHM plus Dor fundoplication (15.0% vs 2.8%, P = 0.001). ¹⁰⁴ In contrast, the relief of dysphagia after LHM plus Dor fundoplication was shown to be comparable to LHM alone. ¹⁰⁵ In addition, 2 types of partial fundoplication (Dor and Toupet) were comparable in terms of the degree of improvement in symptoms after LHM. ¹⁰⁶ Partial fundoplication reportedly decreases reflux after LHM. ¹⁰⁷ Finley et al ¹⁰⁸ reported no difference in the frequency or severity of reflux symptoms between patients with and without anterior fundoplication. However, that study was limited by the significant difference in preoperative upright esophageal clearance between the 2 groups. To draw definitive conclusions, additional large randomized trials are needed.

Management of Achalasia Recurrence After Initial Treatment

If PBD fails as a first-line treatment, additional treatment with PBD may be considered. ^67,109 PBD is also an option when symptoms recur after botulinum toxin injection. ⁶⁹ In cases showing persistent or recurrent symptoms after LHM, retreatment with PBD may be considered. ^110,111 LHM is an effective treatment for the majority of achalasia patients. However, a small proportion of patients suffer persistent or recurrent symptoms after surgery. In such cases, the success rate of PBD after surgery was reported to vary from 50.0% to 78.0%. ^108-110 If the symptoms persist after POEM, PBD may be considered as salvage therapy depending on the clinical symptoms of the patient, although there are relatively few studies supporting this. ^75,76,112

Statement 17: Peroral endoscopic myotomy is recommended for achalasia patients who failed initial endoscopic treatment.

• (Level of evidence, moderate; strength of recommendation, strong)

• Experts' opinions: agree strongly (60.9%), agree with some reservations (34.8%), undecided (4.3%), disagree (0.0%), and disagree strongly (0.0%)

The endoscopic treatment options for achalasia treatment with durable outcomes are PBD and POEM. Although PBD showed a long-term success rate of 72.0-86.0%, re-dilation was required by up to one-third of patients with recurrent symptoms. ^25,70,72,75 Young age, residual LES pressure > 10 mmHg, stasis on TBE, and male sex have been reported as predictive factors for symptom recurrence after PBD. ^113-114 POEM is a treatment option in cases for which PBD failed, as well as an initial treatment for achalasia (Table 7). ^{77,109,115-122} Large-scale observational studies including patients in whom PBD failed have reported that POEM is a safe and effective treatment option. ^96,117,120 Prior treatment did not increase the risk of POEM-related adverse events. ^116,119,120 However, patients with prior treatment showed a longer procedure time and higher rate of clinical failure after POEM compared to those without prior treatment. ¹²⁰ POEM has a reported efficacy rate of > 90% based on short-term follow-up data. Persistence or recurrence of symptoms may occur after POEM. Two studies showed that redo POEM is feasible for patients in whom POEM failed, as a salvage option with a 100.0% technical success rate and an 85.0-100.0% clinical success rate based on short-term follow-up data. ^121,122 For patients with persistent or recurrent symptoms after POEM, redo POEM seems to be an efficacious and safe technique. ¹²³

In summary, POEM appears to be a safe and effective option for patients who failed initial endoscopic treatment. Long-term follow-up and randomized studies comparing other treatment options are required to define the role of POEM for cases of achalasia in which initial endoscopic treatment failed.

Statement 18: Peroral endoscopic myotomy can be considered as a rescue treatment for achalasia patients who were not treated successfully by Heller myotomy.

• (Level of evidence, low; strength of recommendation, weak)

• Experts' opinions: agree strongly (28.3%), agree with some reservations (47.8%), undecided (17.4%), disagree (6.5%), and disagree strongly (0.0%)

Recurrent or persistent symptoms occurred in about 10.0-20.0% of patients who underwent LHM. ²⁵ For such patients, treatment options include repeat LHM, PD, or POEM. Recently, POEM has been used as a rescue treatment for patients who failed LHM. Clinical studies have reported success rates of 92.0-98.0%. ^124-126 Thus, POEM could be a feasible salvage treatment for patients with persistent symptoms after LHM. However, additional large studies with longer follow-up periods are necessary.

Esophagectomy

In patients with end-stage achalasia, when repeated endoscopic or surgical treatments are not effective, some patients may require esophagectomy to relieve their symptoms. Indeed, the presence of a megaesophagus (maximum esophageal diameter > 6 cm), could be a predictive factor for the need of esophagectomy. ^127-129 In a recent systemic review, the postoperative morbidity ranged from 19.0% to 50.0% and the mortality ranged from 0.0% to 5.4%. ¹²⁹ Given the high morbidity and mortality, esophagectomy should be performed in patients with a megaesophagus who are fit for major surgery, complain of long-lasting disabling symptoms not responding to multiple endoscopic and surgical interventions, preferably in specialized centers.

The 2019 Seoul Consensus on Esophageal Achalasia Guidelines for esophageal achalasia introduced herein are designed to serve as a practical, evidence-based guide for clinicians (including primary physicians, gastroenterologists, upper GI tract surgeons, medical students, nurses, and paramedical teams) and patients. Esophageal manometry is the gold standard for diagnosing achalasia, while the Chicago classification for HRM is useful for defining the clinically relevant phenotypes of achalasia. Endoscopic management (PBD or POEM) and LHM show similar efficacy with respect to the initial management of achalasia. POEM can serve as both an initial and rescue therapy for patients with achalasia, and may be the preferred option for patients with type III achalasia. The present guidelines will be updated periodically in response to new evidence. Prospective studies of the long-term therapeutic outcomes of PBD, POEM, and LHM, including their benefits and harm, are needed.

We are grateful to all who participated in this study. We thank Young-Tae Bak (South Korea) and Sutep Gonlachanvit (Thailand) for external review. In addition, we also thank Prof. Mi-Young Choi for helping us develop the guidelines as a methodologist and literature search.

Note: To access the supplementary figure mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm20014.

Financial support: None.

Conflicts of interest: None.

Author contributions: Hye-Kyung Jung, Su Jin Hong, and Oh Young Lee have contributed in writing and editing the paper as the first author and the corresponding author; John Pandolfino, Hyojin Park, Hiroto Miwa, Uday C Ghoshal, Sanjiv Mahadeva, Tadayuki Oshima, Minhu Chen, Andrew S B Chua, Yu Kyung Cho, Tae Hee Lee, Sung Eun Kim, Yang Won Min, Chan Hyuk Park, Joong Goo Kwon, Moo In Park, Kyoungwon Jung, Jong Kyu Park, Kee Wook Jung, Hyun Chul Lim, Da Hyun Jung, Do Hoon Kim, Chul-Hyun Lim, Hee Seok Moon, Jung Ho Park, Suck Chei Choi, Hidekazu Suzuki, Tanisa Patcharatrakul, Justin C Y Wu, Kwang Jae Lee, Shinwa Tanaka, and Kewin T H Siah have contributed in the systematic review, the extraction of recommendations, and writing the paper; Chan Hyuk Park, Da Hyun Jung, Do Hoon Kim, Chul-Hyun Lim, Hee Seok Moon, and Su Jin Hong performed the meta-analysis; and Hye-Kyung Jung and Oh Young Lee have designed the development of guideline as the chairman of the guideline committee and KSNM.